WO2014125426A1

WO2014125426A1 - Trisubstituted heterocyclic derivatives as ror gamma modulators

Info

Publication number: WO2014125426A1
Application number: PCT/IB2014/058957
Authority: WO
Inventors: Mallesham Bejugam; Subramanya Hosahalli; Natarajan Mahalingam
Original assignee: Aurigene Discovery Technologies Limited
Priority date: 2013-02-15
Filing date: 2014-02-13
Publication date: 2014-08-21

Abstract

The present invention provides trisubstituted heterocyclic derivatives of formula (I), which may be therapeutically useful, more particularly as ROR_γ modulators; (I) in which R_1, R₂, R₃, R_a, X, L, m and ring A have the meanings given in the specification, and pharmaceutically acceptable salts thereof that are useful in the treatment and prevention of diseases or disorder, in particular their use in diseases or disorder where there is an advantage in modulating ROR_γ receptor. The present invention also provides preparation of the compounds and pharmaceutical formulations comprising at least one of the trisubstituted heterocyclic derivatives of formula (I) together with a pharmaceutically acceptable carrier, diluent or excipient therefor.

Description

TRISUBSTITUTED HETEROCYCLIC DERIVATIVES AS ROR GAMMA

MODULATORS

This application claims the benefit of Indian provisional application number 674/CHE/2013 filed on 15^th February 2013 which hereby incorporated by reference.

FIELD OF THE INVENTION

This invention relates to compounds useful for treatment of diseases or disorder associated with Retinoic acid receptor-related orphan receptors (RORs), and more particularly compounds that modulate the function of RORy. The invention also provides pharmaceutically acceptable compositions comprising compounds of the present invention and methods of using said compositions in the treatment of diseases or disorder associated with RORy.

BACKGROUND OF THE INVENTION Retinoid -related orphan receptors (RORs) are transcription factors which belong to the steroid hormone nuclear receptor super family (Jetten & Joo (2006) Adv. Dev. Biol. 16:313- 355). Several nuclear receptors are still characterized as orphan receptors because the identification of ligands for these receptors is still elusive or controversial. The ROR family consists of three members, ROR alpha (RORa), ROR beta (ROR ) and ROR gamma (RORy), each encoded by a separate gene (RORA, RORB and RORC, respectively). RORs contain four principal domains shared by the majority of nuclear receptors: an N-terminal A/B domain, a DNA-binding domain, a hinge domain, and a ligand binding domain. Each ROR gene generates several iso forms which differ only in their N-terminal A/B domain. Two isoforms of RORy have been identified: RORyl and RORyt (also known as RORy2). RORy is a term used to describe both RORyl and/or RORyt.

Upon activation by antigen-presenting cells naive T helper cells undergo clonal expansion and will ultimately differentiate in cytokine secreting effector T cells, such as Thl and Th2 subtypes. A third and distinct effector subset has been identified, which plays a key role in providing immunity to bacteria and fungi at mucosal surfaces (Kastelein, et ah, Ann. Rev. Immunol. 25: 221-242, 2007). This effector T helper cell subset can be distinguished based on its ability to produce large quantities of IL-17A/F, IL-21 and IL-22, and is named Thl7 (Miossec, et al, New Eng. J. Med. 2361 : 888-898, 2009). RORyl is expressed in a variety of tissues including thymus, muscle, kidney and liver, while RORyt is exclusively expressed in the cells of the immune system. RORyt is highly expressed in Thl7 cells (He, et al., Immunity 9: 797-806, 1998). Studies have shown that Thl 7 cells are one of the important drivers of the inflammatory process in tissue- specific autoimmunity (Steinman (2008) J. Exp. Med. 205: 1517- 1522; Leung, et al. (2010) Cell. Mol. Immunol. 7: 182- 189). There is evidence that Thl7 cells are activated during the disease process and are responsible for recruiting other inflammatory cells types, especially neutrophils, to mediate pathology in the target tissues (Korn, et al. (2009) Ann. Rev. Immunol. 27:485-517). In addition, Thl7 cells or their products have been shown to be associated with the pathology of a variety of human inflammatory and autoimmune disorders including multiple sclerosis, rheumatoid arthritis, psoriasis, Crohn's disease and asthma (Jetten (2009) Nucl. Recept. Signal. 7: e003; Manel, et al. (2008) Nat. Immunol. 9:641 -649).

RORyt was shown to play a crucial role in non-Thl7 lymphoid cells. In these studies, RORyt was critically important in innate lymphoid cells expressing Thyl, SCA-1 and IL-23R proteins. Genetic disruption of RORy in a mouse colitis model dependent on these innate lymphoid cells, prevented colitis development (Buonocore, et al.. Nature 464: 1371 - 1375, 2010). In addition, RORyt was shown to play a crucial role in other non-Thl7 cells, such as mast cells (Hueber, et al., J Immunol. 184: 3336-3340, 2010). Finally, RORyt expression and secretion of Thl7-type of cytokines was reported for Lymphoid Tissue Inducer cells, NK T-cells, NK cells (Eberl, et al., Nat. Immunol. 5: 64-73, 2004) and gamma-delta T-cells (Sutton, et al , Nat. Immunol. 31 : 331-341, 2009; Louten, et al, J Allergy Clin. Immunol. 123: 1004- 101 1, 2009), suggesting an important function for RORyt in these subtypes of cells.

Based on the role of IL-17 producing cells (either Thl7 or non-Thl7 cells) RORyt has been identified as a key mediator in the pathogenesis of several diseases (Louten, et al., J Allergy Clin. Immunol. 123: 1004- 101 1, 2009; Annuziato, et al., Nat. Rev. Rheumatol. 5: 325-331, 2009). This was confirmed using several disease models representative of autoimmune diseases. Genetic ablation of the RORy gene in mice prevented the development of experimental autoimmune diseases, such as experimental autoimmune encephalomyelitis (EAE) and colitis (Ivanov, et al., Cell 126: 1121-33, 2006; Buonocore, et al.. Nature 464: 1371-1375, 2010). Being a critical mediator in Thl7-cells and other non-Thl7 cells, inhibition of RORyt is expected to have a beneficial effect on autoimmune diseases, such as, but not limited to rheumatoid arthritis, psoriasis, multiple sclerosis, inflammatory bowel disease, Crohn's disease, and asthma (Annunziato, et ah, Nat. Rev. Immunol. 5: 325-331 , 2009; Louten, et ah, J Allergy Clin. Immunol. 123: 1004-1011, 2009). RORyt deficient mice show very little Thl7 cells. In addition, RORyt deficiency resulted in amelioration of EAE. Inhibition of RORyt may also be beneficial in other diseases, which are characterized by increased levels of Thl7 cells and/or elevated levels of Thl7 hallmark cytokines such as IL- 17, IL-22 and IL-23. Examples of such diseases are Kawasaki Disease (Jia, et ah, Clin. Exp. Immunol. 162: 131- 137, 2010) and Hashimoto's thyroiditis (Figueroa-Vega, et al., J Clm.Endocrmol.Metah. 95: 953-62, 2010).

RORy inverse agonist, SR221 1 is a cell-permeable, piperazine containing biphenyl compound that binds directly to retinoic acid receptor related orphan receptor γ (RORy) and acts as a highly selective, inverse agonist ( K, = 105 nM; ICsn ~ 320 nM). It is reported to block the transcriptional activity of RORy and suppress the synthesis of IL-17 in EL-4 murine lymphoma cell line. SR221 1 exhibits only a minimal effect on ROR alpha and LXRalpha activity, indicating that the functional effect is due to selective inhibition of RORy alone.

Recent findings show the nature and relevance of Thl7 cells in mouse models of cancer and human disease {Nature Reviews ImmunologylO, 248-256 (April 2010)). Evidences suggest that the effector T cell subset is also involved in tumor immunology, thus giving a way to a new target for cancer therapy.

In view of the above, a need exists for therapeutic agents that could modulate the activity of RORy and thus will open new methods for treating diseases or condition associated with the modulation of RORy.

Modulators of the RORy receptor were disclosed in WO2011/1 15892, WO2012/027965, WO2012/028100, WO2012/064744, WO2012/074547, WO2012/ 100732, WO2012/100734 and WO2012/139775.

The present application is directed to compounds that may be modulators of the RORy receptor. Thus in light of the role RORy plays in the pathogenesis of diseases, it is desirable to prepare compounds that modulate RORy activity, which can be used in the treatment of diseases mediated by RORy. SUMMARY OF THE INVENTION

Provided herein are trisubstituted heterocyclic derivatives and pharmaceutical compositions thereof, which are useful as RORy modulators.

In one aspect of the present invention, it comprises compounds of formula (I):

(I)

or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable stereoisomer thereof; wherein:

Ring A is aryl or heterocyclyl;

X is CH or N;

Ri is optionally substituted aryl or optionally substituted heterocyclyl; wherein the optional substituent is selected from one or more R₆;

R₂ is selected from optionally substituted aryl, optionally substituted cycloalkyl or optionally substituted heterocyclyl; wherein the optional substituent is selected from one or more

R₇;

each occurrence of R₃ is independently selected from hydrogen, halo, cyano, -S(0)_nR₄ or -C(0)R4;

R₄ is selected from alkyl, hydroxyalkyl, haloalkyl or alkylamino; L is selected from -0-, -C(O)- , -CH(OR₅)- or absent;

R5 is hydrogen or optionally substituted alkyl; wherein the optional substituent is selected from hydroxy or -NR_aRt,;

R₆ at each occurrence is independently selected from halo, alkyl or haloalkyl;

R₇ at each occurrence is independently selected from halo or alkyl;

R_a and R are independently selected from hydrogen or alkyl; m and n are independently selected from 1 or 2.

In yet another aspect, the present invention provides a pharmaceutical composition comprising the compound of formula (I), and at least one pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent).

In yet another aspect, the present invention relates to the preparation of the compounds of formula (I).

In yet another aspect of the present invention, it provides trisubstituted heterocyclic derivatives of formula (I), which are used for the treatment and prevention of diseases or disorder, in particular their use in diseases or disorder where there is an advantage in modulating steroid hormone nuclear receptors - particularly ROR's, more particularly RORy.

DETAILED DESCRIPTION OF THE INVENTION

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in art to which the subject matter herein belongs. As used in the specification and the appended claims, unless specified to the contrary, the following terms have the meaning indicated in order to facilitate the understanding of the present invention.

As used herein the term "alkyl" refers to a hydrocarbon chain radical that includes solely carbon and hydrogen atoms in the backbone, containing no unsaturation, having from one to ten carbon atoms (i.e. C_1-10 alkyl), and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, propyl, butyl, isobutyl, sec -butyl, tert -butyl, isopentyl or neopentyl. The term "Ci-6 alkyl" refers to an alkyl chain having 1 to 6 carbon atoms. The term "C_1-4 alkyl" refers to an alkyl chain having 1 to 4 carbon atoms. Unless set forth or recited to the contrary, all alkyl groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.

As used herein, the term "alkylamino" means amino substituted with one or more alkyl groups, where alkyl groups are as defined above. The term "amino" is used herein means -NH₂ group. Representative examples of an alkylamino group include, but not limited to -NHCH₃, - NHCH₂CH₃, -NHCH₂CH(CH₃)₂, and the like. As used herein, the term "aryl" is a monocyclic or polycyclic aromatic carbocyclic system. Exemplary aryl groups include, but are not limited to, phenyl, naphthyl, and the like. Unless otherwise specified, an aryl group typically has from 6 to about 14 carbon atoms but the invention is not limited in that respect. (C6-Ci2)aryl refers to an aryl group having six to twelve carbon atoms.

As used herein the term "cycloalkyl" alone or in combination with other term(s) means C3-C10 saturated cyclic hydrocarbon ring. A cycloalkyl may be a single ring, which typically contains from 3 to 7 carbon ring atoms. Examples of single -ring cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. A cycloalkyl may alternatively be polycyclic or contain more than one ring. Examples of polycyclic cycloalkyls include bridged, fused, and spirocyclic.

As used herein, the term "halo" or "halogen" alone or in combination with other term(s) means fluorine, chlorine, bromine or iodine.

As used herein, the term "haloalkyl" means alkyl substituted with one or more halogen atoms, where alkyl groups are as defined above. The term "halo" is used herein interchangeably with the term "halogen" means F, CI, Br or I. Examples of "haloalkyl" include but are not limited to trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl and the like.

"Hydroxy" refers to -OH group.

"Cyano" refers to -CN group.

As used herein, the term "hydroxy alkyl" means at least one hydrogen atom of an alkyl group is replaced by a hydroxyl group. Alkyl group is as defined above. Representative examples of hydroxyalkyl groups include one or more of, but are not limited to hydroxymethyl, hydroxyethyl and the like.

As used herein, the term "heterocycle" or "heterocyclyl" alone or in combination with other term(s) means a saturated {i.e., "heterocycloalkyl"), partially saturated {i.e., "heterocycloalkenyl"), or completely unsaturated {i.e., "heteroaryl") ring system containing a total of 3 to 14 ring atoms. At least one of the ring atoms is a heteroatom {i.e., oxygen, nitrogen, or sulfur), with the remaining ring atoms being independently selected from the group consisting of carbon, oxygen, nitrogen, and sulfur. A heterocyclyl may be a single -ring (monocyclic) or polycyclic ring system. Examples of "heterocyclyl" include but are not limited to piperidinyl, morpholinyl, furyl, pyrazolyl, pyridyl, pyrimidinyl, and the like. Unless set forth or recited to the contrary, all heterocyclyl groups described or claimed herein may be substituted or unsubstituted.

As used herein, the term "optionally substituted" refers to the replacement of one or more hydrogen radicals in a given structure with the radical of a specified substituent including, but not limited to: halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, thiol, alkylthio, arylthio, alkylthioalkyl, arylthioalkyl, alkylsulfonyl, alkylsulfonylalkyl, arylsulfonylalkyl, alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, trifluoromethyl, cyano, nitro, alkylamino, arylamino, alkylaminoalkyl, arylaminoalkyl, aminoalkylamino, hydroxy, alkoxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, acyl, aralkoxycarbonyl, carboxylic acid, sulfonic acid, sulfonyl, phosphonic acid, aryl, heteroaryl, heterocyclic and aliphatic. It is understood that the substituent may be further substituted.

The term "pharmaceutically acceptable salt" includes salts prepared from pharmaceutically acceptable bases or acids including inorganic or organic bases and inorganic or organic acids. Examples of such salts include, but are not limited to, acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, camsylate, carbonate, chloride, citrate, clavulanate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate, diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide and valerate. Examples of salts derived from inorganic bases include, but are not limited to, aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, potassium, sodium, and zinc.

As used herein, the term "pharmaceutically acceptable carrier" refers to any of the standard pharmaceutical carriers, such as a phosphate buffered saline solution, water, emulsions {e.g., such as an oil/water or water/oil emulsions), and various types of wetting agents. The compositions also can include stabilizers and preservatives. For examples of carriers, stabilizers and adjuvants. (See e.g., Martin, Remington's Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA [1975]).

The term "stereoisomers" refers to any enantiomers, diastereoisomers, or geometrical isomers of the compounds of formula (I), wherever they are chiral or when they bear one or more double bond. When the compounds of the formula (I) and related formulae are chiral, they can exist in racemic or in optically active form. Since the pharmaceutical activity of the racemates or stereoisomers of the compounds according to the invention may differ, it may be desirable to use the enantiomers. In these cases, the end product or even the intermediates can be separated into enantiomeric compounds by chemical or physical measures known to the person skilled in the art or even employed as such in the synthesis.

The term "SEA Syndrome" refers to Seronegative Enthesopathy and Arthropathy Syndrome.

The term "treating" or "treatment" of a state, disorder or condition includes: (a) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a subject that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition; (b) inhibiting the state, disorder or condition, i.e., arresting or reducing the development of the disease or at least one clinical or subclinical symptom thereof; or (c) relieving the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.

The term "subject" includes mammals (especially humans) and other animals, such as domestic animals (e.g., household pets including cats and dogs) and non-domestic animals (such as wildlife).

As used herein, the term "therapeutically effective amount" means the amount of a compound that, when administered to a subject for treating a state, disorder or condition, is sufficient to effect such treatment. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the subject to be treated. As used herein, the term 'compound(s)' comprises the compounds disclosed in the present invention.

As used herein, the term "comprise" or "comprising" is generally used in the sense of include, that is to say permitting the presence of one or more features or components.

As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. By "pharmaceutically acceptable" it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

As used herein, the term "including" as well as other forms, such as "include", "includes" and "included" is not limiting.

In our endeavor to provide trisubstituted heterocyclic derivatives, the first embodiment of the present invention provides the structure of compounds as set forth in formula (I);

(I)

Ring A is aryl or heterocyclyl;

X is CH or N;

R₇;

each occurrence of R₃ is independently selected from hydrogen, halo, cyano, -S(0)_nR4 or -C(0)R4; R4 is selected from alkyl, hydroxyalkyl, haloalkyl or alkylamino;

L is selected from -0-, -C(O)- , -CH(OR₅)- or absent;

R5 is hydrogen or optionally substituted alkyl; wherein the optional substituent is selected from hydroxy or -NR_aRt>;

R₇ at each occurrence is independently selected from halo or alkyl;

R_a and R are independently selected from hydrogen or alkyl;

m and n are independently selected from 1 or 2.

In another aspect of the present invention provides compounds of formula (IA),

(IA)

Y is CH or N;

Ri, R₂, R₃, L, X and 'm' are same as defined in formula (I).

In another aspect of the present invention provides compounds of formula (IB),

(IB)

Y is CH or N;

Ri, R₂, R₃, L and 'm' are same as defined in formula (I).

In yet another aspect of the present invention provides compounds of formula (IC),

(IC)

Y is CH or N;

Ri, R₂, R₃, L and 'm' are same as defined in formula (I).

In yet another aspect of the present invention provides compounds of formula (ID),

(ID)

p is 0, 1 or 2;

R3, R₆, R7, m, L and X are same as defined in formula (I).

The embodiments below are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified.

According to one embodiment, specifically provided are compounds of the formula (I), in which L is -C(O)-.

According to another embodiment, specifically provided are compounds of the formula (I), in which L is -CH(OH)-.

According to yet another embodiment, specifically provided are compounds of the formula (I), in which L is absent.

According to yet another embodiment, specifically provided are compounds of the formula (I), in which X is CH. According to yet another embodiment, specifically provided are compounds of the formula (I), in which X is N.

According to yet another embodiment, specifically provided are compounds of the formula (I), in which ring A is aryl (e.g. phenyl).

According to yet another embodiment, specifically provided are compounds of the formula (I), in which ring A is phenyl.

According to yet another embodiment, specifically provided are compounds of the formula (I), in which ring A is heterocyclyl (e.g. pyridyl or piperidinyl).

According to yet another embodiment, specifically provided are compounds of the formula (I), in which ring A is pyridin-4-yl or piperidin-4-yl.

According to yet another embodiment, specifically provided are compounds of the formula (I), in which m is 1.

According to yet another embodiment, specifically provided are compounds of the formula (I), in which m is 2.

According to yet another embodiment, specifically provided are compounds of the formula (I), in which Ri is phenyl, fluorobenzene, methylfuran, methylpyrazole, pyrimidine, pyridine, fluoropyridine, chlorobenzene, furan, dichlorobenzene, tert-butylbenzene or (trifluoromethyl)benzene.

According to yet another embodiment, specifically provided are compounds of the

According to yet another embodiment, specifically provided are compounds of the formula (I), in which R₂ is phenyl, fluorobenzene, cyclopentyl, chlorobenzene, cyclopropyl, or morpholine.

According to yet another embodiment, specifically provided are compounds of the

formula (I), in which R₂ is

According to yet another embodiment, specifically provided are compounds of the formula (I), in which R₃ is -S(0)_nR₄; wherein R₄ is alkyl, hydroxyalkyl, haloalkyl or alkylamino and n is 1 or 2.

According to yet another embodiment, specifically provided are compounds of the formula (I), in which R₃ is -S(0)₂CH₂CH₃, -S(0)₂CH₂CH₂OH, -S(0)CH₂CH₃, -S(0)₂CH₂CF₃ or -S(0)₂NH(CH₂CH₃) and m is 1 or 2.

According to yet another embodiment, specifically provided are compounds of the formula (I), in which R₃ is -S(0)₂CH₂CH₃.

According to yet another embodiment, specifically provided are compounds of the formula (I), in which each occurrence of R₃ is independently hydrogen, cyano or -C(0)R₄ and m is 1 or 2. In this embodiment R₄ is alkyl or alkylamino.

According to yet another embodiment, specifically provided are compounds of the formula (I), in which R₃ is -C(0)CH₂CH₃ or -C(0)NH(CH₃).

According to yet another embodiment, specifically provided are compounds of the formula (I), (I A) and (ID) in which X is CH.

According to yet another embodiment, specifically provided are compounds of the formula (I), (I A) and (ID) in which X is N.

According to yet another embodiment, specifically provided are compounds of the formula (IA), (IB) and (IC) in which Y is CH.

According to yet another embodiment, specifically provided are compounds of the formula (I), (IA), (IB), (IC) and (ID) in which L is -C(O). According to yet another embodiment, specifically provided are compounds of the formula (I), (IA), (IB), (IC) and (ID) in which L is absent.

According to yet another embodiment, specifically provided are compounds of the formula (I), (IA), (IB), (IC) and (ID) in which R₃ is -S0₂CH₂CH₃.

According to yet another embodiment, specifically provided are compounds of the formula (ID) in which p is 0.

According to yet another embodiment, specifically provided are compounds of the formula (ID) in which p is 1.

According to yet another embodiment, specifically provided are compounds of the formula (ID) in which p is 2.

According to yet another embodiment, specifically provided are compounds of the formula (ID) in which each occurrence of R₆ is independently fluoro or chloro.

According to yet another embodiment, specifically provided are compounds of the formula (ID) in which each occurrence of R₇ is independently fluoro, chloro -CF₃ or tert -butyl.

According to further yet another particular embodiment of the present invention; the compound of formula ( 1) is selected from the group consisting of

fluorophenyl)acetamide ;

N-(4-benzoyl-5-(l-methyl-lH-pyrazol-4-yl)pyrimidin-2-yl)-2-(4- (ethylsulfonyl)phenyl)acetamide ;

2-(4-(ethylsulfonyl)phenyl)-N-(4-(4-fluorobenzoyl)-[5,5'-bipyrimidin]-2- yl)acetamide;

2-(4-(ethylsulfonyl)phenyl)-N-(4-(4-fluorobenzoyl)-5-(pyridin-4-yl)pyrimidin-2- yl)acetamide;

N-(4-benzoyl-5-(6-fluoropyridin-3-yl)pyrimidin-2-yl)-2-(4- (ethylsulfonyl)phenyl)acetamide ;

N-(4-benzoyl-5-phenylpyrimidin-2-yl)-2-(4-propionylphenyl)acetamide;

4-(2-((4-benzoyl-5-phenylpyrimidin-2-yl)amino)-2-oxoethyl)-N- methylbenzamide ;

4-(2-((4-(4-fluorobenzoyl)-5-(4-fluorophenyl)pyrimidin-2-yl)amino)-2-oxoethyl)- N-methylbenzamide ;

2-(4-(ethylsulfonyl)phenyl)-N-(5-(4-fluorophenyl)-4-((4- fluorophenyl)(hydroxy)methyl)pyrimidin-2-yl)acetamide;

2-(2-fluoro-4-((2-hydroxyethyl)sulfonyl)phenyl)-N-(4-(4-fluorobenzoyl)-5- phenylpyrimidin-2-yl)acetamide ;

2-(4-(ethylsulfonyl)phenyl)-N-(4-(3-fluorobenzoyl)-5-(4-fluorophenyl)pyrimidin- 2-yl)acetamide;

N-(4-(4-fluorobenzoyl)-5-(4-fluorophenyl)pyrimidin-2-yl)-2-(4-((2- hydroxyethyl) sulfonyl)phenyl) acetamide ;

2-(4-cyanophenyl)-N-(4-(4-fluorobenzoyl)-5-(4-fluorophenyl)pyrimidin-2- yl)acetamide;

2-(4-(ethylsulfinyl)phenyl)-N-(4-(4-fluorobenzoyl)-5-(4-fluorophenyl)pyrimidin- 2-yl)acetamide; N-(4-(4-fluorobenzoyl)-5-(4-fluorophenyl)pyrimidin-2-yl)-2-(pyridin-4- yl)acetamide;

2-(l-(ethylsulfonyl)piperidin-4-yl)-N-(4-(4-fluorobenzoyl)-5-(4- fluorophenyl)pyrimidin-2-yl)acetamide;

N-(5-(3-chlorophenyl)-4-(3-fluorobenzoyl)pyrimidin-2-yl)-2-(4- (ethylsulfonyl)phenyl)acetamide ;

N-(4-(3-chlorobenzoyl)-5-(3-chlorophenyl)pyrimidin-2-yl)-2-(4- (ethylsulfonyl)phenyl)acetamide ;

N-(4-(3-chlorobenzoyl)-5-(2-fluorophenyl)pyrimidin-2-yl)-2-(4- (ethylsulfonyl)phenyl)acetamide ;

N-(4-(3-chlorobenzoyl)-5-(2-fluorophenyl)pyrimidin-2-yl)-2-(4-((2,2,2- trifluoroethyl) sulfonyl)phenyl) acetamide ;

N-(4-(3-chlorobenzoyl)-5-(2-fluorophenyl)pyrimidin-2-yl)-2-(4-(N- ethylsulfamoyl)phenyl)acetamide;

2-(4-(ethylsulfonyl)phenyl)-N-(5-(4-fluorophenyl)-4-phenylpyrimidin-2- yl)acetamide;

2-(4-(ethylsulfonyl)phenyl)-N-(5-(6-fluoropyridin-3-yl)-4-phenylpyrimidin-2- yl)acetamide;

2-(4-(ethylsulfonyl)phenyl)-N-(4-(4-fluorophenyl)-5-(pyridin-3-yl)pyrimidin-2- yl)acetamide;

N-(4,5-bis(4-fluorophenyl)pyrimidin-2-yl)-2-(4-(ethylsulfonyl)phenyl)acetamide;

2-(4-(ethylsulfonyl)phenyl)-N-(4-(4-fluorophenyl)-5-(6-fluoropyridin-3- yl)pyrimidin-2-yl)acetamide;

2-(4-(ethylsulfonyl)phenyl)-N-(6-(4-fluorobenzoyl)-5-(3-fluorophenyl)pyridin-2- yl)acetamide;

N-(6-(cyclopropanecarbonyl)-5-(3-fluorophenyl)pyridin-2-yl)-2-(4- (ethylsulfonyl)phenyl)acetamide ;

N-(6-(cyclopropanecarbonyl)-5-(3-fluorophenyl)pyridin-2-yl)-2-(4- propionylphenyl)acetamide ;

2-(4-(ethylsulfonyl)phenyl)-N-(6'-fluoro-2-(4-fluorobenzoyl)-[3,3'-bipyridin]-6- yl)acetamide;

2-(4-(ethylsulfonyl)phenyl)-N-(6-(4-fluorobenzoyl)-5-(furan-3-yl)pyridin-2- yl)acetamide;

N-(6-benzoyl-5-(4-chlorophenyl)pyridin-2-yl)-2-(4- (ethylsulfonyl)phenyl)acetamide ;

N-(6-benzoyl-5-(4-fluorophenyl)pyridin-2-yl)-2-(4- (ethylsulfonyl)phenyl)acetamide ;

2-(4-(ethylsulfonyl)phenyl)-N-(6-(4-fluorobenzoyl)-5-(4-fluorophenyl)pyridin-2- yl)acetamide;

N-(6-benzoyl-5-(2-chlorophenyl)pyridin-2-yl)-2-(4- (ethylsulfonyl)phenyl)acetamide ;

N-(5-(3-chlorophenyl)-6-(3-fluorobenzoyl)pyridin-2-yl)-2-(4- (ethylsulfonyl)phenyl)acetamide ;

N-(6-(3-chlorobenzoyl)-5-(3-chlorophenyl)pyridin-2-yl)-2-(4- (ethylsulfonyl)phenyl)acetamide ;

N-(5-(4-chlorophenyl)-6-(4-fluorobenzoyl)pyridin-2-yl)-2-(4- (ethylsulfonyl)phenyl)acetamide ;

N-(5-(4-chlorophenyl)-6-(morpholine-4-carbonyl)pyridin-2-yl)-2-(4- (ethylsulfonyl)phenyl)acetamide ;

N-(5-(4-chlorophenyl)-6-(hydroxy(phenyl)methyl)pyridin-2-yl)-2-(4- (ethylsulfonyl)phenyl)acetamide ;

N-(6-(4-chlorobenzoyl)-5-(2-chlorophenyl)pyridin-2-yl)-2-(4- (ethylsulfonyl)phenyl)acetamide ;

47 N-(6-benzoyl-5-phenylpyridin-2-yl)-2-(4-(ethylsulfonyl)phenyl)acetamide;

N-(5-(3-chlorophenyl)-6-(4-fluorobenzoyl)pyridin-2-yl)-2-(4-

48

(ethylsulfonyl)phenyl)acetamide ;

N-(6-benzoyl-5-(3,4-dichlorophenyl)pyridin-2-yl)-2-(4-

49

(ethylsulfonyl)phenyl)acetamide ;

N-(6-benzoyl-5-(4-(tert-butyl)phenyl)pyridin-2-yl)-2-(4-

50

(ethylsulfonyl)phenyl)acetamide ;

N-(6-benzoyl-5-(4-chlorophenyl)pyridin-2-yl)-2-(4-(ethylsulfonyl)phenyl)-N-

51

methylacetamide ;

N-(6-benzoyl-5-(4-(trifluoromethyl)phenyl)pyridin-2-yl)-2-(4-

52

(ethylsulfonyl)phenyl)acetamide ;

N-(5-(4-chlorophenyl)-6-phenylpyridin-2-yl)-2-(4-

53

(ethylsulfonyl)phenyl)acetamide ; and

N-(5-(4-chlorophenyl)-6-phenoxypyridin-2-yl)-2-(4-

54

(ethylsulfonyl)phenyl)acetamide ; or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable stereoisomer thereof.

The present application also provides a pharmaceutical composition that includes at least one compound described herein and at least one pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent). Preferably, the pharmaceutical composition comprises a therapeutically effective amount of at least one compound described herein. The compounds described in the present patent application may be associated with a pharmaceutically acceptable excipient (such as a carrier or a diluent) or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container.

The compounds and pharmaceutical compositions of the present invention are useful for inhibiting the activity of RORy, which is believed to be related to a variety of disease states. The present patent application further provides a method of inhibiting RORy in a subject in need thereof by administering to the subject one or more compounds described herein in the amount effective to cause inhibition of such receptor.

The compounds of the invention are typically administered in the form of a pharmaceutical composition. Such compositions can be prepared using procedures well known in the pharmaceutical art and comprise at least one compound of the invention. The pharmaceutical composition of the present patent application comprises one or more compounds described herein and one or more pharmaceutically acceptable excipients. Typically, the pharmaceutically acceptable excipients are approved by regulatory authorities or are generally regarded as safe for human or animal use. The pharmaceutically acceptable excipients include, but are not limited to, carriers, diluents, glidants and lubricants, preservatives, buffering agents, chelating agents, polymers, gelling agents, viscosifying agents, solvents and the like.

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

The pharmaceutical composition may also include one or more pharmaceutically acceptable auxiliary agents, wetting agents, suspending agents, preserving agents, buffers, sweetening agents, flavouring agents, colorants or any combination of the foregoing.

The pharmaceutical compositions may be in conventional forms, for example, tablets, capsules, solutions, suspensions, injectables or products for topical application. Further, the pharmaceutical composition of the present invention may be formulated so as to provide desired release profile.

Administration of the compounds of the invention, in pure form or in an appropriate pharmaceutical composition, can be carried out using any of the accepted routes of administration of pharmaceutical compositions. The route of administration may be any route which effectively transports the active compound of the patent application to the appropriate or desired site of action. Suitable routes of administration include, but are not limited to, oral, nasal, buccal, dermal, intradermal, transdermal, parenteral, rectal, subcutaneous, intravenous, intraurethral, intramuscular, or topical.

Solid oral formulations include, but are not limited to, tablets, capsules (soft or hard gelatin), dragees (containing the active ingredient in powder or pellet form), troches and lozenges.

Liquid formulations include, but are not limited to, syrups, emulsions, and sterile injectable liquids, such as suspensions or solutions.

Topical dosage forms of the compounds include ointments, pastes, creams, lotions, powders, solutions, eye or ear drops, impregnated dressings, and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration.

The pharmaceutical compositions of the present patent application may be prepared by conventional techniques, e.g., as described in Remington: The Science and Practice of Pharmacy, 20^th Ed., 2003 (Lippincott Williams & Wilkins).

Suitable doses of the compounds for use in treating the diseases and disorders described herein can be determined by those skilled in the relevant art. Therapeutic doses are generally identified through a dose ranging study in humans based on preliminary evidence derived from the animal studies. Doses must be sufficient to result in a desired therapeutic benefit without causing unwanted side effects. Mode of administration, dosage forms, and suitable pharmaceutical excipients can also be well used and adjusted by those skilled in the art. All changes and modifications are envisioned within the scope of the present patent application.

Compounds of the present invention are particularly useful because they may inhibit the activity of Retinoid-related orphan receptor gamma(RORy), i.e., they prevent, inhibit, or suppress the action of RORy, and/or may elicit RORy modulating effect. Compounds of the invention are thus useful in the treatment of those conditions in which inhibition of a ROR gamma activity is required.

It is contemplated that compounds disclosed in the present invention, provide therapeutic benefits to subjects suffering from an immune disorder or inflammatory disorder. Accordingly, one aspect of the invention provides a method of treating a disorder selected from the group consisting of an immune disorder or inflammatory disorder. The method comprises administering a therapeutically effective amount of a compound of the present invention, to a subject in need thereof to ameliorate a symptom of the disorder.

According to another embodiment, the disorder is an immune disorder.

According to yet another embodiment, the disorder is an inflammatory disorder.

According to yet another embodiment, the disorder is an autoimmune disorder.

According to yet another embodiment, the disorder is rheumatoid arthritis, psoriasis, chronic graft-versus-host disease, acute graft-versus-host disease, Crohn's disease, inflammatory bowel disease, multiple sclerosis, systemic lupus erythematosus, Celiac Sprue, idiopathic thrombocytopenic thrombotic purpura, myasthenia gravis, Sjogren's syndrome, asthma, epidermal hyperplasia, scleroderma or ulcerative colitis.

According to yet another embodiment, the disorder is cartilage inflammation, bone degradation, arthritis, juvenile arthritis, juvenile rheumatoid arthritis, pauciarticular juvenile rheumatoid arthritis, polyarticular juvenile rheumatoid arthritis, systemic onset juvenile rheumatoid arthritis, juvenile ankylosing spondylitis, juvenile enteropathic arthritis, juvenile reactive arthritis, juvenile Reter's Syndrome, SEA Syndrome, juvenile dermatomyositis, juvenile psoriatic arthritis, juvenile scleroderma, juvenile systemic lupus erythematosus, juvenile vasculitis, pauciarticular rheumatoid arthritis, polyarticular rheumatoid arthritis, systemic onset rheumatoid arthritis, ankylosing spondylitis, enteropathic arthritis, reactive arthritis, Reter's Syndrome, dermatomyositis, psoriatic arthritis, vasculitis, myolitis, polymyolitis, dermatomyo litis, osteoarthritis, polyarteritis nodossa, Wegener's granulomatosis, arteritis, polymyalgia rheumatica, sarcoidosis, sclerosis, primary biliary sclerosis, sclerosing cholangitis, dermatitis, atopic dermatitis, atherosclerosis, Still's disease, chronic obstructive pulmonary disease, Guillain-Barre disease, Type I diabetes mellitus, Graves' disease, Addison's disease, Raynaud's phenomenon, autoimmune hepatitis, psoriatic epidermal hyperplasia, plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, erythrodermic psoriasis, or an immune disorder associated with or arising from activity of pathogenic lymphocytes.

According to yet another embodiment, the psoriasis is plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, or erythrodermic psoriasis.

According to yet another embodiment, the disorder is rheumatoid arthritis. According to yet another embodiment, the subject is a human.

Another aspect of the invention provides for the use of the compounds of the present invention in the manufacture of a medicament.

According to yet another embodiment, the medicament is for treating a disease/disorder mediated by RORy.

Further, it is contemplated that the compounds of the present invention can inhibit the activity of RORy. Accordingly, another aspect of the invention provides a method of inhibiting the activity of RORy. The method comprises exposing a RORy to an effective amount of a compound of the present invention to inhibit said RORy.

Further, it is contemplated that the compounds of the present invention can reduce the amount of interleukin-17 (IL-17) and other effector cytokines of Thl7 cells, in a subject. IL-17 is a cytokine that affects numerous biological functions, including inducing and mediating proinflammatory responses. Accordingly, another aspect of the invention provides a method of reducing the amount of IL-17 and other effector cytokines of Thl7 cells, in a subject. The method comprises administering to a subject an effective amount of a compound of the present invention to reduce the amount of IL-17 and other effector cytokines of Thl7 cells, in the subject

According to yet another embodiment, the subject is a human.

According to yet another embodiment, administering the compound reduces the amount of IL-17 and other effector cytokines produced by Thl7 cells, in the subject. A change in the amount of IL-17 and other effector cytokines produced by, for example, Thl7 cells can be measured using procedures described in the literature, such as an ELISA assay or intracellular staining assay.

Further, it is contemplated that compound of the present invention may inhibit the synthesis of IL-17 and other effector cytokines of Thl7 cells, in a subject.

Accordingly, another aspect of the invention provides a method of inhibiting the synthesis of IL-17 and other effector cytokines of Thl7 cells, in a subject. The method comprises administering to a subject an effective amount of a compound of the present invention to inhibit the synthesis of IL-17 and other effector cytokines of Thl7 cells, in the subject. The method(s) of treatment of the present patent application comprise administering a safe and effective amount of a compound according to formula (I) or a pharmaceutically acceptable salt thereof to a patient (particularly a human) in need thereof.

Compounds of the invention are indicated both in the therapeutic and/or prophylactic treatment of the above-mentioned conditions. For the above-mentioned therapeutic uses the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated.

The following abbreviations refer respectively to the definitions below:

Cone. - Concentrated ; HC1 - Hydrochloric acid; Min - Minutes; °C - Degree Celsius; h - Hour(s); K₂CO₃ - Potassium carbonate; DMF - N N-dimethylformamide; mCPBA - meta- Chloroperbenzoic acid; DCM - Dichloromethane; Mol - Molar; g - Gram; mL - Milli Liter; LC - Liquid Chromatography; ¹H NMR - Proton Nuclear Magnetic Resonance; MHz - Megahertz (frequency); CDCI₃ - Deuterated chloroform; d - Doublet; - Coupling constant; q - Quartet; s - Singlet; t - Triplet; DMSO-<¾ - Deuterated Dimethylsulfoxide; dd - Doublet of doublet; LiOH.H₂0 - Lithium hydroxide monohydrate; THF - Tetrahydrofuran; MeOH - Methanol; H₂0 - Water; NBS - N-Bromosuccinimide; EDCI.HC1 - l-(3-Dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride; HOBt - 1-Hydroxy benzotriazole; Et₃N - Triethyl amine; T₃P - 1- Propanephosphonic anhydride 50 % solution in ethyl acetate; Pd(PPh₃)₄ Tetrakis(triphenylphosphine)palladium(0); PdCl₂(PPh₃)₂ - Bis(triphenylphosphine)palladium(II) dichloride; Na₂S0₄ - Sodium sulfate; Na₂C0₃ - Sodium carbonate; brs - Broad singlet; m - Multiplet; mM - Mill molar; MS - Mass Spectroscopy; μΜ - Micromolar; nM - Nanomolar; CH₃CN - Acetonitrile; Pd/C ( 10 %) - Palladium on activated carbon 10 wt. % ; N - Normality; KMn0₄ - Potassium permanganate; TLC- Thin Layer Chromoatography.

General methods of preparation:

Methods for preparing compounds described herein are illustrated in the following synthetic schemes. The schemes are given for the purpose of illustrating the invention, and are not intended to limit the scope or spirit of the invention. Starting materials shown in the schemes can be obtained from commercial sources or prepared based on procedures described in the literature. Furthermore, in the following schemes, where specific acids, bases, reagents, coupling agents, solvents, etc. are mentioned, it is understood that other suitable acids, bases, reagents, coupling agents etc. may be used and are included within the scope of the present invention. Modifications to reaction conditions, for example, temperature, duration of the reaction or combinations thereof, are envisioned as part of the present invention. All possible stereoisomers are envisioned within the scope of this invention.

Scheme A:

formula 1.8

Some compounds of the present invention may be synthesized utilizing the process outlined in general Scheme A; wherein R_{1 ;} R₂, R₃, m and ring A are as defined herein. The commercially available or synthesized bromo-amino-pyrimidine reacts with ethyl pyruvate in presence of suitable reagents and solvents (30 % aqueous hydrogen peroxide, acetic acid, cone, sulfuric acid, toluene and ferrous sulfate heptahydrate) to get intermediate 1.1. Treatment of 1.1 with Ri-boronic acid or Ri-boronate ester, under Suzuki coupling conditions in the presence of suitable catalyst such as PdCl₂(PPh₃)_2, suitable base such as potassium carbonate and in the presence of suitable solvent(s) such as 1,4-dioxane and/or water gave intermediate 1.2, which on hydrolysis in presence of suitable base such as LiOH.H₂0 and suitable solvent such as ethanol and water to form intermediate 1.3. The carboxylic acid functional group in 1.3 is converted to Weinreb amide 1.4 by reacting with N O-dimethylhydroxyamine hydrochloride using a suitable coupling agent such as l-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI.HC1) and 1 -hydroxy benzotriazole (HOBt); in the presence of suitable base such as TEA and in presence of suitable solvent such as DMF. The intermediate 1.4 undergoes Grignard reaction with R₂MgBr in presence of suitable solvent such as THF under anhydrous conditions to afford intermediate 1.5. Intermediate 1.5 is coupled with appropriately substituted acid 1.6 using suitable coupling agent such as T₃P in presence of suitable organic base such as TEA and in presence of suitable solvent such as DCM to get intermediate 1.7. Reduction of the keto group of intermediate 1.7 using suitable reducing agent such as sodium borohydride in presence of suitable solvent such as methanol gave compound of formula 1.8.

Scheme B:

2.5 2.4 2.3 reduction

formula 2.6 Some compounds of the present invention may be synthesized utilizing the process outlined in Scheme B; wherein R_1; R₂, R₃, m and ring A are as defined herein. Intermediate 1.1 on hydrolysis in presence of suitable base such as LiOH.H₂0 and suitable solvent such as ethanol and water affords intermediate 2.1. The carboxylic acid functional group in 2.1 is converted to Weinreb amide 2.2 by reacting with N O-dimethylhydroxyamine hydrochloride using a suitable coupling agent such as l-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI.HC1) and 1 -hydroxy benzotriazole (HOBt); in the presence of suitable base such as TEA and in the presence of suitable solvent such as DMF. The intermediate 2.2 undergoes Grignard reaction with R₂MgBr in presence of suitable solvent such as THF under anhydrous conditions to afford intermediate 2.3. Treatment of 2.3 with Ri-boronic acid or Ri-boronate ester, under Suzuki coupling conditions, in presence of suitable catalyst such as PdCl₂(PPh₃)_2, suitable base such as potassium carbonate and in the presence of suitable solvent(s) such as 1,4-dioxane and/or water gave intermediate 2.4. Intermediate 2.4 was coupled with appropriately substituted acid 1.6 using suitable coupling agent such as T₃P in presence of suitable organic base such as TEA and in presence of suitable solvent such as DCM to get intermediate 2.5. Reduction of the keto group of intermediate 2.5 using suitable reducing agent such as sodium borohydride in presence of suitable solvent such as methanol affords compound of formula 2.6.

Scheme C:

formula 3.7 Some compounds of the present invention may be synthesized utilizing the process outlined in Scheme C; wherein R_{1 ;} R₂, R₃, m and ring A are as defined herein. The commercially available or synthesized acetyl starting material 3.1 reacts with 3.2 to get intermediate 3.3. The intermediate 3.3 undergoes cyclisation reaction by treating with guanidine hydrochloride in presence of suitable base such as NaOEt to provide intermediate 3.4, which on bromination using suitable brominating agent such as NBS in presence of suitable solvent such as MeCN and CHC1₃ gave intermediate 3.5. Treatment of 3.5 with Ri-boronic acid or Ri-boronate ester, under Suzuki coupling conditions, in presence of suitable catalyst such as Pd(PPh₃)_4i suitable base such as sodium carbonate and in the presence of suitable solvent(s) such as 1,4-dioxane and/or water affords intermediate 3.6. Intermediate 3.6 is coupled with appropriately substituted acid 1.6 using suitable coupling agent such as T₃P, suitable organic base such as TEA and in presence of suitable solvent such as DCM to afford compound of formula 3.7.

Scheme D:

Some compounds of the present invention may be synthesized utilizing the process outlined in Scheme D; wherein R_{1 ;} R₂, R₃, m and ring A are as defined herein. Acylation of 6- amino-2-picoline 4.1 using acetic anhydride in presence of suitable solvent such as THF affords intermediate 4.2. Treatment of intermediate 4.2 with KMn0₄ in presence of suitable inorganic acid such as HC1, suitable solvent such as methanol and water gives intermediate 4.3, which on bromination using suitable brominating agent such as NBS in presence of suitable solvent such as MeCN and CHC1₃ or bromine in acetic acid in presence of sodium carbonate affords intermediate 4.4. Treatment of 4.4 with Ri-boronic acid or Ri-boronate ester, under Suzuki coupling conditions, in presence of suitable catalyst such as PdCl₂(PPh₃)_2, suitable base such as potassium carbonate and in the presence of suitable solvent(s) such as 1,4-dioxane and/or water affords intermediate 4.5. The intermediate 4.5 on hydrolysis in presence of suitable base such as LiOH.H₂0 and suitable solvent such as ethanol and water affords intermediate 4.6. The carboxylic acid functional group in 4.6 is converted to Weinreb amide 4.7 by reacting with N, 0- dimethylhydroxyamine hydrochloride using a suitable coupling agent such as l-(3- Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI.HC1) and 1 -hydroxy benzotriazole (HOBt); in presence of suitable base such as TEA and in the presence of suitable solvent such as DMF. The intermediate 4.7 undergoes Grignard reaction with R₂MgBr in presence of suitable solvent such as THF under anhydrous conditions to afford intermediate 4.8. The intermediate 4.8 is coupled with appropriately substituted acid 1.6 using suitable coupling agent such as T₃P in presence of suitable organic base such as TEA and in presence of suitable solvent such as DCM to get intermediate 4.9. Reduction of the keto group of intermediate 4.9 using suitable reducing agent such as sodium borohydride in presence of suitable solvent such as methanol affords compound of formula 5.0.

The intermediates required for the synthesis are commercially available or alternatively, these intermediates can be prepared using known literature methods. The invention is described in greater detail by way of specific examples.

Unless otherwise stated, work-up includes distribution of the reaction mixture between the organic and aqueous phase indicated within parentheses, separation of layers and drying the organic layer over sodium sulphate, filtration and evaporation of the solvent. Purification, unless otherwise mentioned, includes purification by silica gel chromatographic techniques, generally using ethyl acetate/hexane mixture of a suitable polarity as the mobile phase. Use of a different eluent system is indicated within parentheses.

The MS data provided in the examples described below were obtained as follows:

Mass spectrum: Shimadzu LCMS 2020; Agilent 1100; LCMSD VL and Agilent 1100; API 2000

The NMR data provided in the examples described below were obtained as follows: 'H-NMR: Varian 300 and 400 MHz.

Preparation of Intermediates

Scheme 1(a)

Reagents and conditions: i) Sodium nitrite, conc.HCl, water, 0 °C, 45 min/ potassium ethylxanthate, sodium carbonate, water, room temperature - 45 °C, 2 h; ii) potassium hydroxide, ethanol, water, reflux, 20 h; iii) bromoethane, K₂CO₃, DMF, room temperature, 2-3 h; iv) OTCPBA, DCM, 0 °C - room temperature, 12 h; v) sodium hydroxide, ethanol, water, room temperature, 12 h.

Synthesis of 2-(4-(ethylsulfonyl)phenyl)acetic acid

Step i: 2-(4-((ethoxycarbonothioyl)thio)phenyl)acetic acid

To a 250 mL round bottom flask, were added 4-aminophenylacetic acid (8.5 g, 0.0562 mol), water (28 mL) and conc.HCl (11.5 mL) and then cooled to 0 °C. To the same flask, aqueous sodium nitrite (3.9 g, 0.0562 mol in 28 mL of water) was drop wise added. The reaction mixture was stirred at 0 °C for 45 min. The resulting cold diazonium salt solution was drop wise added to the mixture of potassium ethylxanthate (10.4 g, 0.0648 mol), water (16.8 mL) and 2M sodium carbonate (42 mL). The reaction mixture was stirred at 45 °C for 2 h. The reaction mixture was cooled to 0 °C, acidified with conc.HCl to pH 1.0 and extracted with diethyl ether. The combined organic layer was washed with water, brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to get the crude title compound (19 g). The crude product was used for the next step immediately without any further purification.

Step ii: 2-(4-mercaptophenyl)acetic acid

To a 250 mL round bottom flask, were added 2-(4-((ethoxycarbonothioyl)thio)phenyl) acetic acid (19 g, 0.0741 mol) and ethanol (72 mL). To the same flask, 72 mL of aqueous potassium hydroxide solution (15 g, 0.2670 mol) was added. The reaction mixture was stirred at reflux temperature for 20 h. The major portion of ethanol was evaporated under reduced pressure to get the residue. The residue was acidified with cone. HC1 to pH 2.0 at 0 °C. The aqueous layer was extracted with diethyl ether. The combined organic layer was washed with water, brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to get the crude product (7 g). The crude product was used for next step without any further purification. LC-MS: 166.9 [M-H]⁺.

Step iii: ethyl 2-(4-(ethylthio)phenyl)acetate

To a 100 mL round bottom flask, were added 2-(4-mercaptophenyl)acetic acid (7 g, 0.0416 mol), potassium carbonate (23 g, 0.1664 mol) and NN-dimethylformamide (50 mL). To the same flask, ethyl bromide (13.6 g, 0.1248 mol) was added. The reaction mixture was stirred at room temperature for 2.5 h. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography using 60 - 120 silica gel and 10 % ethyl acetate in hexane to get the title compound [6 g, 65 %]. 1H NMR (400 MHz, CDC1₃): δ 7.30 (d, 7 = 8.0 Hz, 2H), 7.22 (d, 7 = 8.0 Hz, 2H), 4.18 (q, T = 7.2 Hz, 7" = 14.4 Hz, 2H), 3.57 (s, 2H), 2.96 (q, T = 7.6 Hz, 7" = 14.8 Hz, 2H), 1.33 (t, 7 = 7.6 Hz, 3H), 1.25 (t, 7 = 7.6 Hz, 3H).

Step iv: ethyl 2-(4-(ethylsulfonyl)phenyl)acetate

To a 250 mL round bottom flask, were added ethyl 2-(4-(ethylthio)phenyl)acetate (5.5 g, 0.0245 mol) and dichloromethane (82.5 mL). The reaction mixture was cooled to 0 °C. To the same flask, m-chloroperbenzoic acid (12.6 g, 0.073 mol) was added at 0 °C. The reaction mixture was stirred at room temperature for 12 h. The resulting suspension was filtered through a pad of celite. The filtrate was washed with water. The organic layer was separated, washed with saturated sodium bicarbonate solution followed by brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to get the crude product. The crude product was purified by column chromatography using 60 - 120 silica gel and 50 % ethyl acetate in hexane to get the title compound [5.1 g, 82 %]. *H NMR (400 MHz, OMSO-d₆): δ 7.84 (d, = 8.4 Hz, 2H), 7.56 (d, = 8.8 Hz, 2H), 4.10 (q, T = 7.2 Hz, J" = 14.4 Hz, 2H), 3.83 (s, 2H), 3.31 (q, J' = 7.2 Hz, 7" = 14.8 Hz, 2H) 1.21-1.07 (m, 6H); LC-MS: 257.2 [M+H]⁺.

Step v: 2-(4-(ethylsulfonyl)phenyl)acetic acid

To a 50 mL round bottom flask, were added ethyl 2-(4-(ethylsulfonyl)phenyl)acetate (2.5 g, 0.0098 mol) and ethanol ( 18 mL). To the same flask, a solution of sodium hydroxide in water (1.42 g, 0.0355 mol in 18 mL of water) was added. The reaction mixture was stirred at room temperature for 12 h. The volatiles were evaporated under reduced pressure to obtain the residue. The residue was acidified with IN HC1 to pH 5.0 and extracted with ethyl acetate. The organic layer was separated, washed with brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure to get the title compound [2.4 g, 91 %]. 1H NMR (400 MHz, DMSO-i¾): δ 12.5 (brs, 1H), 7.84 (d, = 8.4 Hz, 2H), 7.56 (d, = 8.4 Hz, 2H), 3.74 (s, 2H), 3.13 (q, T = 7.2 Hz, J' ' = 14.8 Hz, 2H), 1.20 (t, =7.6 Hz, 3H).

Scheme Kb)

1 2 3 4 Reagents and conditions: i) Methanol, con. sulfuric acid, reflux, 3 h; ii) methyl iodide, potassium carbonate, NN-dimethylformamide, room temperature, 3 h; iii) m-chloroperbenzoic acid , dichlorome thane, room temperature, 12 h; iv) sodium hydroxide, methanol, water, room temperature, 12 h. Synthesis of 2-(4-(methylsulfonyl)phenyl)acetic acid

Step i: methyl 2-(4-mercaptophenyl)acetate

To a 100 mL round bottom flask, were added 2-(4-mercaptophenyl)acetic acid (5.0 g, 0.0298 mol), methanol (50 mL) and cone, sulfuric acid (0.1 mL). The reaction mixture was stirred at reflux temperature for 3 h. The volatiles were evaporated under reduced pressure to get the residue. The residue was basified with aqueous saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic layer was washed with brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure to get the title compound [4.0 g, 74 %]. The obtained intermediate was used in the next step without any further purification.

Step ii: methyl 2-(4-(methylthio)phenyl)acetate

The process of this step was adopted from step-iii of Scheme 1(a) to get the title compound [1.75 g, 91 %]. 1H NMR (300 MHz, CDC1₃): δ 7.21 (s, 4H), 3.69 (s, 3H), 3.58 (s, 2H), 2.47 (s, 3H).

Step iii: methyl 2-(4-(methylsulfonyl)phenyl)acetate

The process of this step was adopted from step-iv of Scheme-I(a) to get the title compound [0.7 g, 60 %]. 1H NMR (300 MHz, CDC1₃): δ 7.87 -7.84 (m, 2H), 7.54 - 7.51 (m, 2H), 3.83 (s, 2H), 3.61 (s, 3H), 3.19 (s, 3H).

Step iv: 2-(4-(methylsulfonyl)phenyl)acetic acid

The process of this step was adopted from step-v of Scheme-I(a) to obtain the title compound [0.56 g, 51 %]. ^!H NMR (300 MHz, DMSO-J₆): δ 12.58 (s, 1H), 7.88 - 7.85 (m, 2H), 7.54 - 7.52 (m, 2H), 3.73 (s, 2H), 3.20 (s, 3H).

Scheme 1(c)

Reagents and conditions: i) Pd/C (10 %), hydrogen gas, ethyl acetate, 5 h; ii) sodium nitrite, conc.HCl, water, 0 °C, 45 min / potassium ethylxanthate, sodium carbonate, water, room temperature, 45 °C 2 h; iii) potassium hydroxide, ethanol, water, reflux, 12 h; iv) bromoethane, K₂C0₃, DMF, room temperature, 3 h; v) OTCPBA, DCM, 0 °C - room temperature, 12 h; vi) sodium hydroxide, ethanol, water, room temperature, 12 h.

Synthesis of 2-(4-(ethylsulfonyl)-2-fluorophenyl)acetic acid

Step i: 2-(4-amino-2-fluorophenyl)acetic acid

To a 50 mL round bottom flask, were added 2-(2-fluoro-4-nitrophenyl)acetic acid (3 g, 0.0015 mol) and ethyl acetate (30 mL). To the same flask, 10 % palladium on activated carbon (0.54 g) was added. The reaction mixture was stirred under hydrogen gas (using bladder) atmosphere for 5 h. The reaction mixture was filtered through a pad of celite. The filtrate was evaporated under reduced pressure to get the title compound [2.3 g, 92 %].¹H NMR (300 MHz, DMSO-J₆): δ 12.2 (brs, 1H), 6.92 (t, = 9.3 Hz, 1H), 6.32 - 6.26 (m, 2H), 5.27 (brs, 2H), 3.36 (s, 2H).

Step ii: 2-(4-((ethoxycarbonothioyl)thio)-2-fluorophenyl)acetic acid

The process of this step was adopted from step-i of Scheme 1(a) to get the crude product [4.2 g]. The crude product was used for the next step immediately without any further purification.

Step iii: 2-(2-fluoro-4-mercaptophenyl)acetic acid

The process of this step was adopted from step-ii of scheme-I(a) to get the crude product [2.4 g]. The crude product was used in the next step without further purification. LC-MS: 185.1 [M-H]⁺.

Step iv: ethyl 2-(4-(ethylthio)-2-fluorophenyl)acetate

The process of this step was adopted from step-iii of scheme-I(a) to obtain the title compound [1.65 g, 57 %]. *H NMR (300 MHz, DMSO-J₆): δ 7.30 (t, / = 8.1 Hz, 1H), 7.17 (m, 2H), 4.12 (q, T = 6.9 Hz, 7" = 14.4 Hz, 2H), 3.66 (s, 2H), 3.04 (q, T = 7.5 Hz, = 14.7 Hz, 2H), 1.26 (m, 6H).

Step v: ethyl 2-(4-(ethylsulfonyl)-2-fluorophenyl)acetate

The process of this step was adopted from step-iv of Scheme-I(a) to get the title compound [ 1.5 g, 83 %]. *H NMR (300 MHz, DMSO-J₆): δ 7.72 - 7.65 (m, 3H), 4.12 (q, T = 6.9 Hz, J" = 14.4 Hz, 2H), 3.85 (s, 2H), 3.38 (q, J' = 7.5 Hz, 7" = 14.7 Hz, 2H) 1.19 (t, 7 = 7.2 Hz, 3H), 1.1 1 (t, 7 = 7.2 Hz, 3H). Step vi: 2-(4-(ethylsulfonyl)-2-fluorophenyl)acetic acid

The process of this step was adopted from step-v of Scheme 1(a) to get the title compound [0.9 g, 69 %]. %]. 1H NMR (300 MHz, CDC1₃): δ 7.70 (m, 2H), 7.54 (t, 7 = 6.9 Hz, 1H), 3.82 (s, 2H), 3.17 (q, 7' = 7.5 Hz, J" = 14.7 Hz, 2H), 1.32 (t, 7 =7.5 Hz, 3H).

Scheme 1(d)

Reagents and conditions: i) Propanoyl chloride, aluminum chloride, carbon disulfide, 0 °C - room temperature, 1 h and reflux, 16 h; ii) sodium hydroxide, ethanol, water, room temperature, 12 h.

Synthesis of 2-(4-propionylphenyl)acetic acid

Step i: ethyl 2-(4-propionylphenyl)acetate

To a 25 mL round bottom flask, was added ethyl 2-phenylacetate (1 g, 0.0061 mol) followed by carbon disulfide (10 mL). The reaction mixture was cooled to 0 °C. To the same flask, propanoyl chloride (0.67 g, 0.0073 mol) and aluminum chloride (1.05 g, 0.0079 mol) were added at 0°C. The reaction mixture was stirred at room temperature for 1 h and at reflux temperature for 16 h. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was separated, washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to get the crude product. The crude product was purified by column chromatography using 60 - 120 silica gel and 30 % ethyl acetate in hexane to obtain the title compound [0.5 g, 37 %]. *H NMR (300 MHz, CDC1₃): δ 7.94 -7.88 (m, 2H), 7.47 -7.36 (m, 2H), 4.19 (q, T = 7.2 Hz, 7" = 14.4 Hz, 2H), 3.67 (d, = 1.5 Hz, 2H), 3.01 - 2.98 (m, 2H), 1.28 - 1.19 (m, 6H).

Step ii: 2-(4-propionylphenyl)acetic acid

To a 25 mL round bottom flask, were added ethyl 2-(4-propionylphenyl)acetate (0.5 g, 0.0023 mol) and ethanol (10 mL). To the same flask, 10 mL aqueous sodium hydroxide solution (0.45 g, 0.011 mol) was added. The reaction mixture was stirred at room temperature for 12 h. The volatiles were evaporated under reduced pressure to get the residue. The residue was acidified with aqueous 4 N HC1 to pH 3.0 and extracted with ethyl acetate. The organic layer was separated, washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to get the title compound [0.3 g, 69 %]. 1H NMR (300 MHz,

CDC1₃): δ 7.95-7.87 (m, 2H), 7.47 -7.36 (m, 2H), 3.71 (s, 2H), 3.03 - 2.95 (m, 2H), 1.24 (t, = 7.5 Hz, 3H); LC-MS: 191.0 [M-H]⁺. Scheme 1(e)

Reagents and conditions: (i) Potassium hydroxide, water, 110 °C, 4 h; (ii) methanol, thionyl chloride (catalytic), room temperature, 5 h; (iii) methylamine hydrochloride, EDCI.HC1, HOBt, TEA, DMF, room temperature, 10 h; (iv) lithium hydroxide monohydrate, methanol, water, room temperature, 2 h.

Synthesis of 2-(4-(methylcarbamoyl)phenyl)acetic acid

Step i: 4-(carboxymethyl)benzoic acid

To a 25 mL round bottom flask, were added 2-(4-cyanophenyl)acetic acid (2.0 g, 0.0124 mol) and 20 mL aqueous potassium hydroxide solution (3.47 g, 0.062 mol). The reaction mixture was stirred at reflux temperature for 4 h. The reaction mixture was acidified to pH 3.0 with 3 N hydrochloric acid to get the precipitate. The precipitate was collected by filtration and dried under vacuum to get the title compound [1.8 g, 81 %]. ^!H NMR (400 MHz, DMSO-ife): δ 12.64 (brs, 2H), 7.88 (d, = 8.1 Hz, 2H), 7.38 (d,

[M+H]⁺.

Step ii: 4-(2-methoxy-2-oxoethyl)benzoic acid

To a 25 mL round bottom flask, were added 4-(carboxymethyl)benzoic acid (1.7 g,

0.0094 mol), methanol (20 mL) and thionyl chloride (0.034 mL, 0.00047 mol). The reaction mixture was stirred at room temperature for 5 h. The volatiles were evaporated under reduced pressure to get the residue. The residue was partitioned between ethyl acetate and water. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to get the crude product [1.7 g, 93 %]. 1H NMR (300 MHz, CDCI₃): δ 8.08 (d, = 8.1 Hz, 2H), 7.40 (d, = 8.1 Hz, 2H), 3.71 (s, 5H).

Step iii: methyl 2-(4-(methylcarbamoyl)phenyl)acetate

To a 50 mL round bottom flask, were added 4-(2-methoxy-2-oxoethyl)benzoic acid (1.2 g, 0.0065 mol), methylamine hydrochloride (0.66 g, 0.0098 mol), EDCI.HC1 (2.5 g, 0.013 mol), HOBt (1.32 g, 0.0098 mol), Et₃N (2.7 mL, 0.0195 mol) and DMF (00 mL). The reaction mixture was stirred at room temperature for 10 h. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to get the title compound [0.9 g, 67 %]. *H NMR (CDC1₃, 300 MHz): δ 7.73 (d, = 8.4 Hz, 2H), 7.35 (d, = 8.1 Hz, 2H), 6.13 (brs, 1H), 3.70 (s, 3H), 3.67 (s, 2H), 3.01 (d, = 4.8 Hz, 3H); LC-MS: 207.9 [M+H]⁺. Step iv: 2-(4-(methylcarbamoyl)phenyl)acetic acid

To a 50 mL round bottom flask, were added methyl 2-(4-(methylcarbamoyl)phenyl) acetate (0.85 g, 0.0041 mol) and methanol (15 ml). To the same flask, 5 mL of aqueous lithium hydroxide monohydrate solution (0.86 g, 0.0205 mol) was added. The reaction mixture was stirred at room temperature for 2 h. The volatiles were evaporated under reduced pressure to get the residue. The residue was acidified to pH 5.0 with 3N hydrochloric acid in water to get the white precipitate. The precipitate was collected by filtration and dried under vacuum to get the title compound [0.6 g, 76 %]. ^!H NMR (400 MHz, DMSO-J₆): δ 8.40 (d, = 4.4, 1H), 7.77 (d, = 8.4 Hz, 2H), 7.33 (d, =8.0 Hz, 2H), 3.61 (s, 2H), 2.77 (d, = 4.8 Hz, 3H); LC-MS: 193.9 [M+H]⁺.

Scheme 1(f)

Intermediate 3

from Scheme 1(c)

Reagents and conditions: a) Methanol, con.sulfuric acid, 70 °C, 45 min; b) 2-bromoethyl methyl ether, potassium carbonate, NN-dimethylformamide, room temperature, 3 h; c) m- chloroperbenzoic acid, dichloromethane, room temperature, 12 h; d) potassium hydroxide, methanol, water, room temperature, 2 h.

Synthesis of 2-(2-fluoro-4-((2-methoxyethyl)sulfonyl)phenyl)acetic acid

Step i: methyl 2-(2-fluoro-4-mercaptophenyl)acetate

To a 100 mL round bottom flask, were added methyl 2-(2-fluoro-4-mercaptophenyl) acetic acid [intermediate 3 of Scheme 1(c)] (1.5 g, 0.008 mol), methanol (15 mL) and con.sulfuric acid (2 drops). The reaction mixture was stirred at 70 °C for 45 min. The reaction mixture was cooled to 0 °C in an ice bath and neutralized with solid sodium bicarbonate. The volatiles were evaporated under reduced pressure to the volume of 5 mL and diluted with 50 mL of water. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to get the title compound [1.31 g, 82 %]. The obtained intermediate was used in the next step without any further purification. LC-MS: 199.3 [M-H]⁺.

Step ii: methyl 2-(2-fluoro-4-((2-methoxyethyl)thio)phenyl)acetate

To a 25 mL round bottom flask, were added methyl 2-(2-fluoro-4-mercaptophenyl) acetate (1.3 g, 0.0065 mol), potassium carbonate (1.79 g, 0.0129 mol), 2-bromoethyl methyl ether (1.35 g, 0.0097 mol) and NN-dimethylformamide (10 mL). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was partitioned between dichloromethane and water. The organic layer was separated, washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain the crude product [1.1 g, 66 %]. The obtained intermediate was used in the next step without any further purification.

Step iii: methyl 2-(2-fluoro-4-((2-methoxyethyl)sulfonyl)phenyl)acetate

To a 50 mL round bottom flask, were added methyl 2-(2-fluoro-4-((2-methoxyethyl)thio) phenyl)acetate (1.0 g, 0.0039 mol) and dichloromethane (10 mL). To the same flask, m- chloroperbenzoic acid (1.0 g, 0.0058 mol) was added. The reaction mixture was stirred at room temperature for 12 h. The resulting suspension was filtered through a pad of celite. The filtrate was washed with water. The organic layer was separated, washed with saturated sodium bicarbonate solution followed by brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to get the crude product. The crude product was purified by column chromatography using 60 - 120 silica gel and 10 - 30% ethyl acetate in hexane to get the title compound [0.855 g, 76 %]. 1H NMR (300 MHz, CDC1₃): δ 7.69 (m, 2H), 7.51 (t, = 7.5 Hz, 1H), 3.77-3.73 (m, 7H), 3.40 (t, = 6.0 Hz, 2H), 3.24 (s, 3H); LC-MS: 291.2 [M+H]⁺.

Step iv: 2-(2-fluoro-4-((2-methoxyethyl)sulfonyl)phenyl)acetic acid

To a 50 mL round bottom flask, were added methyl 2-(2-fluoro-4-((2-methoxyethyl) sulfonyl)phenyl)acetate (0.85 g, 0.0029 mol) and methanol (15 mL). To the same flask, 3 mL of aqueous potassium hydroxide (0.328 g, 0.0058 mol) was added. The reaction mixture was stirred at room temperature for 2 h. The volatiles were evaporated under reduced pressure to get the residue. The residue was diluted with ice cold water and acidified to pH 1.0 with solid citric acid. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the title compound [0.65 g, 81 %]. 1H NMR (300 MHz, CDC1₃): δ 7.70-7.62 (m, 2H), 7.50 (t, = 6.9 Hz, 1H), 3.80 (s, 2H), 3.77 (t, 7 = 6.3 Hz, 2H), 3.41 (t, = 6.3 Hz, 2H), 3.23 (s, 3H); LC-MS: 277.2 [M+H]⁺.

Examples

The following examples illustrate the present invention. However, these examples are not intended to limit the scope of the present invention. The person skilled in the art can readily recognize a variety of non-critical parameters which can be modified or altered to yield similar results.

Example 1: Synthesis of 2-(4-(ethylsulfonyl)phenyl)-N-(4-(4-fluorobenzoyl)-5-(4-fluoro phenyl) pyrimidin-2-yl)acetamide

Step i: ethyl 2-amino-5-bromopyrimidine-4-carboxylate

To a 50 mL round bottom flask, was added ethyl pyruvate (9.0 mL, 0.0775 mol) and cooled to -10 °C. To the same flask, acetic acid (12 mL) was added, while maintaining the internal temperature below -5 °C. To the same flask, 30 % aqueous hydrogen peroxide (5.8 g, 0.0517 mol) was added drop wise. To another 100 mL round bottom flask, was added 2-amino- 5-bromopyrimidine (3.0 g, 0.0172 mol), cone, sulfuric acid (2.75 mL, 0.0516) and ferrous sulfate heptahydrate ( 14.6 g, 0.052 mol). To this mixture, peroxide solution was added over 1 h, under vigorous stirring, while maintaining the internal temperature at 0 °C. The reaction mixture was stirred at 0 °C for 30 min. The reaction mixture was poured into ice cold water and neutralized with 1 N aqueous sodium hydroxide solution. The neutralized reaction mixture was filtered through a pad of celite. The filtrate was extracted with chloroform. The combined organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to get the crude product. The crude product was purified by column chromatography using 60 - 120 silica gel and 0 - 1 % methanol in chloroform to obtain the title compound. The obtained compound was washed with 30 % ethyl acetate in hexane to get the pure title compound [0.6 g, 15 %]. 1H NMR (300 MHz, DMSO-J₆): δ 8.49 (s, 1H), 7.27 (brs, 2H), 4.38 (q, J' = 7.2 Hz, J" = 14.1 Hz, 2H), 1.33 (t, 7 = 7.2 Hz, 3H); LC-MS: 247.8 [M+H]⁺ _.

Step ii: ethyl 2-amino-5-(4-fluorophenyl)pyrimidine-4-carboxylate

To a 25 mL round bottom flask, were added ethyl 2-amino-5-bromopyrimidine-4- carboxylate (0.6 g, 0.0024 mol), 4-fluorophenylboronic acid (0.5 g, 0.0036 mol), potassium carbonate (0.673 g, 0.0048 mol), 1 ,4-dioxane ( 15 mL) and water (5 mL). The reaction mixture was degassed with nitrogen for 5 min. To the same flask, bis(triphenylphosphine)palladium(II) chloride (0.085 g, 0.00012 mol) was added. The reaction mixture was again degassed with nitrogen for 5 min. The reaction mixture was stirred at 95 °C for 2 h. The volatiles were evaporated under reduced pressure to get the residue. The residue was partitioned between ethyl acetate and water. The combined organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to get the crude product. The crude product was purified by flash column chromatography using 20 - 40 % ethyl acetate in hexane to obtain the title compound [0.51 g, 80 %]. ^!H NMR (300 MHz, OMSO-d₆): δ 8.41 (s, 1H), 7.35-7.22 (m, 4H), 7.13 (s, 2H), 4.17 (q, J' = 7.2 Hz, "= 14.1 Hz, 2H), 1.09 (t, = 7.2 Hz, 3H); LC-MS: 261.9 [M+H]⁺ _.

Step iii: 2-amino-5-(4-fluorophenyl)pyrimidine-4-carboxylic acid

To a 50 mL round bottom flask, were added ethyl 2-amino-5-(4-fluorophenyl) pyrimidine-4-carboxylate (0.4 g, 0.0015 mol) and ethanol ( 15 ml). To the same flask, 4 mL of aqueous lithium hydroxide monohydrate solution (0.257 g, 0.0061 mol) was added. The reaction mixture was stirred at room temperature for 4 h. The volatiles were evaporated under reduced pressure to get the residue. The residue was dissolved in water (5 mL) and acidified with citric acid (1.2 g) to get the solid. The solid was collected by filtration and dried under vacuum to get the title compound [0.31 g, 87 %]. ^!H NMR (300 MHz, DMSO-J₆): δ 8.34 (s, 1H), 7.43-7.38 (m, 2H), 7.27 (t, = 9.0 Hz, 2H), 6.97 (brs, 2H); LC-MS: 234.1 [M+H]⁺ _.

Step iv: 2-arnino-5-(4-fluorophenyl)-N-methoxy-N-methylpyrimidine-4-carboxamide

To a 50 mL round bottom flask, were added 2-amino-5-(4-fluorophenyl)pyrimidine-4- carboxylic acid (0.3 g, 0.00128 mol), N, O-dimethylhydroxyamine hydrochloride (0.149 g, 0.00154 mol), EDCI.HC1 (0.616 g, 0.00321 mol), HOBt (0.26 g, 0.00192 mol), Et₃N (0.54 mL, 0.00385 mol) and DMF (10 mL). The reaction mixture was stirred at room temperature for 6 h. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was separated, washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to get the title compound [0.255 g, 72 %]. ^JH NMR (300 MHz, CDCI₃): δ 8.53 (s, 1H), 7.36-7.31 (m, 2H), 7.12 (t, / = 8.7 Hz, 2H), 5.32 (brs, 2H), 3.51 (s, 3H), 3.17 (s, 3H); LC-MS: 277.3 [M+H]⁺ _.

Step v: (2-amino-5-(4-fluorophenyl)pyrimidin-4-yl)(4-fluorophenyl)methanone

To a 50 mL round bottom flask, were added 2-amino-5-(4-fluorophenyl)-N-methoxy-N- methylpyrimidine-4-carboxamide (0.25 g, 0.0009 mol) and anhydrous tetrahydrofuran (10 mL). The reaction mixture was cooled to 0 °C. To the same flask, 1.0 M 4-fluorophenylmagnesium bromide in tetrahydrofuran (4.5 mL, 0.0045 mol.) was added at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at 0 °C for 30 min. The reaction mixture was quenched with aqueous ammonium chloride solution and extracted with dichloromethane. The combined organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to get the crude product. The crude product was purified by flash column chromatography using 20 - 50 % ethyl acetate in hexane to get the title compound [0.155 g, 55 %]. *H NMR (300 MHz, CDC1₃): δ 8.47 (s, 1H), 7.85-7.81 (m, 2H), 7.26-7.16 (m, 2H), 7.11-6.98 (m, 2H), 7.00-6.98 (m, 2H), 5.30 (brs, 2H); LC-MS: 312.1 [M+H]⁺ _.

Step vi: 2-(4-(ethylsulfonyl)phenyl)-N-(4-(4-fluorobenzoyl)-5-(4-fluorophenyl)pyrimidin-2- yPacetamide

To a 25 mL round bottom flask, were added (2-amino-5-(4-fluorophenyl)pyrimidin-4- yl)(4-fluorophenyl)methanone (0.15 g, 0.00051 mol), 2-(4-(ethylsulfonyl)phenyl)acetic acid (0.175 g, 0.00076 mol) and dichloromethane (5 mL). To the same flask, 1-propanephosphonic acid cyclic anhydride 50 % solution [T₃P] in ethyl acetate (0.97 mL, 0.00153 mol) and triethyl amine (0.21mL, 0.00153 mol) were added. The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with dichloromethane and washed with water. The organic layer was separated, washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography using 30 - 60 % ethyl acetate in hexane to get the title compound [0.025 g, 9 %]. ^!H NMR (300 MHz, DMSO-J₆): δ 11.26 (s, 1H), 8.92 (s, 1H), 7.94 (q, ' = 5.2 Hz, ' ' = 8.4 Hz, 2H), 7.82 (d, = 8.0 Hz, 2H), 7.57 (d, = 8.0 Hz, 2H), 7.36 (m, 4H), 7.24 (t, = 8.8 Hz, 2H), 3.95 (s, 2H), 3.28 (q, / = 3.6 Hz, J" = 10.8 Hz, 2H), 1.09 (t, = 7.6 Hz, 3H); LC-MS: 522.2 [M+H]⁺ _.

Example 14: Synthesis of 2-(4-(ethylsulfonyl)phenyl)-N-(5-(4-fluorophenyl)-4-((4-fluoro phenyl)(hydroxy)methyl)pyrimidin-2-yl)acetamide

To a 25 mL round bottom flask, were added 2-(4-(ethylsulfonyl)phenyl)-N-(4-(4- fluorobenzoyl)-5-(4-fluorophenyl)pyrimidin-2-yl)acetamide [Example 1] (0.015 g, 0.000028 mol) and methanol (5 mL). To the same flask, sodium borohydride (0.0043 g, 0.000115 mol) was added. The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was quenched with water and the volatiles were evaporated under reduced pressure to get the residue. The residue was partitioned between chloroform and water. The organic layer was separated, washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to get the crude product. The crude product was purified by flash column chromatography using 30 - 60 % ethyl acetate in hexane followed by preparative TLC using 2 % methanol in chloroform to get the title compound [0.009 g, 60 %]. 1H NMR (300 MHz, DMSO-d₆): δ 11.02 (s, 1H), 8.51 (s, 1H), 7.84 (d, = 8.4 Hz, 2H), 7.58 (d, = 8.0 Hz, 2H), 7.40-7.37 (m, 2H), 7.32 (t, = 8.8 Hz, 2H), 7.18 (dd, = 6.0 and 8.8 Hz, 2H), 7.04 (t, 9.2 Hz, 2H), 6.10 (d, = 4.8 Hz, 1H), 5.74 (d, = 4.8 Hz, 1H), 1.87 (d, = 3.2 Hz, 2H), 3.31 (q, T = 7.6 Hz, 7" = 14.8 Hz, 2H), 1.11 (t, = 7.2 Hz, 3H) ); LC-MS: 523.7 [M+H]⁺ _.

Example 15: Synthesis of 2-(2-fluoro-4-((2-hydroxyethyl)sulfonyl)phenyl)-N-(4-(4- fluorobenzoyl)-5-phenylpyrimidin-2-yl)acetamide

To a 25 mL round bottom flask, were added 2-(2-fluoro-4-((2-methoxyethyl)sulfonyl) phenyl)-N-(4-(4-fluorobenzoyl)-5-phenylpyrimidin-2-yl)acetamide [Synthesized according to the Scheme A] (0.03 g, 0.000054 mol) and dichloromethane (5 mL). To the same flask, 1.0 M solution of boron tribromide in dichloromethane (0.27 mL, 0.00027) was added. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with water and extracted with dichloromethane. The combined organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to get the crude product. The crude product was purified by flash column chromatography using 30 - 50 % ethyl acetate followed by preparative TLC using 3 % methanol in chloroform to get the title compound [0.018g, 62 %]. *H NMR (300 MHz, DMSO-J₆): δ 11.30 (s, 1H), 8.96 (s, 1H), 7.96-7.92 (m, 2H), 7.72-7.65 (m, 3H), 7.37-7.31 (m, 7H), 4.94 (t, = 5.2 Hz, 1H), 4.05 (s, 2H), 3.69 (q, T = 5.2 Hz, 7" = 11.2 Hz, 2H), 3.53 (t, / = 6.4 Hz, 2H); LC-MS: 537.7 [M+H]⁺.

All the compounds listed in table 1 were prepared by following similar procedure as depicted in either Scheme A or B using appropriate variations in reactants, reagents, solvents and reaction conditions. The detailed procedure is similar to that of Example 1. Table 1

52

53

Example 28: Synthesis of 2-(4-(ethylsulfonyl)phenyl)-N-(5-(6-fluoropyridin-3-yl)-4- phenylpyrimidin-2-yl)acetamide

Step i: 3-(dimethylamino)-l-phenylprop-2-en-l-one

To a 100 mL round bottom flask, was added acetophenone (1.0 g, 0.0083 mol) followed by NN-dimethylformamide dimethyl acetal (1.48 g, 0.012 mol). The reaction mixture was stirred at 115 °C for 20 h. The reaction mixture was cooled to room temperature and ether was added to get the solid. The solid was collected by filtration to get the title compound [1.2 g, 83 %]. ^JH NMR (300 MHz, CDC1₃): δ 7.89-7.86 (m, 2H), 7.80 (d, = 12.3 Hz, 1H), 7.44-7.39 (m, 3H), 5.72 (d, = 12.6 Hz, 1H), 3.11 (s, 3H), 2.91 (s, 3H); LC-MS: 176.0 [M+H]⁺.

Step ii: 4-phenylpyrimidin-2-amine

To a 100 mL round bottom flask, were added 3-(dimethylamino)-l-phenylprop-2-en-l- one (1.0 g, 0.0057 mol) and ethanol (30 mL). To the same flask, guanidine hydrochloride (1.08 g, 0.0114 mol) and NaOEt (2.0 M in ethanol, 0.77 g, 0.0114 mol) were added. The reaction mixture was stirred at reflux temperature for 20 h. The ethanol was removed under reduced pressure to get the residue. The residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to get the crude product. The crude product was purified by column chromatography using 60 - 120 silica gel and 60 % ethyl acetate in hexane to get the title compound [0.6 g, 61 %]. ^!H NMR (300 MHz, DMSO-J₆): δ 8.31 (d, = 5.1 Hz, 1H), 8.07-8.04 (m, 2H), 7.50-7.48 (m, 3H), 7.13 (d, = 5.1 Hz, 1H), 6.67 (brs, 2H); LC-MS: 171.9 [M+H]⁺.

Step iii: 5-bromo-4-phenylpyrimidin-2-amine

To a 100 mL round bottom flask, were added 4-phenylpyrimidin-2-amine (0.4 g, 0.0023 mol) and mixture of acetonitrile and chloroform (1 : 1, 20 mL). To the same flask N- bromosuccinimide (0.499 g, 0,0028 mol) was added. The reaction mixture was stirred at room temperature for 20 h. The solvent was removed under reduced pressure to get the residue. The residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to get the crude product. The crude product was purified by column chromatography using 60 - 120 silica gel and 40 % ethyl acetate in hexane to get the title compound [0.3 g, 51 %]. ^!H NMR (300 MHz, DMSO-J₆): δ 8.43 (s, 1H), 7.65-7.61 (m, 2H), 7.49-7.42 (m, 3H), 6.97 (brs, 2H); LC-MS: 251.9 [M+2H]⁺.

Step iv: 5-(6-fluoropyridin-3-yl)-4-phenylpyrimidin-2-amine

To a 25 mL round bottom flask, were added 5-bromo-4-phenylpyrimidin-2-amine (0.1 g, 0.00039 mol), 2-fluoro-5-pyridineboronic acid pinacol ester (0.106 g, 0.00048 mol), sodium carbonate (0.084 g, 0.00076 mol), 1,4-dioxane (15 mL) and water (5 mL). The reaction mixture was degassed with nitrogen for 5 min. To the same flask, tetrakis(triphenylphosphine) palladium(O) (0.045 g, 0.000039 mol) was added. The reaction mixture was again degassed with nitrogen for 5 min_. The reaction mixture was stirred at 100 °C for 2 h. The volatiles were evaporated under reduced pressure to get the residue. The residue was partitioned between ethyl acetate and water. The combined organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to get the crude product. The crude product was purified by flash column chromatography using 20-40 % ethyl acetate in hexane to obtain the title compound [0.07 g, 66 %]. 1H NMR (300 MHz, CDC1₃): δ 8.31 (brs, 2H), 8.04 (d, = 2.1 Hz, 1H), 7.46-7.43 (m, 1H), 7.36-7.30 (m, 5H), 6.84 (dd, ' = 3.0 Hz, J" = 8.4 Hz, 1H), 5.24 (brs, 1H) ; LC-MS: 266.9 [M+H]⁺.

Step v: 2-(4-(ethylsulfonyl)phenyl)-N-(5-(6-fluoropyridin-3-yl)-4-phenylpyrimidin-2- yPacetamide

To a 25 mL round bottom flask, were added 5-(6-fluoropyridin-3-yl)-4-phenylpyrimidin- 2-amine (0.06 g, 0.224 mmol), 2-(4-(ethylsulfonyl)phenyl)acetic acid (0.07 g, 0.337 mol) and dichloromethane (15 mL). To the same flask, 1-propanephosphonic acid cyclic anhydride [50 % solution T₃P] in ethyl acetate (0.356 g, 1.123 mmol) and triethyl amine (0.06 ml, 0.448 mol) were added. The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with dichloromethane and washed with water. The organic layer was separated, washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography using 5 % methanol in chloroform to get the title compound [0.02 g, 19 %]. ^JH NMR (300 MHz, CDC1₃): δ 8.66 (brs, 1H), 8.60 (s, 1H), 8.09 (d, = 2.4 Hz, 1H), 7.86 (d, = 8.4 Hz, 2H), 7.54 (d, = 8.4 Hz, 2H), 7.47-7.31 (m, 6H), 6.96 (dd, ' = 3.0 Hz, J" = 8.4 Hz, 1H), 4.36 (s, 2H), 3.14 (q, ' = 7.5 Hz, J" = 15.0 Hz, 2H), 1.29 (t, = Hz, 3H) ; LC-MS: 477.1 [M+H]⁺.

All the compounds listed in table 2 were prepared by following similar procedure as depicted in Example 28, using appropriate variations in reactants, reagents, solvents and reaction conditions.

Table 2

30 493.7

31 495.5

Example 32: Synthesis of 2-(4-(ethylsulfonyl)phenyl)-N-(6-(4-fluorobenzoyl)-5-(3- fluorophenyl)pyridin-2-yl)acetamide

Step i: N-(6-methylpyridin-2-yl)acetamide

To a 250 mL round bottom flask, were added 6-methylpyridin-2-amine (25 g, 0.23 mol) and THF (188 mL). To the same flask, acetic anhydride (47 g, 0.46 mol) was added. The reaction mixture was stirred at reflux temperature for 12 h. The reaction mixture was cooled to room temperature. The volatiles were removed under reduced pressure to get the residue. The residue was dissolved in ethyl acetate and washed with aqueous sodium bicarbonate. The organic layer was separated, washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to get the title compound [20 g, 59 %]. ¹H NMR (300 MHz, OMSO-d₆): δ 10.4 (s, 1H), 7.88 (d, 7 = 8.1 Hz, 1H), 7.63 (t,

1H), 2.38 (s, 3H), 2.05 (s, 3H); LC-MS: 151.0 [M+H]⁺.

Step ii: methyl 6-aminopicolinate

To a 250 mL round bottom flask, were added N-(6-methylpyridin-2-yl)acetamide ( 19.0 g, 0.126 mol) and water ( 190 mL). The reaction mixture was stirred at 75 °C and to the same flask, potassium permanganate (99.9 g, 0.632 mol) was added portion wise, while maintaining internal temperature at 75 °C. The reaction mixture was stirred at 75 °C for 3 h. The reaction mixture was cooled to room temperature and filtered through a pad of celite. The filtrate was concentrated under reduced pressure to get the residue. The residue was dissolved in methanolic HC1 (285 mL). The reaction mixture was stirred at reflux temperature for 24 h. The volatiles were removed under reduced pressure to get the residue. The residue was partitioned between ethyl acetate and aqueous sodium bicarbonate. The organic layer was separated, washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to get the title compound [ 11.5 g, 60 %]. 1H NMR (300 MHz, DMSO-J₆): δ 7.54 (t, = 7.2 Hz, 1H), 7.19 (d, = 7.2 Hz, 1H), 6.67 (d, = 8.4 Hz, 1H), 6.31 (brs, 2H), 3.79 (s, 3H); LC-MS: 153.2 [M+H]⁺.

Step iii: methyl 6-amino-3-bromopicolinate

To a 100 mL round bottom flask, were added methyl 6-aminopicolinate (6 g, 0.0394 mol), sodium carbonate (2.64 g, 0.0248 mol) and acetic acid (300 mL). The reaction mixture was cooled to 0 - 5 °C. To the same flask, bromine (2 mL, 0.039 mol) was slowly added. The reaction mixture was stirred at room temperature for 5 h. The volatiles were evaporated under reduced pressure to get the residue. The residue was neutralized with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was separated, washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to get the crude product. The crude product was purified by column chromatography using 60 - 120 silica gel and 30 % ethyl acetate in hexane to get the title compound [1 g, 11 %]. ^!H NMR (400 MHZ, CDC1₃): δ 7.63 (d, / = 8.8 Hz, 1H), 6.51 (d, = 8.8 Hz, 1H), 4.80 (brs, 2H), 3.94 (s, 3H); LC-MS: 232.8 [M+2H]⁺.

Step iv: methyl 6-amino-3-(3-fluorophenyl)picolinate

To a 25 mL round bottom flask, were added methyl 6-amino-3-bromopicolinate (1 g, 0.0043 mol), 3-fluorophenylboronic acid (0.72 g, 0.0052 mol), potassium carbonate (1.52 g, 0.011 mol), 1,4-dioxane (20 mL) and water (4 mL). The reaction mixture was degassed with nitrogen for 5 min. To the same flask, bis(triphenylphosphine)palladium(II) dichloride (0.14 g, 0.00022 mol) was added. The reaction mixture was again degassed with nitrogen for 5 min_. The reaction mixture was stirred at 90 °C for 2 h. The volatiles were evaporated under reduced pressure to get the residue. The residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to get the crude product. The crude product was purified by flash column chromatography using 20 - 40 % ethyl acetate in hexane to obtain the title compound [0.6 g, 57 %]. ^!H NMR (CDC1₃, 400 MHz): δ 7.68-7.63 (m, 1H), 7.48 (d, = 8.8 Hz, 1H), 7.36-7.31 (m, 1H), 7.05-6.97 (m, 2H), 6.67 (d, = Hz, 1H), 4.79 (brs, 2H), 3.72 (s, 3H); LC-MS: 247.1 [M+H]⁺.

Step v: 6-amino-3-(3-fluorophenyl)picolinic acid

To a 50 mL round bottom flask, were added methyl 6-amino-3-(3-fluorophenyl)picolinate (0.6 g, 2.43 mmol) and ethanol (10 ml). To the same flask, LiOH.H₂0 (0.43 g, 24.3 mmol) in water (2 mL) was added. The reaction mixture was stirred at room temperature for 2 h. The volatiles were evaporated under reduced pressure to get the residue. The residue was dissolved in 10 mL of water and acidified with aqueous citric acid to get the precipitate. The precipitate was collected by filtration and dried under vacuum to get the title compound [0.37 g, 60 %]. LC-MS: 233.1 [M+H]⁺.

Step vi: 6-amino-3-(3-fluorophenyl)-N-methoxy-N-methylpicolinamide

To a 50 mL round bottom flask, were added 6-amino-3-(3-fluorophenyl)picolinic acid (0.37 g, 1.59 mmol), N, 0-dimethylhydroxyamine hydrochloride (0.18 g, 1.91 mmol), DMF (10 mL), EDCI.HC1 (0.54 g, 3.98 mmol), HOBt (0.46 g, 2.39 mmol) and Et₃N (0.67 mL, 4.78 mmol). The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was quenched with aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was separated, washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to get the crude product. The crude product was purified by flash column chromatography using 30 % ethyl acetate in hexane to get the title compound [0.11 g, 26 %]. LC-MS: 275.9 [M+H]⁺.

Step vii: (6-amino-3-(3-fluorophenyl)pyridin-2-yl)(4-fluorophenyl)methanone

To a 50 mL round bottom flask, were added 6-amino-3-(3-fluorophenyl)-N-methoxy-N- methylpicolinamide (0.1 g, 0.36 mmol) and anhydrous tetrahydrofuran (10 mL). The reaction mixture was cooled to 0 °C. To the same flask, 1.0 M 4-fluorophenylmagnesium bromide in diethyl ether (1.44 mL, 1.44 mmol) was added at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 0.5 h. The reaction mixture was quenched with aqueous ammonium chloride and extracted with ethyl acetate. The combined organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to get the crude product. The residue was purified by column chromatography using 60 - 120 silica gel and 10 % ethyl acetate in hexane to get the title compound [0.04 g, 36 %]. LC-MS: 311.4 [M+H]⁺.

Step viii: 2-(4-(ethylsulfonyl)phenyl)-N-(6-(4-fluorobenzoyl)-5-(3-fluorophenyl)pyridin-2-yl) acetamide

To a 50 mL round bottom flask, were added (6-amino-3-(3-fluorophenyl)pyridin-2-yl)(4- fluorophenyl)methanone (0.04 g, 0.129 mmol), 2-(4-(ethylsulfonyl)phenyl)acetic acid (0.036 g, 0.154 mmol) and DCM (5 mL). To the same flask, T₃P (50 % in EtOAc, 0.333 mL, 0.516 mmol) and Et₃N (0.054 mL, 0.387 mmol) were added. The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was diluted DCM and washed with water. The organic layer was separated, washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to get the crude product. The crude product was purified by preparative thin layer chromatography using 40 % ethyl acetate in hexane to get the title compound [0.016 g, 24 %]. *H NMR (400 MHz, CDC1₃): δ 11.19 (s, 1H), 8.33 (d, = 8.8 Hz, 1H), 8.07 (d, = 8.4 Hz, 1H), 7.86-7.84 (m, 5H), 7.62 (d, = 8.0 Hz, 1H), 7.34-7.33 (m, 3H), 7.14-7.12 (m, 2H), 7.09 (d, = 7.6 Hz, 1H ), 3.94 (s, 2H), 3.36 (q, ' = 7.2 Hz, J" = 14.8 Hz, 2H), 1.16 (t, 7 = 7.2 Hz, 3H); LC-MS: 521.1 [M+H]⁺.

All the compounds listed in table 3 were prepared by following similar procedure as depicted in Example 32 and Scheme D, using appropriate variations in reactants, reagents, solvents and reaction conditions. Table 3

38 503.5

F

39 521.3

40 519.4

41 537.1

CI

42 553.0

CI

Example 44: Synthesis of N-(5-(4-chlorophenyl)-6-(morpholine-4-carbonyl)pyridin-2-yl)-2- (4-(ethylsulfonyl)phenyl)acetamide

Example 44 Reagents and conditions: i) Morpholine, propylphosphonic anhydride solution >50 wt. % in ethyl acetate , triethylamine, dichloromethane, room temperature, 3 h; ii) 2-(4-(ethylsulfonyl) phenyl)acetic acid, EDCI.HC1, HOBt, DCM, room temperature, 12 h.

Step i: (6-amino-3-(4-chlorophenyl)pyridin-2-yl)(morpholino)methanone

To a 25 mL round bottom flask, were added 6-amino-3-(4-chlorophenyl)picolinic acid [Synthesized according to Scheme D] (0.1 g, 0.0004 mol), morpholine (0.042 g, 0.00048 mol) and dichloro methane (5 mL). To the same flask, propylphosphonic anhydride solution >50 wt. % in ethyl acetate (0.642 g, 0.002 mol) and triethylamine (0.17 mL, 0.0012 mol) were added. The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with dichloromethane and washed with water. The organic layer was separated, washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to get the crude product. The crude product was purified by column chromatography using 60 - 120 silica gel and 5 % methanol in chloroform to get the title compound [0.1 g, 78 %]; LC-MS: 318.2 [M+H]⁺.

Step ii: N-(5-(4-chlorophenyl)-6-(morpholine-4-carbonyl)pyridin-2-yl)-2-(4-(ethylsulfonyl) phenvDacetamide

To a 25 mL round bottom flask, were added (6-amino-3-(4-chlorophenyl)pyridin-2-yl)

(morpholino)methanone (0.1 g, 0.00032 mol), 2-(4-(ethylsulfonyl) phenyl)acetic acid (0.086 g, 0.00038 mol) and dichloromethane (5 mL). To the same flask, EDCI.HC1 (0.09 g, 0.00048 mol) and HOBt (0.064 g, 0.00048 mol) were added. The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with dichloromethane and washed with water. The organic layer was separated, washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to get the crude product. The crude product was purified by column chromatography using 60 - 120 silica gel and 5 % methanol in chloroform followed by preparative high performance liquid chromatography using acetonitrile and methanol to get the title compound [0.04 g, 24 %]. ^!H NMR (300 MHZ, CDC1₃): δ 8.32 (d, = 8.4 Hz, 1H), 8.09 (brs, 1H), 7.94 (d, = 8.4 Hz, 2H), 7.79 (d, = 8.7 Hz, 1H), 7.56 (d, = 8.4 Hz, 2H), 7.44 - 7.37 (m, 4H), 3.84 (s, 2H), 3.62-3.59 (m, 2H), 3.51-3.48 (m, 2H), 3.17 (q, ' = 7.5 Hz, J" = 15.0 Hz, 2H), 3.05-3.04 (m, 2H), 2.88-2.85 (m, 2H), 1.33 (t, = 7.5 Hz, 3H); LC- MS: 528.1 [M+H]⁺.

Example 51: Synthesis of N-(6-benzoyl-5-(4-chlorophenyl)pyridin-2-yl)-2-(4-(ethyl sulfonyl)phenyl)-N-methylacetamide

Synthesized according to

Scheme D

Example 51

Reagents and conditions: i) Di-teri-butyl dicarbonate, 60 % sodium hydride in mineral oil, THF, 0 °C - room temperature, 3 h; ii) methyl iodide, 60 % sodium hydride in mineral oil, THF, room temperature, 2 h; iii) trifluoro acetic acid, dichlorome thane, 0 °C - room temperature, 16 h; iv) 2-(4-(ethylsulfonyl)phenyl)acetic acid, propylphosphonic anhydride solution >50 wt. % in ethyl acetate , triethyl amine, dichloromethane, room temperature,2 h.

Step i: tert -butyl (6-benzoyl-5-(4-chlorophenyl)pyridin-2-yl)carbamate

To a 50 mL round bottom flask, were added (6-amino-3-(4-chlorophenyl)pyridin-2- yl)(phenyl)methanone [Synthesized according to Scheme D] (0.2 g, 0.0065 mol) and THF (20 mL). The reaction mixture was cooled to 0 - 5 °C. To the same flask, 60 % sodium hydride in mineral oil (0.0187 g, 0.00078 mol) was added at 0 - 5 °C and the reaction mixture was stirred at 0 - 5 °C for 5 min. To the same flask, di-tert-buty\ dicarbonate (0.141 g, 0.00065 mol) was added. The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was separated, washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to get the crude product. The crude product was purified by column chromatography using 60 - 120 silica gel and 3 - 5 % ethyl acetate in hexane to get the title compound [0.15 g, 57 %]. 1H NMR (300 MHz, CDC1₃): δ 7.86 - 7.82 (m, 3H), 7.59 - 7.56 (m, 2H), 7.44 - 7.31 (m, 2H), 7.31 - 7.28 (m, 2H), 7.24 - 7.21 (m, 2H), 1.44 (s, 9H).

Step ii: tert-butyl (6-benzoyl-5-(4-chlorophenyl)pyridin-2-yl)(methyl)carbamate

To a 50 mL round bottom flask, were added tert-butyl (6-benzoyl-5-(4-chlorophenyl) pyridin-2-yl)carbamate (0.15 g, 0.00037 mol) and THF (10 mL). To the same flask, 60 % sodium hydride in mineral oil (0.0105 g, 0.00044 mol) was added. The reaction mixture was stirred at room temperature for 5 min and methyl iodide (0.0783 g, 0.00056 mol) was added. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was separated, washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to get the title compound [0.11 g, 71 %]. ^!H NMR (300 MHz, CDC1₃): δ 8.02 - 7.99 (m, 1H), 7.83 - 7.80 (m, 2H), 7.74 - 7.71 (m, 1H), 7.57 - 7.52 (m, 1H), 7.43 - 7.38 (m, 2H), 7.24 - 7.19 (m, 4H), 3.37 (s, 3H), 1.55 (s, 9H); LC-MS: 323.1 [M-Boc]⁺.

Step iii: (3-(4-chlorophenyl)-6-(methylamino)pyridin-2-yl)(phenyl)methanone

To a 50 mL round bottom flask, were added tert-butyl (6-benzoyl-5-(4-chlorophenyl) pyridin-2-yl)(methyl)carbamate (0.1 g, 0.00024 mol) and dichloromethane (10 mL). The reaction mixture was cooled to 0 - 5 °C. To the same flask, trifluoroacetic acid (0.135 g, 0.0022 mol) was added. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with dichloromethane and washed with water. The organic layer was separated, washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to get the title compound [0.07 g, 82 %]. LC-MS: 323.3 [M+H]⁺.

Step iv: N-(6-benzoyl-5-(4-chlorophenyl)pyridin-2-yl)-2-(4-(ethylsulfonyl)phenyl)-N-methyl acetamide

To a 25 mL round bottom flask, were added (3-(4-chlorophenyl)-6-(methylamino) pyridin-2-yl)(phenyl)methanone (0.06 g, 0.00019 mol), 2-(4-(ethylsulfonyl)phenyl)acetic acid (0.085 g, 0.00038 mol) and dichloromethane (10 mL). The reaction mixture was cooled to 0 - 5 °C. To the same flask, propylphosphonic anhydride solution >50 wt. % in ethyl acetate (0.354 g, 0.00057 mol) and triethylamine (0.037 g, 0.00038 mol) were added. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with dichloromethane and washed with water. The organic layer was separated, washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to get the crude product. The crude product was purified by preparative thin layer chromatography using 50 % ethyl acetate in hexane to get the title compound [0.006 g, 6 %]. 1H NMR (400 MHz, CDC1₃): δ 7.86 (d, = 8.4 Hz, 1H), 7.77-7.75 (m, 4H), 7.59-7.53 (m, 2H), 7.43-7.36 (m, 4H), 7.31-7.23 (m, 4H), 3.94(s, 2H), 3.48 (s, 3H), 3.10 (q, ' = 7.2 Hz, " = 14.8 Hz, 2H), 1.28 (t, = 7.2 Hz, 3H); LC-MS: 533.0 [M+H]⁺.

Example 53: Synthesis of N-(5-(4-chlorophenyl)-6-phenylpyridin-2-yl)-2-(4-(ethylsulfonyl) phenyl)acetamide

Example 53 Reagents and conditions: i) N-Bromosuccinimide, N,N-dimethylformamide, room temperature, 12 h; ii) phenylboronic acid, tetrakis(triphenylphosphine)palladium(0), sodium carbonate, toluene, methanol, water, 110 °C, 12 h ; iii) 4-chlorophenylboronic acid, bis(triphenylphosphine)palladium(II) dichloride, potassium carbonate, 1,4-dioxane, water, 110 °C, 12 h; iv) 2-(4-(ethylsulfonyl)phenyl)acetic acid, propylphosphonic anhydride solution >50 wt. % in ethyl acetate, triethylamine, dichloromethane, room temperature, 1 h.

Step i: 5,6-dibromopyridin-2-amine

To a 50 mL round bottom flask, was added 2-amino-6-bromopyridine (1 g, 0.0058 mol) followed by N,N-dimethylformamide (25 mL). To the same flask, N-bromosuccinimide (1.03 g, 0.0058 mol) was added. The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with water to get the solid. The solid was collected by filtration and dried under vacuum to get the title compound [1 g, 69 %]. 1H NMR (300 MHz, CDC1₃): δ 7.54- 7.52 (d, = 8.4 Hz, 1H), 6.35(d, = 8.4 Hz, 1H), 4.65 (brs, 2H).

Step ii: 5-bromo-6-phenylpyridin-2-amine

To a 50 mL round bottom flask, were added 5,6-dibromopyridin-2-amine (0.5 g, 0.0019 mol), phenylboronic acid (0.24 g, 0.0019 mol), sodium carbonate (0.53 g, 0.0049 mol), toluene (9 mL), methanol (1 mL) and water (5 mL). The reaction mixture was degassed with argon for 5 min. To the same flask, tetrakis(triphenylphosphine)palladium(0) (0.069 g, 0.000059 mol) was added. The reaction mixture was again degassed with argon for 5 min. The reaction mixture was stirred at 110 °C for 12 h. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was separated, washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to get the crude product. The crude product was purified by column chromatography using 60 - 120 silica gel and 0 - 30 % ethyl acetate in hexane to get the title compound [0.4 g, 81 %]. ^!H NMR (300 MHz, CDC1₃): δ 7.67- 7.59 (m, 3H), 7.46-7.38 (m, 3H), 6.39(d, = 8.4 Hz, 1H), 4.54 (brs, 2H); LC-MS: 251.0 [M+2H]⁺.

Step iii: 5-(4-chlorophenyl)-6-phenylpyridin-2-amine

To a 50 mL round bottom flask, were added 5-bromo-6-phenylpyridin-2-amine (0.2 g, 0.0008 mol), 4-chlorophenylboronic acid (0.138 g, 0.00088 mol), potassium carbonate (0.277 g, 0.002 mol), 1,4-dioxane (7 mL) and water (3 mL). The reaction mixture was degassed with argon for 5 min. To the same flask, bis(triphenylphosphine)palladium(II) dichloride (0.028 g, 0.00004 mol) was added. The reaction mixture was again degassed with argon for 5 min. The reaction mixture was stirred at 110 °C for 12 h. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was separated, washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to get the crude product. The crude product was purified by column chromatography using 60 - 120 silica gel and 0 - 30 % ethyl acetate in hexane to get the title compound [0.15 g, 68 %]. 1H NMR (300 MHz, CDCls): δ 7.48 (d, = 8.4 Hz, 1H), 7.31-7.15 (m, 7H), 7.04 - 7.01 (m, 2H), 6.56 (d, = 8.7 Hz, 1H), 4.57 (s, 2H); LC-MS: 281.1 [M+H]⁺.

Step iv: N-(5-(4-chlorophenyl)-6-phenylpyridin-2-yl)-2-(4-(ethylsulfonyl)phenyl)acetamide

To a 25 mL round bottom flask, were added 5-(4-chlorophenyl)-6-phenylpyridin-2-amine (0.15 g, 0.00053 mol), 2-(4-(ethylsulfonyl)phenyl)acetic acid (0.16 g, 0.00069 mol) and dichloromethane (20 mL). To the same flask, propylphosphonic anhydride solution >50 wt. % in ethyl acetate (0.84 g, 0.00265 mol) and triethylamine (0.16 g, 0.00159 mol) were added. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with dichloromethane and washed with water. The organic layer was separated, washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to get the crude product. The crude product was purified by preparative thin layer chromatography using 20 % ethyl acetate in hexane to get the title compound [0.06 g, 23 %]. *H NMR (400 MHz, CDCI₃): δ 8.24 - 8.22 (m, 2H), 7.93 (d, = 7.6 Hz, 2H), 7.76 (d, = 8.4 Hz, 1H), 7.57 (d, = 8.0 Hz, 2H), 7.29-7.28 (m, 5H), 7.25 (d, = 8.4 Hz, 2H), 7.09 (d, = 8.4 Hz, 2H), 3.82(s, 2H), 3.16 (q, ' = 7.2 Hz, " = 14.8 Hz, 2H), 1.32 (t, = 7.2 Hz, 3H); LC-MS: 491.2 [M+H]⁺.

Example 54: Synthesis of N-(5-(4-chlorophenyl)-6-phenoxypyridin-2-yl)-2-(4-(ethyl sulfonyl)phenyl)acetamide

xamp e

Reagents and conditions: i) N-Bromosuccinimide, chloroform, room temperature, 16 h; ii) phenol, potassium carbonate, NN-dimethylformamide, 150 °C, 12 h; iii) 4-chlorophenylboronic acid, bis(triphenylphosphine)palladium(II) dichloride, potassium carbonate, 1,4-dioxane, water, 95 °C, 3 h; iv) 2-(4-(ethylsulfonyl)phenyl)acetic acid, propylphosphonic anhydride solution > 50 wt. % in ethyl acetate , triethyl amine, dichloromethane, room temperature, 2 h.

Step i: 5-bromo-6-fluoropyridin-2-amine

To a 250 mL round bottom flask, were added 6-fluoro-2-aminopyridine (3 g, 0.0267 mol) and chloroform (90 mL). To the same flask, N-bromosuccinimide (5 g, 0.028 mol) was added. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with chloroform and washed with water. The organic layer was separated, washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to get the title compound [2 g, 40 %]. *H NMR (300 MHz, CDC1₃): δ 7.62 (t, = 9.0 Hz, 1H), 6.27 (m, 1H), 4.58 (s, 2H); LC-MS: 193.1 [M+2H]⁺.

Step ii: 5-bromo-6-phenoxypyridin-2-amine

To a 25 mL round bottom flask, were added 5-bromo-6-fluoropyridin-2-amine (0.5 g, 0.0026 mol), phenol (0.37 g, 0.0039 mol) sodium carbonate (0.55 g, 0.0052 mol) and N,N- dimethylformamide ( 10 mL). The reaction mixture was stirred at 150 °C for 12 h. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was separated, washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to get the crude product. The crude product was purified by flash column chromatography using 0 - 1 % methanol in chloroform to get the title compound [0.2 g, 29 %]. ^!H NMR (300 MHz, CDC1₃): δ 7.61 (d, = 8.4 Hz, 1H), 7.39 (t, = 7.5 Hz, 2H), 7.19-7.09 (m, 3H), 6.12 (d, = 8.7 Hz, 1H), 4.30 (s, 2H); LC-MS: 267.0 [M+2H]⁺. Step iii: 5-(4-chlorophenyl)-6-phenoxypyridin-2-amine

To a 50 mL round bottom flask, were added 5-bromo-6-phenoxypyridin-2-amine (0.15 g, 0.00056 mol), 4-chlorophenylboronic acid (0.133 g, 0.00085 mol), potassium carbonate (0.156 g, 0.001 12 mol), 1 ,4-dioxane ( 15 mL) and water (5 mL). The reaction mixture was degassed with Argon for 5 min. To the same flask, bis(triphenylphosphine)palladium(II) dichloride (0.02 g, 0.000028 mol) was added. The reaction mixture was again degassed with Argon for 5 min. The reaction mixture was stirred at 95 °C for 3 h. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was separated, washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to get the crude product. The crude product was purified by flash column chromatography using 0 - 1 % methanol in chloroform to get the title compound [0.1 g, 60 %]. LC-MS: 297.0 [M+H]⁺.

Step iv: N-(5-(4-chlorophenyl)-6-phenoxypyridin-2-yl)-2-(4-(ethylsulfonyl)phenyl)acetarnide

To a 25 mL round bottom flask, were added (5-(4-chlorophenyl)-6-phenoxypyridin-2- amine (0.1 g, 0.00034 mol), 2-(4-(ethylsulfonyl)phenyl)acetic acid (0.12 g, 0.00051 mol) and dichloromethane (10 mL). To the same flask, propylphosphonic anhydride solution >50 wt. % in ethyl acetate (0.44 g, 0.00067 mol) and triethylamine (0.085 g, 0.00084 mol) were added. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with dichloromethane and washed with water. The organic layer was separated, washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to get the crude product. The crude product was purified by flash column chromatography using 0 - 50 % ethyl acetate in hexane to get the title compound [0.05 g, 19 %]. *H NMR (400 MHz, DMSO-J₆): δ 10.7 (s, 1H), 8.00-7.94 (m, 2H), 7.86 (d, = 8.4 Hz, 2H), 7.68 (d, = 8.4 Hz, 2H), 7.59 (d, = 8.4 Hz, 2H), 7.53 (d, = 8.8 Hz, 2H), 7.44 (t, = 8.4 Hz, 2H), 7.21-7.14 (m, 3H), 3.87 (s, 2H), 3.32 (q, ' = 6.8 Hz, J" = 14.4 Hz, 2H), 1.13 (t, = 7.6 Hz, 3H); LC-MS: 506.9 [M+H]⁺. Biology:

Expression and Purification of RORy

Gene corresponding to the ligand binding domain of RORy (247-497 amino acids) was sub-cloned into pGEX4Tl vector. Transformants of E.coli BL21 (DE3) containing pGEX4Tl- RORy (247-497) were grown to an OD of 0.8 at 37 °C and induced with 0.5 mM isopropyl- β-D- thiogalactopyranoside (IPTG) for 18 hours at 18 °C. Cells were harvested and resuspended in 20 mM Tris- HCl (pH 8.5), 0.3 M NaCl, 10% Glycerol, 2 mM β -Me (β -Mercaptoethanol), 2 mM CHAPS, protease inhibitors, 0.6 mM PMSF and Lysozyme. Supernatant of lysate was passed through glutathione sepharose 4B affinity beads (GE health care) pre-equilibrated with 20 mM Tris- HCl (pH 8.5), 0.3 M NaCl, 10 % Glycerol, 2 mM β -Me. RORy was eluted using a gradient of reduced glutathione (3 - 20 mM). Fractions containing RORy protein were pooled, concentrated and passed through Superdex 75 gel filtration (GE health care) column equilibrated with 20 mM Na-phosphate pH 8.0, 0.2 M NaCl, 10 % glycerol. The peak fractions from gel filtration column were pooled and stored at -80 °C for Binding assay.

In-vitro Biochemical Data of trisubstituted heterocyclic derivatives:

ROR gamma radioligand assay

ROR gamma radioligand binding was performed using ³H 25- Hydroxycholesterol in a competitive displacement assay using dextran charcoal method. Using 5 nM ³H 25- Hydroxycholesterol with 300 ng RORy LBD (in house expressed in E.coli) along with the compound were incubated in the binding buffer (50 mM HEPES, pH 7.5, 150 mM NaCl, 0.01 % BSA and 5 mM MgCl₂) for 30 min at room temperature. Then dextran-charcoal mixture (0.5 % charcoal: 0.05 % dextran) was used for separation and the supernatant was read on the Perkin Elmer Trilux Microbeta counter. Dose response curves were generated for 10 compound concentrations using GraphPad Prism software Version 5 (San Diego, California, USA) using non linear regression curve fit for sigmoidal dose response (variable slope).

ROR gamma cell based reporter gene assay protocol

HEK293 cells are grown in DMEM media with 10% FBS. Cells are seeded in 96 well plates at a density of 20000 cells/well and are allowed to attach overnight. On the next day, cells are starved in low serum media for 1 h before they are co-transfected with GAL4-RORy LBD fusion construct and the Gal4-UAS Luciferase reporter construct for 3 h followed by recovery in complete media for 1 h. After recovery, test compounds are added to the cells and incubated for 48 h. Bright Glo reagent is added to measure luminescence. Inhibition of reporter activity by test compound is calculated using luminescence reading from DMSO control wells.

The compounds were screened at 10 μΜ concentrations and the results are summarized in the table below along with the IC₅₀ (nM) details for selected examples; wherein "A" refers to an IC₅₀ value of less than or equal to 100 nM, "B" refers to IC₅₀ value in range of 100.01 to 250 nM, "C" refers to IC₅₀ value in range of 250.01 to 500 nM and "D" refers to IC₅₀ value of greater than 500 nM.

% inhibition ICso (nM) % inhibition ICso (nM) at 10 μΜ at 10 μΜ

92 A 45 D

78 D 60 -

48 - 6 -

7 - - -

64 - 51 -

83 - 40 D

0 - 30.6 -

0 - 25.4 -

66 - 38.3 -

73 D 4.0 -

40 - - -

3 - 19.5 -

0 - - -

100 B 32.3 -

79 D -4.8 -

98 C 60.4 -

101 C 4.6 -

88 C 50.4 -

90 D -0.4 -

68 - 33.7 -

0 - 35.3 - 57 - 81.5 D

58 - - D

77 - 57 D

91 - 48 -

100 C -266.6 -

75 B 73.5 D

51 - -82.9 -

99 B 62 -

68 - 61 -

0 - 38.5 -

87 D - -

83 D 54.9 -

100 B 87.1 B

91 B 84.3 D

94 D 71.9 -

72 C 80.6 B

86 A 85.8 D

77 A 81.2 D

- - 73.2 D

- - 39 -

- - 68.1 D

- - 40.4 -

- - 74.3 - - - 45.8 D

- - 80.2 C

- - 50.8 -

- - 17.2 -

- - 58.3 -

- - 0.15 -

- - 80.3 -

Claims

We Claim:

1. A compound of formula (I):

(I)

Ring A is aryl or heterocyclyl;

X is CH or N;

R₇;

R₄ is selected from alkyl, hydroxyalkyl, haloalkyl or alkylamino;

'L' is selected from -0-, -C(O)- , -CH(OR₅)- or absent;

R₇ at each occurrence is independently selected from halo or alkyl;

R_a and R are independently selected from hydrogen or alkyl;

m and n are independently selected from 1 or 2.

2. The compound according to claim 1 is a compound of formula (IA)

(IA)

Y is CH or N;

Ri, R₂, R₃, L, X and 'm' are same as defined in claim (I).

3. The compound according to claim 1 is a compound of formula (IB)

(IB)

Y is CH or N;

Ri, R₂, R3, L and 'm' are same as defined in claim (I).

4. The compound according to claim 1 is a compound of formula (IC)

(IC)

Y is CH or N;

Ri, R₂, R₃, L and 'm' are same as defined in claim (I).

5. The compound according to claim 1 is a compound of formula (ID)

p is 0, 1 or 2;

R₃, R₆, R₇, m, L and X are same as defined in claim (I).

6. The compound according to one of claims 1, 2 or 5, wherein X is CH.

7. The compound according to one of claims 1, 2 or 5, wherein X is N.

8. The compound according to any one of claims 1 to 7, wherein R₃ is -S0₂Et.

9. The compound according to any one of claims 1 to 8, wherein L is -C(O)-.

10. The compound according to any one of claims 1 to 8, wherein L is absent.

11. The compound according to claim 5, wherein R₆ is halo.

12. The compound according to claim 5, wherein R₇ is alkyl.

13. The compound according to claim 5 or 11, wherein R₇ is halo.

14.

15. The compound according to claim 1, wherein R₂ is cyclopropyl, cyclopentyl, phenyl,

16. The compound according to claim 1, wherein each occurrence of R₃ is independently hydrogen, -S0₂CH₂CH₃, -C(0)CH₂CH₃, -C(0)NH(CH₃), -S(0)₂CH₂CH₂OH, -CN, - S(0)CH₂CH₃, -S(0)₂CH₂CF₃ or -S(0)₂NH(CH₂CH₃).

17. A compound selected from the group consisting of

(ethylsulfonyl)phenyl)acetamide;

N-(4-benzoyl-5-phenylpyrimidin-2-yl)-2-(4-propionylphenyl)acetamide;

4-(2-((4-benzoyl-5-phenylpyrimidin-2-yl)amino)-2-oxoethyl)-N- methylbenzamide ;

4-(2-((4-(4-fluorobenzoyl)-5-(4-fluorophenyl)pyrimidin-2-yl)amino)-2- oxoethyl)-N-methylbenzamide;

2-(2-fluoro-4-((2-hydroxyethyl)sulfonyl)phenyl)-N-(4-(4-fluorobenzoyl)-5- phenylpyrimidin-2-yl)acetamide;

2-(4-(ethylsulfonyl)phenyl)-N-(4-(3-fluorobenzoyl)-5-(4- fluorophenyl)pyrimidin-2-yl)acetamide;

N-(4-(4-fluorobenzoyl)-5-(4-fluorophenyl)pyrimidin-2-yl)-2-(4-((2- hydroxyethyl)sulfonyl)phenyl)acetamide;

2-(4-(ethylsulfinyl)phenyl)-N-(4-(4-fluorobenzoyl)-5-(4- fluorophenyl)pyrimidin-2-yl)acetamide;

N-(4-(4-fluorobenzoyl)-5-(4-fluorophenyl)pyrimidin-2-yl)-2-(pyridin-4- yl)acetamide;

N-(5-(3-chlorophenyl)-4-(3-fluorobenzoyl)pyrimidin-2-yl)-2-(4- (ethylsulfonyl)phenyl)acetamide;

N-(4-(3-chlorobenzoyl)-5-(3-chlorophenyl)pyrimidin-2-yl)-2-(4- (ethylsulfonyl)phenyl)acetamide; N-(4-(3-chlorobenzoyl)-5-(2-fluorophenyl)pyrimidin-2-yl)-2-(4- (ethylsulfonyl)phenyl)acetamide;

N-(4-(3-chlorobenzoyl)-5-(2-fluorophenyl)pyrimidin-2-yl)-2-(4-((2,2,2- trifluoroethyl)sulfonyl)phenyl)acetamide;

N-(4-(3-chlorobenzoyl)-5-(2-fluorophenyl)pyrimidin-2-yl)-2-(4-(N- ethylsulfamoyl)phenyl)acetamide ;

2-(4-(ethylsulfonyl)phenyl)-N-(4-(4-fluorophenyl)-5-(pyridin-3-yl)pyrimidin- 2-yl)acetamide;

N-(4,5-bis(4-fluorophenyl)pyrimidin-2-yl)-2-(4- (ethylsulfonyl)phenyl)acetamide;

2-(4-(ethylsulfonyl)phenyl)-N-(4-(4-fluorophenyl)-5-(6-fluoropyridin-3- yl)pyrimidin-2-yl)acetamide ;

2-(4-(ethylsulfonyl)phenyl)-N-(6-(4-fluorobenzoyl)-5-(3- fluorophenyl)pyridin-2-yl)acetamide;

N-(6-(cyclopropanecarbonyl)-5-(3-fluorophenyl)pyridin-2-yl)-2-(4- (ethylsulfonyl)phenyl)acetamide;

N-(6-(cyclopropanecarbonyl)-5-(3-fluorophenyl)pyridin-2-yl)-2-(4- propionylphenyl)acetamide;

2-(4-(ethylsulfonyl)phenyl)-N-(6'-fluoro-2-(4-fluorobenzoyl)-[3,3'-bipyridin]- 6-yl)acetamide;

2-(4-(ethylsulfonyl)phenyl)-N-(6-(4-fluorobenzoyl)-5-(furan-3-yl)pyridin-2- yl)acetamide; N-(6-benzoyl-5-(4-chlorophenyl)pyridin-2-yl)-2-(4- (ethylsulfonyl)phenyl)acetamide;

N-(6-benzoyl-5-(4-fluorophenyl)pyridin-2-yl)-2-(4- (ethylsulfonyl)phenyl)acetamide;

2-(4-(ethylsulfonyl)phenyl)-N-(6-(4-fluorobenzoyl)-5-(4- fluorophenyl)pyridin-2-yl)acetamide;

N-(6-benzoyl-5-(2-chlorophenyl)pyridin-2-yl)-2-(4- (ethylsulfonyl)phenyl)acetamide;

N-(5-(3-chlorophenyl)-6-(3-fluorobenzoyl)pyridin-2-yl)-2-(4- (ethylsulfonyl)phenyl)acetamide;

N-(6-(3-chlorobenzoyl)-5-(3-chlorophenyl)pyridin-2-yl)-2-(4- (ethylsulfonyl)phenyl)acetamide;

N-(5-(4-chlorophenyl)-6-(4-fluorobenzoyl)pyridin-2-yl)-2-(4- (ethylsulfonyl)phenyl)acetamide;

N-(5-(4-chlorophenyl)-6-(morpholine-4-carbonyl)pyridin-2-yl)-2-(4- (ethylsulfonyl)phenyl)acetamide;

N-(5-(4-chlorophenyl)-6-(hydroxy(phenyl)methyl)pyridin-2-yl)-2-(4- (ethylsulfonyl)phenyl)acetamide;

N-(6-(4-chlorobenzoyl)-5-(2-chlorophenyl)pyridin-2-yl)-2-(4- (ethylsulfonyl)phenyl)acetamide;

N-(6-benzoyl-5-phenylpyridin-2-yl)-2-(4-(ethylsulfonyl)phenyl)acetamide;

N-(5-(3-chlorophenyl)-6-(4-fluorobenzoyl)pyridin-2-yl)-2-(4- (ethylsulfonyl)phenyl)acetamide;

N-(6-benzoyl-5-(3,4-dichlorophenyl)pyridin-2-yl)-2-(4- (ethylsulfonyl)phenyl)acetamide;

N-(6-benzoyl-5-(4-(tert-butyl)phenyl)pyridin-2-yl)-2-(4- (ethylsulfonyl)phenyl)acetamide;

N-(6-benzoyl-5-(4-chlorophenyl)pyridin-2-yl)-2-(4-(ethylsulfonyl)phenyl)-N-

51

methylacetamide ;

N-(6-benzoyl-5-(4-(trifluoromethyl)phenyl)pyridin-2-yl)-2-(4-

52

(ethylsulfonyl)phenyl)acetamide;

N-(5-(4-chlorophenyl)-6-phenylpyridin-2-yl)-2-(4-

53

(ethylsulfonyl)phenyl)acetamide; and

N-(5-(4-chlorophenyl)-6-phenoxypyridin-2-yl)-2-(4-

54

(ethylsulfonyl)phenyl)acetamide; or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable stereoisomer thereof.

18. A pharmaceutical composition, comprising at least one compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable stereoisomer thereof, and a pharmaceutically acceptable carrier or excipient.

19. A compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable stereoisomer thereof, for use as a medicament.

20. A method of treating a RORy mediated disorder in a subject comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 17.

21. The method according to claim 20, wherein the disorder is an immune disorder or inflammatory disorder.

22. The method according to claim 21, wherein the disorder is rheumatoid arthritis, psoriasis, chronic graft-versus-host disease, acute graft-versus-host disease, Crohn's disease, inflammatory bowel disease, multiple sclerosis, systemic lupus erythematosus, Celiac Sprue, idiopathic thrombocytopenic thrombotic purpura, myasthenia gravis, Sjogren's syndrome, asthma, epidermal hyperplasia, scleroderma orulcerative colitis.

23. The method according to claim 21, wherein the disorder is cartilage inflammation, bone degradation, arthritis, juvenile arthritis, juvenile rheumatoid arthritis, pauciarticular juvenile rheumatoid arthritis, polyarticular juvenile rheumatoid arthritis, systemic onset juvenile rheumatoid arthritis, juvenile ankylosing spondylitis, juvenile enteropathic arthritis, juvenile reactive arthritis, juvenile Reter's Syndrome, SEA Syndrome, juvenile dermatomyositis, juvenile psoriatic arthritis, juvenile scleroderma, juvenile systemic lupus erythematosus, juvenile vasculitis, pauciarticular rheumatoid arthritis, polyarticular rheumatoid arthritis, systemic onset rheumatoid arthritis, ankylosing spondylitis, enteropathic arthritis, reactive arthritis, Reter's Syndrome, dermatomyositis, psoriatic arthritis, vasculitis, myolitis, polymyolitis, dermatomyolitis, osteoarthritis, polyarteritis nodossa, Wegener's granulomatosis, arteritis, polymyalgia rheumatica, sarcoidosis, sclerosis, primary biliary sclerosis, sclerosing cholangitis, dermatitis, atopic dermatitis, atherosclerosis, Still's disease, chronic obstructive pulmonary disease, Guillain-Barre disease, Type I diabetes mellitus, Graves' disease, Addison's disease, Raynaud's phenomenon, autoimmune hepatitis, psoriatic epidermal hyperplasia, plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, erythrodermic psoriasis, or an immune disorder associated with or arising from activity of pathogenic lymphocytes.

24. A method of reducing the amount of IL-17 and other effector cytokines of Thl7 cells in a subject, comprising administering to a subject an effective amount of a compound according to any one of claims 1-17 to reduce the amount of IL-17 in the subject.

25. The method according to any one of claims 20-24, wherein the subject is a human.