WO2018193297A1

WO2018193297A1 - Novel compounds as ror-gamma modulators

Info

Publication number: WO2018193297A1
Application number: PCT/IB2017/057777
Authority: WO
Inventors: Rajiv Sharma; Sanjay Kumar; Brijesh Kumar Srivastava
Original assignee: Cadila Healthcare Limited
Priority date: 2017-04-21
Filing date: 2017-12-11
Publication date: 2018-10-25

Abstract

The present invention provides compounds which are modulators of RORϒ and their use for the treatment of diseases or conditions mediated by RORϒ. Further, the present invention relates to processes of preparing such compounds, their tautomeric forms, deuterated form, novel intermediates involved in their synthesis, their pharmaceutically acceptable salts, methods for using such compounds and pharmaceutical compositions containing them. formula (I)

Description

NOVEL COMPOUNDS AS ROR-GAMMA MODULATORS

FIELD OF THE INVENTION

The present invention provides compounds which are modulators of RORy (ROR-GAMMA) and their use for the treatment of diseases or conditions mediated by RORy. 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.

formula (I)

BACKGROUND TO THE INVENTION

There has been rapid advancement in the biological roles played by nuclear receptors. Nuclear receptors are involved in regulation of key physiological functions and have been identified as the key regulators in metabolic diseases, cancer and autoimmune disorders. The Retinoic acid receptor-related orphan receptor γ known as RORy belonging to the nuclear receptor superfamily (Hirose, T.; Smith, R. J.; Biochem. Biophys. Res. Commun. 1994, 205, 1976-1983). Till date there are three sub-types of ROR s which is classified as RORa, RORP and RORy. Like other nuclear receptors, structure ROR s consists of four distinct functional regions called N-terminal A/B domain, DNA binding domain (DBD) or C domain, a hinge domain and The E domain or ligand binding domain (LBD).Two isoforms RORyl and RORy2 (which is also called as RORyt) have been identified which differ in N-terminal sequences (He, Y.-W.; Deftos, M. L.; Ojala, Immunity 1998, 9,797-806). Tissue distribution of RORyt isoform is restricted to lymphoid organs, such as the thymus. The isoform RORyt plays important role in the development and regulation of the immune system as it has been identified as a key regulator of T helper cells (TH17 cell) differentiation (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 TH17 in autoimmune diseases. RORy is central transcription factor driving Thl7 differentiation.

In light of the role of RORy in the pathogenesis of autoimmune disease, development of ligands which can modulate RORy activity could lead to specific therapies for diseases mediated by RORy.

WO2017058831 "Pteridine derivatives as modulators of ror gamma" by Boehringer has been disclosed with following general structure.

Glenmark disclosed aryl and heteroaryl ether compounds with following general structure as ROR gamma modulators in WO2017051319

Eli Lilly discloses dihydrospiro piperidine-thienopyran-carboxamide compounds useful for inhibiting ROR-gamma-t and their preparation in the patent application US20170066781

Glenmark disclosed preparation of carbocyclic compounds as ROR gamma modulators in WO2017037595 having the following general formula

Vitae Pharmaceutical claims preparation of ROR-gamma modulators in patent application WO 2017024018 with following structure

Glenmark in its patent application WO2017021879, has disclosed preparation of certain ROR gamma modulators having the following general formula.

Shionogi patent application titled" Preparation of amide compounds having RORyt inhibitory effect", WO2017010399 describes compounds with the following general structure.

Glaxo Pharmaceuticals disclosed novel RORy modulator and their use in treatment of disease mediated by RORy, having the following formula in patent application WO 2013029338

Piramal enterprises describes certain ROR gamma modulators and uses thereof with following general structure in patent application WO2015145371

Formula I

Takeda Pharmaceuticals disclosed novel RORy modulators and their use in the treatment of disease mediated by RORy, having following formula in patent application

WO2013018395.

Though a number of different approaches in terms of different scaffolds, molecular formulae, none of these molecules have advanced far in the clinics. There is therefore an huge unmet need for providing novel compounds which are modulators of RORy. We herein disclose novel compounds of formula (I) useful as RORy modulator which may have a beneficial effect in the treatment of autoimmune or inflammatory diseases such as multiple sclerosis, rheumatoid arthritis, irritable bowel diseases, psoriasis, psoriatic arthritis which are mediated by RORy, and methods for their preparation.

SUMMARY OF THE INVENTION

The invention provides compounds which are modulators of RORy and their use for the treatment of autoimmune or inflammatory diseases such as multiple sclerosis, rheumatoid arthritis, irritable bowel diseases, psoriasis, psoriatic arthritis which are mediated by RORy. The novel compounds are defined by the general formula (I) as given below. 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 autoimmune or inflammatory diseases. EMBODIMENTS 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 a further another 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.

DETAILED DESCRIPTION OF THE INVENTION

Accordin ly, the present invention relates to compounds of the general formula

formula (I)

Wherein Ά' represents either a bond, or the groups selected from -CN, -COOH, optionally substituted groups selected from (Ci-C₈)alkyl, (C3-C₆)cycloalkyl, aryl, heteroaryl or heterocyclyl groups. In an embodiment A may be absent.

Ring 'B' represents aryl, heteroaryl or heterocyclyl wherein Ύ' represents C or N;

'Z' represents either a bond or the atoms C, or -N. In an embodiment Z may be absent.

When 'Z' represents C or N, R₂ and R₃ are each independently selected from the group comprising of hydrogen, hydroxyl, haloalkyl, optionally substituted groups selected from (Ci-C₈)alkyl, (Ci-C₈)alkoxy, (C₃-C₆)cycloalkyl, benzyl or carbocyclic group or R₂ and R₃ together with the atom to which they are attached may form a 3- to 10- membered carbocyclic ring system having optionally one or more than one heteroatoms;

R5 represents hydrogen, optionally substituted (Ci-C₈)alkyl, (Ci-C₈)alkoxy, (C₃- C₆)cycloalkyl;

X represents -O, NR' wherein R' is hydrogen, CN, N0₂, OR" or optionally substituted (Ci-C₈)alkyl wherein R" is hydrogen, haloalkyl, optionally substituted (Ci-

C₈)alkyl, (C₃-C₈)cycloalkyl groups;

R₆ and R₇ are each independently selected from the group comprising of hydrogen, optionally substituted groups selected from (Ci-C₈)alkyl, aryl, heteroaryl, heterocyclyl or In an embodiment R₆ and R₇ together with the atom to which they are attached to form a heterocyclic, bridged or spiro ring system 'C having optionally one or more than one heteroatoms;

In a preferred embodiment, the heterocyclyl group may be selected from heterocyclic ring is 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;

Each of Ri_, R4 and R₈ at each occurrence is independently selected from the group comprising of hydrogen, halogen, hydroxy, cyano, oxo, halo(Ci-C₈)alkyl, optionally substituted (Ci-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₆)cycloalkyl, aryl, heterocyclyl, heteroaryl, aralkyl, heteroaralkyl, heterocyclylalkyl, cycloalkanylalkyl, alkylsulfonyloxy, -COR_a, -COOR_a, -OR_a, -S(0)_tR_a, -S(0)_tNR_a, -

NR_aR_b, -CONR_aR_b, -N(R_a)COR_b, -N(R_a)COOR_b, -OCH₂COR_a, -N(R_a)CH₂COR_b, -

N(R_a)CONR_aR_b, -S(0)_tNR_aR_b, -N(R_a)S(0)_tR_b groups; 'm', 'n' and 'p' represent integers from 0-2;

Each of R_a and R at each occurrence are independently selected from the group comprising of hydrogen, haloalkyl, optionally substituted groups selected from (Ci- C₈)alkyl, (C₂-C₈)alkenyl, (C2-C₈)alkynyl, (C₃-C₈) cycloalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl groups; or wherever feasible, R_a and R_b together with the atom to which they are attached may form an optionally substituted 5- to 10- membered carbocyclic ring optionally containing 0-2 additional heteroatoms selected from -0-, -NR9- or S(0)_t; wherein, R9 represents hydrogen, optionally substituted groups selected from (Ci-C₈)alkyl, (C₃-C₈)cycloalkyl, and (Q- C₈)haloalkyl; 't' represents integers from 1-2;

When any of above defined group is substituted the substitutions on them may be selected from hydrogen, hydroxy, cyano, halo, oxo, imino, haloalkyl, (Ci-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₈)cycloalkyl, (C₅-C₈)cycloalkenyl, aryl, heterocyclyl, heteroaryl, aralkyl, heteroaralkyl, heterocyclylalkyl, alkylsulfonyloxy, - CORa, -COORa, -ORa, -S(0)_tR_a, -NR_aRb, -CONRaRb, -N(R_a)CORb, -N(R_a)COOR_b, - OCH₂COR_a, -N(Ra)CH₂COR_b, -N(R_a)CONR_aR_b, -S0₂NR_aR_b, -N(R_a)S0₂R_b derivatives; wherein, R_a and R_b are as defined earlier;

In a preferred embodiment, the groups referred to above may comprise of:

"Alkyl" by itself or as part of another substituent, means, unless otherwise stated, a straight- or branched-chain, fully saturated aliphatic hydrocarbon radical having the number of carbon atoms designated. For example, "Ci_₆alkyl" refers to a hydrocarbon radical, either straight- or branched-chain, that contains from 1 to 6 carbon atoms and that is derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane. Alkyl includes branched-chain isomers of straight- chain alkyl groups, such as isopropyl, t-butyl, isobutyl, sec -butyl, and the like. Representative alkyl groups include straight- and branched-chain alkyl groups having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms. Further representative alkyl groups include straight and branched chain alkyl groups having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms.

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, z^'so-propoxy, n-butoxy, i-butoxy, z^'so-butoxy, pentyloxy, hexyloxy, and the like;

"Halo" or "halogen" by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as "haloalkyl", are meant to include an alkyl in which one or more hydrogen is replaced by halogen atoms that can be the same or different, in a number ranging from one up to the maximum number of halogens permitted e.g. for alkyl, (2m'+l), where m' is the total number of carbon atoms in the alkyl group. For example, the term "haloCi-galkyl" is meant to include difluoromethyl, trifluoromethyl, 2,2,2- trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. Additionally, term "haloalkoxy" refers to an alkoxy radical substituted with one or more halogen atoms. In one group of embodiments, the haloalkyl and haloalkoxy groups have from one to five or from one to three halogen atoms. Examples of haloalkoxy groups include difluoromethoxy and trifluoromethoxy.

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;

As used herein, the term "heterocycle" or "heterocyclic system" is intended to mean a stable 4 to 7-membered monocyclic or 7 to 14-membered bicyclic heterocyclic ring which is saturated, partially unsaturated or aromatic, and which consists of carbon atoms & also contains from 1 to 3 hetero atoms independently selected from the group consisting of N, O and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The term heterocycle as used in the specification includes both aromatic and non-aromatic single or fused cyclic system containing at least one heteroatom selected from N, O and S. The nitrogen and sulfur hetero atoms may optionally be oxidized. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. A skilled person is well aware of the terms "heterocycle" or "heterocyclic system" and the present invention encompasses all such variations, alterations of definitions which are within the scope of such a skilled person. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. In a further optional embodiment, nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these hetero atoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1. As used herein, the term "aromatic heterocyclic system" is intended to mean a stable 5 to 7 membered monocyclic or bicyclic or 7 to 14 membered bicyclic heterocyclic aromatic ring which consists of carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, O and S. It is preferred that the total number of S and O atoms in the aromatic heterocycle is not more than 1. Also included are fused ring, bridged bicyclic heterocycles, Spiro-compounds containing, for example, the above heterocycles.

As used herein, "carbocycle" or "carbocyclic residue" is intended to mean any stable monocyclic or bicyclic or tricyclic ring, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocycle include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin);

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 "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 "hetero aralkyl" 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 term "alkylsulfonyloxy" represents R_xS0₂-group attached to an oxygen atom, such that oxygen acts as the point of attachment. R_x represents alkyl group;

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

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

Compounds of formula (I) may contain one or more asymmetric centers and can thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. The present invention is meant to comprehend all such isomeric forms of the compounds of formula (I), either as single species or mixtures thereof. Some of the compounds described herein contain olefinic double bonds, and unless specified otherwise, are meant to include both E and Z geometric isomers.

Some of the compounds described herein may exist with different points of attachment of hydrogen, referred to as tautomers. Such an example may be a ketone and its enol form known as keto-enol tautomers. The individual tautomers as well as mixture thereof are encompassed with compounds of formula (I).

List of Abbreviation

DMF: Dimethyl formamide

DCM: Dichloromethane

EDAC.HC1: N-(3-Dimethyl aminopropyl)-N' -ethyl carbodiimide hydrochloride,

HOBT: 1 -Hydroxy benzotriazole

TFA: Trifluoro acetic acid

DCC: Dicyclohexylcarbodiimide

DIPEA: Disopropyl ethyl amine

EtOAc: Ethyl acetate

h: Hour(s)

rt : room temperature

min: Minute(s)

tR_et: Retention time

HC1: Hydrochloric acid

RT: Room temperature [25-30 °C]

CS₂CO₃: Cesium carbonate

TEA: Triethyl amine

HBTU : N,N,N',N'-Tetramethyl-C⁾-(lH-benzotriazol- l-yl)uronium hexafluorophosphate Instrument details

Mass spectrum was recorded on LC-MS 2010-A Shimadzu.

HPLC purity was determined by using Agilent 1100 instrument.

HPLC Column: YMC J Sphere C 18 (150X4.6 ιηιη)4μ

Mobile phase: 0.05 % TFA in water: ACN gradient.

Flow rate: 1.0 ml/min.

Wave length: UV at 220 nm.

UPLC was determined on Acquity Ultra performance instrument.

UPLC Column: BEHC18 (2.1x100mm) 1.7 μ Mobile phase: 0.05 % TFA in water: ACN gradient.

Flow rate: 0.04 ml/min

NMR spectrum: Bruker Advance 400 MHz

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

Preferred compounds according to the present invention include but are not limited to: l-(3,5-dichloro-4-(l-(5-(4-fluorophenyl)-l,2,4-oxadiazol-3-yl)cyclopropyl)phenyl)-3- (4-(ethylsulfonyl)phenyl)urea;

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

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

3- (4-(ethylsulfonyl)phenyl)urea;

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

(ethylsulfonyl)piperazine- 1 -carboxamide;

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

(ethylsulfonyl)hexahydropyrrolo[3,4-c]pyrrole-2(lH)-carboxamide;

N-(3,5-dichloro-4-morpholinophenyl)-4-(ethylsulfonyl)piperazine-l -carboxamide;

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

(ethylsulfonyl)piperazine-l -carboxamide;

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

(ethylsulfonyl)piperazine- 1 -carboxamide;

N-(3,5-dichloro-4-(l-(5-cyclopropyl-l,2,4-oxadiazol-3-yl)cyclopropyl)phenyl)-4- (ethylsulfonyl)piperazine- 1 -carboxamide;

N-(3,5-dichloro-4-(l-(5-(trifluoromethyl)-l,2,4-oxadiazol-3-yl)cyclopropyl)phenyl)-4- (ethylsulfonyl)piperazine-l -carboxamide;

N-(3,5-dichloro-4-(l-(5-(trifluoromethyl)-l,3,4-thiadiazol-2-yl)cyclopropyl)phenyl)-4- (ethylsulfonyl)piperazine- 1 -carboxamide;

4- (Ethylsulfonyl)-N-(4-(l-(5-(4-fluorophenyl)-l,2,4-oxadiazol-3-yl)cyclopropyl)-3,5- dimethylphenyl)piperazine- 1 -carboxamide; N-(3,5-difluoro-4-(l-(5-(4-fluorophenyl)-l,2,4-oxadiazol-3-yl)cyclopropyl)phenyl)-4- (ethylsulfonyl)piperazine- 1 -carboxamide;

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

N-(3,5-dichloro-4-(l-(5-(4-fluorophenyl)-l,2,4-oxadiazol-3-yl)cyclopropyl)phenyl)-4- (ethylsulfonyl)-l,4-diazepane-l -carboxamide;

N-(3,5-dichloro-4-((5-(4-fluorophenyl)-l,2,4-oxadiazol-3-yl)methyl)phenyl)-4- (ethylsulfonyl) piperazine-1 -carboxamide;

N-(3,5-dichloro-4-(2,3-dihydrospiro[indene-l,4'-piperidin]- -yl)phenyl)-4- (ethylsulfonyl)piperazine- 1 -carboxamide;

4-(cyclopropylsulfonyl)-N-(3,5-dichloro-4-(l-(5-(4-fluorophenyl)-l,2,4-oxadiazol-3- yl)cyclopropyl)phenyl)piperazine-l -carboxamide;

N-(3,5-dichloro-4-(l-(5-(4-fluorophenyl)-l,2,4-oxadiazol-3-yl)cyclopropyl)phenyl)-4- (methylsulfonyl)piperazine- 1 -carboxamide;

N-(3-chloro-4-(l-(5-(4-fluorophenyl)-l,2,4-oxadiazol-3-yl)cyclopropyl)phenyl)-4- (ethylsulfonyl)piperazine- 1 -carboxamide;

N-(3,5-dichloro-4-(l-(5-(4-fluorophenyl)-l,2,4-oxadiazol-3-yl)cyclopropyl)phenyl)-4- (isopropylsulfonyl)piperazine-l -carboxamide;

2-(4-((3,5-dichloro-4-(l-(5-(4-fluorophenyl)-l,2,4-oxadiazol-3-yl)cyclopropyl)phenyl) carbamoyl) piperazin-l-yl)acetic acid;

Ethyl-2-(4-((3,5-dichloro-4-(l-(5-(4-fluorophenyl)-l,2,4-oxadiazol-3- yl)cyclopropyl)phenyl)carbamoyl) piperazin-l-yl) acetate;

N-(3,5-dichloro-4-(l-(5-(4-fluorophenyl)-l,2,4-oxadiazol-3-yl)cyclopropyl)phenyl)-4- (ethylsulfonyl)piperidine- 1 -carboxamide; N-(3,5-dichloro-4-(l-(5-(4-fluorophenyl)-l,2,4-oxadiazol-3-yl)cyclopropyl)phenyl)-6- (ethylsulfonyl)-3,6-diazabicyclo[3.1.1]heptane-3-carboxamide; l-(3,5-dichloro-4-(l-(5-(4-fluorophenyl)thiazol-2-yl)cyclopropyl)phenyl)urea; N-(3,5-dichloro-4-(l-(5-(4-fluorophenyl)thiazol-2-yl)cyclopropyl)phenyl)-4- (ethylsulfonyl)piperazine- 1 -carboxamide;

N-(3,5-dichloro-4-morpholinophenyl)-4-(ethylsulfonyl)piperazine-l-carboxamide; N-(3,5-dichloro-4-(l-(5-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl)-l,2,4-oxadiazol-3- yl)cyclopropyl)phenyl)-4-(ethylsulfonyl)piperazine-l-carboxamide; N-(3,5-dichloro-4-(l-(5-(4-fluorophenyl)thiazol-2-yl)cyclopropyl)phenyl)-4- (ethylsulfonyl)piperazine- 1 -carboxamide;

N-(3,5-dichloro-4-(l-(5-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl)-l,2,4-oxadiazol-3- yl)cyclopropyl)phenyl)-4-(ethylsulfonyl)piperazine-l-carboxamide;

4-(cyclopropylsulfonyl)-N-(3,5-dichloro-4-(l-(5-(4-(trifluoromethyl)cyclohexyl)- 1,2,4- oxadiazol-3-yl)cyclopropyl)phenyl)piperazine-l-carboxamide;

N-(3,5-dichloro-4-(l-(5-(4-(methylsulfonyl)phenyl)-l,2,4-oxadiazol-3- yl)cyclopropyl)phenyl)-4-(ethylsulfonyl)piperazine-l-carboxamide;

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

4-(ethylsulfonyl)piperazine- 1 -carboxamide;

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

N-(3,5-dichloro-4-(l-(5-(4-fluorophenyl)-l,2,4-oxadiazol-3-yl)cyclopropyl)phenyl)-6- (ethylsulfonyl)-2,6-diazaspiro[3.3]heptane-2-carboxamide; 4-(cyclopropylsulfonyl)-N-(3,5-dichloro-4-(l-(5-(4,4-difluorocyclohexyl)-l,2,4- oxadiazol-3-yl)cyclopropyl)phenyl)piperazine-l-carboxamide;

N-(2,6-dichloro-3'-(trifluoromethoxy)-[l, -biphenyl]-4-yl)-4-(ethylsulfonyl)piperazine- 1 -carboxamide; N-(2,6-dichloro-2'-fluoro-[l, -biphenyl]-4-yl)-4-(ethylsulfonyl)piperazine- l- carboxamide;

N-(2,6-dichloro-3 '-methyl- [1,1 '-biphenyl] -4-yl)-4-(ethylsulfonyl)piperazine- 1 - carboxamide;

N-(2,6-dichloro-2'-methoxy- [1, 1 '-biphenyl] -4-yl)-4-(ethylsulfonyl)piperazine- 1 - carboxamide;

N-(2,6-dichloro-4'-hydroxy- [1,1 '-biphenyl] -4-yl)-4-(ethylsulfonyl)piperazine- 1 - carboxamide;

N-(3,5-dichloro-4-(l-(5-(4-methoxyphenyl)- l,2,4-oxadiazol-3-yl)cyclopropyl)phenyl)- 4-(ethylsulfonyl)piperazine- 1 -carboxamide;

N-(2,6-dichloro-3'-cyano- [1,1 '-biphenyl] -4-yl)-4-(ethylsulfonyl)piperazine- 1 - carboxamide;

4-(cyclopropylsulfonyl)-N-(3,5-dichloro-4-(l-(5-(4-(trifluoromethyl)phenyl)-l,2,4- oxadiazol-3-yl)cyclopropyl)phenyl)piperazine- l-carboxamide;

4-(cyclopropylsulfonyl)-N-(3,5-dichloro-4-(l-(5-(4-cyanophenyl)- l,2,4-oxadiazol-3- yl)cyclopropyl)phenyl)piperazine-l -carboxamide;

4-(cyclopropylsulfonyl)-N-(3,5-dichloro-4-(l-(5-(4-methoxyphenyl)-l,2,4-oxadiazol-3- yl)cyclopropyl)phenyl)piperazine-l -carboxamide;

N-(3-chloro-5-f uoro-4-(l-(5-(4-(trifluoromethyl)phenyl)- l,2,4-oxadiazol-3- yl)cyclopropyl)phenyl)-4-(cyclopropylsulfonyl)piperazine- l-carboxamide;

N-(3,5-dichloro-4-(2-(5-(4-fluorophenyl)-l,2,4-oxadiazol-3-yl)propan-2-yl)phenyl)-4- (ethylsulfonyl)piperazine- 1 -carboxamide;

4-(cyclopropylsulfonyl)-N-(3,5-dichloro-4-(2-(5-(4-fluorophenyl)- l,2,4-oxadiazol-3- yl)propan-2-yl)phenyl)piperazine- l -carboxamide; 4-(cyclopropylsulfonyl)-N-(3,5-difluoro-4-(l-(5-(4-fluorophenyl)-l,2,4-oxadiazol-3- yl)cyclopropyl)phenyl)piperazine- 1 -carboxamide

4-(cyclopropylsulfonyl)-N-(3,5-dichloro-4-(l-(5-(4-(methylsulfonyl)phenyl)-l,2,4- oxadiazol-3-yl)cyclopropyl)phenyl)piperazine-l-carboxamide;

4-(cyclopropylsulfonyl)-N-(3,5-dichloro-4-((5-(4-fluorophenyl)-l,2,4-oxadiazol-3- yl)methyl)phenyl)piperazine- 1 -carboxamide;

N-(3,5-dichloro-4-(2-oxopyridin-l(2H)-yl)phenyl)-4-(ethylsulfonyl)piperazine-l- carboxamide;

N-(3,5-dichloro-4-(l-(5-(4-(trifluoromethoxy)phenyl)-l,2,4-oxadiazol-3- yl)cyclopropyl)phenyl)-4-(ethylsulfonyl)piperazine-l-carboxamide;

4-(cyclopropylsulfonyl)-N-(3,5-dichloro-4-(l-(5-(4-(trifluoromethoxy)phenyl)-l,2,4- oxadiazol-3-yl)cyclopropyl)phenyl)piperazine-l-carboxamide;

N-(3,5-dichloro-4-(l-(5-(4-fluorophenyl)-l,2,4-oxadiazol-3-yl)cyclopropyl)phenyl)-4- (ethylsulfonyl)-3,5-dimethylpiperazine-l -carboxamide;

N-(3,5-dichloro-4-(l-(5-(4-fluorophenyl)-l,2,4-oxadiazol-3-yl)cyclopropyl)phenyl)-4- (ethylsulfonamido)piperidine- 1 -carboxamide;

N-(3-chloro-4-(l-(5-(4-chlorophenyl)-l,2,4-oxadiazol-3-yl)cyclopropyl)-5- fluorophenyl)-4-(cyclopropylsulfonyl)piperazine-l -carboxamide;

4-(cyclopropylsulfonyl)-N-(3,5-dichloro-4-(l-(5-(4-chlorophenyl)-l,2,4-oxadiazol-3- yl)cyclopropyl)phenyl)piperazine-l -carboxamide; N-(3-chloro-4-(l-(5-(4-cyanophenyl)-l,2,4-oxadiazol-3-yl)cyclopropyl)-5- fluorophenyl)-4-(ethylsulfonyl)piperazine-l-carboxamide; N-(3-chloro-5-fluoro-4-(l-(5-(4-(trifluoromethyl)phenyl)-l,2,4-oxadiazol-3- yl)cyclopropyl)phenyl)-4-(ethylsulfonyl)piperazine-l-carboxamide; N-(2,6-dichloro-3'-methoxy- [1,1 '-biphenyl] -4-yl)-4-(ethylsulfonyl)piperazine- 1 - carboxamide;

The compounds of the present invention may be prepared using the methods described below, together with conventional techniques known to those skilled in the art of organic synthesis or variation thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to those described below, where all symbols are as defined earlier.

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

formula (I)

Nitro compound [II] on reduction with suitable reducing agents such as Pd/C, H₂(g), RaneyNi, FeCl₃, NH₄C1, SnCl₂ in solvents selected from MeOH, EtOH, and the like resulted in amine compound [III]. Amine compound of formula [III] on coupling with suitable acid derivative [IV] in presence of phosgene and the like in solvent selected from DCM, DMF and the like, afforded compound of formula [I]. The compound of formula [II] and [IV] can be synthesized as per the general procedures known in the art along with suitable variations as are well known to a skilled person, in the art such as following procedures set forth in references such as Fieser and Fieser's Reagents for Organic Synthesis; Wiley & Sons: New York, Volumes 1-21; R. C. LaRock, Comprehensive Organic Transformations, 2.nd edition Wiley- VCH, New York 1999; Comprehensive Organic Synthesis, B. Trost and I. Fleming (Eds.) vol. 1-9 Pergamon, Oxford, 1991; Comprehensive Heterocyclic Chemistry, A. R. Katritzky and C. W. Rees (Eds) Pergamon, Oxford 1984, vol. 1-9; Comprehensive Heterocyclic Chemistry II, A. R. Katritzky and C. W. Rees (Eds) Pergamon, Oxford 1996, vol. 1-1 1 ; and Organic Reactions, Wiley & Sons: New York, 1991, Volumes 1- 40, to name some of the known literature processes, each of which are incorporated by reference herein.

Unless otherwise specified, 1H NMR spectral data given in the examples are recorded using a 400 MHz spectrometer (Bruker Topspin 3.5) and reported in δ scale. Tetra methyl silane is used as the internal standard.

The pharmaceutically acceptable salts forming a part of this invention may be prepared by treating the compound of formula (I) with suitable acids in suitable solvents by processes known in the art.

The invention is further exemplified by the following examples below, which provides some of the several preferred embodiments of the present invention. These examples are provided merely as representative embodiments and should not be construed to limit the scope of the invention in any way.

Example 1

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

4-(ethylsulfonyl) aniline (50.9 mg, 0.275 mmol) and triethyl amine (0.042 ml, 0.302 mmol) were dissolved in CH₂CI₂ (5 mL) with stirring at -78°C. To this mixture triphosgene (32.6 mg, 0.110 mmol) dissolved in CH₂CI₂ (5 mL) was added dropwise at -78° C. The reactants were then warmed to 0°C and stirred for 30 min. Thereafter the reactants and reaction products were cooled to 0°C. 3,5-dichloro-4-(l-(5-(4- fluorophenyl)- l,2,4-oxadiazol-3-yl)cyclopropyl)aniline (100 mg, 0.275 mmol) dissolved in CH₂CI₂ (5 mL) and triethyl amine (0.042 ml, 0.302 mmol) were added slowly and the resulting reaction mixture was further stirred at room temperature for 12h.The reaction was then quenched with the addition of HCl solution (1M,15 mL). The organic layer was collected from the reaction mixture and the remaining aqueous layer was further extracted with ethyl acetate. The obtained organic layers were pooled and washed with saturated NaCl solution. The organic layer was separated and dried over anhydrous sodium sulfate. The solvents were removed on rotatory evaporator to get crude product, which was purified by flash chromatography using mobile phase (EtOAc: Hexane /7:3) to get 58 mg of yellow colored solid product

¹HNMR (DMSO-d₆): 9.47 (s, 1H), 9.24 (s, 1H),8.13-8.10 (m, 2H), 7.79 (d, = 8.8 Hz, 2H), 7.72 (d, = 8.8 Hz, 2H), 7.65 (s, 2H), 7.47-7.43 (m, 2H), 3.22 (q, Ji= 7.2 Hz, J₂ = 2.0 Hz ,2H), 1.98-1.89 (m, 2H), 1.59-1.56 (m, 2H), 1.08 (t, = 7.2 Hz, 3H). Synthesis of intermediate: 3,5-dichloro-4-(l-(5-(4-fluorophenyl)-l,2,4-oxadiazol-3-yl) cyclopropyl)aniline

Step 1: ethyl 2-cyano-2-(2,6-d te

To a stirred solution of 1, 2,3 -trichloro-5 -nitrobenzene (50 g, 221 mmol) and cesium carbonate (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 heated at 70-75°C for 1 h before it was cooled and dumped in to 2N 200 mL HCl solution. Solid obtained was filtered to get title product as brown solid. ¹HNMR (DMSO- e): 8.47 (s, 2H), 6.54 (s, 1H), 4.28 (q, = 6.8 Hz, 2H), 1.23 (t, = 6.8 Hz, 3H).

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

To a stirred solution of product of step 1 ethyl 2-cyano-2-(2,6-dichloro-4- nitrophenyl)acetate (52 g, 172 mmol) in DMSO (12 mL) and water (4.5 mL) was added lithium chloride (9.46 g, 223 mmol) at 25-30° C. The reaction mixture was heated at 165° C for lh. The reaction mixture was cooled and dumped in to ice cold water. Solid obtained was filtered to get 25 g title compound. 1HNMR (DMSO-ifc): 8.42 (s, 2H), 4.31 (s, 2H).

Step 3: Preparation of l-(2,6-dichloro-4-nitrophenyl)cyclopropane-l-carbonitrile

To a stirred solution of product of step 2, 2-(2,6-dichloro-4- nitrophenyl)acetonitrile (4.0 g, 17.31 mmol) in acetonitrile (40 mL) was added ethylene dibromide (4.48 ml, 51.9 mmol) followed by tetra butyl ammonium bromide (5.58 g, 17.31 mmol). To this was added 8 mL 50 % NaOH solution at 25-30°C and reaction mixture was stirred at 70-75°C for 12 h. The reaction mixture was poured in to water and extracted with EtOAc. The organic layer was separated, washed with water, dried over sodium sulfate and solvents were removed on rotatory evaporator to get crude product, which was purified by column chromatography (4% EtOAc in hexane) to get titled product. ¹HNMR (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-nitrophenyl)-N'-hydroxycyclopropane- 1-carboximidamide

To a stirred solution of l-(2,6-dichloro-4-nitrophenyl)cyclopropane-l- carbonitrile (5 g, 19.45 mmol) in rectified spirit (50 mL) was added hydroxyl amine hydrochloride (3.38 g, 48.6 mmol) and K₂C0₃ (6.72 g, 48.6 mmol) at 25-30°C. The reaction mixture was refluxed for 16 h. The progress of reaction was monitored by TLC. The reaction mixture was diluted with water and precipitated solid was filtered to get title product. ¹HNMR (DMSO-d₆): 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 stirred solution of 4-fluorobenzoic acid (0.560 g, 4 mmol), HOBT (0.857 g, 5.60 mmol) in DMF (30 mL) was added EDC: HC1 (1.073 g, 5.60 mmol) and stirred at 25-30° C over a period of 15 min.. To this was added product of step 4 (1.16 g, 4 mmol) and stirred at 110°C over a period of 16 h. The progress of reaction was monitored by TLC. The reaction mixture was poured in water and extracted with EtOAc. The organic layer was washed with water followed by sodium bicarbonate solution. The organic layer was separated, dried over sodium sulfate and solvents were removed to get crude product, which was column purified using mobile phase (0-3% EtOAc: Hexane) to get title product. ¹HNMR (DMSO- ₆): 8.38 (s, 2H), 8.13 (dd, = 5.2 and 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 stirred solution of product of step 5 (140 mg, 0.355 mmol) in ethyl acetate

(5 mL) was added stannous chloride dihydrate (401 mg, 1.776 mmol) and stirred at 25- 30° C for 3 h. The progress of reaction was monitored by TLC. The reaction mixture was diluted with EtOAc, basified with aq. ammonia and passed through celite using buchner funnel. The organic layer was separated, solvents were removed on rotatory evaporator to get title product. 1HNMR (DMSO- ₆): 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).

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

1HNMR (DMSO-d₆): 9.49 (s, IH), 9.28 (s, 1H),7.90 -7.80 (m, IH), 7.81 -7.78 (m, 3H), 7.72 (d, = 8.8 Hz, 2H), 7.65 (s, 2H), 7.45-7.44(m, IH), 7.37-7.34 (m, IH), 3.23 (q, = 7.2 Hz, J₂ = 2.8 Hz ,2H), 1.98- 1.88 (m, 2H), 1.59-1.56(m, 2H), 1.09 (t, = 7.2 Hz, 3H).

Example 3

Preparation of l-(3,5-dichloro-4-(l-(5-(2,4-difluorophenyl)-l,2,4-oxadiazol-3- l)cyclopropyl)phenyl)-3-(4-(ethylsulfonyl)phenyl)urea

¹HNMR (DMSO-d₆): 9.50 (s, IH), 9.28 (s, 1H),8.18-8.12 (m, IH), 7.79 (d, = 8.8 Hz, 2H), 7.72 (d, = 8.8 Hz, 2H), 7.65 (s, 2H), 7.63-7.58 (m, IH), 7.37-7.34 (m, IH), 3.22 (q, Ji= 7.2 Hz, J₂ = 2.0 Hz ,2H), 1.91- 1.88 (m, 2H), 1.57-1.54(m, 2H), 1.09 (t, = 7.2 Hz, 3H).

Example 4

N-(3,5-dichloro-4-(l-(5-(4-fluorophenyl)-l,2,4-oxadiazol-3-yl)cyclopropyl)phenyl)- 4-(ethylsulfonyl)piperazine-l-carboxamide

1HNMR (DMSO-d₆): 6 8.99 (s, IH), 8.09-8.12 (m, 2H), 7.66 (s, 2H), 7.42-7.47 (m, 2H), 3.50-3.56 (m, 4H), 3.20-3.29 (m, 4H), 3.06-3.11 (m, 2H), 1.86-1.90 (m, 2H), 1.50- 1.54 (m, 2H), 1.27-1.29 (m, 3H).

Example 5 N-(3,5-dichloro-4-(l-(5-(4-fluorophenyl)-l,2,4-oxadiazol-3-yl)cyclopropyl)phenyl)- 5-(ethylsulfonyl)hexahydropyrrolo[3,4-c]pyrrole-2(lH)-carboxamide

1HNMR (CDC1₃): δ 8.08-8.12 (m, 2H), 7.49 (s, 2H), 7.17-7.21 (m, 2H), 6.35 (s, IH), 3.73- 3.78 (m, 2H), 3.67-3.69 (m, 2H), 3.41-3.45 (m, 2H), 3.03-3.10 (m, 4H), 1.97-2.01 (m, 2H), 1.52-1.37 (m, 2H), 1.03-1.07 (m, 3H),.

Example 6

N-(3,5-dichloro-4-morpholinophenyl)-4-(ethylsulfonyl)piperazine-l-carboxamide

1HNMR (DMSO-d₆): δ 8.86 (s, IH), 7.58 (s, 2H), 3.66-3.68 (m, 4H), 3.50-3.53 (m, 4H), 3.17-3.20 (m, 4H), 3.05-3.10 (m, 8H), 1.19- 1.23 (brt, 3H).

Example 7

N-(3,5-dichloro-4-(l-(5-methyl-l,2,4-oxadiazol-3-yl)cyclopropyl)phenyl)-4- (ethylsulfonyl)piperazine-l-carboxamide

1H NMR (DMSO- 6): 58.97 (s, IH), 7.63 (s, 2H), 3.53 (t, 4H), 3.21-3.19 (m, 4H), 3.09- 3.07 (m, 2H), 1.74 (m, 2H), 1.44 (m, 2H), 1.21, (t, J = 7.6 Hz 3H) Example 8

N-(3,5-dichloro-4-(l-(5-isopropyl-l,2,4-oxadiazol-3-yl)cyclopropyl)phenyl)-4- (ethylsulfonyl)piperazine-l-carboxamide

1H NMR (DMSO- 6): 58.98 (s, 1H), 7.63 (s, 2H), 3.55 - 3.52 (m, 4H), 3.22 - 3.20 (m, 4H), 3.09 - 3.07 (m, 2H), 1.75 (m, 2H), 1.44 (m, 2H), 1.28 - 1.26 (d, = 87.2 Hz, 6H), 1.23 - 1.19 (m, 3H).

Example 9

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

1H NMR (DMSO-iM: 58.96 (s, 1H), 7.62 (s, 2H), 3.53 - 3.52 (m, 4H), 3.20 (m, 4H), 3.09 - 3.07 (m, 2H), 1.72 - 1.71 (m, 2H), 1.41 (m, 2H), 1.23 - 1.17 (m, 6H).

Example 10

N-(3,5-dichloro-4-(l-(5-(trifluoromethyl)-l,2,4-oxadiazol-3-yl)cyclopropyl)phenyl)- 4-(ethylsulfonyl)piperazine-l-carboxamide

1H NMR (DMSO-iM: 59.03 (s, 1H), 7.68 (s, 2H), 3.56 - 3.55 (m, 4H), 3.23 - 3.20 (m, 4H), 3.10 - 3.07 (q, 2H), 1.88 - 1.85 (m, 2H), 1.64 - 1.60 (m, 2H), 1.22 (t, 3H) Example 11

N-(3,5-dichloro-4-(l-(5-(trifluoromethyl)-l,3,4-thiadiazol-2-yl)cyclopropyl)phenyl)- 4-(ethylsulfonyl)piperazine-l-carboxamide

1H NMR (DMSO-iM) 59.08 (s, 1H), 7.73 (s, 2H), 3.53-3.55 (m, 4H), 3.21-3.22(m, 4H), 3.08-3.19 (m, 2H), 2.12-2.13(m, 2H), 1.77-1.78 (m, 2H), 1.20-1.23(m, 3H)

Example 12

4-(Ethylsulfonyl)-N-(4-(l-(5-(4-fluorophenyl)-l,2,4-oxadiazol-3-yl)cyclopropyl)-3,5- dimethylphenyl)piperazine- 1 -carboxamide

1H NMR (DMSO-i¾, 400 MHz) 5: 8.53 (s, 1H), 8.12-8.08 (m, 2H), 7.46-7.42 (m, 2H), 7.13 (s, 2H), 3.51 (t, = 4.8 Hz, 4H), 3.20 (t, J = 4.8 Hz, 4H), 3.09 (q, J = 7.2 Hz, 2H), 2.26 (s, 6H), 1.75-1.72 (m, 2H), 1.32-1.29 (m, 2H), 1.22 (t, J = 7.2 Hz, 3H)

Example 13

N-(3,5-difluoro-4-(l-(5-(4-fluorophenyl)-l,2,4-oxadiazol-3-yl)cyclopropyl)phenyl)- 4-(ethylsulfonyl)piperazine-l-carboxamide

1H NMR (DMSO-iM: 59.03 (s, IH), 8.08-8.11 (m, 2H), 7.44 (t, J = 8.8 Hz, 2H), 7.26 (d, J = 10.8 Hz, 2H), 3.53-3.55 (m, 4H), 3.21-3.22(m, 4H), 3.06-3.12 (m, 2H), 1.71 (d, / = 6.8 Hz, 2H), 1.42(d, J = 6.0 Hz, 2H), 1.15- 1.24(m, 3H)

Example 14

N-(3,5-dichloro-4-(l-(5-(4-fluorophenyl)-l,2,4-oxadiazol-3-yl)cyclopropyl)phenyl)- 4-(ethylsulfonyl)piperidine-l-carboxamide

1H NMR (CDC1₃, 400 MHz): 57.87-7.89 (m, IH), 7.77-7.80 (m, IH), 7.48-7.53 (m, 3H), 7.26-7.30 (m, IH), 6.42 (s, IH), 4.42-4.44 (brd, 2H), 4.32-4.34 (brd, IH), 4.12- 4.14 (brd, 2H), 3.96-3.99 (brd, 2H), 2.99-3.06 (m, 4H), 1.98-2.02 (m, 2H), 1.67- 1.72 (m, IH), 1.35-1.42 (m, 2H).

Example 15

N-(3,5-dichloro-4-(l-(5-(4-fluorophenyl)-l,2,4-oxadiazol-3-yl)cyclopropyl)phenyl)- 4-(ethylsulf onyl) - 1 ,4-diazepane- 1 -carboxamide

1H NMR (DMSO-i¾, 400 MHz) 5: 8.67 (s, IH), 8.14-8.10 (m, 2H), 7.73 (s, 2H), 7.48- 7.44 (m, 2H), 3.61-3.59 (m, 4H), 3.45-3.30 (m, 4H), 3.08 (q, J = 7.2 Hz, 2H), 1.89- 1.81 (m, 4H), 1.54-1.52 (m, 2H), 1.18 (t, J = 7.2 Hz, 3H).

Example 16

N-(3,5-dichloro-4-((5-(4-fluorophenyl)-l,2,4-oxadiazol-3-yl)methyl)phenyl)-4- (ethylsulf onyl) piperazine- 1 -carboxamide

1H NMR (DMSO-iM) 58.98 (s, 1H), 8.12 (dd, = 8.4 Hz & 5.6 Hz, 2H), 7.68 (s, 7.45 (m, 2H), 4.35 (s, 2H), 3.54 (s, 4H), 3.08 (m, 2H), 1.22 (m, 5H).

Example 17

N-(3,5-dichloro-4-(2,3-dihydrospiro[indene-l,4'-piperidin]-l'-yl)phenyl)-4- (ethylsulfonyl)piperazine-l-carboxamide

1H NMR (DMSO-i¾, 400 MHz) δ: 8.84 (s, 1H), 7.63 (d, J = 2.4 Hz, 1H), 7.54 (d, J = 2.4 Hz, 1H), 7.23-7.13 (m, 4H), 3.53-3.44 (m, 6H), 3.31-3.11 (m, 4H), 3.08 (q, J = 7.2 Hz, 2H), 2.90-2.85 (m, 4H), 2.06 (t, J = 7.6 Hz, 2H), 1.95-1.92 (m, 2H), 1.51-1.48 (m, 2H), 1.22 (t, J = 7.2 Hz, 3H).

Example 18

4-(cyclopropylsulfonyl)-N-(3,5-dichloro-4-(l-(5-(4-fluorophenyl)-l,2,4-oxadiazol-3- yl)cyclopropyl)phenyl)piperazine-l-carboxamide

1H NMR (DMSO-i¾, 400 MHz) δ: 9.02 (s, 1H), 8.13-8.09 (m, 2H), 7.67 (s, 2H), 7.47- 7.42 (m, 2H), 3.53 (t, J = 4.8 Hz, 4H), 3.22 (t, J = 4.8 Hz, 4H), 2.66-2.60 (m, 1H), 1.88 (q, J = 4.8 Hz, 2H), 1.54 (q, J = 4.8 Hz, 2H), 1.02-0.96 (m, 4H)

Example 19 N-(3,5-dichloro-4-(l-(5-(4-fluorophenyl)-l,2,4-oxadiazol-3-yl)cyclopropyl)phenyl)- 4-(methylsulfonyl)piperazine-l-carboxamide

1H NMR (DMSO-i¾, 400 MHz) δ: 9.02 (s, 1H), 8.12-8.08 (m, 2H), 7.67 (s, 2H), 7.47- 7.42 (m, 2H), 3.58 (t, J = 4.8 Hz, 4H), 3.15 (t, J = 4.8 Hz, 4H), 2.90 (s, 3H), 1.90-1.87 (m, 2H), 1.54-1.51 (m, 2H).

Example 20

N-(3-chloro-4-(l-(5-(4-fluorophenyl)-l,2,4-oxadiazol-3-yl)cyclopropyl)phenyl)-4- (ethylsulfonyl)piperazine-l-carboxamide

1H NMR (DMSO-i¾, 400 MHz) δ: 8.80 (s, 1H), 8.12-8.09 (m, 2H), 7.67 (d, J = 2.8 Hz, 1H), 7.52 (dd, J = 2.4 & 8.8 Hz, 1H), 7.46-7.42 (m, 2H), 7.34 (d, J = 8.4 Hz, 1H), 3.53 (t, J = 4.4 Hz, 4H), 3.18 (t, J = 4.4 Hz, 4H), 3.07 (q, J = 7.2 Hz, 2H), 1.73 (q, J = 4.8 Hz, 2H), 1.41 (q, J = 4.8 Hz, 2H), 1.21 (t, J = 7.2 Hz, 3H)

Example 21

N-(3,5-dichloro-4-(l-(5-(4-fluorophenyl)-l,2,4-oxadiazol-3-yl)cyclopropyl)phenyl)- 4-(isopropylsulfonyl)piperazine-l-carboxamide

1H NMR (DMSO-i¾, 400 MHz) δ: 8.99 (s, 1H), 8.14-8.10 (m, 2H), 7.67 (s, 2H), 7.48- 7.44 (m, 2H), 3.52 (t, J = 4.8 Hz, 4H), 3.42-3.39 (m, 1H), 3.29 (t, J = 4.8 Hz, 4H), 1.91- 1.88 (m, 2H), 1.55-1.52 (m, 2H), 1.25 (d, J =6.8 Hz, 6H)

Example 22

2-(4-((3,5-dichloro-4-(l-(5-(4-fluorophenyl)-l,2,4-oxadiazol-3-yl)cyclopropyl) phenyl) carbamoyl) piperazin-l-yl)acetic acid

1H NMR (DMSO-i¾, 400 MHz, δ): 8.87-8.92 (brd, 1H), 8.12-8.21 (brd, 2H), 7.68-7.79 (brd, 2H), 7.46 -7.54 (brd, 2H), 3.10-3.60 (brm, 8H), 2.70 (brs, 2H), 1.99 (brs, 2H), 1.53 (brs, 2H).

Example 23

Ethyl-2-(4-((3,5-dichloro-4-(l-(5-(4-fluorophenyl)-l,2,4-oxadiazol-3-yl) cyclopropyl)phenyl)carbamoyl) piperazin-l-yl)acetate

1H NMR (DMSO-i¾, 400 MHz, δ): 8.91(s, 1H), 8.09-8.12 (m, 2H), 7.66 (s, 2H), 7.42- 7.47 (m, 2H), 4.11-4.13 (brd, 2H), 3.32-3.58 (m, 8H), 2.66 (brs, 2H), 1.88- 1.90 (m, 2H), 1.50-1.53 (m, 2H), 1.17- 1.22 (m, 3H).

Example 24

1H NMR (CDCI₃, 400 MHz, δ): 7.46-7.52 (m, 3H), 7.36-7.40 (m, 2H), 7.27-7.29 (m, IH), 6.53 (s, IH), 3.62-3.65 (brt, 4H), 3.38-3.41 (brt, 4H), 2.98-3.04 (m, 2H), 1.41 (t, J = 7.4 Hz, 3H)

Example 25

N-(3,5-dichloro-4-(l-(5-(4-fluorophenyl)-l,2,4-oxadiazol-3-yl)cyclopropyl)phenyl)- 6-(ethylsulfonyl)-3,6-diazabicyclo[3.1.1]heptane-3-carboxamide

IH NMR (CDCI3, 400 MHz, δ): 7.88-7.90 (m, IH), 7.78-7.81 (m, IH), 7.47-7.53 (m, IH), 7.41 (m, 2H), 7.30-7.31 (m, IH), 6.76 (m, IH), 4.23-4.27 (brd, 2H), 2.92-3.07 (m, 5H), 2.14-2.18 (m, 2H), 1.99-2.02 (m, 2H), 1.86- 1.90 (m, 2H), 1.41- 1.44 (m, 4H)

Example 26

N-(3,5-dichloro-4-(l-(5-(4-fluorophenyl)thiazol-2-yl)cyclopropyl)phenyl)-4- (ethylsulfonyl)piperazine-l-carboxamide

1H NMR (CDCI₃, 400 MHz, δ): 7.83-7.86 (m, 2H), 7.45 (s, 2H), 7.23 (s, IH), 7.11-7.16 (m, 2H), 4.10-4.16 (m, 4H), 3.59-3.61 (m, 4H), 2.92-3.01 (m, 2H), 2.00-2.11 (m, 2H), 1.70-1.77 (m, 2H), 1.32- 1.39 (m, 3H).

Example 27

N-(3,5-dichloro-4-morpholinophenyl)-4-(ethylsulfonyl)piperazine-l-carboxamide

1H NMR (DMSO-iM): 58.57 (s, IH), 7.59 (s, 2H), 3.51-3.53 (m, 4H), 3.16-3.19 (m, 8H), 3.08-3.10 (m, 2H), 1.90-2.20 (m, 4H), 1.22 (t, 3H)

Example 28

N-(3,5-dichloro-4-(l-(5-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl)-l,2,4-oxadiazol- 3-yl)cyclopropyl)phenyl)-4-(ethylsulfonyl)piperazine-l-carboxamide

1H NMR (CDC1₃, 400 MHz, δ): 7.36 (s, 2H), 6.80 (s, IH), 3.79-3.85 (m, IH), 3.56-3.61 (m, 8 H), 3.32-3.35 (m, 4H), 2.97-3.03 (m, 2H), 1.91-1.94 (m, 2H), 1.51-1.53 (m, 2H), 1.39-1.42 (t, 3H).

Example 29

1H NMR (CDCI₃, 400 MHz, δ): 7.72 (s, IH), 7.51 (d, 2H), 7.28-7.46 (m, 2H), 6.91 (m, 2H), 3.61-3.65 (m, 4H), 2.98-3.04 (m,2H), 2.09-2.12 (m, 2H), 1.62-1.65 (m, 2H), 1.37- 1.44 (m, 3H).

Example 30

1H NMR (DMSO-d6, 400 MHz, δ): 9 (s, 1H), 8.68 (d, = 2.8 Hz, 1H), 7.87 (d, = 9.6 & 2.4 Hz, 1H), 7.66 (s, 2H), 6.53 (d, = 9.2 Hz, 1H), 3.54 (brd, 7H), 3.20-3.23 (brt, 4 H), 3.07-3.13 (q, = 7.4 Hz, 2H), 1.84-1.87 (m, 2H), 1.49-1.52 (m, 2H), 1.23 (t, = 7.2 Hz, 3H).

Example 31

4-(cyclopropylsulfonyl)-N-(3,5-dichloro-4-(l-(5-(4-(trifluoromethyl)cyclohexyl)- l,2,4-oxadiazol-3-yl)cyclopropyl)phenyl)piperazine-l-carboxamide

1H NMR (CDC1₃):57.36 (s, 2H), 6.8 (s, 1H), 3.6 - 3.57 (m, 4H), 3.35 - 3.32 (m, 4H), 2.90-2.84 (m, 1H), 2.30 - 2.13 (m, 6H),1.92 - 1.89 (m, 2H), 1.68 - 1.64(m, 2H), 1.52- 1.45 (m, 4H), 1.27-1.19 (m, 4H).

Example 32

N-(3,5-dichloro-4-(l-(5-(4-(methylsulfonyl)phenyl)-l,2,4-oxadiazol-3-yl) cyclopropyl)phenyl)-4-(ethylsulfonyl)piperazine-l-carboxamide

1H NMR (DMSO-d6, δ): 9.02 (s, 1H), 8.30 (d, = 8.4 Hz, 2H), 8.15 (d, = 8.4 Hz, 2H), 7.68 (s, 2H), 3.57 - 3.54 (m, 4H), 3.22 - 3.21 (m, 4H), 3.11 - 3.09 (m, 2H), 1.92- 1.91 (m, 2H), 1.57-1.56 (m, 2H), 1.25-1.21 (t, = 7.6 Hz, 3H) Example 33

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

1H NMR (DMSO-J6): δ 9.02 (s, 1H), 7.89 - 7.70 (m, 2H), 7.68 (s, 2H), 7.3 - 7.5 (m, 1H), 3.57 - 3.54 (m, 4H), 3.23 - 3.21 (m, 4H), 3.13 - 3.07 (m, 2H), 1.91 - 1.88 (m, 2H), 1.57 - 1.54 (m, 2H), 1.24 - 1.21 (t, = 7.6 Hz, 3H). Example 34

N-(3,5-dichloro-4-(l-(5-(2-fluorophenyl)-l,2,4-oxadiazol-3-yl)cyclopropyl)phenyl)- 4-(ethylsulfonyl)piperazine-l-carboxamide

1H NMR (DMSO-iM) δ 9.02 (s, 1H), 8.09 - 8.06 (m, 1H), 7.79 - 7.74 (m, 1H), 7.68 (s, 2H), 7.53 -7.43 (m, 2H), 3.56 - 3.54 (m, 4H), 3.23 - 3.21 (m, 4H), 3.13 - 3.09 (m, 2H), 1.91 - 1.88 (m, 2H), 1.56 - 1.53 (m, 2H), 1.24 - 1.21 (t, 3H). Example 35

N-(3,5-dichloro-4-(l-(5-(4-fluorophenyl)-l,2,4-oxadiazol-3-yl)cyclopropyl)phenyl)- 6-(ethylsulfonyl)-2,6-diazaspiro[3.3]heptane-2-carboxamide

1H NMR (CDCI₃, 400 MHz, δ): 8.13-8.17 (m, 2H), 7.22-7.30 (m, 4H), 3.85-3.87 (brd, 2H), 3.72-3.74 (brt, 4H), 3.58-3.59 (brd, 2H), 2.97-3.00 (m, 2H), 2.06-2.07 (brt, 2H), 1.57-1.62 (brs, 2H), 1.35-1.39 (t, 3H)

Example 36

4-(cyclopropylsulfonyl)-N-(3,5-dichloro-4-(l-(5-(4,4-difluorocyclohexyl)-l,2,4- oxadiazol-3-yl)cyclopropyl)phenyl)piperazine-l-carboxamide

1H NMR (CDCI3, 400 MHz) δ 7.28-7.36 (brd, 2H), 6.97 (s, 1H), 3.57-3.59 (m, 4H), 3.31-3.33 (m, 4 H), 2.90-3.0 (m, 1H), 2.19-2.29 (m, 5H), 1.89-2.07 (m, 5H), 1.49-1.61 (m, 2H), 1.26-1.30 (m, 1H), 1.18-1.21 (m, 2H), 1.03-1.06 (m, 2H). Example 37

N-(2,6-dichloro-3'-(trifluoromethoxy)-[l,l'-biphenyl]-4-yl)-4-(ethylsulfonyl) piperazine- 1 -carboxamide

IH NMR (DMSO-ίΜ: δ 9.03 (s, IH), 7.74 (s, 2H), Ί .69-1.59 (m, IH), 7.41-7.38 (m, IH), 7.31-7.27(m, IH), 3.57-3.54 (m, 4H), 3.23-3.21 (m, 4H), 3.10-3.08 (m, 2H), 1.24- 1.20 (t, =7.4Hz, 3H Example 38

N-(2,6-dichloro-2'-fluoro-[l,l'-biphenyl]-4-yl)-4-(ethylsulfonyl)piperazine-l- carboxamide

1H NMR (DMSO- 6): 58.97 (s, IH), 7.63 (s, 2H), 3.53 (t, 4H), 3.21-3.19 (m, 4H), 3.09- 3.07 (m, 2H), 1.74 (m, 2H), 1.44 (m, 2H), 1.21, (t, = 7.6 Hz 3H) Example 39

N-(2,6-dichloro-3'-methyl-[l,l'-biphenyl]-4-yl)-4-(ethylsulfonyl)piperazine-l- carboxamide

IH NMR (DMSO-iM: δ 9.02 (s, IH), 7.72 (s, 2H), 7.35-7.33 (m, IH), 7.23-7.21 (m, IH), 7.04-7.00 (m, 2H), 3.57-3.55 (m, 4H), 3.23-3.21 (m, 4H), 3.13-3.07 (m, 2H), 2.35(s, 3H), 1.23 (t, =7.4Hz, 3H).

Example 40

N-(2,6-dichloro-2'-methoxy-[l,l'-biphenyl]-4-yl)-4-(ethylsulfonyl)piperazine-l- carboxamide

1H NMR (DMSO-iM: 58.99 (s, IH), 7.67 (s, 2H), 7.42-7.38 (m, IH), 7.12-7.10 (m, IH), 7.09-7.00(m, 2H), 3.71(s, 3H), 3.56-3.55 (m, 4H), 3.23-3.21 (m, 4H), 3.13-3.07(m, 2H), 1.23 (t, =7.4Hz, 3H).

Example 41

N-(2,6-dichloro-4'-hydroxy-[l,l'-biphenyl]-4-yl)-4-(ethylsulfonyl)piperazine-l- carboxamide

1H NMR (DMSO-iM):59.59 (s, IH), 8.98(s, IH), 7.70(s, 2H), 7.02 (d, = 8.4 Hz, 2H), 6.82 (d, = 8.8 Hz, 2H), 3.55-3.54 (m, 4H), 3.23-3.22 (m, 4H), 3.11-3.09 (m, 2H), 1.23 (t, =7.4Hz, 3H).

Example 42

N-(3,5-dichloro-4-(l-(5-(4-methoxyphenyl)-l,2,4-oxadiazol-3-yl) cyclopropyl)phenyl)-4-(ethylsulfonyl)piperazine-l-carboxamide

1H NMR (DMSO-iM): 59.01 (s, IH), 7.99 (d, = 8.8Hz, 2H), 7.66 (s, 2H), 7.14 (d, = 8.4 Hz, 2H), 3.86 (s, 3H), 3.55-3.53 (m, 4H), 3.25-3.22 (m, 4H), 3.11-3.07 (m, 2H), 1.87 (m, 2H), 1.51(m, 2H), 1.23 (t, =7.4Hz, 3H). Example 43

N-(2,6-dichloro-3'-cyano-[l,l'-biphenyl]-4-yl)-4-(ethylsulfonyl)piperazine-l- carboxamide

1H NMR (DMSO-d6, δ): 9.08(s, IH), 7.92-7.90 (m, IH), 7.83 (s, IH), 7.76-7.63 (m, 2H), 7.20-7.10(m, 2H), 3.58-3.55 (m, 4H), 3.24-3.21 (m, 4H), 3.13-3.08 (m, 2H), 1.23 (t, 7=7.4Hz, 3H)

Example 44

4-(cyclopropylsulfonyl)-N-(3,5-dichloro-4-(l-(5-(4-(trifluoromethyl)phenyl)-l,2,4- oxadiazol-3-yl)cyclopropyl)phenyl)piperazine-l-carboxamide

1H NMR (DMSO-J6) δ 9.04 (s, IH), 8.26 (d, 7=8.4Hz, 2H), 7.99 (d, 7=8.0Hz, 2H), 7.68 (s, 2H), 3.59-3.57 (m, 4H), 3.24-3.22 (m, 4H), 2.68-2.65(m, IH), 1.93-1.90 (m, 2H), 1.58-1.55 (m, 2H), 1.02-0.96 (m, 4H). Example 45

4-(cyclopropylsulfonyl)-N-(3,5-dichloro-4-(l-(5-(4-cyanophenyl)-l,2,4-oxadiazol-3- yl)cyclopropyl)phenyl)piperazine-l-carboxamide

1H NMR (OMSO-d6), 59.04 (s, IH), 8.22 (d, = 8.8 Hz, 2H), 8.09 (d, =8.8Hz, 2H), 7.68 (s, 2H), 3.59-3.56 (m, 4H), 3.24-3.22 (m, 4H), 2.67-2.65 (m, IH), 1.93- 1.90 (m, 2H), 1.58- 1.56 (m, 2H), 1.1- 0.95 (m, 4H) Example 46

4-(cyclopropylsulfonyl)-N-(3,5-dichloro-4-(l-(5-(4-methoxyphenyl)-l,2,4-oxadiazol- 3-yl)cyclopropyl)phenyl)piperazine-l-carboxamide

1H NMR (DMSO-iM): 59.03 (s, IH), 7.99 (d, =9.2Hz, 2H), 7.67 (s, 2H), 7.14 (d, =8.8Hz, 2H), 3.86 (s, 3H), 3.59-3.56 (m, 4H), 3.24-3.22 (m, 4H), 2.67-2.65(m, IH), 1.88-1.87 (m, 2H), 1.51- 1.50 (m, 2H), 1.02-0.95(m, 4H). Example 47

N-(3-chloro-5-fluoro-4-(l-(5-(4-(trifluoromethyl)phenyl)-l,2,4-oxadiazol-3- yl)cyclopropyl)phenyl) -4- (cyclopropylsulf onyl)piperazine- 1 -carboxamide

1H NMR (DMSO-iM) 59.06 (s, IH), 8.26 (d, 7 = 8.4 Hz, 2H), 7.99 (d, 7=8.0Hz, 2H), 7.51-7.4 (m, 2H), 3.59-3.56 (m, 4H), 3.25-3.22 (m, 4H), 2.67-2.65 (m, IH), 1.90-1.85 (m, 2H), 1.60-1.50 (m, 2H), 1.02-1.96 (m, 4H) Example 48

N-(3,5-dichloro-4-(2-(5-(4-fluorophenyl)-l,2,4-oxadiazol-3-yl)propan-2-yl)phenyl)- 4-(ethylsulfonyl)piperazine-l-carboxamide

1H NMR (DMSO-ίΜ :) 58.97 (s, IH), 8.16-8.13 (m, 2H), 7.61 (s, 2H), 7.47-7.42 (m, 2H), 3.55-3.52 (m, 4H), 3.21-3.20 (m, 4H), 3.10-3.08 (m, 2H), 1.94 (s, 6H), 1.22 (t, 7=7.4Hz, 3H)

Example 49

4-(cyclopropylsulfonyl)-N-(3,5-dichloro-4-(2-(5-(4-fluorophenyl)-l,2,4-oxadiazol-3- yl)propan-2-yl)phenyl)piperazine-l-carboxamide

1H NMR (DMSO-iM): 58.99 (s, IH), 8.16-8.13 (m, 2H), 7.61 (s, 2H), 7.47-7.42 (m, 2H), 3.57-3.54 (m, 4H), 3.23-3.20 (m, 4H), 2.68-2.65(m, IH), 1.94 (s, 6H), 1.01-0.95 (m, 4H). Example 50 4-(cyclopropylsulfonyl)-N-(3,5-difluoro-4-(l-(5-(4-fluorophenyl)-l,2,4-oxadiazol-3- yl)cyclopropyl)phenyl)piperazine-l-carboxamide

1H NMR (DMSO-<ft5):69.07 (s, IH), 8.12-8.09 (m, 2H), 7.48-7.43 (m, 2H), 7.27 (d, =10.8Hz, 2H), 3.59-3.56 (m, 4H), 3.24-3.22 (m, 4H), 2.67-2.63 (m, IH), 1.73-1.70 (m, 2H), 1.45-1.42 (m, 2H), Example 51

4-(cyclopropylsulfonyl)-N-(3,5-dichloro-4-(l-(5-(4-(methylsulfonyl)phenyl)-l,2,4- oxadiazol-3-yl)cyclopropyl)phenyl)piperazine-l-carboxamide

IH NMR (DMSO-ίΜ): δ 9.04 (s, IH), 8.31-8.29 (m, 2H), 8.15 (d, =8.4Hz, 2H), 7.68(s 2H), 3.59-3.57 (m, 4H), 3.32(s, 3H), 3.24-3.22 (m, 4H), 2.67-2.66 (m, IH), 1.92 (m 2H), 1.57-1.55 (m, 2H), 1.02-0.95(m, 4H).

Example 52

4-(cyclopropylsulfonyl)-N-(3,5-dichloro-4-((5-(4-fluorophenyl)-l,2,4-oxadiazol-3- yl)methyl)phenyl)piperazine-l-carboxamide

1H NMR (DMSO-iM) δ 9.02 (s, IH), 8.16-8.12 (m, 2H), 7.69 (s, 2H), 7.49-7.44 (m, 2H), 4.36(s, 2H), 3.58-3.56 (m, 4H), 3.24-3.21 (m, 4H), 2.67-2.64 (m, IH), 1.01-0.94 (m, 4H) Example 53

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

(ethylsulf onyl) piperazine- 1 -carboxamide

1H NMR (DMSO-iM): 58.98 (s, IH), 8.12 (dd, = 8.4 Hz & 5.6 Hz, 2H), 7.68 (s, IH), 7.45 (m, 2H), 4.35 (s, 2H), 3.54 (s, 4H), 3.08 (m, 2H), 1.22 (m, 5H)

Example 54

N-(3,5-dichloro-4-(2-oxopyridin-l(2H)-yl)phenyl)-4-(ethylsulfonyl)piperazine-l- carboxamide

1H NMR (DMSO-iM): 59.12 (s, IH), 7.77 (s, 2H), 7.57 - 7.50 (m, 2H), 6.52 (d, = 9.2 Hz, IH), 6.35 (t, J = 6.8 Hz & 13.6 Hz, IH), 3.56 (t, 4H), 3.22 (t, 4H ), 3.10 (q, 2H), 1.22 (t, 3H)

Example 55

1H NMR (DMSO-iM): 59.05 (s, IH), 8.06 (dd, J= 2.4 Hz & 0.8 Hz, IH), 7.75 (s, 2H), 7.63 (dd, J= 8.4 & 2.4 Hz, IH), 6.92 (dd, J= 8.8 Hz & 0.8 Hz, IH), 3.56 (m, 4H), 3.22 (m, 4H), 3.11 (q, 2H), 1.21 (t, 3H). Example 56

N-(3,5-dichloro-4-(l-(5-(4-(trifluoromethoxy)phenyl)-l,2,4-oxadiazol-3-yl) cyclopropyl)phenyl)-4-(ethylsulfonyl)piperazine-l-carboxamide

1H NMR (DMSO-J6): 59.02 (s, 1H), 8.19 - 8.16 (m, 2H), 7.68 (s, 2H), 7.61 (d, / = 8 Hz, 2H), 3.57 - 3.28 (m, 4H), 3.28 - 3.13 (m, 4H), 3.1 - 3.07 (q, 2H), 1.9 (m, 2H), 1.59 (m, 2H), 1.54 (t, 3H).

Example 57

4-(cyclopropylsulfonyl)-N-(3,5-dichloro-4-(l-(5-(4-(trifluoromethoxy)phenyl)-l,2,4- oxadiazol-3-yl)cyclopropyl)phenyl)piperazine-l-carboxamide

1H NMR (DMSO-iM): δ 9.04 (s, 1H), 8.18 (d, = 9.2 Hz, 2H), 7.68 (s, 2H), 7.62 (d, = 8 Hz, 2H), 3.59 - 3.56 (m, 4H), 3.24 - 3.22 (m, 4H), 1.90 (m, 2H), 1.55 (m, 2H), 1.1 (m, 2H), 0.96 (m, 2H)

Example 58

N-(3,5-dichloro-4-(l-(5-(4-fluorophenyl)-l,2,4-oxadiazol-3-yl)cyclopropyl)phenyl)- 4-(ethylsulfonyl)-3,5-dimethylpiperazine-l-carboxamide

1H NMR (DMSO-iM): 58.86 (s, IH), 8.14 - 8.10 (m, 2H), 7.73 (s, 2H), 7.48 - 7.44 (t, 2H), 4.07 - 3.96 (d, 2H), 3.95 - 3.93 (m, 4H), 3.16 - 3.08 (m, 4H), 1.91 - 1.88 (m, 2H), 1.55 - 1.52 (m, 2H), 1.28 - 1.26 (d, 6H), 1.23 - 1.21 (t, 3H)

Example 59

N-(3,5-dichloro-4-(l-(5-(4-fluorophenyl)-l,2,4-oxadiazol-3-yl)cyclopropyl)phenyl)- 4-(ethylsulfonamido)piperidine-l-carboxamide

1H NMR (DMSO-<ft5):68.90 (s, IH), 8.12 (dd, = 8.8 Hz & 5.2 Hz, 2H), 7.67 (s, 2H), 7.46 (t, 2H), 7.19 (d, / = 8 Hz, IH), 4.0 (m, 2H), 3.04 - 3.02 (m, 2H), 2.94 (m, 2H), 1.89 - 1.87 (m, 4H), 1.54 (m, 2H), 1.4 (m, 2H), 1.23 - 1.19 (m, 5H)

Example 60

N-(3-chloro-4-(l-(5-(4-chlorophenyl)-l,2,4-oxadiazol-3-yl)cyclopropyl)-5- fluorophenyl)-4-(cyclopropylsulfonyl)piperazine-l-carboxamide

1H NMR (DMSO-iM): 59.05 (s, IH), 8.04-8.06 (m, 2H), 7.68-7.69 (m, 2H), 7.42-7.50 (m, 2H), 3.56-3.59 (m, 4H), 3.22-3.33 (m, 4H), 1.88-1.99 (m, IH), 1.52-1.54 (m, 2H), 1.24-1.25 (m, 2H), 1.11-1.19 (m, 2H), 0.96-1.10 (m, 2H). Example 61

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

1H NMR (DMSO-J6): 59.03 (s, IH), 8.05-8.07 (m, 2H), 7.67-7.70 (m, 4H), 3.56-3.59 (m, 4H), 3.22-3.34 (m, 4H), 1.89-1.99 (m, 2H), 1.54-1.55 (m, 2H), 1.14-1.18 (m, IH), 100-1.02 (m, 2H), 0.96-1.01 (m, 3H).

Example 62

N-(3-chloro-4-(l-(5-(4-cyanophenyl)-l,2,4-oxadiazol-3-yl)cyclopropyl)-5- fluorophenyl)-4-(ethylsulfonyl)piperazine-l-carboxamide

1H NMR (DMSO-iM): 59.04 (s, IH), 8.21-8.22 (m, 2H), 8.19-8.20 (m, 2H), 8.07-8.09 (m, 2H), 3.54-3.57 (m, 4H), 3.21-3.33 (m, 4H), 3.09-3.22 (m, 2H), 1.81-1.83 (m, 2H), 1.23-1.25 (m, 2H), 1.21-1.23 (t, 3H).

Example 63

N-(3-chloro-5-fluoro-4-(l-(5-(4-(trifluoromethyl)phenyl)-l,2,4-oxadiazol-3- yl)cyclopropyl)phenyl) -4- (ethylsulf onyl)piperazine- 1 -carboxamide

IH NMR (DMSO-iM): 59.04 (s, IH), 8.26 (d, = 8.4 Hz, 2H), 8.00 (d, = 9.2 Hz, 2H), 7.46-7.51 (m, IH), 7.43-7.46 (m, IH), 3.54-3.57 (m, 4H), 3.33-3.38 (m, 4H), 3.07-3.13 (m, 2H), 1.67-1.77 (m, 2H), 1.45-1.56(m, 2H), 1.27 (t, 3H). Example 64

N-(2,6-dichloro-3'-methoxy-[l,l'-biphenyl]-4-yl)-4-(ethylsulfonyl)piperazine-l- carboxamide

1H NMR (DMSO-iM): 59.02 (s, 1H), 7.22 (s, 2H), 7.37 (d, = 8 Hz, 1H), 6.80-6.99 (m, 1H), 6.77-6.78 (m, 2H), 3.77 (s, 3H), 3.55 - 3.57 (m, 4H), 3.33 - 3.38 (m, 4H), 3.07-3.13 (m, 2H), 1.20- 1.24 (m, 3H)

Example 65

N-(3,5-dichloro-4-thiomorpholinophenyl)-4-(ethylsulfonyl)piperazine-l- carboxamide

1H NMR (DMSO-iM): 58.60 (s, 1H), 7.57 (s, 2H), 3.50 - 3.51 (m, 4H), 3.27 - 3.32 (m,

6H), 3.19 - 3.26 (m, 6H), 3.07-3.09 (m, 2H), 1.21 (t, J = 7.4 Hz , 3H).

The following compounds can be synthesized in the analogous manner as described above -

( ?)-N-(3,5-dichloro-4-(methyl(l-(o-tolyl)ethyl)carbamoyl)phenyl)-4- (ethylsulfonyl)piperazine- 1 -carboxamide;

( ?)-4-(ethylsulfonyl)-N-(4-(methyl(l-(o-tolyl)ethyl)carbamoyl)phenyl)piperazine-l- carboxamide;

(tf)-4-(ethylsulfonyl)-N-(4-(methyl(l-(4-

(trifluoromethyl)phenyl)ethyl)carbamoyl)phenyl)piperazine-l-carboxamide;

( ?)-N-(3,5-dichloro-4-(methyl(l-(4-(trifluoromethyl)phenyl)ethyl)carbamoyl)phenyl)- 4-(ethylsulfonyl)piperazine- 1 -carboxamide; ( ?)-4-(cyclopropylsulfonyl)-N-(3,5-dichloro-4-(methyl(l-(o- tolyl)ethyl)carbamoyl)phenyl)piperazine- 1 -carboxamide;

N-(l-((2,2-difluorobenzo[d][l,3]dioxol-4-yl)methyl)-2-(trifluoromethyl)-lH- benzo[d]imidazol-5-yl)-4-(ethylsulfonyl)piperazine-l-carboxamide;

4-(cyclopropylsulfonyl)-N-(l-((2,2-difluorobenzo[d][l,3]dioxol-4-yl)methyl)-2- (trifluoromethyl)-lH-benzo[d]irnidazol-5-yl)piperazine-l-carboxamide;

Activity data:

In-vitro Activity:

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 until 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.

RORyt inhibitory activity displayed by compounds of the present invention in the form of % inhibition at 100 nM concentration was found to be very good. IC₅₀ of selected compounds were then determined by nonlinear regression analysis of % activity, plotted against compound concentration (Table 1).

Human IL-17 inhibition assay:

Peripheral blood mononuclear cells (PBMCs) were isolated from healthy volunteers and subjected to T cell polarization assay. Two million PBMCs were placed on anti-CD3 (Biolegend, US) coated 96-well plates and ^g/mL of anti-CD28 (Biolegend, US) was added along with RORyt inhibitors or the vehicle control and incubated at 37°C and 5% C0₂ for 72 h. At the end of incubation time, the supernatant was collected and analyzed for secreted IL-17 using sandwich enzyme immunoassay (Mabtech AB, Sweden). The results were analyzed using Graphpad Prism and the half- maximal inhibitory concentrations (IC₅₀) of the test compounds were derived (Table 1). Table 1: IC₅₀ values of selected compounds in luciferase and IL- 17 assay.

Example Luc IC₅₀ (nM) IL17 IC₅₀ (nM)

4 28 61

11 29 -

15 108 -

18 21 7

21 54 -

22 62 -

25 7.2 -

26 111 -

32 35 239

43 40 29

45 25 496

47 23 -

48 4 53

49 21 -

58 105 -

62 41 -

66 83 26

67 78 - In-vivo Activity:

Effect in mouse model of EAE:

EAE was induced in C57BL/6 wild-type mice by s.c. injection at four sites on the back with 200 μg/mouse MOG peptide in an emulsion with IFA supplemented with 5 mg/ml Mycobacterium tuberculosis, strain H37Ra. Pertussis toxin dissolved in PBS was injected i.p. at 200 ng/mouse at the time of immunization (Day 0) and 48 h later. Mice were scored daily on a scale of 0-5. 0, no clinical disease; 1, limp/flaccid tail; 2, moderate hind-limb weakness; 3, complete paralysis of hind-limbs; 4, complete hind- limb paralysis with partial forelimb paralysis; 5, death. All mice were 6-10 weeks of age when experiments were performed. Test compounds or its vehicle was administered per oral from day 0 to day 20.

Selected compounds have shown -70% inhibition of clinical score when given orally at 50 mg/kg BID.

Effect in Collagen-Induced Arthritis model

Male DBAlj (8 to 12-weeks old) mice were injected s.c with native bovine type

II collagen (Chondrex, Redmond, WA), mixed with complete Freund' s adjuvant at the ratio of 2: 1, on days 0 and 21 at the base of the tail. Animals were observed for clinical score and assigned to different groups of similar score. Mice were then dosed and determined for clinical scores for 3 weeks. The degree of arthritis was determined based on a clinical score of 0-4 per paw and summed for all four paws.

Selected compounds has shown -60% reduction in clinical score when given orally at 30 mg/kg BID.

Effect in Imiquimod induced psoriasis model

C57BL/6j Male mice (8-10 week-old at study initiation) were treated with imiquimod (IMQ) cream (5%) or petroleum (non-inflammatory inert cream). Mice were anesthetized before applying IMQ cream on to the skin. Test compounds or its vehicle was administered per oral one hour before the IMQ application. Treatment started at day 0 and continued twice a day for 6 days. The mice were scored daily for skin erythema and scaling. Ear thickness was measured daily using an engineer's caliper (Incyte) before the application of IMQ.

Selected compounds has shown 40% reduction in ear weight when given orally at 30 mg/kg BID. 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 co-administered 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)

formula (I)

Wherein 'A' represents either a bond or the group selected from -CN, -COOH, optionally substituted groups selected from (Ci-C₈)alkyl, (C3-C₆)cycloalkyl, aryl, heteroaryl or heterocyclyl or 'A' may be absent;

Ring 'B' is selected from aryl, heteroaryl or heterocyclyl wherein Ύ' is selected from C or N;

'Z' represents either a bond or the atoms C, -N, or 'Z' may be absent;

R5 represents hydrogen, optionally substituted groups selected from (Ci-C₈)alkyl, (Ci-C₈)alkoxy, (C₃-C₆)cycloalkyl;

X represents -O, NR' wherein R' is hydrogen, CN, N0₂, OR" or optionally substituted (Ci-C₈)alkyl wherein R" is hydrogen, haloalkyl, optionally substituted (Ci-C₈)alkyl, (C₃-C₈)cycloalkyl groups;

R₆ and R₇ are each independently selected from the group comprising of hydrogen, optionally substituted groups selected from (Ci-C₈)alkyl, aryl, heteroaryl, heterocyclyl or R₆ and R₇ together with the atom to which they are attached may form a heterocyclic, bridged or spiro ring system 'C having optionally one or more than one heteroatoms; Each of Ri R4 and R₈ at each occurrence is independently selected from the group comprising of hydrogen, halogen, hydroxy, cyano, oxo, halo(Ci-C₈)alkyl, optionally substituted (Ci-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃- C6)cycloalkyl, aryl, heterocyclyl, heteroaryl, aralkyl, heteroaralkyl, heterocyclylalkyl, cycloalkanylalkyl, alkylsulfonyloxy, -COR_a, -COOR_a, -OR_a, - S(0)_tR_a, -S(0)_tNR_a, -NR_aR_b, -CONR_aR_b, -N(R_a)COR_b, -N(R_a)COOR_b, - OCH₂COR_a, -N(R_a)CH₂COR_b, -N(R_a)CONR_aR_b, -S(0)_tNR_aR_b, -N(R_a)S(0)_tR_b groups;

'm', 'n' and 'p' represent integers from 0-2;

Each of R_a and R_b at each occurrence are independently selected from the group comprising of hydrogen, haloalkyl, optionally substituted groups selected from (Ci-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₈) cycloalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl groups; or wherever feasible, R_a and R_b together with the atom to which they are attached may form an optionally substituted 5- to 10- membered carbocyclic ring optionally containing 0-2 additional heteroatoms selected from -0-, -NR9- or S(0)_t; wherein, R9 represents hydrogen, optionally substituted groups selected from (Ci-C₈)alkyl, (C₃-C₈)cycloalkyl, and (Ci-C₈)haloalkyl; 't' represents integers from 1-2.

2. The compound as claimed in claim 1, wherein when ring 'C represents a heterocyclyl group, the heterocyclyl group may be selected from single or fused mono or bicyclic non-aromatic groups containing one or more hetero atoms selected from O, N or S.

3. The compound as claimed in claim 2, wherein the heterocyclyl group is 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.

4. The compound as claimed in claim 1, wherein heteroaryl group is selected from pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, isothiazolyl, imidazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, benzofuranyl, benzothienyl, indolinyl, indolyl, azaindolyl, azaindolinyl, pyrazolopyrimidinyl, azaquinazolinyl, pyridofuranyl, pyridothienyl, thienopyrimidyl, quinolinyl, pyrimidinyl, pyrazolyl, quinazolinyl, pyridazinyl, triazinyl, benzimidazolyl, benzotriazolyl, phthalazynil, naphthylidinyl, purinyl, carbazolyl, phenothiazinyl, phenoxazinyl, benzoxazolyl, benzothiazolyl.

5. The compound as claimed in claim 1, wherein when any of the above group is substituted the substitution on the substituted groups is selected from hydrogen, hydroxy, cyano, halo, oxo, imino, haloalkyl, (Ci-C₈)alkyl, (C2-C₈)alkenyl, (C₂- C₈)alkynyl, (C3-C₈)cycloalkyl, (C5-C₈)cycloalkenyl, aryl, heterocyclyl, heteroaryl, aralkyl, heteroaralkyl, heterocyclylalkyl, alkylsulfonyloxy, -COR_a, -COOR_a, - OR_a, -S(0)_tR_a, -NR_aR_b, -CONR_aR_b, -N(R_a)COR_b, -N(R_a)COOR_b, -OCH₂COR_a, - N(R_a)CH₂COR_b, -N(R_a)CONR_aR_b, -S0₂NR_aR_b, -N(R_a)S0₂R_b derivatives; wherein, R_a and R_b are as defined in claim 1.

6. A compound as claimed in claim 1 selected from the group comprising of: l-(3,5-dichloro-4-(l-(5-(4-fluorophenyl)-l,2,4-oxadiazol-3- yl)cyclopropyl)phenyl)-3-(4-(ethylsulfonyl)phenyl)urea;

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

l-(3,5-dichloro-4-(l-(5-(2,4-difluorophenyl)-l,2,4-oxadiazol-3- l)cyclopropyl)phenyl)-3-(4-(ethylsulfonyl)phenyl)urea;

N-(3,5-dichloro-4-(l-(5-(4-fluorophenyl)-l,2,4-oxadiazol-3- yl)cyclopropyl)phenyl)-4-(ethylsulfonyl)piperazine-l-carboxamide;

N-(3,5-dichloro-4-(l-(5-(4-fluorophenyl)-l,2,4-oxadiazol-3- yl)cyclopropyl)phenyl)-5-(ethylsulfonyl)hexahydropyrrolo[3,4-c]pyrrole-2(lH)- carboxamide;

N-(3,5-dichloro-4-morpholinophenyl)-4-(ethylsulfonyl)piperazine-l-carboxamide;

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

(ethylsulfonyl)piperazine-l-carboxamide;

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

(ethylsulfonyl)piperazine- 1 -carboxamide; N-(3,5-dichloro-4-(l-(5-cyclopropyl-l,2,4-oxadiazol-3-yl)cyclopropyl)phenyl)-4-

(ethylsulfonyl)piperazine- 1 -carboxamide;

N-(3,5-dichloro-4-(l-(5-(trifluoromethyl)-l,2,4-oxadiazol-3- yl)cyclopropyl)phenyl)-4-(ethylsulfonyl)piperazine-l-carboxamide;

N-(3,5-dichloro-4-(l-(5-(trifluoromethyl)-l,3,4-thiadiazol-2- yl)cyclopropyl)phenyl)-4-(ethylsulfonyl)piperazine-l-carboxamide;

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

3 ,5-dimethylphenyl)piperazine- 1 -carboxamide;

N-(3,5-difluoro-4-(l-(5-(4-fluorophenyl)-l,2,4-oxadiazol-3- yl)cyclopropyl)phenyl)-4-(ethylsulfonyl)piperazine-l-carboxamide;

N-(3,5-dichloro-4-(l-(5-(4-fluorophenyl)-l,2,4-oxadiazol-3- yl)cyclopropyl)phenyl)-4-(ethylsulfonyl)piperidine-l-carboxamide;

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

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

(ethylsulfonyl) piperazine-1 -carboxamide;

4-(cyclopropylsulfonyl)-N-(3,5-dichloro-4-(l-(5-(4-fluorophenyl)- 1,2,4- oxadiazol-3-yl)cyclopropyl)phenyl)piperazine-l-carboxamide;

N-(3,5-dichloro-4-(l-(5-(4-fluorophenyl)-l,2,4-oxadiazol-3- yl)cyclopropyl)phenyl)-4-(methylsulfonyl)piperazine-l-carboxamide;

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

(ethylsulfonyl)piperazine-l -carboxamide; N-(3,5-dichloro-4-(l-(5-(4-fluorophenyl)-l,2,4-oxadiazol-3- yl)cyclopropyl)phenyl)-4-(isopropylsulfonyl)piperazine-l-carboxamide;

2-(4-((3,5-dichloro-4-(l-(5-(4-fluorophenyl)-l,2,4-oxadiazol-3- yl)cyclopropyl)phenyl) carbamoyl) piperazin-l-yl)acetic acid;

N-(3,5-dichloro-4-(l-(5-(4-fluorophenyl)-l,2,4-oxadiazol-3- yl)cyclopropyl)phenyl)-6-(ethylsulfonyl)-3,6-diazabicyclo[3.1.1]heptane-3- carboxamide;

N-(3,5-dichloro-4-(l-(5-(4-fluorophenyl)thiazol-2-yl)cyclopropyl)phenyl)-4- (ethylsulfonyl)piperazine- 1 -carboxamide;

N-(3,5-dichloro-4-morpholinophenyl)-4-(ethylsulfonyl)piperazine-l-carboxamide; N-(3,5-dichloro-4-(l-(5-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl)-l,2,4- oxadiazol-3-yl)cyclopropyl)phenyl)-4-(ethylsulfonyl)piperazine-l-carboxamide; N-(3,5-dichloro-4-(l-(5-(4-fluorophenyl)thiazol-2-yl)cyclopropyl)phenyl)-4- (ethylsulfonyl)piperazine- 1 -carboxamide;

N-(3,5-dichloro-4-(l-(5-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl)-l,2,4- oxadiazol-3-yl)cyclopropyl)phenyl)-4-(ethylsulfonyl)piperazine-l-carboxamide;

4-(cyclopropylsulfonyl)-N-(3,5-dichloro-4-(l-(5-(4-(trifluoromethyl)cyclohexyl)- l,2,4-oxadiazol-3-yl)cyclopropyl)phenyl)piperazine-l-carboxamide;

N-(3,5-dichloro-4-(l-(5-(2,3-difluorophenyl)-l,2,4-oxadiazol-3- yl)cyclopropyl)phenyl)-4-(ethylsulfonyl)piperazine-l-carboxamide; N-(3,5-dichloro-4-(l-(5-(2-fluorophenyl)-l,2,4-oxadiazol-3- yl)cyclopropyl)phenyl)-4-(ethylsulfonyl)piperazine- l-carboxamide;

N-(3,5-dichloro-4-(l-(5-(4-fluorophenyl)-l,2,4-oxadiazol-3- yl)cyclopropyl)phenyl)-6-(ethylsulfonyl)-2,6-diazaspiro[3.3]heptane-2- carboxamide;

4-(cyclopropylsulfonyl)-N-(3,5-dichloro-4-(l-(5-(4,4-difluorocyclohexyl)- l,2,4- oxadiazol-3-yl)cyclopropyl)phenyl)piperazine- l-carboxamide; N-(2,6-dichloro-3'-(trifluoromethoxy)-[l, -biphenyl]-4-yl)-4- (ethylsulfonyl)piperazine- 1 -carboxamide;

N-(2,6-dichloro-2'-fluoro-[l, -biphenyl]-4-yl)-4-(ethylsulfonyl)piperazine- l- carboxamide;

N-(3,5-dichloro-4-(l-(5-(4-methoxyphenyl)- l,2,4-oxadiazol-3- yl)cyclopropyl)phenyl)-4-(ethylsulfonyl)piperazine- l-carboxamide; N-(2,6-dichloro-3'-cyano-[l,l'-biphenyl]-4-yl)-4-(ethylsulfonyl)piperazine- l- carboxamide;

4-(cyclopropylsulfonyl)-N-(3,5-dichloro-4-(l-(5-(4-(trifluoromethyl)phenyl)- l,2,4-oxadiazol-3-yl)cyclopropyl)phenyl)piperazine- l-carboxamide; 4-(cyclopropylsulfonyl)-N-(3,5-dichloro-4-(l-(5-(4-cyanophenyl)- l,2,4- oxadiazol-3-yl)cyclopropyl)phenyl)piperazine- l-carboxamide; 4-(cyclopropylsulfonyl)-N-(3,5-dichloro-4-(l-(5-(4-methoxyphenyl)-l,2,4- oxadiazol-3-yl)cyclopropyl)phenyl)piperazine-l-carboxamide;

N-(3-chloro-5-fluoro-4-(l-(5-(4-(trifluoromethyl)phenyl)-l,2,4-oxadiazol-3- yl)cyclopropyl)phenyl)-4-(cyclopropylsulfonyl)piperazine-l-carboxamide;

N-(3,5-dichloro-4-(2-(5-(4-fluorophenyl)-l,2,4-oxadiazol-3-yl)propan-2- yl)phenyl)-4-(ethylsulfonyl)piperazine-l-carboxamide;

4-(cyclopropylsulfonyl)-N-(3,5-dichloro-4-(2-(5-(4-fluorophenyl)- 1,2,4- oxadiazol-3-yl)propan-2-yl)phenyl)piperazine- 1 -carboxamide;

4-(cyclopropylsulfonyl)-N-(3,5-difluoro-4-(l-(5-(4-fluorophenyl)- 1,2,4- oxadiazol-3-yl)cyclopropyl)phenyl)piperazine-l-carboxamide

4-(cyclopropylsulfonyl)-N-(3,5-dichloro-4-(l-(5-(4-(methylsulfonyl)phenyl)- l,2,4-oxadiazol-3-yl)cyclopropyl)phenyl)piperazine-l-carboxamide;

4-(cyclopropylsulfonyl)-N-(3,5-dichloro-4-((5-(4-fluorophenyl)-l,2,4-oxadiazol-

3- yl)methyl)phenyl)piperazine-l-carboxamide;

4- (cyclopropylsulfonyl)-N-(3,5-dichloro-4-(l-(5-(4-(methylsulfonyl)phenyl)- l,2,4-oxadiazol-3-yl)cyclopropyl)phenyl)piperazine-l-carboxamide;

4-(cyclopropylsulfonyl)-N-(3,5-dichloro-4-(l-(5-(4-(trifluoromethoxy)phenyl)- l,2,4-oxadiazol-3-yl)cyclopropyl)phenyl)piperazine-l-carboxamide; N-(3,5-dichloro-4-(l-(5-(4-fluorophenyl)-l,2,4-oxadiazol-3- yl)cyclopropyl)phenyl)-4-(ethylsulfonyl)-3,5-dimethylpiperazine-l-carboxamide; N-(3,5-dichloro-4-(l-(5-(4-fluorophenyl)-l,2,4-oxadiazol-3- yl)cyclopropyl)phenyl)-4-(ethylsulfonamido)piperidine-l-carboxamide; N-(3-chloro-4-(l-(5-(4-chlorophenyl)-l,2,4-oxadiazol-3-yl)cyclopropyl)-5- fluorophenyl)-4-(cyclopropylsulfonyl)piperazine-l-carboxamide; 4-(cyclopropylsulfonyl)-N-(3,5-dichloro-4-(l-(5-(4-chlorophenyl)-l,2,4- oxadiazol-3-yl)cyclopropyl)phenyl)piperazine-l-carboxamide; N-(3-chloro-4-(l-(5-(4-cyanophenyl)-l,2,4-oxadiazol-3-yl)cyclopropyl)-5- fluorophenyl)-4-(ethylsulfonyl)piperazine- 1-carboxamide;

N-(3-chloro-5-fluoro-4-(l-(5-(4-(trifluoromethyl)phenyl)-l,2,4-oxadiazol-3- yl)cyclopropyl)phenyl)-4-(ethylsulfonyl)piperazine- 1-carboxamide; N-(2,6-dichloro-3'-methoxy- [1,1 '-biphenyl] -4-yl)-4-(ethylsulfonyl)piperazine- 1 - carboxamide;

N-(3,5-dichloro-4-thiomorpholinophenyl)-4-(ethylsulfonyl)piperazine-l- carboxamide.

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.

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.

The pharmaceutical composition as claimed in claim 4 in combination with suitable (1) TNF-a Inhibitors; (2) non-selective COX-l/COX-2 inhibitors; (3) COX-2 inhibitors (4) and other agents suitable 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-adrenoreceptor agonist (12) insulinlike growth factor type I (IGF-I) mimetic; (13) glucocorticosteroids; (14) kinase inhibitors selected from 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, selected from IL-1 inhibitor anakinra, IL-6 inhibitor tocilizumab, and IL12/IL23 inhibitor ustekinumab.