RELATED APPLICATIONS

This application claims the benefit of the Indian Provisional Application No. 201721012117 filed on April 4, 2017; which is hereby incorporated by reference in its entirety.

TECHNICAL FIELD

The present patent application is directed to substituted oxoazetidine compounds which may be useful as retinoid-related orphan receptor gamma t (RORyt) modulators.

BACKGROUND OF THE INVENTION

Retinoid-related orphan receptors (RORs) are transcription factors which belong to the steroid hormone nuclear receptor super family. The ROR family consists of three members, ROR alpha (RORα), ROR beta (RORβ) and ROR gamma (RORy), also known as NR1F1, NR1F2 and NR1F3 respectively (and 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 isoforms which differ only in their N-terminal A/B domain. Two isoforms of RORy, RORyl and RORyt (also known as RORy2) have been identified.

RORyt is a truncated form of RORy, lacking the first N-terminal 21 amino acids and is exclusively expressed in cells of the lymphoid lineage and embryonic lymphoid tissue inducers (Sun et al., Science, 2000, 288, 2369-2372; Eberl et al., Nat Immunol., 2004, 5: 64-73) in contrast to RORy which is expressed in multiple tissues (heart, brain, kidney, lung, liver and muscle).

RORyt has been identified as a key regulator of Thl7 cell differentiation. Thl7 cells are a subset of T helper cells which produce IL-17 and other proinflammatory cytokines and have been shown to have key functions in several mouse autoimmune disease models including experimental autoimmune encephalomyelitis (EAE) and collagen-induced arthritis (CIA). In addition, Thl7 cells have also been associated in the pathology of a variety of human inflammatory and autoimmune disorders including multiple sclerosis, rheumatoid arthritis, psoriasis, Crohn's disease and asthma (Jetten et al., Nucl. Recept. Signal, 2009, 7:e003; Manel et al., Nat. Immunol., 2008, 9, 641-649). The pathogenesis of chronic autoimmune diseases including multiple sclerosis and rheumatoid arthritis arises from the break in tolerance towards self-antigens and the development of auto-aggressive effector T cells infiltrating the target tissues. Studies have shown that Thl7 cells are one of the important drivers of the inflammatory process in tissue-specific autoimmunity (Steinman et al.,J . Exp. Med., 2008, 205: 1517-1522; Leung et al., Cell. Mol. Immunol., 2010 7: 182-189). 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., Annu. Rev. Immunol., 2009, 27:485-517) and RORyt has been shown to play a critical role in the pathogenic responses of Thl7 cells (Ivanov et al., Cell, 2006 126: 1121-1133). RORyt deficient mice have shown no Thl7 cells and also resulted in amelioration of EAE. The genetic disruption of RORy in a mouse colitis model also prevented colitis development (Buonocore et al., Nature, 2010, 464: 1371-1375). The role of RORyt in the pathogenesis of autoimmune or inflammatory diseases has been well documented in the literature. ( Jetten et al., Adv. Dev. Biol., 2006, 16:313-355; Meier et al. Immunity, 2007, 26:643-654; Aloisi et al., Nat. Rev. Immunol., 2006, 6:205-217; Jager et al., J. Immunol., 2009, 183:7169-7177; Serafmi et al., Brain Pathol, 2004, 14: 164-174; Magliozzi et al., Brain, 2007, 130: 1089-1104; Barnes et al., Nat. Rev. Immunol, 2008, 8: 183-192).

In addition, RORyt is also shown to play a crucial role in other non-Thl7 cells, such as mast cells (Hueber et al., J Immunol, 2010, 184: 3336-3340). RORyt expression and secretion of Thl7-type of cytokines has also been reported in NK T-cells (Eberl et al., Nat. Immunol, 2004, 5: 64-73) and gamma-delta T-cells (Sutton et al, Nat. Immunol, 2009, 3J_: 331-341 ; Louten et al., J Allergy Clin. Immunol, 2009, 123: 1004-1011), suggesting an important function for RORyt in these cells.

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

PCT publication numbers WO2012/139775, WO2012/027965, WO2012/028100, WO2012/100732, WO2012/100734, WO2012/064744, WO2013/171729 and WO 2015/008234 discloses heterocyclic compounds which are modulators of retinoid-related orphan receptor gamma (RORy) receptor activity.

In view of the above, a need exists for new therapeutic agents that modulate the activity of RORyt and thus will provide new methods for treating diseases or condition associated with the modulation of RORyt. The present application is directed to compounds that may be modulators of the RORyt receptor.

SUMMARY OF THE INVENTION

In one aspect, the present invention relates to a compound of formula (I)

stereoisomer, diastereoisomer, enantiomer or a pharmaceutically acceptable salt thereof, wherein

R ¹ is selected from C _1-8 alkyl and C _3-12 cycloalkyl;

R ³ is selected from

R ⁴ is selected from

x and y represents point of attachment; Ring A is selected from C ₆ - ₁₄ aryl and 5 to 14 membered heteroaryl;

R ² is selected from halogen, cyano, C _1-8 alkyl, C _1-8 alkoxy and haloC _1-8 alkyl; and

'm' is 0, 1 or 2.

The compounds of formula (I) may involve one or more embodiments. Embodiments of formula (I) include compounds of formula (II) and formula (III) as described hereinafter. It is to be understood that the embodiments below are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified. It is also to be understood that the embodiments defined herein may be used independently or in conjunction with any definition, any other embodiment defined herein. Thus the invention contemplates all possible combinations and permutations of the various independently described embodiments. For example, the invention provides compounds of formula (I) as defined above wherein ring A is phenyl (according to an embodiment defined below); R ¹ is C _1-8 alkyl (according to another embodiment defined below).

According to one embodiment specifically provided are compounds of formula (I), in

According to another embodiment specifically provided are compounds of formula (I), in

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

(I), in which R ³ is

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

(I), in which R ³ is According to yet another embodiment, specifically provided are compounds of formula (I), in which ring A is C _6-14 aryl (e.g. phenyl), 5 to 14 membered heteroaryl (e.g. pyridyl, pyrimidinyl or thiazolyl).

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

According to yet another embodiment, specifically provided are compounds of formula (I), in which R ¹ is C _1-8 alkyl (e.g. methyl, isopropyl or t-butyl) or C _3-12 cycloalkyl (e.g. cyclopropyl).

According to yet another embodiment, specifically provided are compounds of formula (I), in which R ¹ is methyl, isopropyl, t-butyl or cyclopropyl.

According to yet another embodiment, specifically provided are compounds of formula (I), in which R ² is halogen (e.g. fluoro or chloro), cyano, C _1-8 alkyl (e.g. methyl or isopropyl), C _1- 8alkoxy (e.g. methoxy) or haloC _1-8 alkyl (e.g. trifluoromethyl).

According to yet another embodiment, specifically provided are compounds of formula (I), in which R ² is fluoro, chloro, cyano, methyl, isopropyl, methoxy or trifluoromethyl.

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

(I), in which . wherein x and y represents point of attachment.

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

(I), in which wherein x and y represents point of attachment.

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

(I), in which 'm' is 0.

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

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

According to yet another embodiment, specifically provided are compounds of formula (I), in which

ring A is phenyl, pyridyl, pyrimidinyl or thiazolyl;

R ¹ is methyl, isopropyl, t-butyl or cyclopropyl;

R ² is fluoro, chloro, cyano, methyl, isopropyl, methoxy or trifluoromethyl;

wherein x and y represents point of attachment; and

'm' is 0, 1 or 2;

According to yet an embodiment, specifically provided are compounds of formula (I) with an IC50 value of less than 500 nM, preferably less than 100 nM, more preferably less than 50 nM, with respect to RORyt activity.

Further embodiments relating to groups ring A, R ¹ , R ² , R ³ , R ⁴ , L and m (and groups defined therein) are described hereinafter in relation to the compounds of formula (II). It is to be understood that these embodiments are not limited to use in conjunction with formula (II), but apply independently and individually to the compounds of formula (I). For example, in an embodiment described hereinafter, the invention specifically provides compounds of formula (II) in which and consequently there is also provided a compound of formula (I) in which

The invention also provides a compound of formula (II), which is an embodiment of a compound of formula (I).

Accordingly the invention provides a compound of formula (II)

stereoisomer, diastereoisomer, enantiomer or a pharmaceutically acceptable salt thereof, wherein

Ring A is selected from C _6-14 aryl and 5 to 14 membered heteroaryl;

x and y represents point of attachment;

R ¹ is selected from C _1-8 alkyl and C _3-12 cycloalkyl;

R ² is selected from halogen, cyano, C _1-8 alkyl, C _1-8 alkoxy and haloC _1-8 alkyl; and

'm' is 0, 1 or 2;

The compounds of formula (II) may involve one or more embodiments. It is to be understood that the embodiments below are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified. It is also to be understood that the embodiments defined herein may be used independently or in conjunction with any definition, any other embodiment defined herein. Thus the invention contemplates all possible combinations and permutations of the various independently described embodiments. For example, the invention provides compounds of formula (II) as defined above wherein R ¹ is C ₃ - i2cycloalkyl (according to an embodiment defined below) and m is 0 or 1 (according to another embodiment defined below).

According to one embodiment, specifically provided are compounds of formula (II), in which ring A is C _6-14 aryl (e.g. phenyl).

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

According to yet another embodiment, specifically provided are compounds of formula (II), in which R ¹ is C _1-8 alkyl (e.g. isopropyl) or C _3-12 cycloalkyl (e.g. cyclopropyl). According to yet another embodiment, specifically provided are compounds of formula (II), in which R ¹ is isopropyl or cyclopropyl.

According to yet another embodiment, specifically provided are compounds of formula (II), in which R ² is halogen (e.g. fluoro or chloro), C _1-8 alkyl (e.g. isopropyl), C _1-8 alkoxy (e.g. methoxy) or haloC _1-8 alkyl (e.g. trifluoromethyl).

According to yet another embodiment, specifically provided are compounds of formula (II), in which R ² is fluoro, chloro, isopropyl, methoxy or trifluoromethyl.

Accordin to yet another embodiment, specifically provided are compounds of formula

(II), in which wherein x and y represents point of

attachment.

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

(II), in which wherein x and y represents point of attachment.

According to yet another embodiment, specifically provided are compounds of formula (II), in which 'm' is 0.

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

According to yet another embodiment, specifically provided are compounds of formula (II), in which

rin A is phenyl;

x and y represents point of attachment;

R ¹ is isopropyl or cyclopropyl;

R ² is fluoro, chloro, isopropyl, methoxy or trifluoromethyl; and

'm' is 0 or 1.

According to yet an embodiment, specifically provided are compounds of formula (II) with an IC50 value of less than 500 nM, preferably less than 100 nM, more preferably less than 50 nM, with respect to RORyt activity. The invention also provides a compound of formula (III), which is an embodiment of a compound of formula (I).

Accordingly the invention provides a compound of formula (III)

stereoisomer, diastereoisomer, enantiomer or a pharmaceutically acceptable salt thereof, wherein

Ring A is selected from C _6-14 a to 14 membered heteroaryl;

x and y represents point of attachment;

R ¹ is selected from C _1-8 alkyl and C3 i2cycloalkyl;

R ² is selected from halogen, cyano, C _1-8 alkyl, C _1-8 alkoxy and haloC _1-8 alkyl; and

'm' is 0, 1 or 2;

The compounds of formula (III) may involve one or more embodiments. It is to be understood that the embodiments below are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified. It is also to be understood that the embodiments defined herein may be used independently or in conjunction with any definition, any other embodiment defined herein. Thus the invention contemplates all possible combinations and permutations of the various independently described embodiments. For example, the invention provides compounds of formula (III) as defined above wherein

(according to an embodiment defined below). According to one embodiment, specifically provided are compounds of formula (III), in which ring A is C _6-14 aryl (e.g. phenyl), 5 to 14 membered heteroaryl (e.g. pyridyl, pyrimidinyl or thiazolyl).

According to another embodiment, specifically provided are compounds of formula (III), in which ring A is phenyl, pyridyl, pyrimidinyl or thiazolyl.

According to yet another embodiment, specifically provided are compounds of formula (III), in which R ¹ is C _1-8 alkyl (e.g. methyl, isopropyl or t-butyl).

According to yet another embodiment, specifically provided are compounds of formula (III), in which R ¹ is methyl, isopropyl or t-butyl.

According to yet another embodiment, specifically provided are compounds of formula (III), in which R ² is halogen (e.g. fluoro or chloro), cyano, C _1-8 alkyl (e.g. methyl), C _1-8 alkoxy (e.g. methoxy) or haloC _1-8 alkyl (e.g. tnfluoromethyl).

According to yet another embodiment, specifically provided are compounds of formula (III), in which R ² is fluoro, chloro, cyano, methyl, methoxy or trifluoromethyl.

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

(III), in which wherein x and y represents point of attachment.

According to yet another embodiment, specifically provided are compounds of formula (III), in which 'm' is 0.

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

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

According to yet another embodiment, specifically provided are compounds of formula (III), in which

ring A is phenyl, pyridyl, pyrimidinyl or thiazolyl;

R ¹ is methyl, isopropyl or t-butyl;

R ² is fluoro, chloro, cyano, methyl, methoxy or trifluoromethyl;

wherein x and y represents point of attachment; and 'm' is 0, 1 or 2.

According to an embodiment, specifically provided are compounds of formula (III) with an IC50 value of less than 1000 nM, preferably less than 500 nM, more preferably less than 100 nM, with respect to RORyt activity.

Compounds of the present invention include the compounds in Examples 1-35. It should be understood that the formulas (I), (II) and (III) structurally encompasses all geometrical isomers, stereoisomers, enantiomers and diastereomers, N-oxides, and pharmaceutically acceptable salts that may be contemplated from the chemical structure of the genera described herein.

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 herein 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 tablet, capsule, sachet, paper or other container.

The compounds and pharmaceutical compositions of the present invention are useful for inhibiting the activity of RORyt. Thus, the present invention further provides a method of inhibiting RORyt in a subject in need thereof by administering to the subject one or more compounds described herein in an amount effective to cause inhibition of such receptor.

In a further aspect, the present invention relates to a method of treating a disease, disorder or condition modulated by RORyt, such as an autoimmune disease, inflammatory disease, respiratory disorder, pain and cancer comprising administering to a subject in need thereof a compound according to any of the embodiments described herein.

In another aspect, the present invention relates to a method of treating a disease, disorder or condition modulated by RORyt, such as chronic obstructive pulmonary disease (COPD), asthma, cough, pain, inflammatory pain, chronic pain, acute pain, arthritis, osteoarthritis, multiple sclerosis, rheumatoid arthritis, colitis, ulcerative colitis and inflammatory bowel disease, comprising administering to a subject in need thereof a compound according to any of the embodiments described herein.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

The terms "halogen" or "halo" means fluorine (fluoro), chlorine (chloro), bromine

(bromo), or iodine (iodo).

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 eight carbon atoms (i.e. C _1-8 alkyl), and which is attached to the rest of the molecule by a single bond, such as, but not limited to, methyl, ethyl, n-propyl, 1 -methylethyl (isopropyl), n-butyl, n-pentyl, and 1,1- dimethylethyl (t-butyl). The term "C _1- 6alkyl" 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.

The term "alkoxy" denotes an alkyl group attached via an oxygen linkage to the rest of the molecule (i.e. C _1-8 alkoxy). Representative examples of such groups are -OCH3 and -OC2H5. Unless set forth or recited to the contrary, all alkoxy groups described or claimed herein may be straight chain or branched.

The term "haloalkyl" refers to at least one halo group (selected from F, CI, Br or I), linked to an alkyl group as defined above (i.e. haloC _1-8 alkyl). Examples of such haloalkyl moiety include, but are not limited to, trifluoromethyl, difluoromethyl and fluoromethyl groups. The term "haloC _1-4 alkyl" refers to at least one halo group linked an alkyl chain having 1 to 4 carbon atoms. Unless set forth or recited to the contrary, all haloalkyl groups described herein may be straight chain or branched.

The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogen atoms (i.e. haloC _1-8 alkoxy). Examples of "haloalkoxy" include but are not limited to fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, pentachloroethoxy, chloromethoxy, dichlorormethoxy, trichloromethoxy and 1-bromoethoxy. Unless set forth or recited to the contrary, all haloalkoxy groups described herein may be straight chain or branched. The term "hydroxyC _1-8 alkyl" refers to an C _1-8 alkyl group as defined above wherein one to three hydrogen atoms on different carbon atoms is/are replaced by hydroxyl groups (i.e. hydroxyC _1-4 alkyl). Examples of hydroxyC _1-4 alkyl moieties include, but are not limited to - CH2OH and -C2H4OH.

The term "cycloalkyl" denotes a non-aromatic mono or multicyclic ring system of 3 to about 12 carbon atoms, (i.e.C _3-12 cycloalkyl). Examples of monocyclic cycloalkyl include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of multicyclic cycloalkyl groups include, but are not limited to, perhydronapthyl, adamantyl and norbornyl groups, bridged cyclic groups or spirobicyclic groups, e.g., spiro(4,4)non-2-yl. The term " C _3- 6cycloalkyl" refers to the cyclic ring having 3 to 6 carbon atoms. Examples of " C _3-6 cycloalkyl" include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

The term "cycloalkylalkyl" refers to a cyclic ring-containing radical having 3 to about 6 carbon atoms directly attached to an alkyl group (i.e. C _3-6 cycloalkylC _1-8 alkyl). The cycloalkylalkyl group may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure. Non-limiting examples of such groups include cyclopropylmethyl, cyclobutylethyl, and cyclopentylethyl.

The term "aryl" refers to an aromatic radical having 6 to 14 carbon atoms (i.e. C _6-14 aryl), including monocyclic, bicyclic and tricyclic aromatic systems, such as phenyl, naphthyl, tetrahydronapthyl, indanyl, and biphenyl.

The term "heterocyclic ring" or "heterocyclyl" unless otherwise specified refers to substituted or unsubstituted non-aromatic 3 to 15 membered ring radical (i.e. 3 to 15 membered heterocyclyl) which consists of carbon atoms and from one to five hetero atoms selected from nitrogen, phosphorus, oxygen and sulfur. The heterocyclic ring radical may be a mono-, bi- or tricyclic ring system, which may include fused, bridged or spiro ring systems, and the nitrogen, phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic ring radical may be optionally oxidized to various oxidation states. In addition, the nitrogen atom may be optionally quaternized; also, unless otherwise constrained by the definition the heterocyclic ring or heterocyclyl may optionally contain one or more olefinic bond(s). Examples of such heterocyclic ring radicals include, but are not limited to azepinyl, azetidinyl, benzodioxolyl, benzodioxanyl, chromanyl, dioxolanyl, dioxaphospholanyl, decahydroisoquinolyl, indanyl, indolinyl, isoindolinyl, isochromanyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, oxazolinyl, oxazolidinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, octahydroindolyl, octahydroisoindolyl, perhydroazepinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, piperidinyl, phenothiazinyl, phenoxazinyl, quinuclidinyl, tetrahydroisquinolyl, tetrahydrofuryl or tetrahydrofuranyl, tetrahydropyranyl, thiazolinyl, thiazolidinyl, thiamorpholinyl, thiamorpholinyl sulfoxide and thiamorpholinyl sulfone. The heterocyclic ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.

The term "heteroaryl" unless otherwise specified refers to 5 to 14 membered aromatic heterocyclic ring radical with one or more heteroatom(s) independently selected from N, O or S (i.e. 5 to 14 membered heteroaryl). The heteroaryl may be a mono-, bi- or tricyclic ring system. The heteroaryl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure. Examples of such heteroaryl ring radicals include, but are not limited to oxazolyl, isoxazolyl, imidazolyl, furyl, indolyl, isoindolyl, pyrrolyl, triazolyl, triazinyl, tetrazoyl, thienyl, oxadiazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, benzofuranyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzothienyl, benzopyranyl, carbazolyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, naphthyridinyl, pteridinyl, purinyl, quinoxalinyl, quinolyl, isoquinolyl, thiadiazolyl, indolizinyl, acridinyl, phenazinyl and phthalazinyl.

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, clavulanate, citrate, 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, manganic, mangamous, potassium, sodium, and zinc. 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).

A "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.

The compounds of formula (I), (II) or (III) may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomenc forms. It is intended that all stereoisomenc forms of the compounds of formula (I), (II) or (III) as well as mixtures thereof, including racemic mixtures, form part of the present invention. In addition, the present invention embraces all geometric and positional isomers. Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolysing) the individual diastereomers to the corresponding pure enantiomers. Enantiomers can also be separated by use of chiral HPLC column. The chiral centres of the present invention can have the S or R configuration as defined by the IUPAC 1974. The terms "salt" or "solvate", and the like, is intended to equally apply to the salt, solvate and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers or racemates of the inventive compounds.

PHARMACEUTICAL COMPOSITIONS

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 compositions described herein comprise 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 compositions described herein 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, capsules, tablets, 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 such compounds or 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, and 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, but are not limited to, 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 described herein 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.

METHODS OF TREATMENT

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

The compounds of the present patent application are modulators of RORyt and can be useful in the treatment of diseases/disorder mediated by RORyt. Accordingly, the compounds and the pharmaceutical compositions of this invention may be useful in the treatment of inflammatory, metabolic and autoimmune diseases mediated by RORyt. The term "autoimmune diseases" will be understood by those skilled in the art to refer to a condition that occurs when the immune system mistakenly attacks and destroys healthy body tissue. An autoimmune disorder may result in the destruction of one or more types of body tissue, abnormal growth of an organ, and changes in organ function. An autoimmune disorder may affect one or more organ or tissue types which include, but are not limited to, blood vessels, connective tissues, endocrine glands such as the thyroid or pancreas, joints, muscles, red blood cells, and skin. Examples of autoimmune (or autoimmune-related) disorders include multiple sclerosis, arthritis, rheumatoid arthritis, psoriasis, Crohn's disease, gastrointestinal disorder, inflammatory bowel disease, irritable bowel syndrome, colitis, ulcerative colitis, Sjorgen's syndrome, atopic dermatitis, optic neuritis, respiratory disorder, chronic obstructive pulmonary disease (COPD), asthma, type I diabetes, neuromyelitis optica, Myasthenia Gavis, uveitis, Guillain- Barre syndrome, psoriatic arthritis, Gaves' disease, allergy, osteoarthritis, Kawasaki disease, mucosal leishmaniasis, Hashimoto's thyroiditis, Pernicious anemia, Addison's disease, Systemic lupus erythematosus, Dermatomyositis, Sjogren syndrome, Lupus erythematosus, Myasthenia gravis, Reactive arthritis, Celiac disease - sprue (gluten-sensitive enteropathy), Graves's disease, thymopoiesis and Lupus.

Compounds of the present patent application may also be useful in the treatment of inflammation. The term "inflammation" will be understood by those skilled in the art to include any condition characterized by a localized or a systemic protective response, which may be elicited by physical trauma, infection, chronic diseases, and/or chemical and/or physiological reactions to external stimuli (e.g. as part of an allergic response). Any such response, which may serve to destroy, dilute or sequester both the injurious agent and the injured tissue, may be manifest by, for example, heat, swelling, pain, redness, dilation of blood vessels and/or increased blood flow, invasion of the affected area by white.

The term "inflammation" is also understood to include any inflammatory disease, disorder or condition per se, any condition that has an inflammatory component associated with it, and/or any condition characterized by inflammation as a symptom, including inter alia acute, chronic, ulcerative, specific, allergic, infection by pathogens, immune reactions due to hypersensitivity, entering foreign bodies, physical injury, and necrotic inflammation, and other forms of inflammation known to those skilled in the art. The term thus also includes, for the purposes of this present patent application, inflammatory pain, pain generally and/or fever. The compounds of the present invention may be used for treatment of arthritis, including, but are not limited to, rheumatoid arthritis, osteoarthritis, psoriatic arthritis, septic arthritis, spondyloarthropathies, gouty arthritis, systemic lupus erythematosus and juvenile arthritis, osteoarthritis, collagen-induced arthritis (CIA) and other arthritic conditions.

The compounds of the present invention may be used for treatment of respiratory disorders including, but are not limited to, chronic obstructive pulmonary disease (COPD), asthma, bronchospasm, and cough.

Other respiratory disorders include, but are not limited to, bronchitis, bronchiolitis, bronchiectasis, acute nasoparyngitis, acute and chronic sinusitis, maxillary sinusitis, pharyngitis, tonsillitis, laryngitis, tracheitis, epiglottitis, croup, chronic disease of tonsils and adenoids, hypertrophy of tonsils and adenoids, peritonsillar abscess, rhinitis, abscess or ulcer and nose, pneumonia, viral and bacterial pneumonia, bronchopneumonia, influenza, extrinsic allergic alveolitis, coal workers' pneumoconiosis, asbestosis, pneumoconiosis, pneumonopathy, respiratory conditions due to chemical fumes, vapors and other external agents, emphysema, pleurisy, pneumothorax, abscess of lung and mediastinum, pulmonary congestion and hypostasis, postinflammatory pulmonary fibrosis, other alveolar and parietoalveolar pneumonopathy, idiopathic fibrosing alveolitis, Hamman-Rich syndrome, atelectasis, ARDS, acute respiratory failure, mediastinitis.

The compounds of the present invention may also be used for treatment of pain conditions. The pain can be acute or chronic pain. Thus, the compounds of the present invention may be used for treatment of e.g., inflammatory pain, arthritic pain, neuropathic pain, postoperative pain, surgical pain, visceral pain, dental pain, premenstrual pain, central pain, cancer pain, pain due to burns; migraine or cluster headaches, nerve injury, neuritis, neuralgias, poisoning, ischemic injury, interstitial cystitis, viral, parasitic or bacterial infection, post- traumatic injury, or pain associated with irritable bowel syndrome.

The compounds of the present invention may further be used for treatment of gastrointestinal disorder such as, but not limited to, irritable bowel syndrome, inflammatory bowel disease, colitis, ulcerative colitis, biliary colic and other biliary disorders, renal colic, diarrhea-dominant IBS, and pain associated with gastrointestinal distension.

In addition, the compounds of the present invention may be useful in the treatment of cancer, and pain associated with cancer. Such cancers include, e.g., multiple myeloma and bone disease associated with multiple myeloma, melanoma, medulloblastoma, acute myelogenous leukemia (AML), head and neck squamous cell carcinoma, hepatocellular carcinoma, gastric cancer, bladder carcinoma and colon cancer.

The compounds of the present invention may be useful in a treatment of disease, disorder, syndrome or condition selected from the group consisting of Atopic dermatitis and psoriasis.

The compounds of the present invention may be useful in a treatment of disease, disorder, syndrome or condition selected from the group consisting of chronic obstructive pulmonary disease (COPD), asthma and cough.

Any of the methods of treatment described herein comprise administering an effective amount of a compound according to Formula (I), (II) or (III) or a pharmaceutically-acceptable salt thereof, to a subject (particularly a human) in need thereof.

The present inventions further relates to the use of the compounds described herein in the preparation of a medicament for the treatment of diseases mediated by RORyt.

The compounds of the invention are effective both in the therapeutic and/or prophylactic treatment of the above-mentioned conditions. For the above-mentioned therapeutic uses the dosage administered may vary with the compound employed, the mode of administration, the treatment desired and the disorder.

The daily dosage of the compound of the invention administered may be in the range from about 0.05 mg/kg to about 100 mg/kg.

General Methods of Preparation

The compounds, described herein, including those of general formula (I), (II), (III), various intermediates and specific examples are prepared through the synthetic methods as depicted in Schemes 1 to 5. Furthermore, in the following schemes, where specific acids, bases, reagents, coupling reagents, solvents, etc. are mentioned, it is understood that other suitable acids, bases, reagents, coupling reagents, solvents etc. may be used and are included within the scope of the present invention. The modifications to reaction conditions, for example, temperature, duration of the reaction or combinations thereof, are envisioned as part of the present invention. The compounds obtained using the general reaction sequences may be of insufficient purity. These compounds can be purified using any of the methods for purification of organic compounds known to persons skilled in the art, for example, crystallization or silica gel or alumina column chromatography using different solvents in suitable ratios. All possible geometrical isomers and stereoisomers are envisioned within the scope of this invention.

The starting materials used herein are commercially available or were prepared by methods known in the art to those of ordinary skill or by methods disclosed herein. In general, the intermediates and compounds of the present invention can be prepared through the reaction schemes as follows. In some cases the final product may be further modified, for example, by manipulation of substituents. These manipulations may include, but are not limited to, reduction, oxidation, alkylation, acylation, hydrolysis, and cleavage of protecting groups etc., by following procedures known in the art of organic synthesis. A general approach for the preparation of compounds of the formulae (Ila) (wherein R ¹ ,

R ² and 'm' are as defined with respect to a compound of formula (I)) is depicted in synthetic scheme 1.

Synthetic Scheme 1

The acid-amine coupling of suitably substituted aniline derivative of formula (1) with 2-

(4-(ethylsulfonyl) phenyl) acetic acid (2) (Ref: WO 201227965 Al , 2012.) in the presence of a suitable coupling agent(s) and suitable base gives the amide compound of formula (Ila). The suitable coupling agent(s) may be l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) with or without HOBt, NN'-dicyclohexylcarbodiimide (DCC), propylphosphonic anhydride (T3P) or (l-[bis(dimethylamino)methylene]-lH-l ,2,3-triazolo[4,5-&]pyridinium-3-oxid- hexafluorophosphate) (HATU). The suitable base used in the reaction may be Et ₃ N, DIPEA, pyridine or DMAP or a combination. The acid amine coupling reaction may be carried out in a suitable solvent such as dichlorome thane, CHCl ₃ , DMF and THF or mixture thereof.

A general approach for the preparation of compounds of the formulae (lib) (wherein R ¹ , R ² and 'm' are as defined with respect to a compound of formula (I)) is depicted in synthetic scheme 2.

Synthetic Scheme 2

The ester hydrolysis of the compound of formula (3) using lithium or sodium hydroxide in a suitable solvent such as water, methanol, ethanol, THF or combination thereof gives the corresponding benzoic acid derivative which on acid-amine coupling with (4- (ethylsulfonyl)phenyl) methanamine hydrochloride (4) in the presence of a suitable coupling agent(s) and suitable base gives the amide compound of formula (lib). The suitable coupling agent(s) may be l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) with or without HOBt, NN'-dicyclohexylcarbodiimide (DCC), propylphosphonic anhydride (T3P) or (1- [bis(dimethylamino)methylene]-lH-l ,2,3-triazolo[4,5-&]pyridinium-3-oxid- hexafluorophosphate) (HATU). The suitable base used in the reaction may be Et ₃ N, DIPEA, pyridine or DMAP or a combination. The acid amine coupling reaction may be carried out in a suitable solvent such as dichlorome thane, CHC1 ₃ , DMF and THF or mixture thereof.

A general approach for the preparation of compounds of the formulae (1) and (3) (wherein R ¹ , R ² and 'm' are as defined with respect to a compound of formula (I)) is depicted in synthetic scheme 3.

Synthetic Scheme 3

The substitution reaction of appropriate isomer (R or S) of 4-phenyloxazolidin-2-one (5) with appropriate acetyl chloride of formula (6) in the presence of a suitable base and solvent at elevated temperatures yields the acetamide derivative of formula (7). The suitable base for the reaction may be triethylamine, DIPEA, DMAP, pyridine or a combination and the solvent can be selected from dichlorome thane, THF, chloroform or dichloroethane. The reaction of compound (7) with a Schiff base of formula (8) in the presence of titanium tetrachloride, titanium(IV)isopropoxide and DIPEA in a suitable solvent such as dichloromethane affords the adduct of formula (9) {The Schiff base can be prepared by the reaction of a suitably substituted benzaldehyde with a suitably substituted aniline derivative in the presence of PTSA as a catalyst}. (Ref: Org. Process Res. Dev. 2009, 13, 907 910) The compound of formula (9 or 9')

undergoes cyclization in the presence of N,O-bis(trimethylsilyl)acetamide in a suitable solvent such as toluene at elevated temperatures to yield oxoazetidine derivative of formula (10 or 3). The nitro reduction of compound (10) in the presence of iron/acetic acid of iron/ammonium chloride gives the compound of formula (1). The solvent used for the reduction can be selected from ethanol, water or combination thereof.

A general approach for the preparation of compound of the formulae (4) is depicted in synthetic scheme 4.

Synthetic Scheme 4

The diazotization of the 4-aminobenzonitrile derivative of formula (11) followed by reaction with potassium salt of ethyl xanthate in the presence of KOH affords the thioester compound of formula (12). The hydrolysis of the thio-ester (12) at elevated temperature using a strong base such as potassium hydroxide in a suitable solvent yields the aryl thiol derivative of formula (13). The suitable solvent for the reaction may be ethanol, water or combination thereof. Alkylation of the thiol derivative (13) with ethyl bromide in the presence of a suitable base and solvent affords the thio-ether of formula (14). The suitable base for the reaction may be potassium carbonate or cesium carbonate and solvent may be selected from THF, DMF, DMSO, etc. The compound of formula (14) on oxidation in the presence of 3-chloroperbenzoic acid (MCPBA) yields the sulfonyl derivative of formula (15). The oxidation reaction can be carried out in a suitable solvent such as dichloromethane. The reductive amination of the cyano group of the compound (15) using ammonia under hydrogen pressure in the presence of a catalyst such as Raney nickel in a suitable solvent followed by salt formation with hydrochloric acid (gas) affords the 4-(ethylsulfonyl)phenyl)methanamine hydrochloride (4). The suitable solvent for the reductive amination reaction may be ethanol or methanol.

A general approach for the preparation of compounds of the formulae (Ilia) (wherein R ¹ ,

R ² and 'm' are as defined with respect to a compound of formula (I)) is depicted in synthetic scheme 5.

Synthetic Scheme 5

The reaction of compound (7) with a Schiff base of formula (16) in the presence of titanium tetrachloride, titanium(IV)isopropoxide and DIPEA in a suitable solvent such as dichloromethane affords the adduct of formula (17) {The Schiff base can be prepared by the reaction of a suitably substituted benzaldehyde with a suitably substituted aniline derivative in the presence of PTSA as a catalyst} (Ref: Org. Process Res. Dev. 2009, 13, 907□ 910). The benzoic acid derivative of formula (17) on acid-amine coupling with (4- (ethylsulfonyl)phenyl)methanamine hydrochloride (4) in the presence of a suitable coupling agent(s) and suitable base gives the amide compound of formula (18). The suitable coupling agent(s) may be l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) with or without HOBt, NN'-dicyclohexylcarbodiimide (DCC), propylphosphonic anhydride (T3P) or (1- [bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-&]py ridinium-3-oxid- hexafluorophosphate) (HATU). The suitable base used in the reaction may be Et ₃ N, DIPEA, pyridine or DMAP or a combination. The acid amine coupling reaction may be carried out in a suitable solvent such as dichloromethane, CHC1 ₃ , DMF and THF or mixture thereof. The compound of formula (18) undergoes cyclization in the presence of N,0- bis(trimethylsilyl)acetamide in a suitable solvent such as toluene at elevated temperatures to yield oxoazetidine derivative of general formula (Ilia).

Synthesis of Intermediates

Intermediate 1

(4-(Ethylsulfonyl)phenyl)methanamine hydrochloride

Step 1 : (9-Ethyl 2-((4-cyanophenyl)thio)ethanethioate

To a stirred suspension of 4-aminobenzonitrile (5.0 g, 42.3 mmol) in water (30 mL) was added concentrated hydrochloric acid (13 mL) at 0 °C and the mixture was stirred for 10 min. A solution of sodium nitrite (3.50 g, 50.8 mmol) in water (20 mL) was added slowly to the reaction mixture at 0 °C and allowed to stir for 1 h at the same temperature. The mixture was slowly added in to a solution of potassium ethyl xanthate (8.1 g, 50.53 mmol) in 2N KOH (30 mL) at RT. The resultant mixture was stirred at RT for 1 h. The reaction mixture was diluted with water and extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue thus obtained was dried well to yield 9.2 g of the titled product. The compound was as such forwarded to the next step without characterization.

Step 2: 4-Mercaptobenzonitrile

To a stirred solution of O-ethyl 2-((4-cyanophenyl)thio)ethanethioate (Step 1 intermediate) (18.2 g, 76.8 mmol) in ethanol (20 mL) was added a solution of potassium hydroxide (9.0 g, 161 mmol) in water (10 mL) at RT and the mixture was refluxed overnight. The reaction mixture was diluted with water and acidified with dilute hydrochloric acid till pH 3-4. The aqueous mixture was extracted twice with ethyl acetate and the combined organic layers were washed with water followed by brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to yield 9.7 g of the desired product. The compound was as such forwarded to the next step without characterization.

Step 3: 4-(Ethylthio)benzonitrile

To a stirred solution of 4-mercaptobenzonitrile (Step 2 intermediate) (9.7 g, 72.4 mmol) in DMF (20 mL) were added potassium carbonate (20 g, 145 mmol) and ethyl bromide (8.15 mL,109 mmol) at RT under nitrogen atmosphere. The reaction mixture was stirred for 4 h at RT. The reaction mixture was diluted with water extracted twice with ethyl acetate and the combined organic layers were washed with water followed by brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography to yield 8.5 g of the desired product. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.26 (t, =J 7.2 Hz, 3H), 3.08 (q, = 7.J2 Hz, 2H), 7.42 (d, = J 8.1 Hz, 2H), 7.73 (d, =J 8.1 Hz, 2H).

Step 4: 4-(Ethylsulfonyl)benzonitrile

To a stirred solution of 4-(ethylthio)benzonitrile (Step 3 intermediate) (8.5 g, 52.14 mmol) in dichloromethane (70 mL) was added 3-chloroperbenzoic acid (55-75% w/w, 41.5 g, 156 mmol) in small portions at RT under nitrogen atmosphere. The reaction mixture was stirred overnight at RT. The reaction mixture was diluted with water extracted twice with ethyl acetate and the combined organic layers were washed twice with 5% sodium hydroxide solution followed by brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography to yield 6.2 g of the desired product. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.10 (t, = 7.2J Hz, 3H), 3.08 (q, 7 = 7.2 Hz, 2H), 8.08 (d, = J 8.4 Hz, 2H), 8.16 (d, = 8.4J Hz, 2H).

Step 5 : ((4-(Ethylsulfonyl)phenyl)methanamine hydrochloride

To a stirred solution of 4-(ethylsulfonyl)benzonitrile (Step 4 intermediate) ( 1.0 g, 5.12 mmol) in methanol (30 mL) was added Raney nickel (500 mg) and aqueous ammonia (2.0 mL) at RT. The mixture was subjected to hydrogenation in a Parr apparatus under 60 psi hydrogen pressure for 1 h. The reaction mixture was filtered through celite bed and the filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography. The free base was stirred with hydrochloric acid in ethyl acetate to yield 513 mg of the desired product as a HC1 salt. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.09 (t, = 7.5J Hz, 3H), 3.32 (q, = 7.5 J Hz, 2H), 4.15 (s, 2H), 7.76 (d, =J 7.2 Hz, 2H), 7.93 (d, = 8.4J Hz, 2H), 8.50 (br s, 2H); ESI-MS (m/z) 200 (M+H) ⁺ .

Intermediate 2

(3S,4S)-4-(4-Aminophenyl)-3-isopropy -l-phenylazetidin-2-

Step 1 : (R )-3-(3-Methylbutanoyl)-4-phenyloxazolidin-2-one

To a stirred solution of (R )-4-phenyloxazolidin-2-one (1.9 g, 11.65 mmol) in dichloromethane (20 mL) were added isovaleryl chloride (2.84 mL, 23.31 mmol), DIPEA (5.98 mL, 34.95 mmol) followed by DMAP ( 142 mg, 1.16 mmol) at RT. The mixture was stirred at 50 °C for 2 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to yield 3.0 g of the titled product. ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.89 (d, J = 6.0 Hz, 6H), 2.09-2.16 (m, 1H), 2.70-2.93 (m, 2H), 4.22-4.29 (m, 1H), 4.67 (t, = J 9.0 Hz, 1H), 5.39-5.45 (m, 1H), 7.24-7.38 (m, 5H). Step 2: (R )-3-((S)-3-Methyl-2-((S)-(4-nitrophenyl)(phenylarnino)methyl )bu

phenyloxazolidin-2-one

To a stirred solution of (R )-3-(3-methylbutanoyl)-4-phenyloxazolidin-2-one (Step 1 intermediate) (1.2 g, 4.85 mmol) in dichloromethane (10 mL) at -10 °C were added titanium tetrachloride (531 μ·L, 4.85 mmol), titanium(IV)isopropoxide (287 μ·L, 0.97 mmol) followed by DIPEA (1.32 mL, 7.76 mmol) and the mixture was stirred at -10 °C for 1 h. Then, to the reaction mixture was added N-(4-nitrobenzylidene)aniline (Schiff base) (1.64 g, 7.27 mmol) and the resultant mixture was stirred at -10 °C for 3 h. The reaction mixture was diluted with water and extracted twice with ethyl acetate and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography to yield 880 mg of the desired product. ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.02 (d, =J 6.3 Hz, 3H), 1.09 (d, = J 6.3 Hz, 3H), 2.27-2.33 (m, 1H), 4.14 (d,J = 11.1 Hz, 1H), 4.51-4.57 (m, 2H), 4.80-4.84 (m, 1H), 5.32 (d, = 6.3 J Hz, 1H), 6.40 (d, = J 7.8 Hz, 2H), 6.61 (t, =J 7.2 Hz, 1H), 6.79 (d, = 7J.2 Hz, 2H), 7.07 (t, = 7.2J Hz, 2H), 7.19-7.30 (m, 6H), 7.86 (d, =J 8.7 Hz, 2H).

Step 3 : (3S,4S)-3-Isopropyl-4-(4-nitrophenyl)- 1 -phenylazetidin-2-one

To a stirred solution of (R )-3-((S)-3-Methyl-2-((S)-(4- nitrophenyl)(phenylamino)methyl)butanoyl)-4-phenyloxazolidin -2-one (Step 2 intermediate) (850 mg, 1.79 mmol) in toluene (20 mL) was added N,O -bis(trimethylsilyl)acetamide (786 μL·, 3.22 mmol) at 60 °C. After 30 min, tetrabutylammonium fluoride (TBAF) solution (1 , 170 μL, 0.17 mmol) was added to the reaction mixture and the resultant mixture was stirred at 60 °C for another 3 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to yield 310 mg of the desired product. ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.13 (d, =J 6.9 Hz, 3H), 1.19 (d, = J 6.3 Hz, 3H), 2.23-2.27 (m, 1H), 2.93 (d,J = 8.4 Hz, 1H), 4.85 (s, 1H), 7.05-7.12 (m, 1H), 7.23-7.30 (m, 4H), 7.54 (d, = 8.7 HJz, 2H), 8.25 (d, J= 8.7 Hz, 2H).

Step 4: (3S,4S)-4-(4-Aminophenyl)-3-isopropyl-l-phenylazetidin-2-one

To a stirred solution of (3S,4S)-3-isopropyl-4-(4-nitrophenyl)-l-phenylazetidin-2-one (Step 3 intermediate) (100 mg, 0.32 mmol) in ethanol (10 mL) was added a solution of ammonium chloride (174 mg, 3.22 mmol) in water (1.0 mL) at RT. The mixture was heated to 90 °C and iron powder (90 mg, 1.61 mmol) was slowly added in portions at the same temperature. The resultant suspension was allowed to stir at 90 °C for 1 h. The reaction mixture was diluted with water and filtered through celite bed. The filtrate was concentrated to remove ethanol. The residue was partitioned between water and ethyl acetate. The organic layer was separated and washed with water. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to yield 93 mg of the desired product. ¹ H NMR (300 MHz, CDCls) δ 1.06 (d, J = 6.6 Hz, 3H), 1.06 (d, =J 6.3 Hz, 3H), 2.16-2.21 (m, 1H), 2.87 (d, = 6.6J Hz, 1H), 4.62 (s, 1H), 6.71 (d, = J 7.8 Hz, 2H), 6.98-7.03 (m, 1H), 7.15 (d, = 7.8 HJz, 1H), 7.20- 7.32 (m, 5H).

Name, structure, and characterization data for the intermediates prepared by following the procedure described above in the case of Intermediate 2 from the combination of appropriate starting materials are given below in Table 1.

Table 1: Chemical name, structure and analytical data of Intermediate 3-17

Intermediate 18

(S)-3-(3-Methylbutanoyl)-4-phenyloxazolidin-2-one

To a stirred solution of (S)-4-phenyloxazolidin-2-one (5.0 g, 30.63 mmol) in dichloromethane (50 mL) were added isovaleryl chloride (7.5 mL, 61.27 mmol), DIPEA (15.7 mL, 91.89 mmol) followed by DMAP (373 mg, 3.06 mmol) at RT. The mixture was stirred at 50 °C for 2 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to yield 7.1 g of the titled product. ¹ H NMR (300 MHz, CDCI3) δ 0.89 (d, J = 4.8 Hz, 3H), 0.92 (d, =J 4.8 Hz, 3H), 2.07-2.18 (m, 1H), 2.69-2.94 (m, 2H), 4.23- 4.29 (m, 1H), 4.67 (t, =J 8.7 Hz, 1H), 5.40-5.46 (m, 1H), 7.27-7.39 (m, 5H). Name, structure, and characterization data for the intermediates prepared by following the procedure described above in the case of Intermediate 18 from the combination of appropriate starting materials are given below in Table 2. Table 2: Chemical name, structure and analytical data of Intermediate 19-20

Intermediate 21

Methyl 4-((2S,3R )-3-isopropyl-4-oxo- 1 -phenylazetidin-2-yl)benzoate

Step 1 : Methyl 4-((1S,2R )-3-Methyl-2-((S)-2-oxo-4-phenyloxazolidine-3-carbonyl)-l- (phenylamino)butyl)benzoate

The titled compound was prepared by the reaction of (S)- 3-(3-methylbutanoyl)-4- phenyloxazolidin-2-one (Intermediate 18) (500 mg, 2.02 mmol) with methyl 4- ((phenylimino)methyl)benzoate (725 mg, 3.03 mmol) in the presence of titanium(IV)isopropoxide (120 μL , 0.40 mmol) and DIPEA (0.55 mL, 3.23 mmol) in dichloromethane (10 mL) as per the procedure described in step 2 of Intermediate 2 to yield 390 mg of the product. ¹ H NMR (500 MHz, CDCl ₃ ) δ 1.01 (d, = J 7.0 Hz, 3H), 1.09 (d, = 7.J0 Hz, 3H), 2.22-2.31 (m, 1H), 3.93 (s, 3H), 4.06 (dd, =J 9.0, 3.5 Hz, 1H), 4.52 (t, = 8J.5 Hz, 1H), 4.58-4.63 (m, 1H), 4.79-4.83 (m, 1H), 5.30-5.33 (m, 1H), 5.44 (d, = 9.0J Hz, 1H), 6.41 (d, = J 8.5 Hz, 2H), 6.58 (t, =J 7.5 Hz, 1H), 6.68 (d, 7 = 7.5 Hz, 2H), 7.03 (t, = 7.0J Hz, 2H), 7.15 (t, J = 7.5 Hz, 2H), 7.20 (d, =J 8.0 Hz, 2H), 7.79 (d, = 8.J0 Hz, 2H).

Step 2: Methyl 4-((2S,3R )-3-isopropyl-4-oxo- 1 -phenylazetidin-2-yl)benzoate

The titled compound was prepared by the reaction of methyl 4-((1S,2R )-3-Methyl-2-((S)-2-oxo- 4-phenyloxazolidine-3-carbonyl)-l-(phenylamino)butyl)benzoat e (Step 1 intermediate) (380 mg, 0.78 mmol) with N,O-bis(trimethylsilyl)acetamide (344 μ·L, 1.40 mmol) in toluene (10 mL) as per the procedure described in step 3 of Intermediate 2 to yield 189 mg of the product. ¹ H NMR

(400 MHz, CDCI3) δ 1.11 (d, =J 6.6 Hz, 3H), 1.18 (d, = 6J.6 Hz, 3H), 2.20-2.28 (m, 1H), 2.90- 2.95 (m, 1H), 3.93 (s, 3H), 4.79 (s, 1H), 7.03-7.09 (m, 1H), 7.23-7.29 (m, 4H), 7.44 (d, = 8.2 J Hz, 2H), 8.05 (d, =J 8.2 Hz, 2H).

Name, structure, and characterization data for the intermediates prepared by following the procedure described above in the case of Intermediate 21 from the combination of appropriate starting materials are given below in Table 3.

Table 3: Chemical name, structure and analytical data of Intermediate 22-23

Synthesis of Examples

Typical procedure A:

Synthesis of 2-(4-(ethylsulfonyl)phenyl)-N-(4-((2S,3S)-3-isopropyl-4-oxo- 1-phenylazetidin-2- yl)phenyl)acetamide (Example 1)

To a stirred solution of (3S,45)-4-(4-aminophenyl)-3-isopropyl-l-phenylazetidin-2-one (Intermediate 2) (80 mg, 0.29 mmol) in dichloromethane (10 mL) were added 2-(4- (ethylsulfonyl)phenyl)acetic acid (78 mg, 0.29 mmol), l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (EDC. HC1) (82 mg, 0.42 mmol), HOBt (58 mg, 0.42 mmol), and triethylamine (119 μL·, 0.85 mmol) at RT under nitrogen atmosphere. The reaction mixture was stirred overnight at RT. The reaction mixture was diluted with water and extracted thrice with chloroform. The combined organic extracts were washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue obtained was purified by silica gel column chromatography followed by trituration in n-pentane to afford 14 mg of the titled product. ¹ H NMR (300 MHz, CDCI3) δ 1.06 (d, = 6.J9 Hz, 3H), 1.13 (d, J= 6.3 Hz, 3H), 1.28 (t, = J 6.9 Hz, 3H), 1.60 (s, 2H), 2.17-2.21 (m, 1H), 2.85 (d,J = 8.1 Hz, 1H), 3.1 1 (q, =J 6.9 Hz, 2H), 3.79 (s, 2H), 4.68 (s, 1H), 6.99-7.03 (m, 1H), 7.20- 7.31 (m, 5H), 7.46-7.55 (m, 4H), 7.86 (d, = 7J.8 Hz, 2H); APCI-MS (m/z) 491 (M+H) ⁺ . The structure, Intermediate used, chemical name and characterization data of all the examples prepared by the combination of appropriate intermediates, following the procedure described above in the case of Example 1 are given in Table 4. Table 4: Structure, Chemical name, Intermediate No. and Analytical data of Example 2-16

Typical procedure B:

Synthesis of N-(4-(ethylsulfonyl)benzyl)-4-((2S,3R )-3-isopropyl-4-oxo-1-phenylazetidin-2- yl)benzamide (Example 17)

Step 1 : 4-((2S,3R )-3-Isopropyl-4-oxo-l-phenylazetidin-2-yl)benzoic acid

To a stirred solution of methyl 4-((2S,3R )-3-isopropyl-4-oxo-l-phenylazetidin-2-yl)benzoate (Intermediate 21) (180 mg, 0.55 mmol) in methanol (10 mL) was added a solution of sodium hydroxide (111 mg, 2.78 mmol) in water (2.0 mL) at RT. The reaction mixture was stirred at RT for 24 h. The mixture was diluted with water and adjusted the pH to 3-4 by using dilute hydrochloric acid. The aqueous mixture was extracted twice with ethyl acetate and the combined organic layers were washed with water. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to yield 160 mg of the titled product. ^X H

NMR (500 MHz, DMSO-d ₆ ) δ 1.02 (d, =J 6.0 Hz, 3H), 1.07 (d, = 6J.0 Hz, 3H), 2.21-2.25 (m, 1H), 2.92-2.96 (m, 1H), 3.55 (s, 1H), 7.05 (t, = 7J.5 Hz, 1H), 7.20 (d, = 7.5 J Hz, 2H), 7.28 (t, J = 7.0 Hz, 2H), 7.54 (d, =J 8.5 Hz, 2H), 7.92 (d, = 8.J5 Hz, 2H), 12.95 (br s, 1H).

Step 2: N-(4-(Ethylsulfonyl)benzyl)-4-((2S,3R )-3-isopropyl-4-oxo-l-phenylazetidin-2- yl)benzamide

The titled product was prepared by the coupling reaction of 4-((2S,3R )-3-isopropyl-4-oxo-l- phenylazetidin-2-yl)benzoic acid (Step 1 intermediate) (50 mg, 0.16 mmol) with (4- (ethylsulfonyl)phenyl)methanamine hydrochloride (Intermediate 1) (38 mg, 0.16 mmol) in the presence of EDCI. HC1 (47 mg, 0.24 mmol), HOBt (33 mg, 0.24 mmol) and triethylamine (68 μL, 0.48 mmol) in dichloromethane (10 mL) as per the procedure described in Example 1 to afford 20 mg the product. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.10 (d, = 6J.6 Hz, 3H), 1.17 (d, = J 6.6 Hz, 3H), 1.28 (t, =J 7.4 Hz, 3H), 2.19-2.27 (m, 1H), 2.87-2.92 (m, 1H), 3.10 (q, = 7.4 HJz, 2H), 4.73-4.81 (m, 3H), 6.82 (br s, 1H), 7.02-7.09 (m, 1H), 7.22-7.26 (m, 4H), 7.45 (d, = 8.2 J Hz, 2H), 7.52 (d, =J 8.1 Hz, 2H), 7.81-7.88 (m, 4H); APCI-MS (m/z) 491 (M+H) ⁺ .

The structure, Intermediate used, chemical name and characterization data of all the examples prepared by the combination of appropriate intermediates, following the procedure described above in the case of Example 17 are given in Table 5.

Table 5: Structure, Intermediate used, chemical name and characterization data of Example 18-

19

Typical procedure C:

Synthesis of N-(4-(ethylsulfonyl)benzyl)-4-((3R,4S) -3-isopropyl-2-oxo-4-phenylazetidin-l- yl)benzamide (Example 20)

Step 1 : 4-((( 1 S,2R )-3-Methyl-2-((S)-2-oxo-4-phenyloxazolidine-3-carbonyl)- 1 - phenylbutyl)amino)benzoic acid

To a stirred solution of (S)-3-(3-methylbutanoyl)-4-phenyloxazolidin-2-one (Intermediate 18) (1.8 g, 7.28 mmol) in dichloromethane (10 mL) at -10 °C were added titanium tetrachloride (796 μΐ _^ , 7.28 mmol), titanium(IV)isopropoxide (430 μL, 1.45 mmol) followed by DIPEA (2.0 mL, 11.65 mmol) and the mixture was stirred at -10 °C for 1 h. Then, to the reaction mixture was added 4-(benzylideneamino)benzoic acid (Schiff base) (3.27 g, 14.56 mmol) and the resultant mixture was stirred at - 10 °C for 3 h. The reaction mixture was diluted with water and acidified with dilute HCl. The aqueous mixture was extracted twice with ethyl acetate and the combined organic layers were dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography to yield 1.26 g of the desired product. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 0.88 (d,J = 10 Hz, 6H), 1.22-1.26 (m, 1H), 4.02-4.07 (m, 1H), 4.62-4.84 (m, 3H), 5.52-5.57 (m, 1H), 6.65 (d, J= 8.8 Hz, 2H), 6.81 (d, =J 9.6 Hz, 1H), 7.02-7.18 (m, 5H), 7.24-7.43 (m, 5H), 7.55 (d,J = 8.8 Hz, 2H), 12.01 (s, 1H); ESI-MS (m/z) 471 (M-H)-.

Step 2: N-(4-(Ethylsulfonyl)benzyl)-4-(((1S,2R)-3-methyl-2-((S)-2-ox o-4-phenyloxazolidine-3- carbonyl)- 1 -phenylbutyl)amino)benzamide

The titled product was prepared by the coupling reaction of 4-(((1S,2R)-3-methyl-2-((S)-2-oxo-4- phenyloxazolidine-3-carbonyl)-l-phenylbutyl)amino)benzoic acid (Step 1 intermediate) (200 mg, 0.42 mmol) with (4-(ethylsulfonyl)phenyl)methanamine hydrochloride (Intermediate 1) (100 mg, 0.42 mmol) in the presence of EDCI. HCl (121 mg, 0.63 mmol), HOBt (86 mg, 0.63 mmol) and triethylamine (176 μL, 1.26 mmol) in dichloromethane (10 mL) as per the procedure described in Example 1 to afford 255 mg the product. ESI-MS (m/z) 655 (M+H) ⁺ .

Step 3: N-(4-(Ethylsulfonyl)benzyl)-4-((3R ,4S)-3-isopropyl-2-oxo-4-phenylazetidin-l- yl)benzamide (Example 20)

To a stirred solution of N-(4-(ethylsulfonyl)benzyl)-4-(((1S,2R)-3-methyl-2-((S)-2-ox o-4- phenyloxazolidine-3-carbonyl)-l-phenylbutyl)amino)benzamide (Step 2 intermediate) (250 mg, 0.38 mmol) in toluene (20 mL) was added N,O -bis(trimethylsilyl)acetamide (168 μL, 0.69 mmol) at 60 °C. After 30 min, tetrabutylammonium fluoride (TBAF) solution (1 , 75 μL, 0.08 mmol) was added to the reaction mixture and the resultant mixture was stirred at 60 °C for another 1 h. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic extracts were washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to yield 44 mg of the desired product. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.00- 1.09 (m, 9H), 2.13-2.20 (m, 1H), 2.97 (d, = 7J.2 Hz, 1H), 3.25 (q, J = 7.6 Hz, 2H), 4.54 (d, = J 5.2 Hz, 2H), 5.12 (s, 1H), 7.25-7.45 (m, 7H), 7.54 (d, = 8.0J Hz, 2H), 7.80-7.85 (m, 4H), 9.04 (t, = 5.2 Hz, 1H); ESI-MS (m/z) 489 (M-H)\

The structure, chemical name and characterization data of all the examples prepared by the combination of appropriate intermediates, following the procedure described above in the case of Example 20 are given in Table 6.

Table 6: Structure, chemical name and characterization data of Example 21-35

J

PHARMACOLOGICAL ACTIVITY BIOLOGICAL ASSAY

The compounds described herein were screened for ROR gamma modulator activity using the TR-FRET assay by Lantha Screen as described in JBC 2011, 286, 26: 22707-10; and Drug Metabolism and Disposition 2009, 37, 10: 2069-78.

TR-FRET ASSAY FOR ROR GAMMA:

The assay is based on the principle that binding of the agonist to the ROR gamma causes a conformational change around helix 12 in the ligand binding domain, resulting in higher affinity for the co-activator peptide. ROR gamma being constitutively active, the Fluorescein- D22 co-activator peptide used in the assay is recruited in the absence of a ligand. Binding of the co-activator peptide, causes an increase in the TR-FRET signal while binding of an antagonist decreases the recruitment of the co-activator peptide, causing a decrease in the TR-FRET signal compared to control with no compound. The assay was performed using a two-step procedure, pre-incubation step with the compound followed by the detection step on addition of the anti- GST tagged terbium (Tb) and fluorescein tagged fluorophores as the acceptor.

Test compounds or reference compounds such as T0901317 (Calbiochem) were dissolved in dimethyl sulfoxide (DMSO) to prepare 10.0 mM stock solutions and diluted to the desired concentration. The final concentration of DMSO in the reaction was 4% (v/v). The assay mixture was prepared by mixing lOnM of the GST-tagged ROR gamma ligand binding domain (LBD) in the assay buffer containing 25 mM HEPES, 100 mM NaCl, 5mM DTT and 0.01% BSA and 10% Glycerol with or without the desired concentration of the compound. The reaction was incubated at 22°C for 1 hour. The pre-incubation step was terminated by addition of the detection mixture containing 300nM Fluorescein-D22 co-activator peptide and lOnM lantha screen Tb-anti GST antibody into the reaction mixture. After shaking for 5 min the reaction was further incubated for 1 hour at 22°C and this was kept and read at 4°C on an Infinite F500 reader as per the kit instructions (Invitrogen). The inhibition of test compound was calculated based on the TR-FRET ratio of 520/495. The activity was calculated as a percent of control reaction. IC50 values were calculated from dose response curve by nonlinear regression analysis using GraphPad Prism software.

The compounds prepared were tested using the above assay procedure and the results obtained are given in Table 7. Percentage inhibition at concentrations of 1.0 μΜ and 10.0 μΜ are given in the table along with IC50 (nM) details for selected examples. The compounds were found to have IC50 less than 500nM, preferably less than lOOnM, more preferably less than 50nM.

The IC50 (nM) values are set forth in Table 7 wherein "A" refers to an IC50 value of less than 50 nM, "B" refers to IC50 value in range of 50.01 to 100.0 nM and "C" refers to IC50 values than 100 nM.

Table 7:

Although the invention herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and applications of the present invention. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the present invention as described above.

All publications and patent applications cited in this application are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated herein by reference.