WO2015083130A1 - Fused pyridine and pyrimidine derivatives as ror gamma modulators - Google Patents

Abstract

The present invention provides fused pyridine and pyrimidine derivatives of formula (I), which may be therapeutically useful, more particularly as RORγ modulators; in which R_a, R_b, A, B, X, P, Q, L, R₄, R₅ and m 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 disease(s) or disorder(s) where there is an advantage in modulating RORγ receptor. The present invention also provides preparation of the compounds and pharmaceutical formulations comprising at least one of the fused pyridine and pyrimidine derivatives of formula (I), together with a pharmaceutically acceptable carrier, diluent or excipient therefor.

Description

FUSED PYRIDINE AND PYRIMIDINE DERIVATIVES AS ROR GAMMA

MODULATORS

This application claims the benefit of Indian provisional application number 5641/CHE/2013 filed on 06^th December 2013 which hereby incorporated by reference.

FIELD OF THE INVENTION

This invention relates to compounds useful for treatment of disease(s) or disorder(s) 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 disease(s) or disorder(s) 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, Adv. Dev. Biol. 16:313-355, 2006). 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 (RORp) 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 isoforms 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. 361 : 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 Thl7 cells are one of the important drivers of the inflammatory process in tissue- specific autoimmunity (Steinman, J. Exp. Med. 205: 1517- 1522, 2008; Leung, et al, Cell. Mol. Immunol. 7: 182-189, 2010). 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, Ann. Rev. Immunol. 27:485-517, 2009). 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, Nucl. Recept. Signal. 7: e003, 2009; Manel, et al, Nat. Immunol. 9:641-649, 2008).

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: 1004-1011, 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: 1004-1011, 2009; Annunziato 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 al, Nat. Rev. Immunol. 5: 325-331, 2009; Louten, et al, 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 al., Clin. Exp. Immunol. 162: 131-137, 2010) and Hashimoto's thyroiditis (Figueroa-Vega, et al., J Clin.Endocrinol.Metab. 95: 953-62, 2010).

RORy inverse agonist, SR2211 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; IC₅₀ ~ 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. SR2211 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 (Zou et al., Nature Reviews Immunology 10, 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 disorders associated with the modulation of RORy.

Modulators of the RORy receptor were disclosed in WO2011/115892, 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.

BRIEF DESCRIPTION OF ACCOMPANYING DRAWINGS

Figure 1 : Effect of Compound-25 on arthritic score

Figure 2: Effect of Compound-25 on paw swelling

Figure 3: Effect of Compound-25 on histopathology of Paw tissue

SUMMARY OF THE INVENTION Provided herein are fused pyridine and pyrimidine 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 or a stereoisomer thereof; wherein:

A and B are independently -CRiR₂- or -NR₃-;

X is CH or N;

-P-Q- is -C(0)-NH- or -NH-C(O)-;

L is a bond or -NR_C-;

each of R_1; R₂ and R₃ is independently selected from hydrogen, alkyl, alkoxyalkyl, hydroxyalkyl, aryl and -(CH₂)_m-aryl; wherein the said aryl is optionally substituted by one or more hydroxy, halo, cyano, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, -NR_cR_d, heterocyclyl, heteroaryl and alkylheterocyclyl;

or Ri and R₂ can combine together to form an optionally substituted 5-8 membered spiro ring;

R4 at each occurrence is independently selected from hydrogen, halo, cyano and hydroxyalkyl;

R5 is alkyl, -NR_cRd or hydroxyalkyl;

R_a and Rb are independently hydrogen, hydroxy or alkyl;

or R_a and R together represent an oxo (=0) group;

R_c and R_d are independently hydrogen or alkyl; and

m is 1 to 4.

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 fused pyridine and pyrimidine 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 RORs, 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 "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, alky lthio alkyl, 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.

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, and which is attached to the rest of the molecule by a single bond. The alkane radical may be straight or branched. For example, the term "C_\-Ce alkyl" refers to a monovalent, straight, or branched aliphatic group containing 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i- butyl, s-butyl, t- butyl, n-pentyl, 1 -methylbutyl, 2-methylbutyl, 3-methylbutyl, neo-pentyl, 3,3-dimethylpropyl, hexyl, 2-methylpentyl, and the like).

"Alkoxy" as used herein refers the radical -O-alkyl, wherein the alkyl is as defined above. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2- propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy and heptyloxy. The alkyl portion of the alkoxy may be optionally substituted. " Alkoxy alkyl" as used herein, refers to an alkyl as defined above, having one or more of the available hydrogen of the alkyl replaced by a alkoxy group. For example, an alkoxyalkyl includes, but are not limited to, -CH₂OCH₃, -CH₂OCH₂CH₃ and -CH₂CH₂OCH₃.

As used herein the term "alkylheterocyclyl" refers to heterocyclyl as defined herein, having one or more of the available hydrogen of the heterocyclyl replaced by an alkyl group, wherein alkyl is as defined above. For example, an alkylheterocyclyl includes, but are not limited to, 1-methylpiperazinyl and the like.

As used herein, the term "aryl" alone or in combination with other term(s) means a carbocyclic aromatic system containing one or more rings wherein such rings may be fused. The term "fused" means that the second ring is attached or formed by having two adjacent atoms in common with the first ring. The term "fused" is equivalent to the term "condensed". 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-C₁₂) aryl refers to an aryl group having six to twelve carbon atoms. Examples of aryl groups include but are not limited to phenyl, naphthyl, indanyl, and the like. Unless otherwise specified, all aryl groups described herein may be optionally substituted.

"Cyano" refers to -CN group.

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 "haloalkoxy" means alkoxy substituted with one or more halogen atoms, wherein alkoxy is as defined above. Examples of "haloalkoxy" include but are not limited to -OCF₃, -OCHF₂ and the like.

fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl and the like.

As used herein, the term "haloalkyl" means alkyl substituted with one or more halogen atoms, wherein the 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 fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl and the like.

"Hydroxy" or "hydroxyl" refers to -OH group. "Hydroxyalkyl" as used herein, refers to an alkyl as defined above, having one or more of the available hydrogen of the alkyl replaced by a hydroxyl group. For example, a hydroxyalkyl includes, but are not limited to, -CH₂CH₂OH, -CH₂CH₂CH₂OH and -C(OH)(CH₃)(CH₃).

"Oxo" refers to (=0) group.

The term "heteroaryl" refers to an aromatic ring structure containing from 5 to 14 ring atoms in which 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 heteroaryl may be a single ring or 2 or 3 fused rings. Examples of heteroaryl substituents include, but are not limited to tetrazolyl, furanyl, thiophenyl and thiazolyl.

As used herein, the term "heterocyclyl" alone or in combination with other term(s) means a saturated {i.e., "heterocycloalkyl"), or partially saturated {i.e., "heterocycloalkenyl") 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. The heterocyclic group can be attached at a heteroatom or a carbon atom. Examples of "heterocyclyl" include, but are not limited to piperidinyl, piperazinyl and morpholinyl. Unless set forth or recited to the contrary, all heterocyclyl groups described or claimed herein may be optionally 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 known in literature.

As used herein, the term "Spiro ring" or "Spiro compound" refers to a bicyclic organic compound with rings connected through just one atom.

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 fused pyridine and pyrimidine derivatives, the first embodiment of the present invention provides the structure of compounds as set forth in formula

(I)

(I)

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

A and B are independently -CR1R2- or -NR3-;

X is CH or N;

-P-Q- is -C(0)-NH- or -NH-C(O)-;

L is a bond or -NR_C-;

each of R_{1 ;} R₂ and R₃ is independently selected from hydrogen, alkyl, hydroxy alkyl, alkoxyalkyl aryl and -(CH₂)_m-aryl; wherein the said aryl is optionally substituted by one or more hydroxy, halo, cyano, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, -NR_cRd, heterocyclyl, heteroaryl and alkylheterocyclyl;

or Ri and R₂ can combined together to form an optionally substituted 5-8 membered spiro ring;

R4 at each occurrence is independently selected from hydrogen, halo, cyano and hydroxyalkyl;

R5 is alkyl, -NR_cRd or hydroxyalkyl;

R_a and R are independently hydrogen, hydroxy or alkyl;

or R_a and Rb together represent an oxo (=0) group;

R_c and Rd are independently hydrogen or alkyl; and

m is 1 to 4.

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

(IA)

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

R_a, Rb, A, B, X, P, Q, R₄ and m are same as defined in formula (I).

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

(IB)

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

R_a, Rb, A, B, P, Q, R4 and m are same as defined in formula (I).

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

(IC)

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

R_a, Rb, A, B, P, Q, R4 and m are same as defined in formula (I).

In yet another aspect of the present invention provides compound of formula (ID):

(ID)

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

-A-B- is -CR1R2-CR1R2- or -NR3-CR1R2; and

R_a, Rb, Ri, R2, R3, R4, R5 X, P, Q and m are same as defined in formula (I).

In yet another aspect of the resent invention provides compounds of formula (IE),

(IE)

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

Ri and R2 are same as defined in formula (I).

In yet another aspect of the present invention provides compounds of the formula (I), (IA), (IB) and (IC), wherein R4 is hydrogen.

In yet another aspect of the present invention provides compounds of the formula (I), (IA), (IB) and (IC), wherein A is -CR1R2-.

In yet another aspect of the present invention provides compounds of the formula (I), (IA), (IB) and (IC), wherein B is -CH₂-.

In yet another aspect of the present invention provides compounds of the formula (IE), wherein Ri is hydrogen and R2 is aryl, optionally substituted by one or more halo, hydroxy or alkoxy. In yet another aspect of the present invention provides compounds of the formula (IE), wherein Ri is alkyl and R₂ is aryl, optionally substituted by one or more halo, hydroxy or alkoxy.

In yet another aspect of the present invention provides compounds of the formula (IE), wherein Ri is Ci-C₆ alkyl and R₂ is aryl, optionally substituted by one or more halo, hydroxy or alkoxy.

In yet another aspect of the present invention provides compounds of the formula (IE), wherein Ri is Ci-C₆ alkyl and R₂ is phenyl, optionally substituted by one or more halo, hydroxy or alkoxy.

In yet another aspect of the present invention provides compounds of the formula (IE), wherein Ri is Ci-C₆ alkyl.

In yet another aspect of the present invention provides compounds of the formula (IE), wherein R₂ is aryl optionally substituted by one or more halo, hydroxy or alkoxy.

According to preceding aspect R₂ is halophenyl, hydroxyphenyl or alkoxyphenyl.

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 the present invention provides compounds of the formula (I) in which A and B are independently -CRiR₂-.

According to preceding embodiment the present invention provides compounds of the formula (I) in which Ri and R₂ are independently Ci-C₆ alkyl.

According to preceding embodiment the present invention provides compounds of the formula (I) in which Ri is alkyl and R₂ is aryl, optionally substituted by one or more halo, hydroxy or alkoxy.

According to further preceding embodiment the present invention provides compounds of the formula (I) in which Ri is Ci-C₆ alkyl and R₂ is aryl, optionally substituted by one or more halo, hydroxy or alkoxy.

According to further preceding embodiment the present invention provides compounds of the formula (I), wherein Ri is methyl, ethyl or propyl and R₂ is phenyl, optionally substituted by one or more halo, hydroxy or alkoxy.

According to another embodiment, the present invention provides compounds of the formula (I) in which R_a and R_b together represent an oxo (=0) group. According to yet another embodiment, the present invention provides compounds of the formula (I) in which L is a bond.

According to another embodiment, the present invention provides compounds of the formula (I), (IA), (IB) and (IC) in which -P-Q- is -NH-C(O)-.

According to another embodiment, the present invention provides compounds of the formula (I) in which -A-B- is -CRiR₂-CRiR₂-.

According to another embodiment, the present invention provides compounds of the formula (I) in which -A-B- is -NR₃-CRiR₂-.

According to yet another embodiment, the present invention provides compounds of the formula (I), (IA), (IB) and (IC) in which R_a and Rb together represent an oxo (=0) group.

According to yet another embodiment, the present invention provides compounds of the formula (I), (IA), (IB) and (IC) in which L is a bond.

According to yet another embodiment, the present invention provides compounds of the formula (I), (IA), (IB) and (IC) in which m is 1 or 2.

According preceding embodiment, the present invention provides compounds of the formula (I), (IA), (IB) and (IC) in which m is 1.

According to yet another embodiment, the present invention provides compounds of the formula (I), (IA), (IB) and (IC) in which R₅ is alkyl.

According to preceding embodiment, the present invention provides compounds of the formula (I), (IA), (IB) and (IC) in which R₅ is Ci-C₆ alkyl.

According to preceding embodiment, the present invention provides compounds of the formula (I), (IA), (IB) and (IC) in which R₅ is methyl or ethyl.

According to yet another embodiment, the present invention provides compounds of the formula (I), (IA), (IB) and (IC) in which A and B are independently -CRiR₂-.

According to preceding embodiment, Ri is hydrogen, -CH₃, C₂H5, -C₃H_7> -CH₂OCH₃, -

CH₂OH, or -C₆H₅ and R₂ is hydrogen, -CH₃, -C₂H₅, -C₃H₇, -CH₂OCH₃, -CH₂OH, -C₆H₅,

According to yet another embodiment, the present invention provides compounds of the formula (I), (IA), (IB) and (IC) in which A is -NR₃- and B is -CRiR₂-.

According to yet another embodiment, the present invention provides compounds of the formula (IE) in which Ri and R₂ are independently aryl.

According to yet another embodiment, the present invention provides compounds of the formula (IE) in which Ri and R₂ are independently phenyl.

According to yet another embodiment, the present invention provides compounds of the formula (IE) in which Ri is hydrogen and R₂ is phenyl optionally substituted by one or two chloro, hydroxy or methoxy.

According to yet another embodiment, the present invention provides compounds of the formula (IE) in which Ri is methyl and R₂ is phenyl optionally substituted by one or two chloro, hydroxy or methoxy.

According to yet another embodiment, the present invention provides compounds of the formula (IE) in which Ri is ethyl or propyl and R₂ is phenyl optionally substituted by one or two chloro, hydroxy or methoxy. According to yet another embodiment, the present invention provides compounds of the formula (IE) in which Ri is hydrogen and R₂ is -(CH₂)2-aryl, wherein the said aryl is optionally substituted by halo (e.g. CI) or haloalkyl (e.g. -CF₃).

According to preceding embodiment, the present invention provides compounds of the formula (IE) in which the aryl is phenyl.

According to yet another embodiment, the present invention provides compounds of the formula (I), (IA), (IB) and (IC) in which R_a and R are independently Ci-C₆ alkyl (e.g. methyl).

According to another particular embodiment of the present invention, the compound of formula (I) is selected from the group consisting of:

Compound

IUPAC Name

No.

N-(6,6-dimethyl-5-oxo-5,6,7,8-tetrahydroquinolin-2-yl)-2-(4-(ethylsulfonyl)-2-

1

fluorophenyl)acetamide ;

N-(6,6-dimethyl-5-oxo-5,6,7,8-tetrahydroquinolin-2-yl)-2-(4-

2

(ethylsulfonyl)phenyl)acetamide ;

N-(6-(2-chlorophenyl)-6-methyl-5-oxo-5,6,7,8-tetrahydroquinolin-2-yl)-2-(4-

3

(ethylsulfonyl)phenyl)acetamide ;

N-(6-(2-chlorophenyl)-5-oxo-5,6,7,8-tetrahydroquinolin-2-yl)-2-(4-

4

(ethylsulfonyl)phenyl)acetamide ;

2-(4-(ethylsulfonyl)phenyl)-N-(5'-oxo-7',8'-dihydro-5'H-spiro[cyclopentane-l,6'-

5

quino lin] -2 '- yl)acet amide ;

N-(6-(2-chlorophenyl)-5-oxo-5,6,7,8-tetrahydroquinolin-2-yl)-2-(4-

6

(ethylsulfonyl)-2-fluorophenyl)acetamide;

N-(6-(2-chlorophenyl)-6-methyl-5-oxo-5,6,7,8-tetrahydroquinolin-2-yl)-2-(4-

7

(ethylsulfonyl)-2-fluorophenyl)acetamide;

2-(4-(ethylsulfonyl)phenyl)-N-(5-oxo-6-(4-(trifluoromethyl)phenethyl)-5, 6,7,8-

8

tetrahydroquinolin-2-yl)acetamide;

9 2-(4-(ethylsulfonyl)-2-fluorophenyl)-N-(5-oxo-6-(4-(trifluoromethyl)phenethyl)- 5,6,7,8-tetrahydroquinolin-2-yl)acetamide;

N-(6-(4-chlorophenethyl)-5-oxo-5,6,7,8-tetrahydroquinolin-2-yl)-2-(4-

10

(ethylsulfonyl)phenyl)acetamide ; Compound

IUPAC Name

No.

N-(6-(4-chlorophenethyl)-5-oxo-5,6,7,8-tetrahydroquinolin-2-yl)-2-(4-

11

(ethylsulfonyl)-2-fluorophenyl)acetamide;

N-(6-(4-chlorophenyl)-6-methyl-5-oxo-5,6,7,8-tetrahydroquinolin-2-yl)-2-(4-

12

(ethylsulfonyl)phenyl)acetamide ;

13

2-(4-(ethylsulfonyl)phenyl)-N-(5-oxo-5,6,7,8-tetrahydroquinolin-2-yl)acetamide;

N-(6-(2,4-dichlorophenethyl)-5-oxo-5,6,7,8-tetrahydroquinolin-2-yl)-2-(4-

14

(ethylsulfonyl)phenyl)acetamide ;

N-(6-(2,4-dichlorophenyl)-6-methyl-5-oxo-5,6,7,8-tetrahydroquinolin-2-yl)-2-(4-

15

(ethylsulfonyl)phenyl)acetamide ;

N-(6-(4-chlorophenyl)-6-methyl-5-oxo-5,6,7,8-tetrahydroquinolin-2-yl)-2-(4-

16

(ethylsulfonamido )pheny 1) acet amide ;

N-(6-(4-chlorophenyl)-6-methyl-5-oxo-5,6,7,8-tetrahydroquinolin-2-yl)-2-(4-(N-

17

ethylsulf amo yl)pheny 1) acet amide ;

N-(6-(4-chlorophenyl)-5-oxo-6-propyl-5,6,7,8-tetrahydroquinolin-2-yl)-2-(4-

18

(ethylsulfonyl)phenyl)acetamide ;

2-(4-(ethylsulfonyl)phenyl)-N-(6-methyl-5-oxo-6-(4-(trifluoromethyl)phenyl)-

19

5,6,7,8-tetrahydroquinolin-2-yl)acetamide;

N-(6-(4-chlorophenyl)-5-oxo-5,6,7,8-tetrahydroquinolin-2-yl)-2-(4-

20

(ethylsulfonyl)phenyl)acetamide ;

N-(6-(4-chlorophenyl)-6-methyl-5-oxo-5,6,7,8-tetrahydroquinolin-2-yl)-2-(4-

21

(methylsulfonyl)phenyl)acetamide;

22 2-(4-(ethylsulfonyl)phenyl)-N-(6-methyl-5-oxo-6-phenyl-5, 6,7,8- tetrahydroquinolin-2-yl)acetamide;

N-(6-(4-chlorophenyl)-6-ethyl-5-oxo-5,6,7,8-tetrahydroquinolin-2-yl)-2-(4-

23

(ethylsulfonyl)phenyl)acetamide ;

N-(6-(4-chlorophenyl)-6-methyl-5-oxo-5,6,7,8-tetrahydroquinolin-2-yl)-2-(4-

24

(ethylsulfonyl)phenyl)acetamide ; (Isomer-2) Compound

IUPAC Name

No.

N-(6-(4-chlorophenyl)-6-methyl-5-oxo-5,6,7,8-tetrahydroquinolin-2-yl)-2-(4-

25

(ethylsulfonyl)phenyl)acetamide ; (Isomer- 1 )

2-(4-(ethylsulfonyl)phenyl)-N-(6-methyl-6-(4-morpholinophenyl)-5-oxo-5, 6,7,8-

26

tetrahydroquinolin-2-yl)acetamide;

27 2-(4-(ethylsulfonyl)phenyl)-N-(6-(4-methoxyphenyl)-6-methyl-5-oxo-5, 6,7,8- tetrahydroquinolin-2-yl)acetamide;

N-(6-(4-(dimethylamino)phenyl)-6-methyl-5-oxo-5,6,7,8-tetrahydroquinolin-2-

28

yl)-2-(4-(ethylsulfonyl)phenyl)acetamide;

2-(4-(ethylsulfonyl)phenyl)-N-(6-(4-methoxyphenyl)-6-methyl-5-oxo-5, 6,7,8-

29

tetrahydroquinolin-2-yl)acetamide; (Isomer- 1)

2-(4-(ethylsulfonyl)phenyl)-N-(6-(4-methoxyphenyl)-6-methyl-5-oxo-5, 6,7,8-

30

tetrahydroquinolin-2-yl)acetamide; (Isomer-2)

N-(6-(4-chlorophenyl)-5-oxo-6-propyl-5,6,7,8-tetrahydroquinolin-2-yl)-2-(4-

31

(ethylsulfonyl)phenyl)acetamide ; (Isomer- 1 )

N-(6-(4-chlorophenyl)-5-oxo-6-propyl-5,6,7,8-tetrahydroquinolin-2-yl)-2-(4-

32

(ethylsulfonyl)phenyl)acetamide ; (Isomer-2)

2-(4-(ethylsulfonyl)phenyl)-N-(6-methyl-6-(3-morpholinophenyl)-5-oxo-5, 6,7,8-

33

tetrahydroquinolin-2-yl)acetamide;

N-(6-(4-cyanophenyl)-6-methyl-5-oxo-5,6,7,8-tetrahydroquinolin-2-yl)-2-(4-

34

(ethylsulfonyl)phenyl)acetamide ;

2-(4-(ethylsulfonyl)phenyl)-N-(6-methyl-6-(3-(4-methylpiperazin-l-yl)phenyl)-

35

5-oxo-5,6,7,8-tetrahydroquinolin-2-yl)acetamide;

2-(4-(ethylsulfonyl)phenyl)-N-(5-oxo-6,6-diphenyl-5,6,7,8-tetrahydroquinolin-2-

36

yl)acetamide;

37 2-(4-(ethylsulfonyl)phenyl)-N-(6-methyl-5-oxo-6-(2-(trifluoromethoxy)phenyl)- 5,6,7,8-tetrahydroquinolin-2-yl)acetamide;

N-(6-(3,5-difluoro-4-methoxyphenyl)-6-methyl-5-oxo-5, 6,7,8-

38

tetrahydroquinolin-2-yl)-2-(4-(ethylsulfonyl)phenyl)acetamide; Compound

IUPAC Name

No.

N-(6-(3,5-difluoro-4-hydroxyphenyl)-6-methyl-5-oxo-5,6,7,8-tetrahydroquinolin-

39

2-yl)-2-(4-(ethylsulfonyl)phenyl)acetamide;

2-(4-(ethylsulfonyl)phenyl)-N-(6-(3-methoxyphenyl)-6-methyl-5-oxo-5, 6,7,8-

40

tetrahydroquinolin-2-yl)acetamide;

N-(6-(3-chlorophenyl)-6-methyl-5-oxo-5,6,7,8-tetrahydroquinolin-2-yl)-2-(4-

41

(ethylsulfonyl)phenyl)acetamide ;

N-(6-(3-(dimethylamino)phenyl)-6-methyl-5-oxo-5,6,7,8-tetrahydroquinolin-2-

42

yl)-2-(4-(ethylsulfonyl)phenyl)acetamide;

2-(4-(ethylsulfonyl)phenyl)-N-(6-(4-(2-hydroxypropan-2-yl)phenyl)-6-methyl-5-

43

oxo-5,6,7,8-tetrahydroquinolin-2-yl)acetamide;

N-(6-(4-chlorophenyl)-6-(methoxymethyl)-5-oxo-5,6,7,8-tetrahydroquinolin-2-

44

yl)-2-(4-(ethylsulfonyl)phenyl)acetamide;

N-(6-(4-chlorophenyl)-6-methyl-5,6,7,8-tetrahydroquinolin-2-yl)-2-(4-

45

(ethylsulfonyl)phenyl)acetamide ;

2-(4-(ethylsulfonyl)phenyl)-N-(6-(2-hydroxyphenyl)-6-methyl-5-oxo-5, 6,7,8-

46

tetrahydroquinolin-2-yl)acetamide;

2-(4-(ethylsulfonyl)phenyl)-N-(6-(2-methoxyphenyl)-6-methyl-5-oxo-5, 6,7,8-

47

tetrahydroquinolin-2-yl)acetamide;

N-(6-(4-chlorophenyl)-6-methyl-5,6,7,8-tetrahydroquinolin-2-yl)-2-(4-

48

(ethylsulfonyl)phenyl)acetamide ; (Isomer- 1 )

N-(6-(4-chlorophenyl)-6-methyl-5,6,7,8-tetrahydroquinolin-2-yl)-2-(4-

49

(ethylsulfonyl)phenyl)acetamide ; (Isomer-2)

2-(4-(ethylsulfonyl)phenyl)-N-(6-(4-hydroxyphenyl)-6-methyl-5-oxo-5, 6,7,8-

50

tetrahydroquinolin-2-yl)acetamide;

2-(4-(ethylsulfonyl)phenyl)-N-(6-(3-methoxyphenyl)-6-methyl-5-oxo-5, 6,7,8-

51

tetrahydroquinolin-2-yl)acetamide; (Isomer- 1)

2-(4-(ethylsulfonyl)phenyl)-N-(6-(3-methoxyphenyl)-6-methyl-5-oxo-5, 6,7,8-

52

tetrahydroquinolin-2-yl)acetamide; (Isomer-2) Compound

IUPAC Name

No.

2-(4-(ethylsulfonyl)phenyl)-N-(6-(3-hydroxyphenyl)-6-methyl-5-oxo-5, 6,7,8-

53

tetrahydroquinolin-2-yl)acetamide;

N-(6-(4-chlorophenyl)-6-methyl-5-oxo-5,6,7,8-tetrahydroquinolin-2-yl)-2-(4-((2-

54

hydroxyethyl) sulfonyl)phenyl) acetamide ;

2-(4-(ethylsulfonyl)phenyl)-N-(6-methyl-6-(4-(4-methylpiperazin-l-yl)phenyl)-

55

5-oxo-5,6,7,8-tetrahydroquinolin-2-yl)acetamide;

N-(6-(4-(lH-tetrazol-5-yl)phenyl)-6-methyl-5-oxo-5,6,7,8-tetrahydroquinolin-2-

56

yl)-2-(4-(ethylsulfonyl)phenyl)acetamide;

N-(6-(4-chlorophenyl)-6-(hydroxymethyl)-5-oxo-5,6,7,8-tetrahydroquinolin-2-

57

yl)-2-(4-(ethylsulfonyl)phenyl)acetamide;

N-(6-(4-chlorophenyl)-5-hydroxy-6-methyl-5,6,7,8-tetrahydroquinolin-2-yl)-2-

58

(4-(ethylsulfonyl)phenyl)acetamide; (Isomer- 1)

N-(6-(4-chlorophenyl)-5-hydroxy-6-methyl-5,6,7,8-tetrahydroquinolin-2-yl)-2-

59

(4-(ethylsulfonyl)phenyl)acetamide; (Isomer-2)

N-(6-(2-chlorophenyl)-6-methyl-5-oxo-5,6,7,8-tetrahydroquinolin-2-yl)-2-(4-

60

(ethylsulfonyl)phenyl)acetamide ; (Isomer- 1 )

N-(6-(2-chlorophenyl)-6-methyl-5-oxo-5,6,7,8-tetrahydroquinolin-2-yl)-2-(4-

61

(ethylsulfonyl)phenyl)acetamide ; (Isomer-2)

N-(6-(2,4-dichlorophenyl)-6-methyl-5-oxo-5,6,7,8-tetrahydroquinolin-2-yl)-2-(4-

62

(ethylsulfonyl)phenyl)acetamide ; (Isomer-2)

N-(6-(2,4-dichlorophenyl)-6-methyl-5-oxo-5,6,7,8-tetrahydroquinolin-2-yl)-2-(4-

63

(ethylsulfonyl)phenyl)acetamide ; (Isomer- 1 )

2-(4-(ethylsulfonyl)phenyl)-N-(6-methyl-5-oxo-6-(4-(trifluoromethyl)phenyl)-

64

5,6,7,8-tetrahydroquinolin-2-yl)acetamide; (Isomer- 1)

2-(4-(ethylsulfonyl)phenyl)-N-(6-methyl-5-oxo-6-(4-(trifluoromethyl)phenyl)-

65

5,6,7,8-tetrahydroquinolin-2-yl)acetamide; (Isomer-2)

2-(4-(ethylsulfonyl)phenyl)-N-(6-(2-hydroxyphenyl)-6-methyl-5-oxo-5, 6,7,8-

66

tetrahydroquinolin-2-yl)acetamide; (Isomer- 1) Compound

IUPAC Name

No.

2-(4-(ethylsulfonyl)phenyl)-N-(6-(2-hydroxyphenyl)-6-methyl-5-oxo-5, 6,7,8-

67

tetrahydroquinolin-2-yl)acetamide; (Isomer-2)

N-(6-(2-chlorophenyl)-5-oxo-5,6,7,8-tetrahydro-l,6-naphthyridin-2-yl)-2-(4-

68

(ethylsulfonyl)-2-fluorophenyl)acetamide;

N-(6, 6-dimethyl-5 -oxo-5 , 6,7 , 8-tetrahydroquinazolin-2-yl)-2-(4-

69

(ethylsulfonyl)phenyl)acetamide ;

N-(6-(2-chlorophenyl)-5-oxo-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-2-

70

(4-(ethylsulfonyl)-2-fluorophenyl)acetamide;

N-(6-(2-chlorophenyl)-5,6,7,8-tetrahydro-l,6-naphthyridin-2-yl)-2-(4-

71

(ethylsulfonyl)-2-fluorophenyl)acetamide;

N-(4-(ethylsulfonyl)benzyl)-6,6-dimethyl-5-oxo-5,6,7,8-tetrahydroquinoline-2-

72

carboxamide;

N-(5,5-dimethyl-5,6,7,8-tetrahydroquinolin-2-yl)-2-(4-

73

(ethylsulfonyl)phenyl)acetamide ;

2-(4-(ethylsulfonyl)phenyl)-N-(6-(2-hydroxy-4-methylphenyl)-6-methyl-5-oxo-

74

5,6,7,8-tetrahydroquinolin-2-yl)acetamide;

2-(4-(ethylsulfonyl)phenyl)-N-(6-(3-fluoro-2-hydroxyphenyl)-6-methyl-5-oxo-

75

5,6,7,8-tetrahydroquinolin-2-yl)acetamide;

2-(4-(ethylsulfonyl)phenyl)-N-(6-(2-fluorophenyl)-6-methyl-5-oxo-5, 6,7,8-

76

tetrahydroquinolin-2-yl)acetamide;

N-(6-(3-cyanophenyl)-6-methyl-5-oxo-5,6,7,8-tetrahydroquinolin-2-yl)-2-(4-

77

(ethylsulfonyl)phenyl)acetamide ; and

2-(3-(4-(ethylsulfonyl)phenyl)-2-oxopropyl)-6-(2-hydroxy-3-methylphenyl)-6-

78

methyl-7 , 8 -dihydroquinolin- 5 ( 6H) -one

or a pharmaceutically acceptable salt or a 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 known in literature.

Suitable doses of the compounds for use in treating the diseases or 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 immune or inflammatory disorder or disease. Accordingly, one embodiment of the invention provides a method of treating a disorder or disease selected from the group consisting of immune or inflammatory disorder or disease. 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 or disease.

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

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

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

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

According to yet another embodiment the present invention provides compounds for use as a medicament.

According to yet another embodiment the invention provides the use of the compounds of the present invention in the manufacture of a medicament.

According to yet another embodiment the invention provides the use of the compounds of the present invention in the manufacture of a medicament for the treatment of immune or inflammatory disorder or disease.

Another yet another embodiment the present invention provides compounds for use as a medicament for the treatment of immune or inflammatory disorder or disease.

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

Further, it is contemplated that the compounds of the present invention can inhibit the activity of RORy. Accordingly, another embodiment 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.

Also, 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, 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.

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

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 or disease indicated.

According to one embodiment, the compounds of the present invention can also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the present invention also embraces isotopically-labeled variants of the present invention which are identical to those recited herein, but for the fact that one or more atoms of the compound are replaced by an atomhaving the atomic mass or mass numberdifferentfirom the predominantatomic mass or mass numberusuallyfound in nature for the atom. All isotopes of anyparticularatom or element as specified are contemplatedwithin the scope of the compounds of the invention, and their uses. Exemplary isotopes thatcanbeincorporated in to compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine and iodine, such as ²H ("D"), ¾ ⁿC, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵0, ¹⁷0, ¹⁸0, ³²P, ³³P, ³⁵S, ¹⁸F, ³⁶C1, ¹²³I and ¹²⁵I. Isotopicallylabeled compounds of the present inventions cangenerallybeprepared by followingproceduresanalogous to thosedisclosed in the Schemes and/or in the Exampleshereinbelow, by substituting an isotopicallylabeledreagent for a non-isotopicallylabeledreagent.

The following abbreviations refer respectively to the definitions below:

Xantphos - 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene; K₂CO₃ - potassium carbonate; °C- Degree Celsius; M⁺- Molecular ion; m - Multiplet; mL - Milliliter; h - Hour(s); δ- Delta; Pd/C - Palladium on activated Carbon; MS - Mass Spectroscopy; DMF - NN-dimethyl formamide; RM - Reaction mixture; RT - Room temperature; RB/RBF - Round Bottom Flask THF - Tetrahydrofuran; Cone - Concentrated; LC-MS - Liquid Chromatography- Mass Spectroscopy; ¾ or H - proton; NMR - Nuclear Magnetic Resonance; MHz - Megahertz (frequency); CDCI3 -Deuterated Chloroform; Hz - Hertz; s - Singlet; brs - Broad singlet; d - Doublet; q - Quartet; t - Triplet; DMSO-d⁶ - Deuterated dimethylsulfoxide; % - Percentage; H₂ - Hydrogen; M - Molarity; N - Normality; g - Gram; min - Minutes; mol - Moles; wt - Weight. 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.

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.

It is contemplated that some of the intermediates disclosed in the present invention are used for the next step without any characterization data.

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.

Scheme-I

Most of the compounds of the present invention may be synthesized utilizing the process outlined in general Scheme I; wherein R_{1 ;} R₂ are as defined in Compound of formula (I). Compound of formula (A) was coupled with compound of formula (B) using standard acid and amine coupling reagents known in literature afforded compound of formula (C). In another way compound of formula (A) was coupled with compound of formula (E) using standard halo/ triflate and amine coupling reagents which are known in the literature (Buchwald Reaction) afforded compound of formula (F), which on further reduction gives compound of formula (D).

Compound of formula (A) may be prepared in several methods as depicted below.

Method 1:

R_j is optionally substituted aryl;

R₂ is alkyl, alkoxyalkyl or hydroxyalkyl;

X is halo or -OTf

Compound of formula (i) was treated with DMF-DMA followed by ethylcyanoacetate in presence of solvents like DCM or acetonitrile to afford compound of formula (ii), which on further hydrolysis gives compound of formula (iii). Decarboxylation of compound of formula (iii) provides compound of formula (iiia) which on halogenation with appropriate agents like POCl₃/POBr₃ etc. provide compound of formula (A).

Method 2:

X is halo or -OTf;

Ri is optionally substituted aryl;

R₂ is alkyl, alkoxyalkyl or hydroxyalkyl;

Compound of formula (iv) reacts with aryl halides in presence of suitable palladium catalyst and solvent gives compound of formula (v), which undergoes nucleophilic substitution reaction with alkyl halides/ alkoxyalkyl halides / hydroxyalkyl halides in presence of appropriate base like sodium hydride to afford compound of formula (A).

Method 3:

Compound of formula (vi) undergoes nuclophilic substitution reaction in presence of suitable alkyl halides/ alkoxyalkyl halides / hydroxyalkyl halides and phase transfer catalyst like Benzyltrimethylammonium chloride to give compound of formula (vii), which undergoes cyclization in presence of methyl acrylate and solvents like xylene to give compound of formula (viii). Compound of formula (viii) reacts with ammonium acetate in presence of solvent like toluene gives compound of formula (ix), which undergoes further cyclization by using ethyl propiolate afforded compound of formula (x). Compound of formula (x) on halogenation with appropriate agents like POCl₃/POBr₃ etc. provide compound of formula (A).

Method 4:

R-_\ and R₂ are independently alkyl or hydrogen;

X is halo or -OTf

Compound of formula (xiii) may be obtained by treating with appropriate cyanide (NaCN and the like) in presence of suitable solvents like DMSO which may on hydrolysis with appropriate reagents like NaOH and the like give compound of formula (A).

Preparation of Intermediates

Intermediate- 1: Synthesis of 2-chloro-6,6-dimethyl-7,8-dihydroquinolin-5(6H)-one

-| _a i b 1c lntermediate-1

Reagents and conditions: i) Ethyl acrylate, potassium teri-butoxide, THF, 0 °C-room temperature, 1 h; ii) ammonium acetate, toluene, reflux, 4 h; iii) ethyl propiolate, 110 °C, 2 h; iv) phosphorus oxychloride, reflux, 12 h.

Step-i: 4,4-dimethylcyclohexane-l,3-dione (la)

To a 250 mL round bottom flask, were added 3-methyl-2-butanone (10 g, 0.1162 mol) and THF (150 mL). To the same flask, potassium feri-butoxide (36.28 g, 0.2324 mol) was added. The reaction mixture was cooled to 0 °C and stirred at 0 °C for 5 min. To the same flask, ethyl acrylate (11.62 g, 0.1162 mol) was added drop wise at 0 °C. The resulting reaction mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with saturated aqueous ammonium chloride and washed with ethyl acetate. The aqueous layer was separated, acidified to pH 6.0 with 2 N hydrochloric acid and extracted with ethyl acetate. The organic layer was separated, washed with brine and dried over anhydrous sodium sulphate. The organic layer was evaporated under reduced pressure to get the crude product. The crude product was purified by column chromatography over silica gel (60-120) using 50 % ethyl acetate in hexane as eluent to get the titled compound [5 g, 31 %]. 1H NMR (300 MHz, CDC1₃): δ 3.28 (s, 2H), 2.64 (t, 2H), 1.87 (t, 2H), 1.22 (s, 6H); LC-MS: 141.0 [M+H]⁺.

Step-ii: 3-amino-6,6-dimethylcyclohex-2-enone (lb)

A 50 mL round bottom flask was charged with 4,4-dimethylcyclohexane-l,3-dione (la) (3 g, 0.0214 mol), ammonium acetate (1.97 g, 0.0257 mol) and toluene (50 mL). The round bottom flask was fitted with Dean-Stark reflux condenser. The reaction mixture was stirred at reflux temperature for 4 h. The volatiles were evaporated under reduced pressure to get the residue. The residue was triturated with ethyl acetate to get the solid. The solid was collected by filtration to obtain the titled compound [1.8 g, 62 %]. ^!H NMR (300 MHz, DMSO-d⁶): δ 6.47 (brs, 2H), 4.79 (s, 1H), 2.30 (t, 2H), 1.66 (t, 2H), 0.94 (s, 6H); LC-MS: 140.2 [M+H]⁺.

Step-iii: 6,6-dimethyl-7,8-dihydroquinoline-2,5(lH,6H)-dione (lc)

To a 25 mL round bottom flask, were added 3-amino-6,6-dimethylcyclohex-2-enone (lb) (1.5 g, 0.0107 mol) and ethyl propiolate (1.5 mL). The reaction mixture was stirred at 110 °C for 2 h. The excess of ethyl propiolate was evaporated at 130 °C to get the residue. The residue was cooled to room temperature and triturated with dichloromethane to get the solid. The solid was collected by filtration to obtain the titled compound [0.7 g, 35 %]. 1H NMR (CDC1₃, 400 M Hz): δ 7.59 (d, 1H), 6.63 (d, 1H), 5.26 (brs, 1H), 2.56 (t, 2H), 1.83 (t, 2H), 1.13 (s, 6H); LC-MS: 192.3 [M+H]⁺.

Step-iv: 2-chloro-6,6-dimethyl-7,8-dihydroquinolin-5(6H)-one

To a 25 mL round bottom flask, was added 6,6-dimethyl-7,8-dihydroquinoline-2,5(lH,6H)-dione (lc) (0.5 g, 0.0026 mol) and phosphorus oxychloride (5 mL). The reaction mixture was stirred at reflux temperature for 12 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 sulphate. The organic layer was evaporated under reduced pressure to get the crude product. The crude product was purified by column chromatography over silica gel (60-120) using 20 % ethyl acetate in hexane as eluent to get the titled compound [0.15 g, 27 %]. *H NMR (300 MHz, DMSO-d⁶): δ 8.22 (d, 1H), 7.53 (d, 1H), 3.09 (t, 2H), 2.00 (t, 2H), 1.14 (s, 6H); LC-MS: 210.2 [M+H]⁺.

Intermediate-2: Synthesis of 2-chloro-6-(2-chlorophenyl)-6-methyl-7,8-dihydroquinolin- 5(6H)-one

Reagents and conditions: i) Methyl iodide, 50 % aqueous sodium hydroxide, benzyltrimethylammonium chloride , 0 °C-room temperature, 2 h; ii) methyl acrylate, sodium, methanol, xylene, reflux, 3 h; iii) ammonium acetate, toluene, 120 °C, 4 h; iv) ethyl propiolate, 120 °C, 3 h; v) phosphorus oxychloride, reflux, 12 h.

Step-i: 3-(2-chlorophenyl)butan-2-one (2a)

To a 25 mL round bottom flask, was added l-(2-chlorophenyl)propan-2-one (2 g, 0.0118 mol) and cooled to 0 °C. To the same flask, 50 % aqueous sodium hydroxide (10 mL) and benzyltrimethylammonium chloride (0.22 g, 0.0011 mol) were added. The reaction mixture was stirred at 0 °C for 10 min. To the reaction mixture, methyl iodide (2.02 g, 0.0142 mol) was added and stirred at room temperature for 2 h. The reaction mixture was diluted with water and extracted with dichloromethane. The organic layer was separated, washed with brine and dried over anhydrous sodium sulfate. The organic layer was evaporated under reduced pressure to get the crude product. The crude product was purified by column chromatography over silica gel (60-120) using 3 % ethyl acetate in hexane as eluent to get the titled compound [1.5 g, 69 %].¹H NMR (300 MHz, CDC1₃): δ 7.43-7.40 (m, 1H), 7.27-7.14 (m, 3H), 4.30 (q, 1H), 2.08 (s, 3H), 1.39 (d, 3H).

Step-ii: 4-(2-chlorophenyl)-4-methylcyclohexane- L3-dione (2b)

To a 100 mL round bottom flask, was added methanol (10 mL). To the same flask, sodium metal (0.289 g, 0.0126 mol) was added portion wise. The reaction mixture was stirred at room temperature until all sodium metal had dissolved. To the same flask, xylene (50 mL), 3-(2- chlorophenyl)butan-2-one (2a) (2.1 g, 0.0114 mol) and methyl acrylate (0.984 g, 0.0114 mol) were added. The resulting solution was stirred at reflux temperature for 3 h. The volatiles were evaporated under reduced pressure to get the residue. The residue was partitioned between diethyl ether and water. The aqueous layer was separated and acidified with cone, hydrochloric acid. The aqueous layer was extracted with chloroform. 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 [2 g]. The obtained crude product was used in the next step without any further purification. LC-MS: 237.9 [M+H]⁺.

Step-iii: 4-amino-2'-chloro-l-methyl-5,6-dihydro-[l J'-biphenyll-2(lH)-one (2c)

A 50 mL round bottom flask was charged with 4-(2-chlorophenyl)-4-methylcyclohexane-l,3- dione (2b) (2 g, 0.0084 mol), ammonium acetate (0.78 g, 0.0101 mol) and toluene (20 mL). The round bottom flask was fitted with Dean-Stark reflux condenser. The reaction mixture was stirred at 120 °C for 4 h. The volatiles were evaporated under reduced pressure to get the residue. The residue was triturated with ethyl acetate to get the solid. The solid was collected by filtration to obtain the titled compound [1.6 g, 80 %]. ^!H NMR (300 MHz, DMSO-d⁶): δ 7.39-7.16 (m, 4H), 6.61 (brs, 2H), 4.94 (s, 1H), 2.69-2.59 (m, 1H), 2.53-2.43 (m, 1H), 2.20-2.13 (m, 1H), 1.57- 1.45 (m, 4H); LC-MS: 236.1 [M+H]⁺.

Step-iv: 6-(2-chlorophenyl)-6-methyl-7,8-dihydroquinoline-2,5( lH,6H)-dione (2d) To a 25 mL round bottom flask, were added 4-amino-2'-chloro-l-methyl-5,6-dihydro-[l, l'- biphenyl]-2(lH)-one (2c) (0.5 g, 0.0021 mol) and ethyl propiolate (0.5 mL). The reaction mixture was stirred at 120 °C for 3 h. The excess of ethyl propiolate was evaporated at 170 °C to get the residue. The residue was triturated with dichloromethane to get the solid. The solid was collected by filtration to obtain the titled compound [0.4 g, 66 %]. LC-MS: 287.9 [M+H]⁺.

Step-v: 2-chloro-6-(2-chlorophenyl)-6-methyl-7,8-dihydroquinolin-5(6H)-one

To a 25 mL round bottom flask, were added 6-(2-chlorophenyl)-6-methyl-7,8-dihydroquinoline- 2,5(lH,6H)-dione (2d) (0.4 g, 0.0014 mol) and phosphorus oxychloride (5 mL). The reaction mixture was stirred at 120 °C for 12 h. The volatiles were evaporated under reduced pressure to get the residue. The residue was triturated with ice cold water to get the solid. The solid was filtered to get the crude product. The crude product was purified by column chromatography over silica gel (60-120) using 10 % ethyl acetate in hexane as eluent to get the titled compound as racemic mixture (0.18 g, 42 %). LC-MS: 306.0 [M+H]⁺.

The below intermediates were prepared by procedure similar to the one described in the synthesis of Intermediate-2 with appropriate variations in reactants, quantities of reagents, solvents and reaction conditions. The characterization data of the compounds are summarized herein below table.

Intermediate-11: Synthesis of 2-chloro-6-(4-(trifluoromethyl)phenethyl)-7,8- dihydroquinolin-5(6H)-one

Reagents and conditions: i) Ethyl acetoacetate, Na, ethanol, reflux 12 h; ii) methyl acrylate, sodium, methanol, xylene, reflux, 3 h; iii) ammonium acetate, toluene, 120 °C, 4 h; iv) ethyl propiolate, 120 °C, 3 h; v) phosphorus oxychloride, reflux, 12 h.

Step-i: Synthesis of 5-(4-(trifluoromethyl)phenyl)pentan-2-one (11a)

To a suspension of sodium metal (0.65 g, 0.0282 mol) in ethanol (20 mL) was added ethyl acetoacetate at RT, refluxed for an hour, then RM was cooled to RT. To this mixture was then added l-(2-bromoethyl)-4-(trifluoromethyl)benzene (7.5 g, 0.0296 mol) and refluxed for 12 h. The reaction mixture was then cooled to RT, filtered. Solids washed with ethanol, filtrate concentrated to get residue. To the residue obtained was added 5% NaOH (30 mL) and heated to 90 °C for 5 h, then cooled to RT. This mixture was again treated with 50% sulphuric acid (13 mL) and heated to 90 °C for 5 h, cooled to RT, diluted with water, extracted into diethyl ether. The organic portion was washed with water and brine solution, then, dried over Na₂S04, filterd and concentrated to get residue. The residue was purified by column chromatography over silica gel (60-120) using 10% ethyl acetate in hexane as to get the pure titled compound (4.5 g, 66%). Step- ii to Step-v: Synthesis of 2-chloro-6-(4-(trifluoromethyl)phenethyl)-7,8-dihydroquinolin- 5(6H)-one

For Step-ii to Step-v, used the similar protocol described in Step-ii to Step-v of intermediate-2 with appropriate variations in reactants, quantities of reagents, solvents and reaction conditions., Yield: (0.3 g, 63 %), LC-MS: 254.0 [M+H]⁺.

The below Intermediates were prepared according to the above protocol depicted in the synthesis of Intermediate- 11.

Reagents and conditions: i) Methyl acrylate, sodium, methanol, xylene, reflux, 3 h; ii) ammonium acetate, toluene, 120 °C, 4 h; iii) ethyl propiolate, 120 °C, 3 h; iv) phosphorus oxychloride, reflux, 12 h. Intermediate- 14 was prepared as described in the preparation of intermediate-2, excluding Step-i, with appropriate variations in reactants, quantities of reagents, solvents and reaction conditions. Yield: (0.12 g, 45.11 %), LC-MS: 292.2 [M+H]⁺.

Intermediate-15: Synthesis of 2-chl l)-7,8-dihydroquinolin-5(6H)-one

Intermediate-15

This intermediate was prepared using the similar protocol depicted in the synthesis of Intermediate- 14 with appropriate variations in reactants, quantities of reagents, solvents and reaction conditions. LC-MS: 292.0 [M+H]⁺

Intermediate-16: Synthesis of 2-chloro-6-(3-methoxyphenyl)-6-methyl-7,8-dihydroquinolin- 5(6 -one

Reagents and conditions: i) Methyl iodide, 50 % aqueous sodium hydroxide, benzyltrimethylammonium chloride , 0 °C - room temperature, 2 h; ii) methyl acrylate, sodium, methanol, xylene, reflux, 3 h; iii) DMF-DMA, DCM, 1 h, RT, methyl cyanoacetate, methanol reflux, 12 h; iv) LiOH, MeOH, H₂0, 80 °C, 2 h; v) Heat neat compound till it melts; vi) phosphorus oxychloride, reflux, 12 h.

Step-i to Step-ii: Synthesis of 4-(3-methoxyphenyl)-4-methylcvclohexane-l,3-dione (16b)

Experimental protocol for Step-i to Step-ii is similar to that described in Step-i to Step-ii of Intermediate-2.

LC-MS: 233.0 [M+H]⁺.

Step-iii: Synthesis of ethyl 2-hydroxy-6-(3-methoxyphenyl)-6-methyl-5-oxo-5, 6,7,8- tetrahydroquinoline-3-carboxylate (16c) To a solution of 4-(3-methoxyphenyl)-4-methylcyclohexane-l,3-dione (16b) (2.0 g, 0.00862 mol) in DCM (30 mL) was added DMF-DMA (1.81g, 0.0112 mol), allowed to stir for 2 h at RT. The DCM was evaporated and the residue was added ethyl cyanoacetate, then the mixture was heated to reflux for 12 h. RM was cooled to RT, diluted with ethyl acetate and washed with water, dried over sodium sulphate, concentrated to get the crude compound. This was purified by silica gel (60-120) column chromatography using ethyl acetate-hexanes (6:4) as eluent to give pure titled compound (1.3 g, 43.3%), LC-MS: 342.0 [M+H]⁺.

Step-iv: Synthesis of 2-hvdroxy-6-(3-methoxyphenyl)-6-methyl-5-oxo-5, 6,7,8- tetrahydroquinoline-3-carboxylic acid (16d)

To a mixture of ethyl 2-hydroxy-6-(3-methoxyphenyl)-6-methyl-5-oxo-5, 6,7,8- tetrahydroquinoline-3-carboxylate (16c) (1.3g, 0.0038 mol) in methanol/water (30mL/10mL) was added lithium hydroxide (1.6 g, 0.038 mol) at RT and heated to reflux for 2 h. After the evaporation of methanol, the mixture obtained was acidified with dil HC1. This was then extracted into ethyl acetate; organic portion was dried, concentrated to get the titled compound (1.0 g, 84 %), LC-MS: 328.0 [M+H]⁺.

Step-v: Synthesis of 6-(3-methoxyphenyl)-6-methyl-7,8-dihydroquinoline-2,5(lH,6H)-dione LL6e)

2-hydroxy-6-(3-methoxyphenyl)-6-methyl-5-oxo-5,6,7,8-tetrahydroquinoline-3-carboxylic acid (16d) (1.0 g, 0.0030 mol) taken in a single neck RB, fitted with a condenser, was heated on a heating mantle till compound completely melts and gradually cooled to RT to get titled compound. LC-MS: 284.0 [M+H]⁺.

Step-vi: Synthesis of 2-chloro-6-(3-methoxyphenyl)-6-methyl-7,8-dihydroquinolin-5(6H)-one Experimental protocol for the synthesis is similar to that described in Step- v of Intermediate-2. LC-MS: 288.1 [M+H]⁺.

Following intermediates were prepared using the above protocol with appropriate variations in reactants, quantities of reagents, solvents and reaction conditions.

Intermediate

Structure LC-MS

No.

17 334.2 [M+H]⁺ 18 356.0 [M+H]⁺

19 338.0 [M+H]⁺

Intermediate-20: Synthesis of 2-chloro-6-(4-(dimethylamino)phenyl)-6-methyl-7,8- dihydroquinolin-5(6H)-one

20d 20e 20f Intermediate-20

Reagents and conditions: i) Methyl iodide, 50 % aqueous sodium hydroxide, benzyltrimethylammonium chloride , 0 °C, RT, 2 h; ii) methyl acrylate, sodium, methanol, xylene, reflux, 3 h; iii) ammonium acetate, toluene, 120° C, 4 h; iv) ethyl propiolate, 120 °C, 3 h; v) Aq. Ammonia, L-Proline, Cul, DMSO, 100 °C; vi) Formaldehyde, acetic acid, Na₂S0_4> NaBH(OAc)₃; vi) phosphorus oxychloride, reflux, 12 h.

Step-i to Step-iv: Synthesis of 6-(4-bromophenyl)-6-methyl-7,8-dihydroquinoline-2,5(lH,6H)- dione (20d)

6-(4-bromophenyl)-6-methyl-7,8-dihydroquinoline-2,5(lH,6H)-dione was prepared using the similar protocol described in Step-i, to Step-iv of Intermediate-2 with appropriate variations in reactants, quantities of reagents, solvents and reaction conditions. LC-MS: 334.0 [M+H]⁺.

Step-v: Synthesis of 6-(4-aminophenyl)-2-hvdroxy-6-methyl-7,8-dihydroquinolin-5(6H)-one (20e)

To a stirred mixture of 6-(4-bromophenyl)-6-methyl-7,8-dihydroquinoline-2,5(lH,6H)-dione (20d) (1 g, 0.00301 mol), L-proline (0.086 g, 0.0006 mol) and Cul (0.058 g, 0.00030 mol) in DMSO (10 mL) was added aqueous ammonia (10 mL) at RT. The reaction mixture was stirred at 100 °C in a steel bomb, for overnight. The RM was cooled to RT, neutralized with citric acid, diluted with ethyl acetate, organic portion was dried and concentrated to get crude compound. This upon purification by silica gel column chromatography using chloroform: methanol (7:3) afforded titled compound (0.47 g, 58.2 %). LC-MS: 269.2 [M+H]⁺.

Step-vi: Synthesis of 6-(4-(dimethylamino)phenyl)-2-hydroxy-6-methyl-7,8-dihydroquinolin- 5(6H)-one (20f)

To a solution of 6-(4-aminophenyl)-2-hydroxy-6-methyl-7,8-dihydroquinolin-5(6H)-one (20e) (0.450 g, 0.00167 mol) in acetic acid (5 mL) was added 37% aqueous formaldehyde followed by sodium sulphate (0.672 g, 0.0167 mol) at RT. The reaction mixture was stirred at RT for overnight. This mixture was then treated with sodium triacetoxyborohydride (1.7 g, 0.0083 mol) and stirred further for 3h, RM was neutralized with sodium bicarbonate solution, extracted into ethyl acetate, dried and concentrated to get crude compound. This was further purified on Silica gel column using Chloroform: MeOH (9.5:0.5) to afford pure titled compound (0.28 g, 56.3 %). Step-vii: Synthesis of 2-chloro-6-(4-(dimethylamino)phenyl)-6-methyl-7,8-dihydroquinolin- 5(6H)-one

Synthesis of 2-chloro-6-(4-(dimethylamino)phenyl)-6-methyl-7,8-dihydroquinolin-5(6H)-one was done using the same protocol described in Step-v of Intermediate-2 with appropriate variations in reactants, quantities of reagents, solvents and reaction conditions. LC-MS: 315.1 [M+H]⁺.

Intermediate-21: Synthesis of 4-(2-chloro-6-methyl-5-oxo-5,6,7,8-tetrahydroquinolin-6- yl)benzonitrile

lntermediate-20d 21a lntermediate-21

Reagents and conditions: i) ZnCN₂, Zn, Pd₂dba₃, DPPF, DMA, 120° C, 24h; ii) phosphorus oxychloride, reflux, 12 h.

Step-i: Synthesis of 4-(2-hvdroxy-6-methyl-5-oxo-5,6,7,8-tetrahydroquinolin-6-yl)benzonitrile Ola]

To a degased solution of 6-(4-bromophenyl)-6-methyl-7,8-dihydroquinoline-2,5(lH,6H)-dione (20d) (lg, 0.0030 mol) in DMA (20mL) were added ZnCN₂ (0.624 g, 0.006 mol), Zn (0.097 g, 0.0015 mol), Pd₂dba₃(0.137 g, 0.00015 mol) and DPPF (0.166 g, 0.0003 mol) at RT and this mixture was heated to 120 °C for 24 h. The RM was cooled and diluted with ethyl acetate, washed with ammonium hydroxide solution, brine and organic layer was dried over Na₂S0₄ and concentrated to get the titled compound (0.7 g, 83.9 %). LC-MS: 279.1 [M+H]⁺.

Step-ii: Synthesis of 4-(2-chloro-6-methyl-5-oxo-5,6,7,8-tetrahydroquinolin-6-yl)benzonitrile Synthesis of 4-(2-chloro-6-methyl-5-oxo-5,6,7,8-tetrahydroquinolin-6-yl)benzonitrile was done using the similar protocol described in Step-v of Intermediate-2 with appropriate variations in reactants, quantities of reagents, solvents and reaction conditions. LC-MS: 297.1 [M+H]⁺.

Intermediate-22: Synthesis of 2-chloro-6-(3,5-difluoro-4-hydroxyphenyl)-6-methyl-7,8- dihydroquinolin-5(6H)-one

lntermediate-19 lntermediate-22

Reagents and conditions: i) BBr3, DCM, -78 °C.

A stirred solution of 2-chloro-6-(3,5-difluoro-4-methoxyphenyl)-6-methyl-7,8-dihydroquinolin- 5(6H)-one (lntermediate-19) (0.2 g, 0.000592 mol) in dichloromethane (15 mL) was cooled to - 78 °C, and added BBr₃ (0.74 g, 0.00296 mol). This was stirred for 30 min at the same temperature, and then quenched with sodium bicarbonate solution. The organic portion was washed with brine, dried over sodium sulphate, concentrated to get residue. The residue was further purified by silica gel column chromatography using ethyl acetate: hexanes (3:7) to afford the titled compound (0.1 g, 50%). LC-MS: 324.2 [M+H]⁺.

Intermediate-23: Synthesis of 2-chloro-6-methyl-6-(4-morpholinophenyl)-7,8- dihydroquinolin-5(6H)-one

lntermediate-20d 23a lntermediate-23

Reagents and conditions: i) Pd(OAc)₂, X-Phos, Cs₂C0₃, Toluene; ii) phosphorus oxychloride, reflux, 12 h..

Step-i: Synthesis of 2-hydroxy-6-methyl-6-(4-morpholinophenyl)-7,8-dihydroquinolin-5(6H)- one (23a) To a degassed stirred mixture of 6-(4-bromophenyl)-6-methyl-7,8-dihydroquinoline-2,5(lH,6H)- dione (20d) (0.5 g, 0.00151 mol) in toluene (10 mL), caesium carbonate (1.22 g, 0.0037 mol) and morpholine (0.197 g, 0.0026 mol) was added palladium acetate (0.038 g, 0.000015 mol) followed by X-Phos (0.071 g, 0.000015 mol) a RT. The RM was heated to 110 °C in a screw cap sealed tube. After 10 h, the RM was cooled and diluted with ethyl acetate, washed with water, brine, dried over sodium sulphate, concentrated to get residue. The residue was purified by silica gel column using ethyl acetate-hexanes (6:4) as eluent to get the pure product (0.15 g, 28.5 %), LC-MS: 339.2 [M+H]⁺.

Step-ii: Synthesis of 2-chloro-6-methyl-6-(4-morpholinophenyl)-7,8-dihydroquinolin-5(6H)-one Synthesis of 2-chloro-6-methyl-6-(4-morpholinophenyl)-7,8-dihydroquinolin-5(6H)-one was done using the experimental protocol described in Step-v of Intermediate-2. LC-MS: 357.1 [M+H]⁺.

All the intermediates listed in below table were prepared by following similar procedure as depicted in intermediate 23, with appropriate variations in reactants, reagents, solvents and reaction conditions.

Intermediate-26: 2-chloro-6-(3-(dimethylamino)phenyl)-6-methyl-7,8-dihydroquinolin-

5 -one

Reagents and conditions: i) Pd(Amphos)Cl₂, NaOBu , toluene, 60 °C, 3 h; ii) NaH, Mel, DMF, 0 °C, 15 min.

Step-i: Synthesis of 2-chloro-6-(3-chlorophenyl)-7,8-dihydroquinolin-5(6H)-one (26a) To a degased mixture of 2-chloro-7,8-dihydroquinolin-5(6H)-one (0.5 g, 0.0027 mol)) and 3- iodo-N,N-dimethylaniline (0.68 g, 0.00276 mol) in toluene (20 mL) was added sodium tert- butoxide (0.53, 0.0055 mol) followed by Pd(Amphos)Cl₂ (0.043 g, 0.000055 mol) and stirred under nitrogen for 15 min. The reaction mixture was then heated to 60 °C for 6 h. The RM was then cooled to RT, extracted into ethyl acetate, organic portion was dried over sodium sulphate, concentrated to dryness to afford 0.3g of titled compound. This was taken as such into next step without further purification. LC-MS: 301.0 [M+H]⁺.

Step-ii: Synthesis of 2-chloro-6-(3-(dimethylamino)phenyl)-6-methyl-7,8-dihydroquinolin- 5(6H)-one

To a solution of 2-chloro-6-(3-chlorophenyl)-7,8-dihydroquinolin-5(6H)-one (0.3 g, 0.001 mol) in DMF (5 mL) was added sodium hydride (0.36 g, 0.0015 mol) and cooled to 0 °C. This mixture was then treated with methyl iodide (0.17 g, 0.0012 mol) for 15 min. The RM was quenched with water, extracted into ethyl acetate, and organic portion was dried over sodium sulphate, concentrated to get residue. This was purified by flash column chromatography (silica gel) using 20% ethyl acetate in hexanes as eluents to give the titled compound (0.065 g, 20.8%). LC-MS: 315.0 [M+H]⁺.

The below Intermediates were prepared according to the similar protocol described in Step-iv to Step-v of Intermediate-26, with appropriate variations in reactants, quantities of reagents, solvents and reaction conditions.

Intermediat

-methyl-7,8- dihydroquinolin-5(6H)

lntermediate-29 lntermediate-31

Reagents and conditions: i) Methyl magnesium bromide, THF, 0 °C to RT, 45 min.

Methyl magnesium bromide (1.59 mL of 3M solution, 0.0047 mol) was added to a cooled solution of 6-(4-acetylphenyl)-2-chloro-6-methyl-7,8-dihydroquinolin-5(6H)-one (lntermediate- 29) (0.5 g, 0.00159 mol) in dry THF (20 mL). The RM was gradually warmed to RT over 45 min. The RM was then quenched with ice, extracted with ethyl acetate, organic portion was washed with water, brine, dried over sodium sulphate, concentrated to get the titled compound. Further this was purified by preparative HPLC to get pure product (0.4 g, 76.19 %) LC-MS: 330.3 [M+H]⁺.

Intermediate-32: Synthesis of 2-chloro-6-(4-chlorophenyl)-6-(methoxymethyl)-7,8- dihydroquinolin-5(6 -one

lntermediate-15 Intermediate-32

Reagents and conditions: i) NaH, bromo(methoxy)methane, DMF, 0 °C to RT lh,

Sodium hydride (0.012 g, 0.00051 mol) was added to an ice cold solution of 2-chloro-6-(4- chlorophenyl)-7,8-dihydroquinolin-5(6H)-one (Intermediate- 15) (0.15 g, 0.00051 mol) in DMF (5 mL). This mixture was stirred at the same temperature for 10 min and treated with bromo(methoxy)methane (0.072 g, 0.00059 mol) before it was gradually allowed to warm to RT in 1 h. The RM was quenched with ice, extracted with ethyl acetate, organic portion was washed with water, brine, dried over sodium sulphate and concentrated to get residue. This was further purified by flash chromatography to get pure compound (0.105 g, 82%). ¹H NMR (300 MHz, DMSO-D⁶) δ 7.75 (d, 1H), 7.58 (d, 2H), 7.45 (d, 2H), 7.39 (d, 1H), 4.656 (s, 2H), 3.30 (s, 3H), 2.95-2.75 (m, 4H).

Intermediate-33: Synthesis of 6-(((tert-butyldimethylsilyl)oxy)methyl)-2-chloro-6-(4- chlorophenyl)-7,8-dihydroquinolin-5(6H)-one

lntermediate-15 33a Intermediate-33

Reagents and conditions: i) NaOMe, paraformaldehyde, DMSO, 0.5 h; ii) tert- butyldimethylsilyl chloride, triethylamine, DCM, 8 h;

Step-i: Synthesis of 2-chloro-6-(4-chlorophenyl)-6-(hydroxymethyl)-7,8-dihydroquinolin-5(6H)- one (33a)

To a stirred solution of 2-chloro-6-(4-chlorophenyl)-7,8-dihydroquinolin-5(6H)-one (Intermediate- 15) (0.3 g, 0.00103 mol) in DMSO (10 iriL) was added sodium methoxide (0.0027 g, 0.00005 mol) and paraformaldehyde (0.032 g, 0.00108 mol) at RT. The RM was stirred at RT for 30 min, then it was quenched with ice cold dilute HCl and extracted into ethyl acetate. The organic portion was dried over sodium sulphate, concentrated to get the crude compound. This was purified on silica gel column using 30% ethyl acetate in hexane as eluent to get the titled compound (0.25 g, 75%). LC-MS: 322.0 [M+H]⁺.

Step-ii Synthesis of 6-(((tert-butyldimethylsilyl)oxy)methyl)-2-chloro-6-(4-chlorophenyl)-7,8- dihydroquinolin-5(6H)-one

To a solution of 2-chloro-6-(4-chlorophenyl)-6-(hydroxymethyl)-7,8-dihydroquinolin-5(6H)-one (0.1 g, 0.00031 mol) and triethylamine (0.062 g, 0.00062 mol) in DCM was added tert- butyldimethylsilyl chloride (0.069 g, 0.00046 mol) dropwise. The RM was stirred at RT for 8 h, and then quenched with ice cold water, extracted with ethyl acetate, organic portion was washed with water, dried over sodium sulphate, concentrated to get crude product. This was purified on silica gel column using 20% ethyl acetate in hexanes as eluent. *H-NMR (300 MHz, DMSO-D⁶) δ = 8.32(d, 1H), 7.58 (d, 1H), 7.45 (d, 2H), 7.29(d, 2H), 3.65-3.60 (m, 2H), 3.02-2.98(m, 2H), 0.28-0.87(m, 14H).

Intermediate-34: Synthesis of 2-chloro-6-(2-hydroxyphenyl)-6-methyl-7,8-dihydroquinolin- 5(6H)-one

lntermediate-28 Intermediate-34

Reagents and conditions: i) BBr₃, DCM, 0 °C.

A stirred solution of 2-chloro-6-(2-methoxyphenyl)-6-methyl-7,8-dihydroquinolin-5(6H)-one (lntermediate-28) (0.2 g, 0.0006622 mol) in dichloromethane (10 mL) was cooled to 0 °C, and added BBr₃ (0.6 mL, 1M solution in DCM, 0.00096 mol). This was stirred at the same temperature for 30 min, and then quenched with ice. The RM was diluted with DCM, and separated oganic portion was washed with brine, dried over sodium sulphate, concentrated to get residue. The residue was further purified by silica gel column using ethyl acetate: hexanes (3:7) to afford titled compound (0.1 g, 50 %). LC-MS: 288.2 [M+H]⁺.

The below Intermediates were prepared according to the similar protocol depicted in Intermediate-34 with appropriate variations in reactants, quantities of reagents, solvents and reaction conditions.

Intermediate-37 and Intermedia te-38:

(lsomer-1)

lntermediate-2 (lsomer-2)

Intermediate-37 lntermediate-38

The racemic mixture of Intermediate-2 (3.5 g, 0.011 mol) was separated by preparative HPLC to give two separated enantiomers (Isomer- 1 and Isomer-2). COLUMN : LUX Amylose 2 ( 21.2mm x 150mm particle size 5μπι); FLOW: 20ML/MIN; with water in acetonitrile ISOCRATIC:A:B::3:2(60:40). This yielded 1.5g of Intermediate-38 (Isomer-2), LC-MS: 306.2 [M+H]⁺ and 1.4 g of Intermediate-37 (Isomer-1), LC-MS: 306.2 [M+H]⁺.

The below Intermediates were separated as described above.

Intermediate-45: Synthesis of 6-(4-chlorophenyl)-6-methyl-5,6,7,8-tetrahydroquinolin-2-yl trifluoromethanesulfonate

45d 45e lntermediate-45

lsomer-1

Reagents and conditions: i) NaOMe, methanol, dioxane, ii) NaBH_4i MeOH; iii) NaH, CS₂, 0 °C-RT; iv) Tributyltin hydride, 85 °C, 3 h; v) BBr₃, DCM, 0 °C-RT; vi) Trifluoromethanesulfonic anhydride, DMAP, 0 °C-RT;

Step-i: Synthesis of 6-(4-chlorophenyl)-2-methoxy-6-methyl-7,8-dihydroquinolin-5(6H)-one (45a}

To a stirred solution of 2-chloro-6-(4-chlorophenyl)-6-methyl-7,8-dihydroquinolin-5(6H)-one (Intermediate-37, Isomer-1) (0.9 g, 0.0029 mol) in dioxane/methanol(20 mL/15 mL) was added sodium methaoxide (0.23 g, 0.044 mol) and stirred at RT for 24 h. The volatiles were evaporated under reduced pressure to get residue. The residue was dissolved in ethyl acetate, washed with water, brine, dried over sodium sulphate and concentrated to get crude compound. This was purified on silica gel column using 10% ethyl acetate in hexanes as eluent to afford the titled compound (0.8 g, 91 %) 302.1 [M+H]⁺.

Step-ii: Synthesis of 6-(4-chlorophenyl)-2-methoxy-6-methyl-5,6,7,8-tetrahydroquinolin-5-ol (45b)

To a stirred solution of 6-(4-chlorophenyl)-2-methoxy-6-methyl-7,8-dihydroquinolin-5(6H)-one (45a) (0.75 g, 0.00248 mol) in methanol was added sodium borohydride (0.376 g, 0.0099 mol) in portions. The resultant mixture was stirred at RT for an hour. The RM was then quenched with ice and the methanol was evaporated under reduced pressure to get residue. The residue obtained was extracted with ethyl acetate and the organic portion was washed with water, dried over sodium sulphate, concentrated to get residue. The residue was purified on silica gel column using 20% ethyl acetate in hexane to afford the titled compound (0.65 g, 86 %) LC-MS: 304.2 [M+H]⁺. Step-iii: Synthesis of 0-(6-(4-chlorophenyl)-2-methoxy-6-methyl-5,6,7,8-tetrahydroquinolin-5- yl) S-methyl carbonodithioate (45c) A solution of 6-(4-chlorophenyl)-2-methoxy-6-methyl-5,6,7,8-tetrahydroquinolin-5-ol (45b) (0.64 g, 0.0021 mol) in THF was cooled to 0 °C and added sodium hydride (0.053 g, 0.0023 mol) under nitrogen atmosphere. The RM was stirred at RT for an hour and again cooled to 0 °C before treating with carbon disulphide (0.32 g, 0.0042 mol) and then stirred at RT for 3 h. The resultant mixture was then cooled back to 0 °C, and treated with methyl iodide (0.329 g, 0.0023 mol) at the same temperature for 30 min. The RM was quenched with ice cold water, extracted with ethyl acetate, organic portion was washed with water, brine and dried over sodium sulphate, concentrated to get residue. The residue was purified on silica gel column using 5% ethyl acetate in hexanes as eluent to afford the title product (0.35 g, 42.6 %). LC-MS: 394.2 [M+H]⁺.

Step-iv: Synthesis of 6-(4-chlorophenyl)-2-methoxy-6-methyl-5, 6,7, 8-tetrahydroquino line (45d) A mixture of 0-(6-(4-chlorophenyl)-2-methoxy-6-methyl-5,6,7,8-tetrahydroquinolin-5-yl) S- methyl carbonodithioate (45c) (0.32 g, 0.00812 mol), tributyltin hydride (0.26 g, 0.00089 mol) and AIBN (0.004 g, 0.000024 mol) in toluene (15 mL) was heated to 85 °C for 3 h. The RM was cooled to RT, diluted with hexane, washed with water, brine solution, dried over sodium sulphate and concentrated to get crude compound. This was purified on silica gel column using 0-5% ethylacetate in hexanes as eluent to get the tilted compound (0.21 g, 91.3 %). LC-MS: 288.3 [M+H]⁺.

Step-v: Synthesis of 6-(4-chlorophenyl)-6-methyl-5,6,7,8-tetrahydroquinolin-2-ol (45e)

6-(4-chlorophenyl)-2-methoxy-6-methyl-5,6,7,8-tetrahydroquinoline (45d) was demethylated using the similar protocol depicted in the synthesis of Intermediate-34. LC-MS: 274.1 [M+H]⁺.

Step-vi: Synthesis of 6-(4-chlorophenyl)-6-methyl-5, 6,7, 8-tetrahydroquino lin-2-yl trifluoromethanesulfo nate

Compound 6-(4-chlorophenyl)-6-methyl-5,6,7,8-tetrahydroquinolin-2-ol (0.16 g, 0.00058 mol) in pyridine (10 mL), was cooled to 0°C and added DMAP (0.0014 g, 0.0000116 mol) followed by trifluoromethanesulfo nic anhydride (0.18 g, 0.00064 mol) for 30 min at 0°C. Pyridine was evaporated and the residue was dissolved in ethyl acetate, washed with water, brine, dried over sodium sulphate, concentrated to get the titled compound (0.1 g, 42.2%). LC-MS: 406.2 [M+H]⁺.

The below Intermediates were prepared according to the similar protocol as described above with appropriate variations in reactants, quantities of reagents, solvents and reaction conditions. Intermedi

48c 48d 48e Intermediate-48

Reagents and conditions: i) Sodium nitrite, cone, hydrochloric acid, 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) OT-chloroperbenzoic acid, dichloromethane, 0 °C-room temperature, 12 h; v) sodium hydroxide, ethanol, water, room temperature, 12 h; vi) thionyl chloride, room temperature, 4-10 h followed by aqueous ammonia, dichloromethane, room temperature, 4-12 h.

Step-i: 2-(4-((ethoxycarbonothioyl)thio)phenyl)acetic acid (48a)

To a 250 mL round bottom flask, were added 4-aminophenylacetic acid (8.5 g, 0.0562 mol), water (28 mL) and cone, hydrochloric acid (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 and reaction mixture was stirred at 0 °C for 45 minutes. The resulting cold diazonium salt solution was drop wise added to a mixture of potassium ethylxanthate (10.4 g, 0.0648 mol), water (16.8 mL) and 2 M sodium carbonate (42 mL). The reaction mixture was maintained at 45 °C for 2 h. The reaction mixture was cooled to 0 °C, acidified to pH 1.0 with cone, hydrochloric acid and 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 title compound (19 g). The crude product was used for the next step without any further purification. Step-ii: 2-(4-mercaptophenyl)acetic acid (48b)

To a 250 mL round bottom flask, were added 2-(4-((ethoxycarbonothioyl)thio)phenyl)acetic acid (48a) (19 g, 0.0741 mol) and ethanol (72 mL). To the same flask, was added potassium hydroxide (15 g, 0.2670 mol) in water (72 mL) and then refluxed for 20 h. The major portion of ethanol was evaporated under reduced pressure to get the residue. The residue was acidified to pH 2.0 with cone, hydrochloric acid 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 (48c)

To a 100 mL round bottom flask, were added 2-(4-mercaptophenyl)acetic acid (48b) (7 g, 0.0416 mol), potassium carbonate (23 g, 0.1664 mol) and NN-dimethylformamide (50 mL). To the same flask, was added ethyl bromide (13.6, 0.1248 mol) and stirred at room temperature for 2.5 h. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was separated and washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography using 10% ethyl acetate in hexane as eluent to get the title compound [6 g, 65 %]. ^!H NMR (400 MHz, CDC1₃): δ 7.30 (d, 2H), 7.22 (d, 2H), 4.18 (q, 2H), 3.57 (s, 2H), 2.96 (q, 2H), 1.33 (t, 3H), 1.25 (t, 3H).

Step-iv: ethyl 2-(4-(ethylsulfonyl)phenyl)acetate (48d)

To a 250 mL round bottom flask, was added ethyl 2-(4-(ethylthio)phenyl)acetate (48c) (5.5 g, 0.0245 mol) and dichloromethane (82.5 mL). The reaction mixture was cooled to 0 °C. To the same flask, was added m-chloroperbenzoic acid (12.6 g, 0.0730 mol) 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, saturated sodium bicarbonate solution, brine, dried over anhydrous sodium sulfate and 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, DMSO-d⁶): δ 7.84 (d, 2H), 7.56 (d, 2H), 4.10 (q, 2H), 3.83 (s, 2H), 3.31 (q, 2H) 1.21-1.07 (m, 6H); LC-MS: 257.2 [M+H]⁺.

Step-v: 2-(4-(ethylsulfonyl)phenyl)acetic acid (48e) To a 50 mL round bottom flask, were added ethyl 2-(4-(ethylsulfonyl)phenyl)acetate (48d) (2.5 g, 0.0098 mol) and ethanol (18 mL). To the same flask, was added a solution of sodium hydroxide in water (1.42 g, 0.0355 mol in 18 mL of water) and then stirred at room temperature for 12 h. The volatiles were evaporated under reduced pressure to obtain the residue. The residue was acidified to pH 5.0 with 1.0 N hydrochloric acid and was extracted with ethyl acetate. The organic layer was separated and washed with brine, dried over sodium sulfate and evaporated under reduced pressure to get the title compound [2.4 g, 91 %]. *H NMR (400 MHz, DMSO-d⁶): δ 12.5 (brs, 1H), 7.84 (d, 2H), 7.56 (d, 2H), 3.74 (s, 2H), 3.13 (q, 2H), 1.20 (t, 3H).

Step-vi: 2-(4-(ethylsulfonyl)phenyl)acetamide

To a 50 mL round bottom flask, were added 2-(4-(ethylsulfonyl)phenyl)acetic acid (48e) (0.5 g, 0.0023 mol) and thionyl chloride (5 mL). The reaction mixture was stirred at room temperature for 6 h. The volatiles were evaporated under reduced pressure to get the solid. The solid was dissolved in dichloromethane (10 mL) and treated with aqueous ammonia (5 mL) at room temperature for 12 h. The volatiles were evaporated to get the crude residue. The crude residue was extracted with 10 % methanol in chloroform. The combined organic phase was washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure to get the title compound [0.36 g, 72 %]. ^!H NMR (300 MHz, DMSO- d⁶): δ 7.83-7.80 (m, 2H), 7.58 (brs, 1H), 7.54-7.51 (m, 2H), 7.00 (brs, 1H), 3.52 (s, 2H), 3.33 (q, 2H), 1.21 (t, 3H). LC-MS: 228.1 [M+H]⁺.

All the intermediates listed in below table were prepared by following similar procedure as depicted in the synthesis of Intermediate-48 with appropriate variations in reactants, reagents, solvents and reaction conditions.

Intermediate-52: Synthesis of 2-(4-(ethylsulfonyl)phenyl)acetamide

52a Intermediate-52

Reagents and conditions: i) Ethylamine in THF, RT; ii) Thionyl chloride, DCM, Amonia solution.

Step-i: Synthesis of 2-(4-(N-ethylsulfamoyl)phenyl)acetic acid (52a)

A 50 ML RB was charged with 2-(4-(chlorosulfonyl)phenyl)acetic acid (2 g, 0.0085 mol) and ethylamine solution in THF (8.5mL) and stirred for 5 h. The RM was concentrated to get residue. The obtained residue was dissolved in water, acidified with dil. HCl and extracted into ethyl acetate. The organic portion was dried over sodium sulphate, concentrated to afford the titled compound (1 g, 50 %).

Step-ii: Synthesis of 2-(4-(ethylsulfonyl)phenyl)acetamide

To a solution of 2-(4-(N-ethylsulfamoyl)phenyl)acetic acid (52a) (0.5 g, 0.002 mol) in DCM (10 mL) was added thionyl chloride (lOmL) and stirred for 5 h at RT. The RM was concentrated to get residue. The obtained residue was dissolved in DCM and with ammonia at RT for 5 h. The RM was then extracted with DCM, organic portion was dried over sodium sulphate, concentrated to get the titled compound (0.35 g, 70 %). LC-MS: 243.3 [M+H]⁺.

Intermediate-53: Synthesis of 2-(4-(ethylsulfonyl)phenyl)acetamide

53a 53b lntermediate-53 Reagents and conditions: i) Triethylamine, ethanesulfonyl chloride, DCM, RT; ii) LiOH, MeOH, water, RT; iii) Thionyl chloride, DCM, ammonia solution.

Step-i: Synthesis of methyl 2-(4-(ethylsulfonamido)phenyl)acetate (53a) A solution of methyl 2-(4-aminophenyl)acetate (2.0 g, 0.0121 mol) in DCM (25 mL) was treated with ethanesulfonyl chloride (1.8 g, 0.0145 mol) at RT for 2 h. The RM was diluted with DCM, washed with water, brine, dried over sodium sulphate, concentrated to get the titled compound (1.5 g, 48.4 %). LC-MS: 258.0 [M+H]⁺

Step-ii: Synthesis of 2-(4-(ethylsulfonamido)phenyl)acetic acid (53b)

53b was synthesized using the similar protocol described in step-iv of intermediate- 16. Yield (1.0 g, 71.4 %).

Step-iii: Synthesis of 2-(4-(ethylsulfonamido)phenyl)acetamide

Intermediate-53 was synthesized using the similar protocol described in step-ii of intermediate- 52.

^!H NMR (300 MHz, DMSO-d⁶): δ 7.78-7.59 (m, 4H), 7.0 (brs, 1H), 3.52 (s, 2H), 3.28 (q, 2H), 3.12 (t, 3H).

Intermediate-54: Synthesis of 2-chloro-6-(2-hydroxy-4-methylphenyl)-6-methyl-7,8- dihydroquinolin-5(6H)-one

2-chloro-6-(2-hydroxy-4-methylphenyl)-6-methyl-7,8-dihydroquinolin-5(6H)-one was prepared using the similar protocol described in Intermediate-34. LC-MS: 302.1 [M+H]⁺

Intermediate-55: Synthesis of 2-chloro-6-(3-fluoro-2-hydroxyphenyl)-6-methyl-7,8- dihydroquinolin-5(6H)-one

The Intermediate-55 was prepared according to the similar protocol described in the synthesis of Intermediate-34, with appropriate variations in reactants, quantities of reagents, solvents and reaction conditions. LC-MS: 306.2 [M+H]⁺

The below Intermediates (56 and 57) were prepared according to the similar protocol described in the synthesis of Intermediate-26, with appropriate variations in reactants, quantities of reagents, solvents and reaction conditions.

Intermediate-58: Synthesis 5,5-dimethyl-5,6,7,8-tetrahydroquinolin-2-yl trifl rometh nesulfonate

58e 58f Intermediate-58

Step-i: Synthesis of 7,8-dihydro-5H-spirorquinoline-6,2'-rL31dioxolanl-2-ol (58a)

A mixture of l,4-dioxaspiro[4.5]decan-8-one (15 g, 0.096 mol), ethyl propiolate (20 g, 0.201 mol) and methanolic ammonia (150 mL) in isopropanol (240 mL) was heated to 135 °C in a sealed tube for 12 h. The RM was cooled to RT, and concentrated to minimum volume then again cooled to 0 °C and stirred for 2 h to get the solid. The solid formed was filtered and washed with IPA and dried to get the titled compound (7.5 g, 37.5 %).

Step-ii: Synthesis of 2-methoxy-7,8-dihydro-5H-spirorquinoline-6,2'-rL31dioxolanel (58b)

To a mixture of intermediate-58a (7.4 g, 0.035 mmol), benzyltriethylammonium chloride (4.07 g, 0.0178 mol), silver carbonate (9.8 g, 0.035 mol) and iodomethane (15.2 g, 0.107 mol) in DCM (75 mL) was added aqueous sodium hydroxide (1.6 g, 0.0392 mol) and stirred at RT for 5 h. The RM was filtered through celite, washed with DCM. The filtrate was dried over sodium sulfate and concentrated to get the titled compound (4.5 g, 56.2 %) LC-MS: 206.1 [M+H]⁺.

Step-iii: Synthesis of 2-methoxy-7,8-dihvdroquinolin-6(5H)-one (58c)

To intermediate- 58b (4.4 g, 0.0198 mol) in water (40 mL) was added poly phosphoric acid (19 mL) and stirred until complete dissolution and heated to 75 °C for 3 h. The RM was then cooled to 0 °C, neutralized with 60% sodium hydroxide, extracted with ethyl acetate. The organic portion was dried over sodium sulfate and concentrated to get the titled compound (2.5 g, 71.4 %); LC-MS: 178.0 [M+H]⁺

Step-iv: Synthesis of 2-methoxy-5,5-dimethyl-7,8-dihydroquinolin-6(5H)-one (58d)

To a mixture of sodium tert-butoxide (2.8 g, 0.0297mol) in THF (30 mL) was added a solution of 58c (2.4 g, 0.0135 mol) and methyl iodide (4.2 g, 0.297 mol) dropwise at 0 °C. The RM was then stirred at RT for 10 min, quenched with water and extracted into ethyl acetate. The organic portion was washed with brine and dried over sodium sulfate, concentrated to get residue. The residue was purified on silica gel column using 10% ethyl acetate in hexanes to afford the titled compound (5.4 g, 49 %). LC-MS: 206.1 [M+H]⁺

Step-v: Synthesis of 2-methoxy-5,5-dimethyl-5,6,7,8-tetrahydroquinoline (58e)

To a mixture of 58d (0.5 g, 0.0024 mol) and 85% aqueous KOH (1.2 g, 0.022 mol) in ethylene glycol (15 mL) was added hydrazine hydrate (1.4 g, 0.0029 mol) and heated to 130 °C for 1 h and then refluxed for 16 h. The RM was cooled and added water, extracted into ethyl acetate . The organic portion was wahsed with water, brine, dried over sodium sulfate, concentrated to get the titled compound (O. lg, 25%).

Step-vi: Synthesis of 5,5-dimethyl-5,6,7,8-tetrahydroquinolin-2-ol (58f)

The intermediate- 58e (0.4 g, 0.002 mol) in acetic acid (4.0 mL) was heated to 90 °C in a sealed tube for 12 h. The RM was cooled to RT and concentrated to get residue, which was neutralized with sodium bicarbonate solution and then extracted into ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated to get the titled compound (0.25 g, 67.5 %).

Step-vi: Synthesis of 5,5-dimethyl-5,6,7,8-tetrahvdroquinolin-2-yl trifluoromethanesulfonate (Intermediate-58)

To a stirred solution of 58f (0.25 g, 0.0013 mol) and DMAP (0.016 g, 0.00013 mol) in pyridine (10 mL) was added triflic anhydride (0.4 g, 0.0014 mol) at 0 °C and then stirred at RT for 1 h. The RM was quenched by adding cold water, extracted into ethyl acetate. The organic portion was washed with water, brine, dried over sodium sulfate and concentrated to get residue. The residue was purified on silica gel column using 15% ethyl acetate in hexanes to get the pure titled compound (0.265 g, 66 %) LC-MS: 310.1 [M+H]⁺. EXAMPLES

Example-1: Synthesis of N-(6,6-dimethyl-5-oxo-5,6,7,8-tetrahydroquinolin-2-yl)-2-(4- ethylsulfonyl)phenyl)acetamide (Compound- 1)

Reagents and conditions: i) 2-(4-(ethylsulfonyl)phenyl)acetamide, Xantphos, palladium(II) acetate, K₂C0₃, 1, 4-dioxane, 100 °C, 3 h.

A 25 mL sealed tube was charged with 2-chloro-6,6-dimethyl-7,8-dihydroquinolin-5(6H)-one (Intermediate- 1) (0.08 g, 0.00038 mol), 2-(4-(ethylsulfonyl)phenyl)acetamide (Intermediate-48) (0.174 g, 0.00076 mol), K₂C0₃ (0.078 g, 0.00057 mol) and 1, 4-dioxane (15 mL). The reaction mixture was degassed with nitrogen. To the same sealed tube, Xantphos (0.022 g, 0.000038 mol), and palladium(II)acetate (0.004 g, 0.000019 mol) were added. The reaction mixture was again degassed with nitrogen. The reaction mixture was stirred at 100 °C for 3 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The organic layer was 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 CombiFlash^® chromatography using 2 % methanol in chloroform to get the title compound [0.03 g, 20 %].

*H NMR (300 MHz, CDC1₃): δ 8.33 (d, 1H), 8.14-8.09 (m, 2H), 7.93 (d, 2H), 7.56 (d, 2H), 3.85 (s, 2H), 3.16-3.09 (m, 2H), 2.99 (t, 2H), 2.01 (t, 2H), 1.32 (t, 3H), 1.20 (s, 6H).

The compounds listed in below table were prepared by procedure similar to the one described in Example-1 with appropriate variations in reactants, quantities of reagents, solvents and reaction conditions. The characterization data of the compounds are summarized herein below table. Compound

Structure Characterization data

No.

H NMR (300 MHz, CDC1₃): δ 8.33 (d, IH), 8.20 (s, IH), 8.12 (d, IH), 7.74-7.61 (m, 3H), 3.88 (s, 2H), 3.18-3.11 (m, 2H), 3.02 (t, 2H), 2.03 (t, 2H), 1.34 (t, 3H),

1.22 (s, 6H). LC-MS: 419.5 (M+l)⁺.

IH NMR (400 MHz, CDC1₃): δ 8.42 (d, IH), 8.17 (d, IH), 8.01 (s, IH), 7.92 (d, 2H), 7.55 (d, 2H), 7.40-7.32 (m, 2H), 7.28-7.18 (m, 2H), 3.84 (s, 2H), 3.13-3.00

(m, 4H), 2.94-2.89 (m, IH), 1.86-1.83 (m, IH), 1.66 (s, 3H), 1.29- (t, 3H). LC-MS: 497.0 (M+l)⁺.

IH NMR (400 MHz, DMSO-d°): δ 11.2 (s, IH), 8.22 (d, IH) , 8.08 (d, IH), 7.85(d, 2H), 7.63 (d, 2H), 7.48 - 7.46 (m, 1H),7.33 - 7.31 (m, 3H), 4.34 - 4.30 (m, IH), 3.93 (s, 2H), 3.35-3.25 (m, 2H), 3.05

- 3.01 (m, IH), 2.67 - 2.55 (m, 2H), 2.3- 2.2 (m, IH), 1.09 (t, 3H). LC-MS: 483.1 (M+l)⁺.

H NMR (300 MHz, CDC1₃): δ 8.33 (d, IH), 8.14-8.11 (m, 2H), 7.93 (d, 2H), 7.56 (d, 2H), 3.85 (s, 2H), 3.16-3.08 (m, 2H),

2.99 (t, 2H), 2.10-2.04 (m, 4H), 1.77-1.70

(m, 4H), 1.55-1.53 (m, 2H), 1.32 (t, 3H); LC-MS: 427.1 (M+l)⁺.

^JH NMR (400 MHz, DMSO-J⁶): δ 11.38 (brs,lH), 8.24 (d, IH), 8.07 (d, IH), 7.74 (s, 1H),7.73 (d,2H),7.48-7.47 (m, IH), Compound

Structure Characterization data

No.

7.34 (d, 3H), 4.02(s, 2H), 3.40 (q, 2H), 3.07-3.02 (m, IH), 2.67-2.56 (m, 2H), 2.28-2.24 (m, IH), 1.14 (t, 3H). LC-MS: 501.0 (M+l)⁺.

H NMR (400 MHz, DMSO-if + D₂0): δ 8.24-8.22 (d, IH), 8.03-8.00 (d, IH), 7.68 (s, 3H), 7.55 (d, IH), 7.39 (t, 2H), 7.31 (d, IH), 3.97 (s, 2H), 3.32-3.23 (m, 3H),

2.95-2.91 (m, 2H), 1.85-1.82 (m, IH),

1.59 (s, 3H), 1.10 (t, 3H). LC-MS: 515 (M+l)⁺.

H NMR 400 MHz, CDC1₃): δ 8.31 (d,lH), 8.15 (d, lH), 7.97 (s, IH), 7.94 (d, 2H), 7.56-7.53 (m, 4H), 7.35- (d, 2H), 3.85 (s, 2H), 3.16 (q, 2H), 3.02-2.98 (m, 2H), 2.82-2.80(m, 2H), 2.52-2.48 (m,

IH), 2.32-2.27 (m, 2H), 2.20-2.92 (m, IH), 1.84-1.78 (m, IH), 1.32 (t, 3H). LC- MS: 545.2 (M+l)⁺.

H NMR (400 MHz, CDC1₃): δ 8.31-8.29 (d,lH), 8.12 (d,2H), 7.74-7.67(m 2H), 7.62 (t, lH), 7.55 (d, 2H) 7.35 (d, 2H), 3.87 (s, 2H), 3.15- (q, 2H), 3.04-3.02 (m, 2H), 2.83-2.81 (m, 2H),2.52- 2.48

(m, lH), 2.32-2.30 (m, 2H), 2.20-1.92 (m,

IH), 1.84-1.76 (m, IH), 1.33 (t, 3H). LC- MS: 563.1 (M+l)⁺.

(t,

(t,

Compound

Structure Characterization data

No.

3H), 4.7-4.2 (m, 1H), 3.89 (s, 2H), 3.34- 3.26 (m, 4H), 1.42 (s, 3H), 1.09 (t, 3H). LC-MS: 463.1 (M+l)⁺.

1H NMR (400 MHz, CDC13): δ 8.38 (d, 1H), 8.12 (d, 1H), 7.94-7.89 (m, 3H), 7.53 (d, 2H), 7.26 (d, 2H), 7.14 (d, 2H),

23 3.81 (s, 2H), 3.14-3.08 (m, 2H), 2.88-2.85

(m, 2H), 2.61-2.57 (m, 1H), 2.34-2.27 (m,

1H), 2.00-1.56 (m, 2H), 1.30 (t, 3H), 0.83 (t, 3H). LC-MS: 510.7 (M+l)⁺.

H NMR (400 MHz, CDC1₃): δ 8.41 (d, 1H), 8.15 (d, 1H), 7.93 (s, 1H),7.92 (d, 2H) 7.53- (d, 2H), 7.25 (d, 2H),7.12 (d,

24 2H), 3.82 (s, 2H), 3.14 (q, 2H), 2.83-2.79

(m, 2H), 2.62-2.59 (m, 1H), 2.30-2.20 (m,

Isomer-2

1H), 1.49 (s, 3H), 1.30-1.27 (t, 3H). LC- MS: 497.1 (M+l)⁺.

H NMR (400 MHz, CDC1₃): δ 8.41 (d, 1H), 8.15 (d, 1H), 7.93 (s, 1H),7.92 (d, 2H) 7.53 (d, 2H), 7.25 (d, 2H), 7.12 (d,

25 2H), 3.82 (s, 2H), 3.14 (q, 2H), 2.83-2.79

(m, 2H), 2.62-2.59 (m, 1H), 2.30-2.20 (m,

Isomer- 1

1H), 1.49 (s, 3H), 1.30 (t, 3H). LC-MS: 497.2 (M+l)⁺.

H NMR (300 MHz, DMSO-d°): δ 8.38 (d, 1H), 8.12 (d, 1H), 7.91(t, 3H), 7.53

26 (d, 2H), 7.08 (d, 2H), 6.81 (d, 2H), 3.83

(t, 6H), 3.15-3.07 (m, 6H), 2.86-2.81 (m,

2H), 2.63-2.58 (m, 1H), 2.28-2.18 (m,

Compound

Structure Characterization data

No.

^JH NMR (400 MHz, CDC1₃): δ 8.41-8.31 (d, IH), 8.16 (d, IH), 8.02 (bs, IH), 7.90 (d, 2H), 7.53 (d, 2H), 6.73 (d, 2H), 3.83

39 (s, 3H), 3.15 (q, 2H), 2.85-2.83 (m, 2H),

2.52-2.49 (m, IH), 2.28-2.18 (m, 2H),

1.58 (s, 3H), 1.29 (t, 3H). LC-MS: 515.3 (M+l)⁺.

Ή NMR (400 MHz, CDC1₃): δ 8.41 (d, IH), 8.13 (d, IH), 8.02 (s, IH), 7.91 (d, 2H), 7.53 (d, 2H), 7.21 (t, IH), 6.75-6.72

40 N N (m, 3H), 3.82 (s, 2H), 3.74 (s, 3H),3.14- H

3.08 (m, 2H), 2.87-2.81 (m, 2H), 2.66- 2.60 (m, lH), 2.27-2.17(m, IH), 1.50 (s, 3H), 1.30 (t, 3H). LC-MS: 492.7(M+1)⁺.

Ή NMR (300 MHz, CDC1₃): δ 8.65 (d, IH), 7.88 (d, 7.58 (d, 2H), 7.24-7.22 (m, 3H), 7.13 (brs, IH), 7.03-6.99 (m, IH),

41 — N N — 3.92 (s, 2H), 3.19-3.13 (m, 3H), 3.08-2.98

H

(m, 2H), 2.75-2.68 (m, IH), 2.34-2.17 (m, IH), 1.51 (s, 3H), 1.29 (t, 3H). LC-MS: 497.1 (M+l)⁺.

^JHNMR (400 MHz CD₃OD): 8.35 (d, IH), 8.09 (d, IH), 7.89 (d, 2H), 7.63 (d, 2H), 7.14 (t, IH), 6.65 (d, IH), 6.56 (d,

42 2H), 3.89 (s, 2H), 3.23-3.14 (m, 2H), 2.87

(d, 8H), 2.73 (d, 2H), 2.28-2.20 (m, IH),

1.48 (s, 3H), 1.24-1.20 (m, 3H). LC-MS: 506.4 (M+l)⁺.

Example-2: Synthesis of N-(6-(4-chlorophenyl)-6-methyl-5-oxo-5,6,7,8-tetrahydroquinolin- 2-yl)-2-(4-((2-hydroxyethyl)sulfonyl)phenyl)acetamide (Compound-54)

Reagents and conditions: i) Xantphos, palladium(II) acetate, K₂CO₃, 1,4-dioxane, 100 °C, 3 h; Step-i: Synthesis of N-(6-(4-chlorophenyl)-6-methyl-5-oxo-5,6,7,8-tetrahydroquinolin-2-yl)-2- (4-((2-methoxyethyl)sulfonyl)phenyl)acetamide

Synthesis of N-(6-(4-chlorophenyl)-6-methyl-5-oxo-5,6,7,8-tetrahydroquinolin-2-yl)-2-(4-((2- methoxyethyl)sulfonyl)phenyl)acetamide was done using the similar protocol described in Example- 1. LC-MS: 512.6 (M-14)⁺.

Step-ii: Synthesis of N-(6-(4-chlorophenyl)-6-methyl-5-oxo-5,6,7,8-tetrahydroquinolin-2-yl)-2- (4-((2-hydroxyethyl)sulfonyl)phenyl)acetamide

Demethylation of this compound was done using the similar protocol described in the synthesis of Intermediate-22.

^!H NMR (400 MHz, DMSO-d⁶): δ 8.42 (d, 1H), 8.12 (d, 2H), 8.09 (s, 1H), 7.93 (d, 2H), 7.54 (d, 2H), 7.25 (d, 1H), 7.12 (d, 2H), 4.01 (d, 2H), 3.83 (s, 2H), 3.36 (t, 2H), 2.91-2.82 (m, 3H), 2.66- 2.59 (m, 1H), 2.3-2.2 (m, 1H), 1.49 (s, 3H); LC-MS: 512.6 (M+H)⁺.

Example-3: Synthesis of 2-(4-(ethylsulfonyl)phenyl)-N-(6-methyl-6-(4-(4-methylpiperazin- l-yl)phenyl)-5-oxo-5,6,7,8-tetrahydroquinolin-2-yl)acetamide (Compound-55)

Reagents and conditions: i) 2-(4-(ethylsulfonyl)phenyl)acetamide, Xantphos, palladium(II) acetate, K₂C0₃, 1,4-dioxane, 100 °C, 3 h; ii) 1-methylpiperazine, Cul, L-Proline, K₃P0₄, DMSO. Synthesis of 6-(4-bromophenyl)-2-chloro-6-methyl-7,8-dihydroquinolin-5(6H)-one

6-(4-bromophenyl)-2-chloro-6-methyl-7,8-dihydroquinolin-5(6H)-one was synthesized using the similar protocol explained in the synthesis of Intermediate-2. Step-i: Synthesis of N-(6-(4-bromophenyl)-6-methyl-5-oxo-5,6,7,8-tetrahydroquinolin-2-yl)-2- (4-(ethylsulfonyl)phenyl)acetamide

Synthesis of N-(6-(4-bromophenyl)-6-methyl-5-oxo-5,6,7,8-tetrahydroquinolin-2-yl)-2-(4- (ethylsulfonyl)phenyl)acetamide was done using the similar protocol described in Example- 1. LC-MS: 541 (M)\ 543.3 (M+2H)⁺.

Step-ii: Synthesis of 2-(4-(ethylsulfonyl)phenyl)-N-(6-methyl-6-(4-(4-methylpiperazin-l- yl)phenyl)-5-oxo-5,6,7,8-tetrahydroquinolin-2-yl)acetamide

A stirred mixture of N-(6-(4-bromophenyl)-6-methyl-5-oxo-5,6,7,8-tetrahydroquinolin-2-yl)-2- (4-(ethylsulfonyl)phenyl)acetamide (Intermediate-2 of Example-3) (0.1 g, 0.00018 mol), 1- methylpiperazine (0.22 g, 0.0022 mol), potassium phosphate (0.076 g, 0.00036 mol), L-proline (0.013 g, 0.0009 mol), cuprous iodide (0.008 g, 0.00003 mol) and DMSO (10 mL) taken in a screw cap sealed tube was heated to 120 °C for 5 h. The RM cooled to RT, added water and extracted into ethyl acetate. The organic layer was dried over Na₂S0₄ and concentrated to get the crude compound. This was further purified by preparative TLC (Silica gel) using ethyl acetate as eluent.

^!H NMR (400 MHz, CDC1₃): δ 8.40 (d, 1H), 8.11 (d, 1H), 8.02 (s, 1H) 7.91 (d, 2H), 7.52 (d, 2H), 7.06 (d, 2H), 6.82 (d, 2H), 3.80 (s, 2H), 3.16-3.08 (m, 6H), 2.86-2.79 (m, 2H), 2.62-2.57 (m, 1H), 2.55-2.52 (m, 4H), 2.33 (s, 3H), 2.25-2.15 (m, 1H), 1.46 (s, 3H), 1.30 (t, 3H). LC-MS: 561.2 (M+l)⁺.

Example-4: Synthesis of N-(6-(4-(lH-tetrazol-5-yl)phenyl)-6-methyl-5-oxo-5,6,7,8- tetrahydroquinolin-2-yl)-2-(4-(ethylsulfonyl)phenyl)acetamide (Compound-56)

Compound-34 Compound-56

Reagents and conditions: i) Azidotrimethyltin (IV), DMA, 110 °C, 12 h.

A solution of N-(6-(4-cyanophenyl)-6-methyl-5-oxo-5,6,7,8-tetrahydroquinolin-2-yl)-2-(4- (ethylsulfonyl)phenyl)acetamide (Compound-34) (0.17 g, 0.000348 mol) in a mixture of DMA, toluene (1 mL + 5mL) was added azidotrimethyltin (0.288g, 0.0013 mol) and heated to 110 °C for 12 h. The RM was cooled to RT, concentrated to minimum volume and extracted with 10% methanol in DCM, dried over sodium sulphate and concentrated to get the titled compound (0.01 g, 5.5 %).

^!H NMR (400 MHz CD₃OD): δ 8.40 (d, IH), 8.12 (d, IH), 7.98 (d, 2H), 7.89 (d, 2H), 7.63 (d, 2H), 7.49 (d, IH), 6.79 (d, 2H), 3.90 (s, 2H), 3.51-3.41 (m, IH), 3.23-3.20 (m, 2H), 2.96-2.90 (m, IH), 2.86-2.78 (m, 2H), 2.4-2.3 (m, IH), 1.55 (s, 3H), 1.23-1.17 (m, 3H). LC-MS: 531.3 (M+l)⁺.

Example-5: Synthesis of N-(6-(4-chlorophenyl)-6-(hydroxymethyl)-5-oxo-5,6,7,8- tetrahydroquinolin-2-yl)-2-(4-(ethylsulfonyl)phenyl)acetamide (Compound-57)

lntermediate-33 57a Compound-57

Reagents and conditions: i) 2-(4-(ethylsulfonyl)phenyl)acetamide, Xantphos, palladium(II) acetate, K₂C0₃, 1,4-dioxane, 100 °C, 3 h. ii) TBAF, THF, 0 °C-RT.

Step-i: Synthesis of N-(6-(((tert-butyldimethylsilyl)oxy)methyl)-6-(4-chlorophenyl)-5-oxo- 5,6 ,8-tetrahydroquinolin-2-yl)-2-(4-(ethylsulfonyl)phenyl)acetamide

N-(6-(((tert-butyldimethylsilyl)oxy)methyl)-6-(4-chlorophenyl)-5-oxo-5, 6,7,8- tetrahydroquinolin-2-yl)-2-(4-(ethylsulfonyl)phenyl)acetamide was synthesized using the protocol described in Example- 1. LC-MS: 627.4 (M+l)⁺.

Step-ii: Synthesis of N-(6-(4-chlorophenyl)-6-(hydroxymethyl)-5-oxo-5, 6,7,8- tetrahydroquinolin-2-yl)-2-(4-(ethylsulfonyl)phenyl)acetamide

To a stirred solution of N-(6-(((tert-butyldimethylsilyl)oxy)methyl)-6-(4-chlorophenyl)-5-oxo- 5,6,7,8-tetrahydroquinolin-2-yl)-2-(4-(ethylsulfonyl)phenyl)acetamide (0.15 g, 0.000239 mol) in THF (5 mL) was added tetrabutylammonium fluoride (0.062 g, 0.000239 mol). The resultant mixture was stirred at RT for 10 min and quenched with ice cold water. The mixture was then extracted with ethyl acetate; organic portion was dried over sodium sulphate and concentrated to residue. The residue was purified by preparative HPLC (Method: Column: XBRIDGE C18 ( 19mm x 150mm particle size 5μπι), , 0.02% Ammonia in Water and acetonitrile in MeOH (1: 1) with gradient 20% at beginning, 30% at 2^nd min, 80% at 8^th min, 90% at 10^th min with the flow Rate of 15 mL/min.) to afford pure titled compound (0.05 g, 14 %). *H-NMR (300 MHz, CD₃OD) δ 8.35 (d, IH), 8.12 (d, IH), 7.89 (d, 2H), 7.56 (d, IH), 7.71 (d, 2H), 7.33 (d, 2H), 7.29 (d, 2H), 4.21-4.10 (m, 3H), 3.85-3.75 (m, IH), 3.51-3.54 (m, 2H), 3.22-2.54 (m, 5H), 1.25 (t, 3H). LC-MS: 511.1 [M-H]⁺.

Exapmle-6: Synthesis of N-(6-(4-chlorophenyl)-5-hydroxy-6-methyl-5,6,7,8- tetrahydroquinolin-2-yl)-2-(4-(ethylsulfonyl)phenyl)acetamide (compound-58)

Compound-25 Compound-58

(lsomer-1) (lsomer-1)

Reagents and conditions: (i) NaBH₄, MeOH, 0 °C-RT.

To a stirred solution of N-(6-(4-chlorophenyl)-6-methyl-5-oxo-5,6,7,8-tetrahydroquinolin-2-yl)- 2-(4-(ethylsulfonyl)phenyl)acetamide (Compound-25, Isomer- 1) (0.04 g, 0.00008 mol) in methanol (10 mL) was added sodium borohydride (0.012 g, 0.00032 mol) in portions at 0 °C. The RM was gradually warmed to RT and stirred at RT for 2 h. The RM was quenched with ammonium chloride and evaporated the methanol to get residue. The residue was dissolved in ethyl acetate, organic portion was washed with water, brine dried over sodium sulphate and concentrated to get the residue. The crude was purified by column chromatography (silica gel) using 30-50% ethyl acetate in hexanes to afford (0.01 g, 25 %). 1H NMR (400 MHz, CDC1₃): δ 8.06 (d, IH), 7.95 (s, IH), 7.92 (d, 2H), 7.74 (d, IH), 7.56 (d, 2H), 7.42 (d, 2H), 7.36 (d, 2H), 4.70 (s, IH), 3.81 (s, 2H), 3.15 (q, 2H), 2.91-2.87 (m, 2H), 2.59-2.54 (m, IH), 2.04-2.01 (m, IH), 1.68 (d, IH), 1.31 (s, 3H), 1.29 (t, 3H). LC-MS: 499.2 (M+l)⁺.

Compound-59: Synthesis of N-(6-(4-chlorophenyl)-5-hydroxy-6-methyl-5,6,7,8- tetrahydroquinolin-2-yl)-2-(4-(ethylsulfonyl)phenyl)acetamide (Isomer-2)

The compound-59 was prepared by procedure similar to the one described in Example-6 with appropriate variations in reactants, quantities of reagents, solvents and reaction conditions.

H NMR (400 MHz, CDC1₃): δ 8.06 (d, IH), 7.93 (s, IH), 7.92 (d, 2H), 7.74 (d, IH), 7.56 (d, 2H), 7.42 (d, 2H), 7.36 (d, 2H), 4.70 (s, IH), 3.81 (s, 2H), 3.15 (q, 2H), 2.91-2.87 (m, 2H), 2.59- 2.54 (m, IH), 2.04-2.01 (m, 1H),1.68 (d, IH), 1.31 (s, 3H), 1.29 (t, 3H); LC-MS: 499.1 (M+l)⁺. Example-7: Separation of Enantiomeric mixture of N-(6-(2-chlorophenyl)-6-methyl-5-oxo- 5,6,7,8-tetrahydroquinolin-2-yl)-2-(4-(ethylsulfonyl)phenyl)acetamide (Compound-60 and Compound-61)

Chiral

Compound-3 seperation

Racemate

Compound-60 Compound-61

lsomer-1 lsomer-2

Enantiomeric mixture of N-(6-(2-chlorophenyl)-6-methyl-5-oxo-5,6,7,8-tetrahydroquinolin-2- yl)-2-(4-(ethylsulfonyl)phenyl)acetamide was separated by chiral preparative HPLC to give two separated enantiomers (Isomer- 1 and Isomer-2).

Method: Column: Chiralpak IA (250mmxl0.00mm), 5.0μ; Hexane: 0.1% DEA in EtOH: Ethanol: (40:60); Flow Rate: 7 mL/min.

Physicochemical data of Isomer- 1

^!H NMR (400 MHz, CDC1₃): δ 8.44 (d, IH), 8.19 (d, IH), 8.02 (s, IH), 7.94 (d, 2H) 7.57 (d, 2H), 7.43 (d, IH), 7.36 (d, IH), 7.29 (d, IH), 7.23 (d, IH) 3.86 (s, 2H), 3.16 (q, 2H), 3.10-3.06 (m, 2H) 2.96-2.94 (m, IH), 1.88-1.85 (m, IH), 1.68 (s,3H), 1.32 (t, 3H)

Physicochemical data of Isomer-2

*H NMR (400 MHz, CDC1₃): δ 8.44 (d, IH), 8.95 (d, IH), 8.02 (s, IH), 7.94 (d, 2H), 7.57 (d, 2H), 7.43 (d, IH), 7.36 (d, IH), 7.29 (d, IH), 7.23 (d, IH) 3.86 (s, 2H), 3.16 (q, 2H), 3.06-3.10 (m, 2H) 2.96-2.94 (m, IH), 1.88-1.85 (m, IH), 1.68 (s, 3H), 1.32 (t, 3H).

The below compounds were isolated by the procedure similar to the one described in Example-7.

Compound

Structure Characterization data

No.

^JH NMR (300 MHz, CDC1₃): δ 8.41 (d, IH), 8.16 (d, IH), 8.06 (s, IH), 7.94 - 7.91 (m, 2H), 7.55 (d, 2H), 7.37- 7.34 (m, 2H),

62

H 7.28 (m, IH), 3.86 (s, 2H), 3.16 (q, 4H),

Isomer-2 2.99 - 2.96 (m, 2H), 1.65 (s, 3H), 1.29 (t,

3H). LC-MS: 531.1 (M+l)⁺.

Compound

Structure Characterization data

No.

1H), 3.82 (s, 2H), 3.14 (q, 2H), 3.01-2.96 (m, 3H), 2.01-1.95 (m, 1H), 1.60 (s, 3H), 1.30 (t, 3H). LC-MS: 479 [M+H]⁺.

Example-8: N-(6-(2-chlorophenyl)-5-oxo-5,6,7,8-tetrahydro-l,6-naphthyridin-2-yl)-2-(4-

(ethylsulfonyl)-2-fluorophenyl)acetamide (Compound-68)

Reagents and conditions: i) Lithium aluminum hydride, THF, 0 °C - room temperature, 5 h; ii) (a) m-chloroperbenzoic acid, dichloromethane, 0 °C - room temperature, 5 h (b) phosphorus oxychloride, reflux, 12 h; iii) 2-(4-(ethylsulfonyl)-2-fluorophenyl)acetamide, Xantphos, palladium(II)acetate, K₂C0₃, l,4-dioxane,100 °C, 12 h.

Step-i: ethyl 2-vinylnicotinate

To a 50 mL round bottom flask, were added ethyl 2-chloronicotinate (2 g, 0.0108 mol), potassium vinyltrifluoroborate (1.4 g, 0.0108 mol), 2,6-di-feri-butyl-4-methylphenol (0.071 g, 0.00032 mol) and DMF (20 mL). The reaction mixture was degassed with nitrogen for 5 min. To the same flask, bis(triphenylphosphine)palladium(II) dichloride (0.15 g, 0.00022 mol) was added. The reaction mixture was stirred at 100 °C for 12 h. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to get the crude product. The crude product was purified by CombiFlash^® chromatography using 5 % ethyl acetate in hexane to get the title compound [1.2 g, 63 %]. 1H NMR (300 MHz, CDC1₃): δ 8.71 - 8.69 (m, 1H), 8.18 - 8.15 (m, 1H), 7.67 - 7.57 (m, 1H), 7.25 - 7.22 (m, 1H), 6.52 - 6.46 (m, 1H), 5.61 - 5.57 (m, 1H), 4.44 (q, 2H), 1.41 (t, 3H); LC-MS: 178.3 [M+H]⁺.

Step-ii: 6-(2-chlorophenyl)-7,8-dihydro-L6-naphthyridin-5(6H)-one

To a 25 mL round bottom flask, were added ethyl 2-vinylnicotinate (1.2 g, 0.0067 mol), 2- chloroaniline (1.03 g, 0.0081 mol) and acetic acid (10 mL). The reaction mixture was stirred at 110 °C for 12 h. The volatiles were evaporated to get the residue. The residue was partitioned between dichloromethane and water. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to get the crude product. The crude product was purified by CombiFlash^® chromatography using ethyl acetate to get the title compound [0.8 g, 47 %]. *H NMR (300 MHz, CDC1₃): δ 8.69 - 8.67 (m, 1H), 8.44 - 8.41 (m, 1H), 7.56 - 7.44 (m, 1H), 7.39 - 7.31 (m, 4H), 4.01 - 3.94 (m, 2H), 3.51 - 3.46 (m, 1H), 3.37 - 3.30 (m, 1H); LC-MS: 259.0 [M+H]⁺.

Step-iii: 2-chloro-6-(2-chlorophenyl)-7,8-dihvdro-l,6-naphthyridin-5(6H)-one

To a 50 mL round bottom flask, were added 6-(2-chlorophenyl)-7,8-dihydro-l,6-naphthyridin- 5(6H)-one (0.08 g, 0.0031 mol) and dichloromethane (20 mL). The reaction mixture was cooled to 0 °C. To the same flask, m-chloroperbenzoic acid (1.06 g, 0.0062 mol) was added. The reaction mixture was stirred at room temperature for 5 h. The reaction mixture was diluted with dichloromethane and washed with water followed by saturated aqueous sodium bicarbonate. The organic layer was separated, dried over anhydrous sodium sulfate and evaporated under reduced pressure to get 6-(2-chlorophenyl)-5-oxo-5,6,7,8-tetrahydro-l,6-naphthyridine 1-oxide [0.8 g]. This intermediate was treated with phosphorus oxychloride (10 mL) at 130 °C for 12 h. The volatiles were evaporated under reduced pressure to get the residue. The residue was partitioned between ethyl acetate and saturated 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 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 [0.07 g, 8 %]. *H NMR (400 MHz, CDC1₃): δ 8.35 (d, 1H), 7.52 (d, 1H), 7.36-7.30 (m, 4H), 3.97- .90 (m, 2H), 3.49-3.26 (m, 2H); LC-MS: 293.0 [M+H]⁺.

Step-iv: N-(6-(2-chlorophenyl)-5-oxo-5,6,7,8-tetrahydro-L6-naphthyridin-2-yl)-2-(4- (ethylsulfonyl)-2-fluorophenyl)acetamide

A 25 mL sealed tube was charged with 2-chloro-6-(2-chlorophenyl)-7,8-dihydro-l,6- naphthyridin-5(6H)-one (0.05 g, 0.00017 mol), 2-(4-(ethylsulfonyl)-2-fluorophenyl)acetamide (0.084 g, 0.00034 mol), K₂C0₃ (0.035 g, 0.00025 mol) and 1, 4-dioxane (10 mL). The reaction mixture was degassed and filled with nitrogen. To the sealed tube, Xantphos (0.01 g, 0.000017 mmol), and palladium(II)acetate (0.002 g, 0.000008 mol) were added. The reaction mixture was again degassed and filled with nitrogen. The reaction mixture was stirred at 100°C for 3 h. The reaction mixture was cooled to room temperature, 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 CombiFlash^® chromatography using 2% methanol in chloroform followed by preparative thin layer chromatography using 2% methanol in chloroform to get the title compound [0.006 g, 7 %]. ^!H NMR (300 MHz, DMSO- d⁶): δ 11.23 (brs, 1H), 8.22 (d, 1H), 8.06 (d, 1H), 7.72-7.69 (m, 3H), 7.61-7.38 (m, 4H), 3.99-3.97 (m, 3H), 3.82-3.74 ( m, 1H), 3.39- 3.32 (m, 2H), 3.25-3.18 (m, 2H), 1.25 (t, 3H); LC-MS: 502.1 [M+H]⁺.

Example-9: N-(6,6-dimethyl-5-oxo-5,6,7,8-tetrahydroquinazolin-2-yl)-2-(4-(ethylsulfonyl) phenyl)acetamide (Compound-69)

Reagents and conditions: i) Methoxy-bis(dimethylamino)methane, toluene, 110°C, 12 h; ii) guanidine hydrochloride, triethylamine, ethanol, water, 75 °C, 12 h; iii) 2-(4- (ethylsulfonyl)phenyl)acetic acid, propylphosphonic anhydride solution >50 wt. % in ethyl acetate, triethylamine, dichloromethane, room temperature, 3 h.

Step-i: 2-((dimethylamino)methylene)-4,4-dimethylcyclohexane- 1 ,3-dione

To a 50 mL round bottom flask, were added 4,4-dimethylcyclohexane-l,3-dione (1 g, 0.0071 mol) and toluene (20 mL). To the same flask, methoxy-bis(dimethylamino)methane (0.95 mL, 0.0071 mol) was added. The reaction mixture was stirred at 110 °C for 12 h. The volatiles were evaporated under reduced pressure to get the crude title compound [1.2 g]. The obtained crude product was used in the next step without any further purification.

Step-ii: 2-amino-6,6-dimethyl-7,8-dihydroquinazolin-5(6H)-one

To a 50 mL round bottom flask, were added 2-((dimethylamino)methylene)-4,4- dimethylcyclohexane-l,3-dione (1.2 g, 0.0006 mol), guanidine hydrochloride (0.59 g, 0.0006 mol), triethylamine (1.9 mL, 0.0015 mol), ethanol (30 mL) and water (1 mL). The reaction mixture was stirred at 75 °C for 12 h. The volatiles were evaporated under reduced pressure to get the residue. The residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The organic layer was separated, washed with brine and dried over anhydrous sodium sulfate. The organic layer was evaporated under reduced pressure to get the crude product. The crude product was purified by column chromatography using 60 - 120 silica gel and 20 % ethyl acetate in hexane to get the title compound [0.25 g, 23 %]. *H NMR (300 MHz, DMSO-d⁶): δ 8.62 (s, 1H), 7.50 (s, 2H), 2.79 (t, 2H), 1.89 (t, 2H), 1.09 (s, 6H); LC-MS: 192.5 [M+H]⁺.

Step-iii: N-(6,6-dimethyl-5-oxo-5,6 ,8-tetrahydroquinazolin-2-yl)-2-(4-(ethylsulfonyl)phenyl) acetamide

To a 50 mL round bottom flask, was added 2-amino-6,6-dimethyl-7,8-dihydroquinazolin-5(6H)- one (0.04 g, 0.0002 mol), 2-(4-(ethylsulfonyl)phenyl)acetic acid (0.071 g, 0.0003 mol) and dichloromethane (20 mL). To the same flask, propylphosphonic anhydride solution >50 wt. % in ethyl acetate (0.63 mL, 0.001 mol) and triethylamine (0.05 mL, 0.0004 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 organic layer was evaporated under reduced pressure to get the crude product. The crude product was purified by preparative thin layer chromatography using 2 % methanol in chloroform to get the title compound [0.02 g, 24 %]. ^JH NMR (300 MHz, CDC1₃): δ 9.08 (s, 1H), 8.38 (brs, 1H), 7.89 (d, 2H), 7.55 (d, 2H), 4.35 (s, 2H), 3.15 (q, 2H), 3.05 (t, 2H), 2.03 (t, 2H), 1.31 (t, 3H), 1.23 (s, 6H); LC-MS: 402.1 [M+H]⁺.

Example-10: N-(6-(2-chlorophenyl)-5-oxo-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)- -(4-(ethylsulfonyl)-2-fluorophenyl)acetamide (Compound-70)

Reagents and conditions: i) 2-Chloroaniline, 100 °C, 16 h; ii) ethyl malonyl chloride, N,N- diisopropylethylamine, dichloromethane, 0 °C-room temperature, 3 h; iii) 21 % sodium ethoxide in ethanol, ethanol, 90 °C, 16 h; iv) acetic acid, water, 100 °C, 16 h; v) methoxy- bis(dimethylamino)methane, toluene, 110 °C, 12 h; guanidine hydrochloride, triethylamine, ethanol, water, 75 °C, 12 h; vi) 2-(4-(ethylsulfonyl)-2-fluorophenyl)acetic acid, propylphosphonic anhydride solution >50 wt. % in ethyl acetate, triethylamine, DCM, room temperature, 3 h.

Step-i: ethyl 3-((2-chlorophenyl)amino)propanoate

To a 25 mL sealed tube, were added 2-chloroaniline (3.5 g, 0.0275 mol), ethyl acrylate (3.3 g, 0.033 mol) and acetic acid (2 mL). The reaction mixture was maintained at 100 °C for 16 h. The reaction mixture was cooled to room temperature, poured into aqueous saturated sodium bicarbonate solution 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 crude product was purified by column chromatography using 60-120 silica gel and 5 % ethyl acetate in n-hexane to get the title compound [6 g, 96 %]. ^!H NMR (CDC1₃, 300 MHz): δ 7.27-7.22 (m, 2H), 7.17-7.03 (m, 2H), 4.21 (q, 2H), 3.54 (q, 2H), 2.67 (t, 2H), 1.30 (t, 3H); LC-MS: 227.9 [M+H] ⁺ _.

Step-ii: ethyl 3-((2-chlorophenyl)(3-ethoxy-3-oxopropyl)amino)-3-oxopropanoate

To a 100 mL round bottom flask, was added ethyl 3-((2-chlorophenyl)amino)propanoate (1.8 g, 0.0079 mol), NN-diisopropylethylamine ( 2.75 mL, 0.0158 mol) and dichloromethane (30 mL). The reaction mixture was cooled to 0 °C. To the same flask, ethyl malonyl chloride (1.42 g, 0.0095 mol) was added. The reaction mixture stirred at room temperature for 3 h. The reaction mixture was poured into ice cold water and extracted with dichloromethane. The organic layer was separated, washed with brine and dried over anhydrous sodium sulfate. The organic layer was evaporated under reduced pressure to get the crude product. The crude product was purified by column chromatography using 60-120 silica gel and 25 % ethyl acetate in hexane to get the title compound [1.6 g, 59 %]. 1H NMR (CDCI₃, 300 MHz): δ 7.53-7.50 (m, 1H), 7.36-7.31 (m, 3H), 4.25-4.18 (q, 1H), 4.12-4.05 (m, 4H), 3.76 (q, 1H), 3.16 (q, 2H), 2.68 (m, 2H), 1.24-1.18 (m, 6H); LC-MS: 342.1 [M+H] ⁺ _.

Step-iii: ethyl l-(2-chlorophenyl)-2,4-dioxopiperidine-3-carboxylate:

To a 50 mL round bottom flask, were added ethyl 3-((2-chlorophenyl)(3-ethoxy-3-oxopropyl) amino)-3-oxopropanoate (1.6 g, 0.0047 mol) and ethanol (20 mL). To the same flask, 21 % sodium ethoxide in ethanol (0.63 g, 0.0094 mol) was added. The reaction mixture was maintained at 90 °C for 16 h. The volatiles were evaporated under reduced pressure to get the residue. The residue was washed with ethyl acetate, acidified to pH 3.0 using aqueous 4N hydrochloric acid and extracted with chloroform. 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 [0.5 g, 37 %]. *H NMR (CDC1₃, 300 MHz): δ 7.58-7.55 (m, 1H), 7.46-7.41 (m, 2H), 7.35-7.29 (m, 1H), 4.37-4.28 (m, 1H), 4.13 (q, 2H), 3.84 (m, 1H), 3.07 (s, 1H), 2.73-2.63 (m, 2H), 1.25 (t, 3H); LC-MS: 296.1 [M+H] ⁺ _.

Step-iv: l-(2-chlorophenyl)piperidine-2,4-dione:

To a 100 mL round bottom flask, was added ethyl l-(2-chlorophenyl)-2,4-dioxopiperidine-3- carboxylate (0.47 g, 0.0016 mol), acetic acid (50 mL) and water (10 mL). The reaction mixture was stirred at 100 °C for 16 h. Acetic acid was evaporated under reduced pressure. The remaining aqueous layer was partitioned with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate and evaporated under reduced pressure to get the title compound [0.2 g, 56 %]. 1H NMR (CDC1₃, 300 MHz): δ 7.53-7.50 (m, 1H), 7.36-7.29 (m, 3H), 4.23-4.08 (m, 1H), 3.94-3.84 (m, 2H), 3.71-3.66 (m, 1H), 2.98-2.88 (m, 2H); LC-MS: 223.9 [M+H] ⁺ _.

Step-v: 2-amino-6-(2-chlorophenyl)-7,8-dihydropyrido[4,3-dlpyrimidin-5(6H)-one

To a 50 mL round bottom flask, were added l-(2-chlorophenyl)piperidine-2,4-dione (0.5 g, 0.00224 mol) and toluene (20 mL). To same flask, methoxy-bis(dimethylamino)methane (0.295 g, 0.00224 mol) was added. The reaction mixture was stirred at 110 °C for 12 h. The volatiles were evaporated under reduced pressure to get l-(2-chlorophenyl)-3- ((dimethylamino)methylene)piperidine-2,4-dione [0.6 g, crude product].

This intermediate was treated with guanidine hydrochloride (0.207 g, 0.0021 mol), triethylamine (0.68 mL, 0.0052 mol), ethanol (20 mL) and water (1 mL) at 75 °C for 12 h. The volatiles were evaporated under reduced pressure to get the residue. The residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The organic layer was separated, washed with brine and dried over anhydrous sodium sulfate. The organic layer was evaporated under reduced pressure to get the crude product. The crude product was purified by CombiFlash chromatography using 60 % ethyl acetate in hexane to get the title compound [0.1 g, 16 %]. 1H NMR (300 MHz, CDC1₃): δ 8.93 (s, 1H), 7.53-7.50 (m, 1H), 7.36-7.28 (m, 3H), 5.43 (brs, 2H), 3.92-3.85 (m, 2H), 3.24-3.21 (m, 1H), 3.04-3.02 (m, 1H); LC-MS: 275.2 [M+H]⁺.

Step-vi: N-(6-(2-chlorophenyl)-5-oxo-5,6,7,8-tetrahydropyrido[4,3-dlpyrimidin-2-yl)-2-(4- (ethylsulfonyl)-2-fluorophenyl)acetamide To a 50 mL round bottom flask, was added 2-amino-6-(2-chlorophenyl)-7,8-dihydropyrido[4,3- d]pyrimidin-5(6H)-one (0.06 g, 0.00022 mol), 2-(4-(ethylsulfonyl)-2-fluorophenyl)acetic acid (0.08 g, 0.000328 mol) and dichloromethane (10 mL). To the same flask, propylphosphonic anhydride solution >50 wt. % in ethyl acetate (0.35 mL, 0.0011 mol) and triethylamine (0.05 mL, 0.00044 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, dried over anhydrous sodium sulfate. The organic layer was evaporated under reduced pressure to get the crude product. The crude product was purified by preparative thin layer chromatography using 2 % methanol in chloroform to get the title compound [0.025 g, 23 %]. ^!H NMR (300 MHz, CDC1₃): δ 9.18 (s, 1H), 8.55 (brs, 1H), 7.71- 7.63 (m, 2H), 7.57-7.53 (m, 2H), 7.38-7.32 (m, 3H), 4.40 (s, 2H), 3.99-3.92 (m, 2H), 3.40-3.35 (m, 1H), 3.25-3.21 (m, 1H), 3.15 (q, 2H), 1.33 (t, 3H); LC-MS: 503.1 [M+H]⁺.

Example-11: Synthesis of N-(6-(2-chlorophenyl)-5,6,7,8-tetrahydro-l,6-naphthyridin-2-yl)- 2-(4-(ethylsulfonyl)-2-fluorophenyl)acetamide (Compound-71)

Reagents and conditions: i) Lithium aluminium hydride, THF, 0 °C - room temperature, 5 h; ii) (a) OT-chloroperbenzoic acid, dichloromethane, 0 °C - room temperature, 5 h (b) phosphorus oxychloride, reflux, 12 h; iii) 2-(4-(ethylsulfonyl)-2-fluorophenyl)acetamide, Xantphos, palladium(II)acetate, K₂C0₃, l,4-dioxane, 100 °C, 12 h.

Step-i: 6-(2-chlorophenyl)-5,6J,8-tetrahydro-L6-naphthyridine (71a)

To a 50 mL round bottom flask, were added THF (20 mL) and lithium aluminium hydride (0.471 g, 0.0124 mol). The resulting suspension was cooled to 0 °C. To the same flask, 6-(2- chlorophenyl)-7,8-dihydro-l,6-naphthyridin-5(6H)-one [intermediate 2 of scheme 1(b)] (0.8 g, 0.0031 mol) in THF (20 mL) was added at 0 °C. The reaction mixture was stirred at room temperature for 5 h. The reaction mixture was quenched with saturated aqueous sodium sulfate to get the precipitate. The precipitate was filtered through a pad of Celite^®. The filtrate was evaporated under reduced pressure to get the crude product. The crude product was purified by CombiFlash^® chromatography using 40 % ethyl acetate in hexane to get the title compound [0.3 g, 40 %]. *H NMR (CDC1₃, 300 MHz): δ 8.46 (d, 1H), 7.4 -7.27 (m, 2H), 7.27-7.22 (m, 1H), 7.15-7.11 (m, 2H), 7.04-6.99 (m, 1H), 4.26 (s, 2H), 3.50 (t, 2H), 3.21 (t, 2H); LC-MS: 245.0 [M+H]⁺.

Step-ii: 2-chloro-6-(2-chlorophenyl)-5,6,7,8-tetrahvdro-l,6-naphthyridine (71b)

To a 50 mL round bottom flask, was added 6-(2-chlorophenyl)-5,6,7,8-tetrahydro-l,6- naphthyridine (71a) (0.3 g, 0.0012 mol) followed by dichloromethane (20 mL). The reaction mixture was cooled to 0 °C. To the same flask, m-chloroperbenzoic acid (0.423 g, 0.0024 mol) was added. The reaction mixture was stirred at room temperature for 5 h. The reaction mixture was diluted with dichloromethane and washed with water followed by saturated aqueous sodium bicarbonate. The organic layer was separated, dried over anhydrous sodium sulfate and evaporated under reduced pressure to get 6-(2-chlorophenyl)-5-oxo-5,6,7,8-tetrahydro-l,6- naphthyridine 1-oxide [0.3 g].

This intermediate was treated with phosphorus oxychloride (10 mL) at reflux temperature for 12 h. The volatiles were evaporated under reduced pressure to get the residue. The residue was partitioned between ethyl acetate and saturated 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 crude product. The crude product was purified by column chromatography using 60-120 silica gel and 20 % ethyl acetate in hexane to get the title compound [0.055 g, 16 %]. LC-MS: 279.0 [M+H]⁺.

Step-iii: N-(6-(2-chlorophenyl)-5,6J,8 etrahydro-L6-naphthyridin-2-yl)-2-(4-(ethylsulfonyl)-2- fluorophenyDacetamide

A 25 mL sealed tube was charged with 2-chloro-6-(2-chlorophenyl)-5,6,7,8-tetrahydro-l,6- naphthyridine (0.055 g, 0.00019 mol), 2-(4-(ethylsulfonyl)-2-fluorophenyl)acetamide (0.096 g, 0.000394 mol), K₂C0₃ (0.04 g, 0.00028 mol) and 1,4-dioxane (10 mL). The reaction mixture was degassed with nitrogen. To the same sealed tube, Xantphos (0.011 g, 0.000019 mmol), and palladium (Il)acetate (0.003 g, 0.0000098 mol) were added. The reaction mixture was again degassed with nitrogen. The reaction mixture was stirred at 100 °C for 12 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The organic layer was 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 CombiFlash chromatography using 2 % methanol in chloroform followed by preparative high performance liquid chromatography using 0.01 % trifluoro acetic acid in water and acetonitrile to get the title compound [0.005 g, 5 %]. 1H NMR (CDC1₃, 400 MHz): δ 8.07 (brs, IH), 7.97 (d, IH), 7.70 (d, IH), 7.65-7.57 (m, 2H), 7.42-7.37 (m, 2H), 7.23- 7.20 (m, IH), 7.10-7.08 (m, IH), 7.01-6.97 (m, IH), 4.19 (s, 2H), 3.82 (s, 2H), 3.44 (t, 2H), 3.14 (q, 2H), 3.04 (t, 2H), 1.30 (t, 2H); LC-MS: 488.1 [M+H]⁺.

Example-12: Synthesis of N-(4-(ethylsulfonyl)benzyl)-6,6-dimethyl-5-oxo-5,6,7,8- tetrahydroquinoline-2-carboxamide (Compound-72)

Compound-72

Reagents and conditions: i) NaCN, Propionitrile, DMAP, 100 °C, 12 h; ii) KOH, 100 °C, 12 h; iii) (4-(ethylthio)phenyl)methanamine, triethylamine, EDC.HC1, HOBt, DMF, RT, 12 h; iv) m- CPBA, DCM, RT, 0.5 h.

Step-i: Synthesis of 6,6-dimethyl-5-oxo-5,6,7,8-tetrahvdroquinoline-2-carbonitrile

A mixture of sodium cyanide in propionitrile (20 mL) and water (1 mL) was added DMAP (0.23 g, 0.0019 mol), Intermediate- 1 (2 g, 00953 mol) and heated to 100 °C for 12 h. The RM was cooled to RT, filtered through celite pad and he filtrate was diluted with water, extracted with ethyl acetate. Organic portion was washed with water, brine, dried over sodium sulfate and concentrated to get the crude product. Crude compound was purified by silica gel column using 30% ethyl acetate in hexanes as eluent (0.5 g, 26 %)

Step-ii: Synthesis of 6,6-dimethyl-5-oxo-5,6,7,8-tetrahydroquinoline-2-carboxylic acid

6,6-dimethyl-5-oxo-5,6,7,8-tetrahydroquinoline-2-carbonitrile(0.25 g, 0.0012 mol) in aqueous potassium hydroxide (0.1 g in 15 mL water) was heated to 100 °C for 12h. RM was cooled to RT, washed with ethyl acetate, acidified with 6N HC1, extracted into ethyl acetate, organic portion was washed with water, dried over sodium sulfate, concentrated to give titled compound (0.15g, 55%) LC-MS: 220.4 [M+H]⁺.

Step-iii: Synthesis of N-(4-(ethylthio)benzyl)-6,6-dimethyl-5-oxo-5,6,7,8-tetrahydroquinoline-2- carboxamide A stirred mixture of 72b (0.2 g, 0.00091 mol), triethylamine (0.138 g, 0.00136 mol), HOBt (0.184 g, 0.00136 mol), EDC.HC1 (0.262 g, 0.00136 mol) in DMF (10 iriL) was added (4- (ethylthio)phenyl)methanamine (0.152 g, 0.00091 mol) and stirred at RT for 12h. RM was diluted with water, extracted into ethyl acetate, washed with sodium bicarbonate solution, dried over sodiumsulfae, concentrated to residue. The residue was purified on silica gel column using 30% ethyl acetate in hexanes to get the titled compound (0.15 g, 45 %). LC-MS: 369.1 [M+H]⁺.

Step-iv: Synthesis of N-(4-(ethylsulfonyl)benzyl)-6,6-dimethyl-5-oxo-5, 6,7,8- tetrahvdroquinoline-2-carboxamide.

A solution of N-(4-(ethylthio)benzyl)-6,6-dimethyl-5-oxo-5,6,7,8-tetrahydroquinoline-2- carboxamide (0.15 g, 0.00407 mol) in DCM (10 iriL) was added mCPBA (0.147 g, 0.00085 mol) and stirred at RT for 30 min. RM was quenched by adding aqueous sodium bicarbonate solution, organic layer separated and washed with brine, stirred over sodium sulfate, concentrated to get residue. The residue was purified by column chromatography using 30% ethyl acetate ion hexanes to get the pure titled compound (0.036 g, 23 %).

Example-13: Synthesis of N-(5,5-dimethyl-5,6,7,8-tetrahydroquinolin-2-yl)-2-(4- (ethylsulfonyl)phenyl)acetamide (Compound-73)

Reagents and conditions: i) 2-(4-(ethylsulfonyl)phenyl)acetamide, Xantphos, palladium(II) acetate, K₂C0₃, 1,4-dioxane, 100 °C, 3 h.

The above compound was prepared using the same protocol described in Example- 1.

*H NMR (400 MHz, CDC1₃): δ 7.93-7.84 (m, 4H), 7.63 (d, 1H), 7.55 (d, 2H), 3.78 (s, 2H), 3.14- (q, 2H), 2.75 (t, 2H), 1.88-1.85 (m, 2H), 1.66-1.63 (m, 2H), 1.26 (t, 3H), 1.24 (s, 6H). LC-MS: 387.1 (M+l)⁺.

The compounds listed in below table were prepared by procedure similar to the one described in Example- 1 with appropriate variations in reactants, quantities of reagents, solvents and reaction conditions. The characterization data of the compounds are summarized herein below table.

Compound

Structure Characterization data

No.

*H NMR (400 MHz, CDC1₃) δ 8.08 (d, 2H), 7.90 (d, 2H), 7.72 (d, 2H), 7.56-7.540 (m, 3H), 7.43-7.38 (m,

77 2H), 3.82 (s, 2H), 3.39 (t, 3H), 3.12- 2.98 (m, 4H), 2.76-2.74 (m, 2H),

1.29-1.26 (m, 3H). LC-MS: 488.3 [M+H]⁺.

Exapmle-14: Synthesis of 2-(3-(4-(ethylsulfonyl)phenyl)-2-oxopropyl)-6-(2-hydroxy-3- methylphenyl)-6-methyl-7,8-dihydroquinolin-5(6H)-one (Compound-78)

Compound-78

Reagents and conditions: i) 4-methoxybenzyl chloride, K₂C0₃, DMF, 25 °C, 12 h; ii)

Pd(Amphos)Cl₂, NaOBu¹, toluene, 60 °C, 3 h; iii) NaH, Mel, DMF, 0 °C, 15 min; iv) 2-(4- (ethylsulfonyl)phenyl)acetamide, Xantphos, palladium(II) acetate, K₂C0₃, 1,4-dioxane, 100 °C, 3 h; v) H₂, 10% Pd/C, methanol, ethyl acetate, 12 h. Step-i: Synthesis of 2-chloro-6-(3-(dimethylamino)phenyl)-6-methyl-7,8-dihydroquinolin- 5(6H)-one

To a solution of 2-bromo-6-methylphenol (10 g, 0.0537 mol) in DMF (100 mL) were added potassium carbonate (14.8 g, 0.1075 mol) and 4-methoxynenzyl chloride (10 g, 0.0645 mol). The resulting mixture was stirred at 25 °C for 12 h. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was washed with brine, dried over sodium sulfate and concentrated to get the crude product. The crude product was purified by column chromatography (silica gel) using 0-30% ethyl acetate in hexanes as eluent to get the title compound (12 g, 72%). LC-MS: 305.05 [M-2H]⁺.

Step-ii-iii:

Step-ii and step-iii were performed according to the similar protocol described in Step-i and Step-ii of Intermediate-26.

Step-iv: 2-(3-(4-(ethylsulfonyl)phenyl)-2-oxopropyl)-6-(2-((4-methoxybenzyl)oxy)-3- methylphenyl)-6-methyl-7,8-dihydroquinolin-5(6H)-one

2-(3-(4-(ethylsulfonyl)phenyl)-2-oxopropyl)-6-(2-((4-methoxybenzyl)oxy)-3-methylphenyl)-6- methyl-7,8-dihydroquinolin-5(6H)-one was prepared according to the similar protocol described in Example- 1.

Step v: 2-(4-(ethylsulfonyl)phenyl)-N-(6-(2-hvdroxy-3-methylphenyl)-6-methyl-5-oxo-5, 6,7,8- tetrahydroquinolin-2-yl)acetamide

To a solution of 2-(4-(ethylsulfonyl)phenyl)-N-(6-(2-((4-methoxybenzyl)oxy)-3-methylphenyl)- 6-methyl-5-oxo-5,6,7,8-tetrahydroquinolin-2-yl)acetamide (0.2 g, 0.00033 mol) in a mixture of methanol: ethyl acetate (20 m L, 1: 1) was added 10% Pd/C (0.02 g) and stirred under hydrogen atmosphere for 12 h. The reaction mixture was filtered through a pad of celite®. The filtrate was evaporated under reduced pressure to get the crude product. The crude product was purified by preparative HPLC to get pure compound Mobile Phase:_A= 0.1% TFA IN WATER; B= ACN: WATER (1: 1); Column: XBridegePrepC18 (150mmx21.20mm), 5.0μ; Flow: 15.0 ml/min with gradient 20% at beginning, 30% at 2^nd min, 70% at 9^th min. Yield: (007g; 4.4%); LC-MS: 493.0 [M+H]⁺.

Example 15: 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- HC1 (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- HC1 (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:

RORy radioligand binding assay

ROR gamma radioligand binding was performed using ³H 25- Hydroxycholesterol in a competitive displacement assay using dextran charcoal method. 5 nM ³H 25- Hydroxycholesterol was incubated with 300 ng RORy LBD (in house expressed in E.coli) along with the compound 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).

The compounds were screened at 1 μΜ /10 μΜ concentration followed by IC₅₀ measurement and the results are summarized in the table below along with the IC₅₀ (nM) details for selected examples. The IC₅₀ values of the compounds are set forth in below Table wherein "A" refers to an IC50 value of less than 50 nM, "B" refers to IC50 value in range of 50.01 to 250 nM and "C" refers to IC₅₀ value of greater than 250 nM.

RORy ligand RORy ligand RORy ligand

Compound

binding assay: % binding assay: % binding assay:

No.

inhibition @1μΜ inhibition @ 10μΜ IC50 (nM)

1 - - B

2 - - A RORy ligand RORy ligand RORy ligand

Compound

binding assay: % binding assay: % binding assay: No.

inhibition @1μΜ inhibition @ 10μΜ ICso (nM)

3 - - B

5 - - B

7 - - B

8 85 100 -

10 49 81 -

12 89 98 B

14 84 92 -

15 72 76 -

18 100 100 -

19 40 51 -

21 100 100 -

27 93 100 A

28 89 94 B

32 80 85 A

33 85 87 A

34 81 54 -

35 90 88 B

36 82 96 A

37 9 43 -

38 64 79 C

40 100 100 A

42 54 96 -

43 27 44 -

44 28 52 -

45 46 69 -

46 91 100 A

47 96 97 -

48 58 50 - RORy ligand RORy ligand RORy ligand

Compound

binding assay: % binding assay: % binding assay:

No.

inhibition @1μΜ inhibition @ 10μΜ ICso (nM)

49 90 100 -

51 - - A

52 80 87 -

58 91 97 A

60 98 100 A

63 90 97 B

64 95 100 A

65 82 100 B

68 - - A

69 39 77 C

70 9 11 -

Example 16: Analysis of therapeutic effect of compound-25 in mouse collagen induced arthritis model

Male DBA1 mice of 6-7 weeks procured from Harlan were acclimatized to animal facility. Mice at the age of 9-10 weeks were sensitized with 50 μΐ of emulsion containing Bovine Type II collagen (4 mg/ml) mixed with equal volume of Complete Freund' s Adjuvant (CFA) 2mg/ml by intradermal tail injections. Booster injections were given with Collagen emulsified with equal volume of Incomplete Freund' s Adjuvant (IFA) 21 days after sensitization. Test formulations administration was initiated 1 day before booster injection and continued up to 21 days once daily by p.o route. Animals were scored daily for arthritic symptoms on a scale of (0-4) for fore paws and hind paws (total score of 16) and hind paw thickness measured for every 3 days using digital micrometer. At the end of study, animals were sacrificed and hind paw collected for histopathology evaluation.

Result: Collagen induced arthritis caused significant increase in arthritis score (from 6 days after booster injection) and paw thickness (from 9 days after booster injection) compared to non- immunized animals. Compound-25 at 25 mpk dose showed trend towards reduction in arthritis score ( 22%) and significant reduction in paw swelling ( 56% day 21 ) whereas at 50 mg/kg dose showed significant reduction in both arthritis score ( 55%) and paw swelling ( 77% day 21). The efficacy observed with Compound-25 is on par with leflunomide 10 mg/kg which showed significant reduction in both arthritis score (53%) and paw swelling (76% day 21). Compound-25 50 mg/kg administration also showed significant reduction in histopathology of paw tissue compared to vehicle control.

Claims

A compound of formula (I):

(I)

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

A and B are independently -CRiR₂- or -NR₃-;

X is CH or N;

-P-Q- is -C(0)-NH- or -NH-C(O)-;

L is a bond or -NR_C-;

each of R_1; R₂ and R₃ is independently selected from hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aryl and -(CH₂)_m-aryl; wherein the said aryl is optionally substituted by one or more hydroxy, halo, cyano, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, -NR_cR_d, heterocyclyl, heteroaryl and alkylheterocyclyl;

or Ri and R₂ can combine together to form an optionally substituted 5-8 membered spiro ring;

R4 at each occurrence is independently selected from hydrogen, halo, cyano and hydroxyalkyl;

R5 is alkyl, -NR_cRd or hydroxyalkyl;

R_a and Rb are independently hydrogen, hydroxy or alkyl;

or R_a and Rb together represent an oxo (=0) group;

R_c and R_d are independently hydrogen or alkyl; and

m is 1 to 4.

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

(ΙΑ)

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

R_a, Rb, A, B, X, P, Q, R₄ and m are same as defined in claim 1.

The compound according to any one of claims 1 or 2 is a compound of formula (IB):

(I B)

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

R_a, Rb, A, B, P, Q, R₄ and m are same as defined in claim 1.

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

(IC)

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

R_a, Rb, A, B, P, Q, R4 and m are same as defined in claim 1.

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

or a pharmaceutically acceptable salt or a stereoisomer thereof; wherein: -A-B- is -CR1R2-CR1R2- or -NR3-CR1R2; and

R_a, Rb, Ri, R2, R3, R4, R5 X, P, Q and m are same as defined in claim 1.

The compound according to any one of claims 1 to 3 is a compound of formula (IE):

(IE) or a pharmaceutically acceptable salt or a stereoisomer thereof; wherein:

Ri and R2 are same as defined in claim 1.

7. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt or a stereoisomer thereof; wherein R4 is hydrogen.

8. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt or a stereoisomer thereof; wherein A is -CR1R2- and B is -CH2-.

9. The compound according to any one of claims 5 to 8 or a pharmaceutically acceptable salt or a stereoisomer thereof; wherein Ri is hydrogen and R2 is aryl optionally substituted by one or more halo, hydroxy or alkoxy.

10. The compound according to any one of claims 5 to 8, or a pharmaceutically acceptable salt or a stereoisomer thereof; wherein Ri is alkyl and R2 is aryl optionally substituted by one or more halo, hydroxy or alkoxy.

11. The compound according to any one of claims 5, 6, 7, 8 or 10, or a pharmaceutically acceptable salt or a stereoisomer thereof; wherein Ri is Ci-C₆ alkyl and R2 is phenyl optionally substituted by one or more halo, hydroxy or alkoxy.

12. The compound according to any one of claims 5 to 11, or a pharmaceutically acceptable salt or a stereoisomer thereof; wherein R₂ is halophenyl, hydroxyphenyl or alkoxyphenyl.

13. The compound according to any one of claims 5 to 12, or a pharmaceutically acceptable

-CH₂OH

14. The compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt or a stereoisomer thereof; is selected from the group consisting of: Compound

IUPAC Name

No.

N-(6,6-dimethyl-5-oxo-5,6,7,8-tetrahydroquinolin-2-yl)-2-(4-(ethylsulfonyl)-2-

1

fluorophenyl)acetamide ;

N-(6,6-dimethyl-5-oxo-5,6,7,8-tetrahydroquinolin-2-yl)-2-(4-

2

(ethylsulfonyl)phenyl)acetamide ;

N-(6-(2-chlorophenyl)-6-methyl-5-oxo-5,6,7,8-tetrahydroquinolin-2-yl)-2-(4-

3

(ethylsulfonyl)phenyl)acetamide ;

N-(6-(2-chlorophenyl)-5-oxo-5,6,7,8-tetrahydroquinolin-2-yl)-2-(4-

4

(ethylsulfonyl)phenyl)acetamide ;

2-(4-(ethylsulfonyl)phenyl)-N-(5'-oxo-7',8'-dihydro-5'H-spiro[cyclopentane-l,6'-

5

quino lin] -2 '- yl)acet amide ;

N-(6-(2-chlorophenyl)-5-oxo-5,6,7,8-tetrahydroquinolin-2-yl)-2-(4-

6

(ethylsulfonyl)-2-fluorophenyl)acetamide;

N-(6-(2-chlorophenyl)-6-methyl-5-oxo-5,6,7,8-tetrahydroquinolin-2-yl)-2-(4-

7

(ethylsulfonyl)-2-fluorophenyl)acetamide;

2-(4-(ethylsulfonyl)phenyl)-N-(5-oxo-6-(4-(trifluoromethyl)phenethyl)-5, 6,7,8-

8

tetrahydroquinolin-2-yl)acetamide;

9 2-(4-(ethylsulfonyl)-2-fluorophenyl)-N-(5-oxo-6-(4-(trifluoromethyl)phenethyl)- 5,6,7,8-tetrahydroquinolin-2-yl)acetamide;

N-(6-(4-chlorophenethyl)-5-oxo-5,6,7,8-tetrahydroquinolin-2-yl)-2-(4-

10

(ethylsulfonyl)phenyl)acetamide ;

N-(6-(4-chlorophenethyl)-5-oxo-5,6,7,8-tetrahydroquinolin-2-yl)-2-(4-

11

(ethylsulfonyl)-2-fluorophenyl)acetamide; Compound

IUPAC Name

No.

N-(6-(4-chlorophenyl)-6-methyl-5-oxo-5,6,7,8-tetrahydroquinolin-2-yl)-2-(4-

12

(ethylsulfonyl)phenyl)acetamide ;

13 2-(4-(ethylsulfonyl)phenyl)-N-(5-oxo-5,6,7,8-tetrahydroquinolin-2-yl)acetamide;

N-(6-(2,4-dichlorophenethyl)-5-oxo-5,6,7,8-tetrahydroquinolin-2-yl)-2-(4-

14

(ethylsulfonyl)phenyl)acetamide ;

N-(6-(2,4-dichlorophenyl)-6-methyl-5-oxo-5,6,7,8-tetrahydroquinolin-2-yl)-2-(4-

15

(ethylsulfonyl)phenyl)acetamide ;

N-(6-(4-chlorophenyl)-6-methyl-5-oxo-5,6,7,8-tetrahydroquinolin-2-yl)-2-(4-

16

(ethylsulfonamido )pheny 1) acet amide ;

N-(6-(4-chlorophenyl)-6-methyl-5-oxo-5,6,7,8-tetrahydroquinolin-2-yl)-2-(4-(N-

17

ethylsulf amo yl)pheny 1) acet amide ;

N-(6-(4-chlorophenyl)-5-oxo-6-propyl-5,6,7,8-tetrahydroquinolin-2-yl)-2-(4-

18

(ethylsulfonyl)phenyl)acetamide ;

2-(4-(ethylsulfonyl)phenyl)-N-(6-methyl-5-oxo-6-(4-(trifluoromethyl)phenyl)-

19

5,6,7,8-tetrahydroquinolin-2-yl)acetamide;

N-(6-(4-chlorophenyl)-5-oxo-5,6,7,8-tetrahydroquinolin-2-yl)-2-(4-

20

(ethylsulfonyl)phenyl)acetamide ;

N-(6-(4-chlorophenyl)-6-methyl-5-oxo-5,6,7,8-tetrahydroquinolin-2-yl)-2-(4-

21

(methylsulfonyl)phenyl)acetamide;

22 2-(4-(ethylsulfonyl)phenyl)-N-(6-methyl-5-oxo-6-phenyl-5, 6,7,8- tetrahydroquinolin-2-yl)acetamide; Compound

IUPAC Name

No.

N-(6-(4-chlorophenyl)-6-ethyl-5-oxo-5,6,7,8-tetrahydroquinolin-2-yl)-2-(4-

23

(ethylsulfonyl)phenyl)acetamide ;

N-(6-(4-chlorophenyl)-6-methyl-5-oxo-5,6,7,8-tetrahydroquinolin-2-yl)-2-(4-

24

(ethylsulfonyl)phenyl)acetamide ; (Isomer-2)

N-(6-(4-chlorophenyl)-6-methyl-5-oxo-5,6,7,8-tetrahydroquinolin-2-yl)-2-(4-

25

(ethylsulfonyl)phenyl)acetamide ; (Isomer- 1 )

2-(4-(ethylsulfonyl)phenyl)-N-(6-methyl-6-(4-morpholinophenyl)-5-oxo-5, 6,7,8-

26

tetrahydroquinolin-2-yl)acetamide;

27 2-(4-(ethylsulfonyl)phenyl)-N-(6-(4-methoxyphenyl)-6-methyl-5-oxo-5, 6,7,8- tetrahydroquinolin-2-yl)acetamide;

N-(6-(4-(dimethylamino)phenyl)-6-methyl-5-oxo-5,6,7,8-tetrahydroquinolin-2-

28

yl)-2-(4-(ethylsulfonyl)phenyl)acetamide;

2-(4-(ethylsulfonyl)phenyl)-N-(6-(4-methoxyphenyl)-6-methyl-5-oxo-5, 6,7,8-

29

tetrahydroquinolin-2-yl)acetamide; (Isomer- 1)

2-(4-(ethylsulfonyl)phenyl)-N-(6-(4-methoxyphenyl)-6-methyl-5-oxo-5, 6,7,8-

30

tetrahydroquinolin-2-yl)acetamide; (Isomer-2)

N-(6-(4-chlorophenyl)-5-oxo-6-propyl-5,6,7,8-tetrahydroquinolin-2-yl)-2-(4-

31

(ethylsulfonyl)phenyl)acetamide ; (Isomer- 1 )

N-(6-(4-chlorophenyl)-5-oxo-6-propyl-5,6,7,8-tetrahydroquinolin-2-yl)-2-(4-

32

(ethylsulfonyl)phenyl)acetamide ; (Isomer-2)

2-(4-(ethylsulfonyl)phenyl)-N-(6-methyl-6-(3-morpholinophenyl)-5-oxo-5, 6,7,8-

33

tetrahydroquinolin-2-yl)acetamide; Compound

IUPAC Name

No.

N-(6-(4-cyanophenyl)-6-methyl-5-oxo-5,6,7,8-tetrahydroquinolin-2-yl)-2-(4-

34

(ethylsulfonyl)phenyl)acetamide ;

2-(4-(ethylsulfonyl)phenyl)-N-(6-methyl-6-(3-(4-methylpiperazin-l-yl)phenyl)-

35

5-oxo-5,6,7,8-tetrahydroquinolin-2-yl)acetamide;

2-(4-(ethylsulfonyl)phenyl)-N-(5-oxo-6,6-diphenyl-5,6,7,8-tetrahydroquinolin-2-

36

yl)acetamide;

37 2-(4-(ethylsulfonyl)phenyl)-N-(6-methyl-5-oxo-6-(2-(trifluoromethoxy)phenyl)- 5,6,7,8-tetrahydroquinolin-2-yl)acetamide;

N-(6-(3,5-difluoro-4-methoxyphenyl)-6-methyl-5-oxo-5, 6,7,8-

38

tetrahydroquinolin-2-yl)-2-(4-(ethylsulfonyl)phenyl)acetamide;

N-(6-(3,5-difluoro-4-hydroxyphenyl)-6-methyl-5-oxo-5,6,7,8-tetrahydroquinolin-

39

2-yl)-2-(4-(ethylsulfonyl)phenyl)acetamide;

2-(4-(ethylsulfonyl)phenyl)-N-(6-(3-methoxyphenyl)-6-methyl-5-oxo-5, 6,7,8-

40

tetrahydroquinolin-2-yl)acetamide;

N-(6-(3-chlorophenyl)-6-methyl-5-oxo-5,6,7,8-tetrahydroquinolin-2-yl)-2-(4-

41

(ethylsulfonyl)phenyl)acetamide ;

N-(6-(3-(dimethylamino)phenyl)-6-methyl-5-oxo-5,6,7,8-tetrahydroquinolin-2-

42

yl)-2-(4-(ethylsulfonyl)phenyl)acetamide;

2-(4-(ethylsulfonyl)phenyl)-N-(6-(4-(2-hydroxypropan-2-yl)phenyl)-6-methyl-5-

43

oxo-5,6,7,8-tetrahydroquinolin-2-yl)acetamide;

N-(6-(4-chlorophenyl)-6-(methoxymethyl)-5-oxo-5,6,7,8-tetrahydroquinolin-2-

44

yl)-2-(4-(ethylsulfonyl)phenyl)acetamide; Compound

IUPAC Name

No.

N-(6-(4-chlorophenyl)-6-methyl-5,6,7,8-tetrahydroquinolin-2-yl)-2-(4-

45

(ethylsulfonyl)phenyl)acetamide ;

2-(4-(ethylsulfonyl)phenyl)-N-(6-(2-hydroxyphenyl)-6-methyl-5-oxo-5, 6,7,8-

46

tetrahydroquinolin-2-yl)acetamide;

2-(4-(ethylsulfonyl)phenyl)-N-(6-(2-methoxyphenyl)-6-methyl-5-oxo-5, 6,7,8-

47

tetrahydroquinolin-2-yl)acetamide;

N-(6-(4-chlorophenyl)-6-methyl-5,6,7,8-tetrahydroquinolin-2-yl)-2-(4-

48

(ethylsulfonyl)phenyl)acetamide ; (Isomer- 1 )

N-(6-(4-chlorophenyl)-6-methyl-5,6,7,8-tetrahydroquinolin-2-yl)-2-(4-

49

(ethylsulfonyl)phenyl)acetamide ; (Isomer-2)

2-(4-(ethylsulfonyl)phenyl)-N-(6-(4-hydroxyphenyl)-6-methyl-5-oxo-5, 6,7,8-

50

tetrahydroquinolin-2-yl)acetamide;

2-(4-(ethylsulfonyl)phenyl)-N-(6-(3-methoxyphenyl)-6-methyl-5-oxo-5, 6,7,8-

51

tetrahydroquinolin-2-yl)acetamide; (Isomer- 1)

2-(4-(ethylsulfonyl)phenyl)-N-(6-(3-methoxyphenyl)-6-methyl-5-oxo-5, 6,7,8-

52

tetrahydroquinolin-2-yl)acetamide; (Isomer-2)

2-(4-(ethylsulfonyl)phenyl)-N-(6-(3-hydroxyphenyl)-6-methyl-5-oxo-5, 6,7,8-

53

tetrahydroquinolin-2-yl)acetamide;

N-(6-(4-chlorophenyl)-6-methyl-5-oxo-5,6,7,8-tetrahydroquinolin-2-yl)-2-(4-((2-

54

hydroxyethyl) sulfonyl)phenyl) acetamide ;

2-(4-(ethylsulfonyl)phenyl)-N-(6-methyl-6-(4-(4-methylpiperazin-l-yl)phenyl)-

55

5-oxo-5,6,7,8-tetrahydroquinolin-2-yl)acetamide; Compound

IUPAC Name

No.

N-(6-(4-(lH-tetrazol-5-yl)phenyl)-6-methyl-5-oxo-5,6,7,8-tetrahydroquinolin-2-

56

yl)-2-(4-(ethylsulfonyl)phenyl)acetamide;

N-(6-(4-chlorophenyl)-6-(hydroxymethyl)-5-oxo-5,6,7,8-tetrahydroquinolin-2-

57

yl)-2-(4-(ethylsulfonyl)phenyl)acetamide;

N-(6-(4-chlorophenyl)-5-hydroxy-6-methyl-5,6,7,8-tetrahydroquinolin-2-yl)-2-

58

(4-(ethylsulfonyl)phenyl)acetamide; (Isomer- 1)

N-(6-(4-chlorophenyl)-5-hydroxy-6-methyl-5,6,7,8-tetrahydroquinolin-2-yl)-2-

59

(4-(ethylsulfonyl)phenyl)acetamide; (Isomer-2)

N-(6-(2-chlorophenyl)-6-methyl-5-oxo-5,6,7,8-tetrahydroquinolin-2-yl)-2-(4-

60

(ethylsulfonyl)phenyl)acetamide ; (Isomer- 1 )

N-(6-(2-chlorophenyl)-6-methyl-5-oxo-5,6,7,8-tetrahydroquinolin-2-yl)-2-(4-

61

(ethylsulfonyl)phenyl)acetamide ; (Isomer-2)

N-(6-(2,4-dichlorophenyl)-6-methyl-5-oxo-5,6,7,8-tetrahydroquinolin-2-yl)-2-(4-

62

(ethylsulfonyl)phenyl)acetamide ; (Isomer-2)

N-(6-(2,4-dichlorophenyl)-6-methyl-5-oxo-5,6,7,8-tetrahydroquinolin-2-yl)-2-(4-

63

(ethylsulfonyl)phenyl)acetamide ; (Isomer- 1 )

2-(4-(ethylsulfonyl)phenyl)-N-(6-methyl-5-oxo-6-(4-(trifluoromethyl)phenyl)-

64

5,6,7,8-tetrahydroquinolin-2-yl)acetamide; (Isomer- 1)

2-(4-(ethylsulfonyl)phenyl)-N-(6-methyl-5-oxo-6-(4-(trifluoromethyl)phenyl)-

65

5,6,7,8-tetrahydroquinolin-2-yl)acetamide; (Isomer-2)

2-(4-(ethylsulfonyl)phenyl)-N-(6-(2-hydroxyphenyl)-6-methyl-5-oxo-5, 6,7,8-

66

tetrahydroquinolin-2-yl)acetamide; (Isomer- 1) Compound

IUPAC Name

No.

2-(4-(ethylsulfonyl)phenyl)-N-(6-(2-hydroxyphenyl)-6-methyl-5-oxo-5, 6,7,8-

67

tetrahydroquinolin-2-yl)acetamide; (Isomer-2)

N-(6-(2-chlorophenyl)-5-oxo-5,6,7,8-tetrahydro-l,6-naphthyridin-2-yl)-2-(4-

68

(ethylsulfonyl)-2-fluorophenyl)acetamide;

N-(6, 6-dimethyl-5 -oxo-5 , 6,7 , 8-tetrahydroquinazolin-2-yl)-2-(4-

69

(ethylsulfonyl)phenyl)acetamide ;

N-(6-(2-chlorophenyl)-5-oxo-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-2-

70

(4-(ethylsulfonyl)-2-fluorophenyl)acetamide;

N-(6-(2-chlorophenyl)-5,6,7,8-tetrahydro-l,6-naphthyridin-2-yl)-2-(4-

71

(ethylsulfonyl)-2-fluorophenyl)acetamide;

N-(4-(ethylsulfonyl)benzyl)-6,6-dimethyl-5-oxo-5,6,7,8-tetrahydroquinoline-2-

72

carboxamide;

N-(5,5-dimethyl-5,6,7,8-tetrahydroquinolin-2-yl)-2-(4-

73

(ethylsulfonyl)phenyl)acetamide ;

2-(4-(ethylsulfonyl)phenyl)-N-(6-(2-hydroxy-4-methylphenyl)-6-methyl-5-oxo-

74

5,6,7,8-tetrahydroquinolin-2-yl)acetamide;

2-(4-(ethylsulfonyl)phenyl)-N-(6-(3-fluoro-2-hydroxyphenyl)-6-methyl-5-oxo-

75

5,6,7,8-tetrahydroquinolin-2-yl)acetamide;

2-(4-(ethylsulfonyl)phenyl)-N-(6-(2-fluorophenyl)-6-methyl-5-oxo-5, 6,7,8-

76

tetrahydroquinolin-2-yl)acetamide;

N-(6-(3-cyanophenyl)-6-methyl-5-oxo-5,6,7,8-tetrahydroquinolin-2-yl)-2-(4-

77

(ethylsulfonyl)phenyl)acetamide ; and Compound

IUPAC Name

No.

2-(3-(4-(ethylsulfonyl)phenyl)-2-oxopropyl)-6-(2-hydroxy-3-methylphenyl)-6-

78

methyl-7 , 8 -dihydroquinolin- 5 ( 6H) -one.

15. A pharmaceutical composition, comprising at least one compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt or a stereoisomer thereof, and a pharmaceutically acceptable carrier or excipient.

16. The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt or a stereoisomer thereof, for use as a medicament.

17. The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt or a stereoisomer thereof, for use as a medicament for the treatment of an immune disorder or an inflammatory disorder.

18. A method of treating a RORy mediated disorder or disease in a subject comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 14.

19. The method according to claim 18, wherein the RORy mediated disorder is an immune disorder or an inflammatory disorder.

20. The method according to claim 19, wherein the disease or 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.

21. The method according to claim 19, wherein the disease or 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.

22. A method of reducing 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 to 14.

23. Use of a compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt or a stereoisomer thereof, in the manufacture of a medicament for the treatment of an immune disorder or an inflammatory disorder.