Substituted bicyclic sulfonamide derivatives as modulators of CBL-b

Abstract

The present invention relates to substituted bicyclic sulfonamide derivatives and their use as modulators of the E3 ligase Cbl-b. The compounds are characterized by a specific formula wherein X, Y, W, Z1, Z2, Z3, n, R, A, E, and D can take various forms. The compounds are novel, selective over c-Cbl, and capable of modulating the immune system. The present invention also provides methods for the synthesis of these compounds, involving a series of chemical reactions, including the synthesis of intermediates. The compounds may find potential applications in the field of medicinal chemistry, particularly in the modulation of immune responses.

Description

TITLE OF THE INVENTION SUBSTITUTED BICYCLIC SULFONAMIDE DERIVATIVES AS MODULATORS OF CBL-B FIELD OF INVENTION

[0001] The present disclosure generally relates to the field of medicinal chemistry, specifically to substituted bicyclic sulfonamide derivatives and their use as modulators of the E3 ligase Cbl-b. CROSS REFERENCE TO RELATED APPLICATIONS

[0002] Applicant claims priority and the benefit of Indian Provisional Patent application 202441039182, filed 20 May 2024 (20-05-2024), said application being hereby incorporated herein in its entirety by reference. BACKGROUND

[0003] The immune system plays a central role in maintaining the health of an organism by protecting it from disease-causing pathogens. It is a complex network of cells, tissues, and organs that work together to defend the body against harmful invaders. One of the primary components of the immune system is the leukocyte, or white blood cell, which is responsible for identifying and eliminating pathogens.

[0004] Among the various types of leukocytes, T cells, B cells, and natural killer (NK) cells are particularly noteworthy. These cells are involved in adaptive immunity, which is the part of the immune system that adapts to fight specific pathogens. T cells and B cells are responsible for recognizing specific antigens, while NK cells are involved in the destruction of infected cells.

[0005] The function of these immune cells is tightly regulated by a variety of signaling pathways. One such pathway involves the E3 ligase Cbl-b, a protein that plays a central role in controlling the activation and function of T cells, B cells, and NK cells. Cbl-b is part of the Cbl family of proteins, which also includes Cbl and Cbl-c. These proteins are characterized by their N-terminal tyrosine kinase binding (TKB) domain and a RING finger domain, which are involved in binding to specificphosphotyrosine motifs on activated protein tyrosine kinases (PTKs) and interacting with ubiquitin-conjugating enzymes, respectively.

[0006] The expression levels of Cbl-b are closely regulated by co-stimulatory and inhibitory signals, and it has been shown to play a central role in the negative control of T cell activation. This makes Cbl-b a potential target for modulating immune responses, particularly in the context of cancer immunotherapy. However, the development of effective modulators of Cbl-b activity requires a detailed understanding of the structure and function of this protein, as well as the ability to design and synthesize compounds that can selectively target Cbl-b without affecting the function of other proteins in the Cbl family. SUMMARY OF INVENTION

[0007] This summary is provided to introduce a selection of concepts in a simplified form that are further described below in the detailed description. This summary is not intended to identify key features or essential features of the claimed subject matter, nor is it intended to be used as an aid in determining the scope of the claimed subject matter.

[0008] According to an aspect of the present disclosure, there are provided compounds, their pharmaceutical acceptable salts, tautomers, stereoisomers, enantiomers, and isotopes thereof having a specific formula. In this formula, X, Y, and W can independently or in combination be either CH, C, N, NH, O, or S. Z1, Z2, and Z3 are individually or a combination of CH, C, N, NH, S, or O, or suitably substituted. The variable n can be 0, 1, 2, or 3. R can be taken from alkyl, branched alkyl, alkynyl, alkoxy, cyanoalkyl, halogen substituted alkyls, hydroxyalkyl, haloalkoxy, alkoxyalkyl, heteroalkyls, cycloalkyls, multicyclic cycloalkyl, heterocycloalkyls, substituted heterocycloalkyls, aryl, substituted aryl, heteroaryl, their deuterated analogs, and their substitutions.

[0009] The term “alkyl” refers to a hydrocarbon chain radical that includes solely carbon and hydrogen atoms in the backbone, containing no unsaturation, having from one to eight carbon atoms (i.e. C1-8 alkyl), and which is attached to the rest ofthe molecule by a single bond, such as, but not limited to, methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, and 1,1-dimethylethyl (t-butyl).

[0010] The term “alkynyl” refers to a straight or branched hydrocarbon chain radical that having at least one carbon-carbon triple bond, and having 2 to about 12 carbon atoms (with radicals having 2 to about 10 carbon atoms being preferred), e.g., ethynyl, propynyl, and butynyl.

[0011] The term “alkoxy” denotes an alkyl group attached via an oxygen linkage to the rest of the molecule. Representative examples of such groups are –OCH3 and –OC2H5.

[0012] The term “cyanoalkyl” refers to cyano group, linked to an alkyl group as defined above (i.e. cyano C1-8 alkyl). Examples of such haloalkyl moiety include, but are not limited to, cyanomethyl, cyanoethyl and cyanopropyl groups.

[0013] The term “haloalkyl” refers to at least one halo group (selected from F, Cl, Br or I), linked to an alkyl group as defined above (i.e. haloC1-8alkyl). Examples of such haloalkyl moiety include, but are not limited to, trifluoromethyl, difluoromethyl and fluoromethyl groups. The term “halo C1-8alkyl” refers to at least one halo group linked an alkyl chain having 1 to 8 carbon atoms.

[0014] The term “hydroxyalkyl” refers to an alkyl group as defined above wherein one to three hydrogen atoms on different carbon atoms is / are replaced by hydroxyl groups (i.e. hydroxyC1-8alkyl). Examples of hydroxyalkyl moiety include, but are not limited to –CH2OH, -C2H4OH and –CH(OH)C2H4OH.

[0015] The term “alkoxy” denotes an alkyl group attached via an oxygen linkage to the rest of the molecule (i.e. C1-8alkoxy). Representative examples of such groups are –OCH3 and – OC2H5.

[0016] The term “haloalkoxy” refers to an alkoxy group substituted with one or more halogen atoms (i.e. halo C1-8alkoxy). Examples of “haloalkoxy” include but are not limited to fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, pentachloroethoxy, chloromethoxy, dichlorormethoxy, trichloromethoxy and 1-bromoethoxy. The term “alkoxyalkyl” or “alkyloxyalkyl” refers to an alkoxy or alkyloxy group as defined above directly bonded to an alkyl group as defined above (i.e. C1-8 alkoxy C1-8alkyl or C1-8alkyloxy C1-8alkyl). Example of such alkoxyalkyl moiety includes, but are not limited to, -CH2OCH3(methoxymethyl) and – CH2OC2H5 (ethoxymethyl).

[0017] The term “hydroxy C1-8 alkyl” refers to a C1-8 alkyl group as defined above wherein one to three hydrogen atoms on different carbon atoms is / are replaced by hydroxyl groups (i.e. hydroxy C1-4 alkyl). Examples of hydroxy C1-4 alkyl moieties include, but are not limited to – CH2OH and –C2H4OH.

[0018] The term “cycloalkyl” denotes a non-aromatic mono or multicyclic ring system of 3 to about 12 carbon atoms, (i.e. C3-12 cycloalkyl). Examples of monocyclic cycloalkyl include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of multicyclic cycloalkyl groups include, but are not limited to, perhydronapthyl, 31yridine31 and norbornyl groups, bridged cyclic groups or spirobicyclic groups, e.g., spiro(4,4)non-2-yl. The term “C3-6cycloalkyl” refers to the cyclic ring having 3 to 6 carbon atoms. Examples of “C3- 6cycloalkyl” include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0019] The term “cycloalkylalkyl” refers to a cyclic ring-containing radical having 3 to about 6 carbon atoms directly attached to an alkyl group (i.e. C3-6cycloalkylC1-8alkyl). The cycloalkylalkyl group may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure. Non- limiting examples of such groups include cyclopropylmethyl, cyclobutylethyl, and cyclopentylethyl

[0020] The term “aryl” refers to an aromatic radical having 6 to 14 carbon atoms (i.e. C6-14aryl), including monocyclic, bicyclic and tricyclic aromatic systems, such as phenyl, naphthyl, tetrahydronapthyl, indanyl, and biphenyl.

[0021] The term “heterocyclic ring” or “heterocyclyl” unless otherwise specified refers to substituted or unsubstituted non-aromatic 3 to 15 membered ring radical (i.e.3 to 15 membered heterocyclyl) which consists of carbon atoms and from one to five hetero atoms selected from nitrogen, phosphorus, oxygen and sulfur. The heterocyclic ring radical may be a mono-, bi- or tricyclic ring system, which may include fused, bridged or spiro ring systems, and the nitrogen, phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic ring radical may be optionally oxidized to various oxidation states. In addition, the nitrogen atom may be optionally quaternized; also, unless otherwise constrained by the definition the heterocyclic ring or heterocyclyl may optionally contain one or more olefinic bond(s). Examples of such heterocyclic ring radicals include, but are not limited to azepinyl, azetidinyl, oxetanyl, benzodioxolyl, benzodioxanyl, chromanyl, dioxolanyl, dioxaphospholanyl, decahydroisoquinolyl, indanyl, indolinyl, isoindolinyl, isochromanyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, oxazolinyl, oxazolidinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2- oxoazepinyl, octahydroindolyl, octahydroisoindolyl, perhydroazepinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, piperidinyl, phenothiazinyl, phenoxazinyl, quinuclidinyl, tetrahydroisquinolyl, tetrahydrofuryl or tetrahydrofuranyl, tetrahydropyranyl, thiazolinyl, thiazolidinyl, thiamorpholinyl, thiamorpholinyl sulfoxide and thiamorpholinyl sulfone. The heterocyclic ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.

[0022] The term “heterocyclylalkyl” refers to a heterocyclic ring radical directly bonded to an alkyl group (i.e. heterocyclyl C1-8 alkyl). The heterocyclylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure.

[0023] The term “heteroaryl” unless otherwise specified refers to 5 to 14 membered aromatic heterocyclic ring radical with one or more heteroatom(s) independently selected from N, O or S (i.e.5 to 14 membered heteroaryl). The heteroaryl may be a mono-, bi- or tricyclic ring system. The heteroaryl ring radical may be attached tothe main structure at any heteroatom or carbon atom that results in the creation of a stable structure. Examples of such heteroaryl ring radicals include, but are not limited to oxazolyl, isoxazolyl, imidazolyl, furyl, indolyl, isoindolyl, pyrrolyl, triazolyl, triazinyl, tetrazoyl, thienyl, oxadiazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, benzofuranyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzothienyl, benzopyranyl, carbazolyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, naphthyridinyl, pteridinyl, purinyl, quinoxalinyl, quinolyl, isoquinolyl, thiadiazolyl, indolizinyl, acridinyl, phenazinyl and phthalazinyl.

[0024] The variable m can be 0, 1, 2 or 3.

[0025] A can be taken from but not limited to their positional isomers and derivatives ofE and D can be from alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and their derivatives.

[0026] According to other aspects of the present disclosure, the compounds may include one or more of the following features.

[0027] In one embodiment, the compound with formula-1 having [W]n=0 is a compound with formula 2. In another embodiment, the compound having [W]n as carbon and their substitutions in formula-1 is a compound with formula-3a and [W]n as nitrogen in formula-1 is a compound with formula 3b. In yet another embodiment, the compound having Z1 as zero in formula 3a and formula 3b results in compounds with formula 3c and formula 3d respectively

[0028] According to another aspect of the present disclosure, there are provided methods for the synthesis of these compounds. The methods involve a series of chemical reactions, including the synthesis of intermediates, which are then used to produce the final compounds.

[0029] According to other aspects of the present disclosure, the compounds may be used to modulate the immune system. The compounds are novel, selective over c- Cbl, and were able to modulate the immune system. The selectivity over c-Cbl was determined by a thermal shift assay.

[0030] To further clarify the advantages and features of the present disclosure, a more particular description of the disclosure will follow by reference to specific embodiments thereof, which are illustrated in the appended figures. It is to be appreciated that these figures depict only typical embodiments of the disclosure and are therefore not to be considered limiting in scope. The disclosure will be described and explained with additional specificity and detail with the appended figures. DETAILED DESCRIPTION OF THE INVENTION

[0031] For the purpose of promoting an understanding of the principles of the disclosure, reference will now be made to the embodiment illustrated in the figures and specific language will be used to describe them. It will nevertheless be understood that no limitation of the scope of the disclosure is thereby intended. Such alterations and further modifications in the illustrated system, and such further applications of the principles of the disclosure as would normally occur to those skilled in the art are to be construed as being within the scope of the present disclosure.

[0032] The terms "comprises", "comprising", or any other variations thereof, are intended to cover a non-exclusive inclusion, such that a process or method that comprises a list of steps does not include only those steps but may include other steps not expressly listed or inherent to such a process or method. Similarly, one or more components, compounds, and ingredients preceded by "comprises... a" doesnot, without more constraints, preclude the existence of other components or compounds or ingredients or additional components. Appearances of the phrase "in an embodiment", "in another embodiment" and similar language throughout this specification may, but not necessarily do, all refer to the same embodiment.

[0033] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs. The system, methods, and examples provided herein are only illustrative and not intended to be limiting.

[0034] In the following specification and the claims, reference will be made to a number of terms, which shall be defined to have the following meanings. The singular forms “a”, “an”, and “the” include plural references unless the context clearly dictates otherwise.

[0035] Embodiments of the present invention relate to bicyclic sulfonamide derivatives and their use as modulators of the E3 ligase Cbl-b.

[0036] The present disclosure relates to compounds, their pharmaceutical acceptable salts, tautomer’s, stereoisomers, enantiomers and isotopes thereof having formula 1Wherein X, Y and W can be independently or combinedly taken from either CH, C, N, NH, O, S. Z1, Z2 & Z3 are individually or combination of CH, C, N, NH, S, O or suitably substituted. n= 0, 1, 2 or 3. m= 0,1, 2 or 3R can be taken from alkyl, branched alkyl, alkynyl, alkoxy, cyanoalkyl, halogen substituted alkyls, hydroxyalkyl, haloalkoxy, alkoxyalkyl, heteroalkyls, cycloalkyls, multicyclic cycloalkyl, heterocycloalkyls, substituted heterocycloalkyls, aryl, substituted aryl, heteroaryl, their deuterated analogs, and their substitutions.The term “alkyl” refers to a hydrocarbon chain radical that includes solely carbon and hydrogen atoms in the backbone, containing no unsaturation, having from one to eight carbon atoms (i.e. C1-8alkyl), and which is attached to the rest of the molecule by a single bond, such as, but not limited to, methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, and 1,1- dimethylethyl (t-butyl).

[0037] The term “alkynyl” refers to a straight or branched hydrocarbon chain radical that having at least one carbon-carbon triple bond, and having 2 to about 12 carbon atoms (with radicals having 2 to about 10 carbon atoms being preferred), e.g., ethynyl, propynyl, and butynyl. The term “alkoxy” denotes an alkyl group attached via an oxygen linkage to the rest of the molecule. Representative examples of such groups are –OCH3and –OC2H5.

[0038] The term “cyanoalkyl” refers to cyano group, linked to an alkyl group as defined above (i.e. cyano C1-8 alkyl). Examples of such haloalkyl moiety include, but are not limited to, cyanomethyl, cyanoethyl and cyanopropyl groups.

[0039] The term “haloalkyl” refers to at least one halo group (selected from F, Cl, Br or I), linked to an alkyl group as defined above (i.e. halo C1-8 alkyl). Examples of such haloalkyl moiety include, but are not limited to, trifluoromethyl, difluoromethyl and fluoromethyl groups. The term “halo C1-8alkyl” refers to at least one halo group linked an alkyl chain having 1 to 8 carbon atoms.

[0040] The term “hydroxyalkyl” refers to an alkyl group as defined above wherein one to three hydrogen atoms on different carbon atoms is / are replaced by hydroxyl groups (i.e. hydroxy C1-8 alkyl). Examples of hydroxyalkyl moiety include, but are not limited to –CH2OH, -C2H4OH and –CH(OH)C2H4OH.

[0041] The term “alkoxy” denotes an alkyl group attached via an oxygen linkage to the rest of the molecule (i.e. C1-8alkoxy). Representative examples of such groups are –OCH3 and – OC2H5.

[0042] The term “haloalkoxy” refers to an alkoxy group substituted with one or more halogen atoms (i.e. haloC1-8alkoxy). Examples of “haloalkoxy” include but are not limited to fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2- trifluoroethoxy, pentafluoroethoxy, pentachloroethoxy, chloromethoxy, dichlorormethoxy, trichloromethoxy and 1-bromoethoxy.

[0043] The term “alkoxyalkyl” or “alkyloxyalkyl” refers to an alkoxy or alkyloxy group as defined above directly bonded to an alkyl group as defined above (i.e. C1- 8alkoxyC1-8alkyl or C1-8alkyloxyC1-8alkyl). Example of such alkoxyalkyl moiety includes, but are not limited to, -CH2OCH3(methoxymethyl) and – CH2OC2H5 (ethoxymethyl).

[0044] The term “hydroxy C1-8 alkyl” refers to a C1-8 alkyl group as defined above wherein one to three hydrogen atoms on different carbon atoms is / are replaced by hydroxyl groups (i.e. hydroxy C1-4alkyl). Examples of hydroxy C1-4alkyl moieties include, but are not limited to – CH2OH and –C2H4OH.

[0045] The term “cycloalkyl” denotes a non-aromatic mono or multicyclic ring system of 3 to about 12 carbon atoms, (i.e. C3-12cycloalkyl). Examples of monocyclic cycloalkyl include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of multicyclic cycloalkyl groups include, but are not limited to, perhydronapthyl, 31yridine31 and norbornyl groups, bridged cyclic groups or spirobicyclic groups, e.g., spiro(4,4)non-2-yl. The term “C3- 6cycloalkyl” refers to the cyclic ring having 3 to 6 carbon atoms. Examples of “C3-6cycloalkyl” include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0046] The term “cycloalkylalkyl” refers to a cyclic ring-containing radical having 3 to about 6 carbon atoms directly attached to an alkyl group (i.e. C3-6cycloalkyl C1-8alkyl). The cycloalkylalkyl group may be attached to the main structure at anycarbon atom in the alkyl group that results in the creation of a stable structure. Non- limiting examples of such groups include cyclopropylmethyl, cyclobutylethyl, and cyclopentylethyl

[0047] The term “aryl” refers to an aromatic radical having 6 to 14 carbon atoms (i.e. C6-14aryl), including monocyclic, bicyclic and tricyclic aromatic systems, such as phenyl, naphthyl, tetrahydronapthyl, indanyl, and biphenyl.

[0048] The term “heterocyclic ring” or “heterocyclyl” unless otherwise specified refers to substituted or unsubstituted non-aromatic 3 to 15 membered ring radical (i.e.3 to 15 membered heterocyclyl) which consists of carbon atoms and from one to five hetero atoms selected from nitrogen, phosphorus, oxygen and sulfur. The heterocyclic ring radical may be a mono-, bi- or tricyclic ring system, which may include fused, bridged or spiro ring systems, and the nitrogen, phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic ring radical may be optionally oxidized to various oxidation states. In addition, the nitrogen atom may be optionally quaternized; also, unless otherwise constrained by the definition the heterocyclic ring or heterocyclyl may optionally contain one or more olefinic bond(s). Examples of such heterocyclic ring radicals include, but are not limited to azepinyl, azetidinyl, oxetanyl, benzodioxolyl, benzodioxanyl, chromanyl, dioxolanyl, dioxaphospholanyl, decahydroisoquinolyl, indanyl, indolinyl, isoindolinyl, isochromanyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, oxazolinyl, oxazolidinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2- oxoazepinyl, octahydroindolyl, octahydroisoindolyl, perhydroazepinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, piperidinyl, phenothiazinyl, phenoxazinyl, quinuclidinyl, tetrahydroisquinolyl, tetrahydrofuryl or tetrahydrofuranyl, tetrahydropyranyl, thiazolinyl, thiazolidinyl, thiamorpholinyl, thiamorpholinyl sulfoxide and thiamorpholinyl sulfone. The heterocyclic ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.

[0049] The term “heterocyclylalkyl” refers to a heterocyclic ring radical directly bonded to an alkyl group (i.e. heterocyclyl C1-8alkyl). The heterocyclylalkyl radicalmay be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure.

[0050] The term “heteroaryl” unless otherwise specified refers to 5 to 14 membered aromatic heterocyclic ring radical with one or more heteroatom(s) independently selected from N, O or S (i.e.5 to 14 membered heteroaryl). The heteroaryl may be a mono-, bi- or tricyclic ring system. The heteroaryl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure. Examples of such heteroaryl ring radicals include, but are not limited to oxazolyl, isoxazolyl, imidazolyl, furyl, indolyl, isoindolyl, pyrrolyl, triazolyl, triazinyl, tetrazoyl, thienyl, oxadiazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, benzofuranyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzothienyl, benzopyranyl, carbazolyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, naphthyridinyl, pteridinyl, purinyl, quinoxalinyl, quinolyl, isoquinolyl, thiadiazolyl, indolizinyl, acridinyl, phenazinyl and phthalazinyl.

[0051] A can be taken from but not limited to their positional isomers and derivatives ofE and D can be from Alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl and their derivatives

[0052] In one of the embodiment, compound with formula-1 having [W]n=0 is a compound with formula 2

[0053] In one of the embodiments, compound having [W]nas carbon and their substitutions in formula-1 is a compound with formula-3a and [W]nas nitrogen in formula-1 is a compound with formula 3bWherein R2 is taken from but not limited to -H, alkyl, branched alkyl, halogen substituted alkyls, heteroalkyls, cycloalkyls, substituted cycloalkyls, their deuterated analogs, aryl, substituted aryl, heteroaryl and their substitutions

[0054] The Wherein Z1, Z2 & Z3 are individually or combination of CH, C, N, NH, S or O or suitably substituted

[0055] In one of the embodiments, compound having Z1 as zero in formula 3a and formula 3b results in compounds with formula 3c and formula 3d respectively

[0056] Table 1: List of inhibitors of Cbl-b Compd ID Structure LCMS (ESI) m / z1H NMR (400 MHz, DMSO d6) δ Example-1 574.5 [M+H]+8.33 (s, 1H), 7.86 (s, 1H), 7.77 - 7.75 (m, 1H), 7.68 (s, 2H), 7.63 (s, 1H),7.34 (s, 1H), 5.19 (s, 2H), 3.54 (s, 2H), 3.27 (s, 3H), 3.18 - 3.16 (m, 1H), 2.92 - 2.88 (m, 2H), 2.70 - 2.67 (m, 3H), 2.63 - 2.58 (m, 2H), 1.91 - 1.88 (m, 1H), 1.63 - 1.61 (m, 4H), 1.48 - 1.45 (m, 1H), 1.11 (d, J = 6 Hz, 3H), 0.819 (d, J = 5.6 Hz, 3H). Example-2 506.5 [M+H]+8.29 (s, 1H), 7.82 (br. s, 1H), 7.74 - 7.65 (m, 2H), 7.47- 7.31 (m, 3H), 7.10 (d, 2H, J = 7.6 Hz), 5.5 (s, 2H), 3.58 (s, 2H), 3.2 (s, 3H), 2.84 (s, 2H), 2.71 - 2.67 (m, 3H), 2.56 - 2.54 (m, 3H),1.91 (br. s, 1H), 1.67 - 1.46 (m, 5H),1.11 - 1.08 (m, 3H), 0.82 - 0.813 (m, 4H). Example-3 574.3 [M+H]+8.29 (s, 1H), 8.20 (s, 1H), 8.07 (s, 1H), 7.5 -7.34 (m, 3H), 7.19 (d, J =7.6Hz, 1H), 5.24 (s, 2H), 3.68 (s, 2H), 3.20 (s, 3H), 3.15 -3.10 (m, 1H), 2.84 - 2.83 (m, 2H), 2.70-2.67 (m, 2H), 2.56 - 2.55 (m, 2H), 2.27 - 2.22 (m, 1H), 1.70 - 1.59 (m, 4H), 1.52 -1.46 (m, 1H), 1.11 -1.08 (m, 3H), 0.88 - 0.86 (m, 1H), 0.82 (d, J = 6 Hz, 3H). Example-4 575.3 [M+H]+8.66 (d, J = 2.4 Hz, 1H), 8.46 (s, 1H), 8.34 (s, 1H), 8.24 (s, 1H), 8.10 (s, 1H), 7.83 (s, 1H), 5.35 (s, 2H), 3.68 (s, 2H), 3.32 - 3.29 (m, 1H), 3.24 (s, 3H), 2.92 – 2.88 (m, 2H), 2.70 – 2.67 (m, 2H), 2.60 – 2.58 (m, 2H), 1.96 - 1.94 (m, 1H), 1.67 - 1.59 (m, 6H), 1.09 (d, J = 5.2 Hz, 3H), 0.82 (d, J = 6.0 Hz, 3H). Example-5 562.3 [M+H]+8.20 (s, 2H), 8.07 (s, 1H), 7.44 (s, 1H), 7.41 – 7.37 (m, 2H), 7.18 (d, J = 6.8 Hz, 1H), 5.19 (s, 2H), 3.678 (s, 2H), 3.11 (s, 3H), 3.00 (s, 2H), 2.70 (t, J = 7.6 Hz, 2H), 1.96 (t, J = 10.8 Hz, 1H), 1.70-1.59 (m, 5H), 1.45 (s, 6H),0.92 - 0.88 (m, 1H), 0.827 (d, J = 6.0 Hz, 3H). Example-6 546.2 [M+H]+8.48 (s, 1H), 8.23 (s, 1H), 8.09 (s,1H), 7.71 (s, 1H), 7.57-7.54 (m, 3H), 6.69 (s, 1H), 5.32 (s, 2H), 3.70 (s, 3H), 3.69 (s, 1H), 3.17-3.16 (m, 1H), 2.71-2.67 (m, 3H), 2.61 (s, 3H),1.99-1.94 (m, 1H), 1.70-1.60 (m, 4H), 1.50-1.46 (m, 1H), 0.82 (d, J = 6 Hz, 3H). Example-7 548.2 [M+H]+8.27 (s, 1H), 8.21 (s, 1H), 8.15 (s,1H), 8.08 (s, 1H), 7.40 - 7.36 (m, 3H), 7.16 - 7.15 (m, 1H), 5.20 (s, 2H), 3.68 (s, 2H), 3.43 (s, 1H), 3.34 - 3.29 (m, 2H), 3.05 - 2.97 (m, 2H), 2.73 - 2.67 (m, 2H), 1.99 - 1.94 (m, 1H), 1.70 - 1.59 (m, 5H), 1.50 - 1.47 (m, 1H), 1.30 (d, J = 6.8 Hz, 3H), 0.88 (br.s, 1H), 0.82 (d, J = 6.4Hz, 3H). Example-8 586.4 [M+H]+8.29 (s, 1H), 8.13 (d, J=17.6 Hz, 2H), 7.56 - 7.51 (m, 1H), 7.44 (d, J = 8 Hz, 1H), 7.32 – 7.30 (m, 3H), 6.59 (d, J = 7.2 Hz, 1H), 3.67 (s, 2H), 3.19 (s, 3H), 3.23 (s, 1H), 3.08 (t, J = 13.2 Hz, 1H), 2.83 (s, 2H), 2.71 (d, J = 18.8 Hz, 2H), 2.50 (s, 2H), 2.27 (t, J = 10.8 Hz, 1H), 1.63 (t, J = 14 Hz, 4H), 1.48 (d, J = 12 Hz, 1H), 1.07 (t, J = 11.2 Hz, 3H), 0.83 (d, J = 6 Hz, 3H).Example-9 587.3 [M+H]+8.30 (s, 1H), 8.23 - 8.18 (m, 2H), 8.14 (s, 1H), 7.63 – 7.60 (m, 2H), 7.58 – 7.53 (m, 2H), 3.70 (s, 2H), 3.23 – 3.21 (m, 2H), 3.19 (s, 3H), 2.87 – 2.85 (m, 2H), 2.71 – 2.69 (m, 2H), 2.59 – 2.56 (m, 2H), 2.33 – 2.27 (m, 1H), 1.70 - 1.68 (m, 1H), 1.65 – 1.63 (m, 2H), 1.49 – 1.47 (m, 2H), 1.07 (d, J = 5.6 Hz, 3H), 0.82 (d, J = 6.4 Hz, 3H) Example-10 589.5 [M+H]+8.22 (s, 1H), 7.69 (d, J = 10.8 Hz, 2H), 7.38 - 7.34 (m, 2H), 7.28 (s, 1H), 7.21 (d, J = 8 Hz, 1H), 7.07 (d, J = 6.8 Hz, 1H), 5.30 (d, J = 2.4 Hz, 2H), 3.40-3.35 (m, 2H), 3.02 (s, 3H), 2.67 - 2.60 (m, 4H), 2.45 – 2.42 (m, 1H), 2.32 - 2.29 (m, 1H), 1.88 - 1.84 (m, 1H), 1.65 - 1.55 (m, 5H), 1.43 – 1.35 (m, 1H), 1.23 (s, 1H), 1.00 (d, J = 6.4 Hz, 3H), 0.79 (d, J = 4.8 Hz, 3H). Example-11 631.6 [M+H]+8.25(s, 1H), 7.34 - 7.51 (m, 5H), 7.11 (d, J = 8.4 Hz, 1H), 5.29 (s, 2H), 4.22 - 4.19 (m, 1H), 3.3 (s, 2H), 3.02 (s, 3H), 2.71 - 2.68 (m, 5H), 2.43 - 2.32 (m, 2H), 1.63 - 1.57 (m, 6H), 1.23(s,1H), 1.1 – 0.98 (m, 9H), 0.80 (d, J = 6.4 Hz, 3H). Example-12 546.3 [M+H]+8.29 (s, 1H), 7.59 (s, 1H), 7.52 (s, 1H), 7.47 - 7.43 (m, 1H), 7.41 - 7.39 (m, 1H), 7.22 (s, 1H),7.10 (d, J = 7.2 Hz, 1H), 5.12 (s, 2H), 3.53 (s, 2H), 3.22 (s, 3H), 2.89 - 2.85 (m, 2H), 2.70 - 2.67 (m, 2H), 2.57 - 2.53 (m, 3H), 2.08 - 2.04 (m, 1H), 1.89 - 1.87 (m, 1H), 1.62 - 1.60 (m, 4H), 1.49 - 1.47 (m, 1H), 1.09 - 1.08 (m, 6H), 0.85 - 0.81 (m, 5H). Example-13 546.3 [M+H]+8.36 (s, 1H), 7.59 (s, 1H), 7.52 (s, 1H), 7.45 - 7.40 (m, 1H), 7.36 (d, J = 2.0 Hz, 1H), 7.22 (s, 1H), 6.95 (d, J = 7.6 Hz, 1H), 5.11 (s, 2H), 3.53 (s, 2H), 3.25 (s, 3H), 3.15 - 3.11 (m, 2H), 2.70 - 2.67 (m, 2H), 2.37 - 2.35 (m, 1H), 2.27 - 2.23 (m, 2H), 2.04 - 2.03 (m, 1H), 1.92 - 1.87 (m, 1H), 1.66 - 1.60 (m, 4H), 1.50 - 1.47 (m, 1H), 1.27 - 1.22 (m, 2H), 1.10 (d, J = 6.4 Hz, 3H),1.07 - 1.05 (m, 2H), 0.87 - 0.85 (m, 2H), 0.81 (d, J = 5.6 Hz, 2H)Example-14 534.3 [M+H]+8.22 (s, 1H), 7.59 (s, 1H), 7.40 - 7.33 (m, 3H), 7.22 (s, 1H), 7.12 (d, J =7.2Hz, 1H), 5.06 (s, 2H), 3.53 (s, 2H), 3.11 (s, 3H), 3.00 (s, 2H), 2.69 - 2.67 (m, 2H), 2.05 (m, 1H), 1.92 – 1.87 (m, 1H), 1.66 - 1.59 (m, 5H), 1.45 (s, 6H), 1.07 (d, 2H), 0.82 - 0.81(m, 6H). Example-15 520.4 [M+H]+8.28 (s, 1H), 7.63–7.57 (m, 1H), 7.41–7.34 (m, 3H), 7.25 (s, 1H), 7.11 (d, J = 6.6 Hz, 1H), 5.10 (s, 2H), 3.56 (s, 1H), 3.45 (s, 3H), 3.04 – 2.97 (m, 2H), 2.68 (s, 2H), 2.08 – 2.02 (m, 1H), 1.93 – 1.85 (m, 1H), 1.69 – 1.44 (m, 7H), 1.31 (d, J = 6.9 Hz, 3H), 1.08 (d, J= 7.4 Hz, 2H), 0.84 (s, 6H). Example-16 547.4 [M+H]+8.67 (s, 1H), 8.39 (d, J = 6Hz,1H), 8.33 (s, 1H), 7.81 (s, 1H), 7.64 (d, J = 9.2 Hz, 1H), 7.22 (s, 1H), 5.22 (s, 2H), 3.53 (s, 2H), 3.25 (s, 3H), 2.93 - 2.92 (m, 2H), 2.67 - 2.63 (m, 2H), 2.61 - 2.59 (m, 2H), 2.08 - 2.04 (m, 1H), 1.89 - 1.87 (m, 1H), 1.62 - 1.60 (m, 4H), 1.49 - 1.47 (m, 1H), 1.09 - 1.08 (m, 6H), 0.85 - 0.81 (m, 6H).Example-17 548.4 [M+H]+8.19 (s, 1H), 7.59 (s, 1H), 7.45 (d, J =8 Hz, 1H), 7.36 (t, J = 7.6 Hz, 1H), 7.22 (s, 1H), 6.97 (s, 1H), 6.76 (d, J = 7.6 Hz, 1H), 5.0-4.87 (m, 6H), 3.51 (m, 4H), 2.89 (s, 3H), 2.67 (m, 2H), 2.07 (m, 1H), 1.87 (m, 1H), 1.6-1.4 (m, 5H), 1.08 (m, 2H), 0.8 (m, 6H). Example-18 575.3 [M+H]+8.33 (s, 1H), 8.20 (s, 1H), 8.07 (s, 1H), 7.49 - 7.42 (m, 3H), 7.02 (d, J = 7.6 Hz, 1H), 5.23 (s, 2H), 3.71(s, 2H), 3.20 (s, 2H), 3.15 (s, 1H), 2.84 (s, 2H), 2.56 (m, 2H), 2.42 (m, 4H), 2.32 (m, 3H), 2.27 (m, 1H), 3.15 (s, 3H), 1.23 (s, 1H), 1.09 (t, J = 5.6 Hz, 3H). Example-19 577.4 [M+H]+8.67 (s, 1H), 8.47 (s, 1H), 8.33 (s, 1H), 8.27 (s, 1H), 8.12 (s, 1H), 7.82 (s, 1H), 5.35 (s, 2H), 3.71 (s, 3H), 3.54 - 3.49 (m, 2H), 3.24 (s, 3H), 2.92 - 2.91 (m, 2H ), 2.70 (s, 1H), 2.63 - 2.58 (m, 4H), 2.14 - 2.09 (m, 1H), 1.82 (t, J = 10.4 Hz, 1H), 1.09 (d, J = 5.2 Hz, 3H ), 1.03 (d, J = 6.4Hz, 3H).Example-20 576.4 [M+H]+8.29 (s, 1H), 8.23 (s, 1H), 8.09 (s, 1H), 7.49 - 7.40 (m, 3H), 7.19 (d, J = 8.4Hz, 1H), 5.24 (s, 2H), 3.75- 3.71(m, 3H), 3.49 (d, J = 11.5Hz, 2H), 2.84 (s, 3H), 2.68 (s, 3H), 2.62 (s, 1H ),2.62 (s, 2H), 2.14 - 2.07 (m,1H), 1.84 - 1.79 (m, 1H), 1.23 (s,1H), 1.08 (d, J = 5.2Hz, 3H ), 1.03 (d, J = 6.4Hz, 3H). Example-21 578.4 [M+H]+8.23 (s, 1H), 8.17 (s, 1H), 8.09 (s, 1H), 7.46 (d, J = 8.4 Hz, 1H), 7.38 (t, J = 7.6 Hz, 1H), 7.03 (s, 1H), 6.82 (d, J = 7.6 Hz, 1H), 5.13(s, 2H), 4.96 (d, J = 5.6 Hz, 2H), 4.87 (d, J = 6.0 Hz, 2H), 3.71 (m, 3H), 3.52 (m, 4H), 2.89 (s, 3H), 2.70 - 2.60 (m, 2H), 2.11 (m, 1H), 1.82 (t, J = 10.4 Hz, 1H), 1.03 (d, J = 6.0 Hz, 3H). Example-22 573.0 [M+H]+8.41 (s, 1H), 8.19 (s, 1H), 8.06 (s, 1H), 7.67 (s, 1H), 7.54 (d, J = 8Hz, 1H), 7.28 - 7.25 (m, 1H), 6.34 (s, 1H), 5.62 (s, 2H), 5.16 (s, 2H), 3.69 (s, 2H), 3.57 (s, 3H ), 2.74 - 2.67 (m, 2H), 2.33 (s, 3H), 1.97 - 1.94 (m, 1H), 1.71 - 1.59 (m, 4H),1.50 - 1.47 (m, 1H ), 0.88 (s, 1H), 0.83 (d, J = 8 Hz, 3H). Example-23 576.0 [M+H]+8.20 (s, 1H), 8.18 (s, 1H), 8.08 (s, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.38 (t, J = 8.0 Hz, 1H), 7.03 (s, 1H), 6.82 (d, J = 7.2 Hz, 1H), 5.13 (s, 2H), 4.96 (d, J = 6.0 Hz, 2H), 4.87 (d, J = 6.0 Hz, 2H), 3.71 (s, 2H), 3.50 (s, 2H), 2.89 (s, 3H), 2.69 (m, 2H), 1.96 (m, 1H), 1.67 (m, 4H), 1.49 (m, 1H), 0.83 (m, 4H). Example-24 560.0 [M+H]+8.39 (s, 1H), 8.17 (s, 1H), 8.05 (s, 1H), 7.43 (s, 2H), 7.13 (s, 1H), 5.17 (s, 2H), 3.66 (s, 2H), 3.17 (s, 3H), 3.15 – 3.03 (m, 3H), 2.71 – 2.67 (m, 2H), 2.20 – 2.15 (m, 1H), 1.97 – 1.92 (m, 1H), 1.72 (s, 3H), 1.69 – 1.58 (m, 5H), 0.91 – 0.87 (m, 1H), 0.82 (d, J = 3.6 Hz, 3H) Example-25 590.4 [M+H]+8.15 (s, 1H), 8.00 (s, 1H), 7.94 (s, 1H), 7.67 (s, 1H), 7.30 (d, J = 8Hz, 1H), 7.10 (d, J = 8Hz, 1H), 6.88 (d, J = 8Hz, 1H), 6.81 (s,1H), 4.89 (d, J = 4Hz, 2H), 4.77 (d, J = 8Hz, 2H), 3.12 (t, J = 8Hz, 2H ), 3.60 (s, 2H), 3.44 (s,2H), 3.22 (t, J = 8 Hz, 2H), 2.82 (s, 3H), 2.67 (s, 2H), 1.96 - 1.87 (m, 1H), 1.65 - 1.58 (m, 3H), 1.47 - 1.44 (m, 1H), 0.87 (s, 1H), 0.81(d, J = 4Hz, 3H). Example-26 576.1 [M+H]+8.18 (s, 1H), 8.01 (s, 1H), 7.96 (s, 1H), 7.30 (t, J = 8Hz, 1H), 7.21 (d, J = 8Hz, 1H), 7.06 (d, J = 8Hz, 2H), 4.15 (t, J = 4Hz, 2H), 3.60 (s, 2H), 3.22 (t, J = 8Hz, 2H), 2.98 (s, 3H), 2.90 (s, 2H), 2.67 (s, 2H), 1.95 - 1.90 (m,1H), 1.65 - 1.57 (m, 5H), 1.35 (s, 6H), 0.86 – 0.81 (m, 4H). Example-27 574.1 [M+H]+8.33 (s, 1H), 7.97 (s, 1H), 7.91 (s, 1H), 7.35 (d, 1H, J = 8 Hz), 7.13 (d, J = 8 Hz, 1H,), 6.76 (d, , J = 8 Hz, 1H), 4.13 (t, J = 6 Hz, 2H), 3.58(s, 2H), 3.23 (s, 3H), 3.10 (s, 3H), 3.07 - 3.02 (m, 2H), 2.65 (m, 2H), 2.46 (s, 1H), 2.17 - 2.11 (m, 1H), 1.92 (m, 1H), 1.67 - 1.63 (m, 7H), 1.45 (m, 1H), 0.81 (d, J = 4 Hz ,3H). Example-28 589.1 [M+H]+8.47 (d, J = 8 Hz, 1H), 8.43 (d, J = 8 Hz, 1H), 8.28 (s, 1H), 8.02 (s, 1H), 7.96 (s, 1H), 7.48 (s, 1H), 4.27 (m,2H), 3.60 (s, 2H), 3.17 (s, 1H), 3.15 (s, 3H), 2.80 - 2.77 (m, 2H), 2.67 (m, 5H), 1.93 (m, 1H), 1.65 - 1.57 (m, 4H), 1.43 (m, 1H), 1.24 (s, 1H), 1.04 (d, J = 4 Hz , 3H), 0.87 (m, 1H), 0.81 (d, J = 8 Hz , 3H). Example-29 587.1 [M+H]+8.39 (s,1H), 8.01 (s,1H), 7.46 (s, 1H), 7.42 (d, J = 8 Hz, 1H), 6.81 (d, J = 8 Hz, 1H), 5.57 (s, 2H), 4.15 (t, J = 6 Hz, 2H), 6.34 (s, 2H), 3.53 (s, 3H), 3.26 (t, J = 6 Hz, 2H), 2.69 - 2.67 (m, 2H), 2.40 (s, 3H), 1.96 -1.9 (m, 1H), 1.66 -1.58 (m, 4H), 1.48 -1.45 (m, 1H), 0.87 - 0.83 (m, 1H), 0.81 (d, J = 6 Hz, 3H). Example-30 588.1 [M+H]+8.25 (s, 1H), 8.01 (s, 1H), 7.95 (s, 1H), 7.43-7.39 (m, 1H), 7.23 (d, J = 8 Hz, 1H), 7.17 (d, J = 8 Hz, 1H), 7.11 (s, 1H), 4.22 (m, 2H), 3.59 (s, 2H), 3.23 (m, 3H), 3.10 (s, 3H), 2..67 (m, 4H), 1.93 (m, 1H), 1.65 - 1.57 (m, 5H), 1.47 (m, 1H), 1.24 (m, 1H), 1.03 (d, J = 8 Hz, 3H), 0.90 (m, 1H), 0.81 (d, J = 8 Hz, 3H).Example-31 582.5 [M+H]+8.28 (s, 1H), 7.84 (s, 1H), 7.70 (s, 1H), 7.64 (d, J = 7.2 Hz, 2H), 7.56– 7.41 (m, 5H), 7.32 (d, J = 8.0 Hz, 1H), 7.14 (d, J = 7.6 Hz, 1H), 5.08 (s, 2H), 3.65 (s, 2H), 3.19 (s, 3H), 2.82- 2.73 (m, 4H), 2.57 - 2.50 (m, 3H), 1.94 (t, J = 10.8 Hz, 1H), 1.69 - 1.58 (m, 4H), 1.49 -1.46 ((m, 1H), 1.07 (d, J = 5.2 Hz, 3H), 0.87-0.81 (m, 4H). Example-32 582.5 [M+H]+8.35 (s, 1H), 7.84 (s, 1H), 7.70 (s, 1H), 7.64 (d, J = 7.2 Hz, 2H), 7.56 – 7.38 (m, 4H), 7.32 - 7.27 (m, 2H), 6.97 (d, J = 7.6 Hz, 1H), 5.08 (s, 2H), 3.65 (s, 2H), 3.23 (s, 3H), 3.13 - 3.09 (m, 2H), 2.77 - 2.73 (m, 2H), 2.27 - 2.33 (m, 1H), 2.24 - 2.19 (m, 2H), 1.94 (t, J = 10.8 Hz, 1H), 1.69 - 1.52 (m, 4H), 1.48 - 1.46 ((m, 1H), 1.09 (d, J = 6.8 Hz, 3H), 0.87 - 0.81 (m, 4H). Example-33 583.5 [M+H]+8.59 (d, J = 2 Hz, 1H), 8.43 (d, J = 2 Hz, 1H), 8.32 (s, 1H), 7.88 (s, 1H), 7.77 – 7.72 (m, 2H), 7.65 - 7.63 (m, 2H), 7.5 – 7.49 (m, 3H), 5.21 (s, 2H), 3.65 (s, 2 H), 3.22 (s, 3H), 2.90 - 2.88(m, 2H), 2.75 (m, 2H), 2.67 - 2.57 (m, 3H), 1.95 (m, 1H), 1.66 - 1.58 (m, 4H), 1.49 (m, 1H), 1.09 - 1.07 (d, J = 5.6 Hz, 3H), 0.87 (m,1H), 0.83 - 0.81 (d, J = 6 Hz, 3H). Example-34 583.5 [M+H]+8.56 (d, J = 2 Hz, 1H), 8.40 (d, J = 2 Hz, 1H), 8.27 (s, 1H), 7.87 (s, 1H), 7.72 (s, 1H), 7.65 - 7.63 (m, 3H), 7.5 – 7.49 (m, 3H), 5.2 (s, 2H), 3.65 (s, 2 H), 3.26 (s, 3H), 3.17 - 3.13 (m, 2H), 2.74 (m, 2H), 2.39 - 2.27 (m, 3H), 1.97 - 1.92 (m, 1H), 1.66 - 1.56 (m, 5H), 1.11 - 1.09 (d, J = 6.4 Hz, 3H), 0.87 (m, 1H), 0.83 - 0.81 (d, J = 6 Hz, 3H). Example-35 570.5 [M+H]+8.19 (s, 1H), 7.84 (s, 1H), 7.70 (s, 1H), 7.66 (d, J = 7.2 Hz, 2H), 7.57 - 7.53 (m, 2H), 7.50 - 7.49 (m, 1H), 7.40 (s, 1H), 7.34 (d, J = 4.4 Hz, 2H), 7.13 (s, 1H), 5.04 (s, 2H ), 3.65 (s, 2H ), 3.08 (s, 3H), 2.97 (s, 3H), 2.75 - 2.67 (t, J = 8 Hz, 1H), 1.92 (t, J = 5.2 Hz, 1H), 1.67 - 1.59 (m, 4H), 1.50 (s, 1H), 1.42 (s, 6H), 0.87 ( s, 1H), 0.82 (d, J = 6Hz, 3H).Example-36 541.3 [M+H]+8.66 (d, J = 2 Hz, 1H), 8.42 (s, 1H), 8.33 (s, 1H), 7.90 (s, 1H), 7.85 (s, 1H), 7.80 (s, 1H), 5.17 (s, 2H), 3.60 (s, 2H), 3.24 (s, 3H), 2.93 (d, J = 3.6 Hz, 2H), 2.70 (t, J = 7.2 Hz, 2H), 2.60 (d, J = 40.4 Hz, 3H), 1.93 – 1.89 (m, 1H), 1.67 - 1.43 (m, 6H), 1.10 (d, J = 5.2 Hz, 3H), 0.90 - 0.81 (m, 3H). Example-37 541.3 [M+H]+8.62 (d, J = 2 Hz, 1H), 8.40 (s, 1H), 8.26 (s, 1H), 7.90 (s, 1H), 7.85 (s, 1H), 7.65 (s, 1H), 5.16 (s, 2H), 3.60 (s, 2H), 3.27 (s, 3H), 3.18 - 3.14 (m, 2H), 2.96 (s, 1H), 2.70 – 2.68 (m, 3H), 2.40- 2.30 (m, 4H), 1.95 – 1.93 (m, 1H), 1.67 - 1.46 (m, 3H), 1.12 (d, J = 6 Hz, 3H), 0.91 - 0.82 (m, 3H). Example-38 540.1 [M+H]+8.29 (s, 1H), 7.84 (d, J = 15.2 Hz, 2H), 7.47-7.39 (m, 3H), 7.14 (d, J= 7.6 Hz,1H), 5.07 (s, 2H), 3.59 (s, 2H),3.20 (s, 3H), 2.85 (s, 2H), 2.70 (t, J = 8 Hz, 3H), 2.56 (d, J= 7.2 Hz, 3H), 1.93 (d, J = 10.4 Hz,1H), 1.67 - 1.58 (m, 4H), 1.49 (d, J = 7.6 Hz,1H), 1.09 (d, J= 5.2 Hz, 3H), 0.83 (d, J= 6 Hz, 3H). Example-39 542.0 [M+H]+8.18 (s, 1H), 7.87 (s, 1H), 7.83(s, 1H), 7.44 (d, J = 7.2 Hz, 1H), 7.36 (t, J = 8.0 Hz, 1H), 7.01 (s, 1H), 6.77 (d, J = 7.2 Hz, 1H), 4.96 (m, 4H), 4.88 (d, J = 6.0 Hz, 2H), 3.59 (s, 2H), 3.50 (s, 2H), 2.89 (s, 3H), 2.69 (m, 2H), 1.93 (m, 1H), 1.64 (m, 4H), 1.49(m, 1H), 0.83 (m, 4H). Example-40 528.1 [M+H]+8.21 (s, 1H), 7.87 (s, 1H), 7.83 (s, 1H), 7.42-7.34 (s, 3H), 7.15 (d, J = 8.0 Hz , 1H), 5.02 (s, 2H), 3.60 (s, 2H), 3.11 (s, 4H), 3.01 (s, 2H), 2.71 (m, 2H), 1.93(m , 1H), 1.67-1.59 (m, 6H), 1.45 (s, 6H), 0,92 - 0.83 (m, 2H). Example-41 539.0 [M+H]+8.42 (s, 1H), 7.85 (s, 1H), 7.81 (s, 1H), 7.66 (s, 1H), 7.53 (d, J = 8 Hz, 1H), 7.25 (d, J = 12 Hz, 1H), 6.33 (s, 1H), 5.62 (s, 2H), 4.99 (s, 2H), 3.60 (s, 2H), 3.57 (s, 3H), 2.74 - 2.67 (m, 2H), 2.40 (s, 3H), 1.96 - 1.91 (m, 1H), 1.67 - 1.53 (m, 4H), 1.50 - 1.47 (m,1H), 0.87 (br.s, 1H) 0.82 (d, J = 4 Hz, 3H) Example-42 526.0 [M+H]+8.39 (s, 1H), 7.81 (d, 2H, J =1.2Hz), 7.42 (s, 2H), 7.08 (s, 1H), 5.0 (s, 2H), 3.58 (s, 2H), 3.17 (s, 3H), 3.14 - 3.06 (m, 2H), 2.72 - 2.66 (m, 3H), 2.20 - 2.15 (m, 1H), 1.94 - 1.89 (m, 1H), 1.72 (s, 3H), 1.61 - 1.57 (m, 4H), 1.48 - 1.45 (m, 1H), 0.86 - 0.81 (m, 4H). Example-43 516.0 [M+H]+8.28 (s, 1H), 7.8 (s, 1H), 7.83 (s, 1H), 7.39-7.35 (m, 3H), 7.13 (d, J = 8.0 Hz, 1H), 5.04 (s, 2H), 3.60 (s, 2H), 3.44 (s, 3H), 3.27 (s, 1H), 3.06 - 2.95 (m, 2H), 2.74 - 2.69 (m, 2H), 1.94 – 1.92 (m, 1H), 1.68 - 1.44 (m, 5H), 1.31 – 1.29 (m , 3H), 0.90 - 0.87 (m, 1H), 0.83 (d, J = 4.0 Hz, 3H). Example-44 509.4 [M+H]+8.30 (s, 1H), 8.15 (s, 1H), 8.06 (d, J = 1.2 Hz, 1H), 7.81 (s, 1H), 7.49 - 7.41 (m, 3H), 7.34 (s, 1H), 7.16 (d, J = 7.6 Hz, 1H), 5.12 (s, 2H), 3.77 (s, 3H), 3.21 (s, 3H), 2.86 - 2.84 (m, 2H), 2.57 - 2.55 (m, 2H), 1.23 (s,1H), 1.09 (d, J = 5.2 Hz, 3H).Example-45 511.0 [M+H]+8.19 (s, 1H), 8.15 (s, 1H), 8.06 (s, 1H), 7.81 (s, 1H), 7.47 (d, J = 9.6Hz, 1H), 7.39 - 7.34 (m, 2H), 7.04 (s, 1H), 6.80 (d, J = 7.2Hz, 1H), 5.02 (s, 2H), 4.96 (d, J = 6Hz, 2H), 4.88 (d, J = 6.4Hz, 2H), 3.77 (s, 3H), 3.51(s, 2H), 2.91 (s, 3H).

[0057] Synthesis of Intermediate-12: 3-(3-methyl-1-(4-methyl-4H-1,2,4- triazol-3- yl)cyclobutyl) aniline Scheme of synthesis

[0058] Synthesis of 1-(m-bromo phenyl)-3-methylcyclobutanecarbonitrile (3):.A stirred solution of (m-bromo phenyl)acetonitrile, (1) (3.8 g, 19.4 mmol) in dimethylformamide (38 mL, 491 mmol) was added sodium hydride (1.55 g, 38.8 mmol) in a portion wise manner at 0°C and stirred for 15 min. 1,3-dibromo-2- methylpropane, (2) (5.0 g, 23.3 mmol) was added to the reaction mixture and was allowed to warm to room temperature and stirred for 16 h. Progress of the reaction was monitored through TLC. The reaction mixture was quenched with ice cold water (50 mL) and extracted with ethyl acetate (2 X 100 mL). Combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and evaporated over vacuum to get crude product. The crude was purified over silica gel flash column chromatography by using EtOAc and Hexane as Eluents. Compound eluted out in 3% EtOAc: Hexanes. Pure fractions were evaporated off to obtain product -(m-bromo phenyl)-3-methylcyclobutanecarbonitrile as a colourless oil (4.6 g, 72 %).1H NMR (400 MHz, DMSO-d6) δ 7.70 (s, 1H), 7.59 – 7.39 (m, 3H), 2.88 – 2.78 (m, 2H), 2.50 – 2.40 (m, 2H), 2.23 – 2.17 (m, 1H), 1.22 (d, J = 6.0 Hz, 3H).

[0059] Synthesis of 1-(m-bromo phenyl)-3-methylcyclobutanecarbonitrile (4):To a stirred solution of 1-(m-bromo phenyl)-3-methylcyclobutanecarbonitrile (3) (7 g, 28 mmol) in ethanol (17.5 mL) was added potassium hydroxide (15.7 g) in water (17.5 mL) at room temperature and was heated at 110°C for 24h. Progress of the reaction was monitored through TLC. The reaction mixture was evaporated under vacuum then acidified with dilute HCl to get precipitates. The precipitates were filtered off and dried over vacuum to get 1-(m-bromo phenyl)-3- methylcyclobutanecarbonitrile (7 g) as an oily compound. The material was forward to next step without any further purification. LCMS (ESI)m / z=266.4[M- H]+.

[0060] Synthesis of 1-(m-bromo phenyl)-3-methylcyclobutanecarboxylic acid (5):To a stirred solution of 1-(m-bromo phenyl)-3-methylcyclobutanecarboxamide (4) (7.5 g, 28 mmol) in ethanol (20 mL) was added potassium hydroxide (31.4 g, 560 mmol) in water (5 mL) at room temperature and was allowed to stir at 110°C for 24h. Progress of the reaction was monitored through TLC. The reaction mixture was evaporated under vacuum, acidified with dilute HCl to get precipitates. The precipitates were filtered off and dried over vacuum to get 1-(m-bromo phenyl)-3- methylcyclobutanecarboxylic acid (5 g, 66 %).1H NMR (400 MHz, DMSO-d6) δ 12.42 (s, 1H), 7.70 (s, 1H), 7.59 – 7.29 (m, 3H), 2.58 – 2.48 (m, 2H), 2.37 – 2.29 (m, 2H), 2.20 – 2.10 (m, 1H), 1.058 (d, J = 6.8 Hz, 3H).

[0061] Synthesis of [1-(m-bromophenyl)-3-methylcyclobutyl](4- methylthiosemi carbazido)methanone (7):To a stirred solution of 1-(m-bromo phenyl)-3-methylcyclobutanecarboxylic acid (5) (6 g, 22.3 mmol) in tetrahydrofuran (47.9 mL) was added 4- methylthiosemicarbazide (6) (2.81 g, 26.8 mmol), bis(1-imidazolyl)methanone (7.23 g, 44.6 mmol) and triethylamine (9.32 mL, 66.9 mmol).The reaction mixture was allowed to stir at room temperature for 16h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reactionmixture was poured into water (100 mL) and extracted with ethyl acetate. The organic phase was washed with water, brine and dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The crude material was purified by silica gel flash column chromatography using 70% EtOAc: Hexane as the eluent. Compound eluted out as a mixture. Fractions pertaining to the compound were evaporated off to afford [1-(m-bromophenyl)-3-methylcyclobutyl](4- methylthiosemicarbazido)methanone (6 g) as an off-white solid. LCMS (ESI)m / z=358.4[M+H]+.

[0062] Synthesis of 5-[1-(m-bromophenyl)-3-methylcyclobutyl]-4-methyl-4H- 1,2,4-triazole-3-thiol (8):To a stirred solution of [1-(m-bromophenyl)-3-methylcyclobutyl](4-methyl thiosemicarbazido)methanone (7) (6 g, 16.8 mmol) in methanol (15 mL) was added potassium hydroxide (3.78 g, 67.4 mmol) dissolved in minimum water (3.61 mL). The reaction mixture was allowed to stir at 70°C for 2 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was slightly acidified and the precipitate was filtered to get 5-[1-(m- bromophenyl)-3-methylcyclobutyl]-4-methyl-4H-1,2,4-triazole-3-thiol (5 g, 87%) as a pale brown solid. LCMS (ESI) m / z=338.4[M+H]+1H NMR (400 MHz, DMSO- d6) δ 13.76 (s, 1H), 7.52 – 7.47 (m, 2H), 7.38 – 7.32 (m, 2H), 3.00 (s, 3H), 2.77 – 2.72 (m, 2H), 2.47 – 2.42 (m, 2H), 2.24 – 2.19 (m, 1H), 1.066 (d, J = 6.0 Hz, 3H).

[0063] Synthesis of 3-[1-(m-bromophenyl)-3-methylcyclobutyl]-4-methyl-4H- 1,2,4- triazole (9):A stirred solution of 5-[1-(m-bromophenyl)-3-methylcyclobutyl]-4-methyl-4H- 1,2,4-triazole-3-thiol (8) (5 g, 14.8 mmol) in dichloromethane (20 mL) was cooled to 0°C and added hydrogen peroxide (1 mL) and acetic acid (2 mL). The reaction mixture was gradually allowed to warm to room temperature and then allowed to stir for 1 h. The reaction was monitored by TLC. The reaction mixture was poured into ice cold water and extracted with DCM. The organic phase was washed with sodium bicarbonate solution, brine and dried over anhydrous sodium sulfate. The organic layer was filtered and concentrated in vacuum to get as 3-[1-(m- bromophenyl)-3-methylcyclobutyl]-4-methyl-4H-1,2,4-triazole (4 g, 55 %). LCMS (ESI)m / z=308.0[M+H]+,1H NMR (400 MHz, DMSO-d6) δ 8.30 (s, 1H), 7.52 – 7.47 (m, 2H), 7.38 – 7.32 (m, 2H), 3.20 (s, 3H), 2.77 – 2.72 (m, 2H), 2.47 – 2.42 (m, 2H), 2.24 – 2.19 (m, 1H), 1.66 (d, J = 6.0 Hz, 3H).

[0064] Synthesis of tert-butyl {m-[3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl) cyclobutyl] phenyl} carbamate (11)To a stirred solution of 3-[1-(m-bromophenyl)-3-methylcyclobutyl]-4-methyl-4H- 1,2,4-triazole (9) (4 g, 13.1 mmol) and tert-butyl carbamate (10) (2.3 g, 19.6 mmol) in acetonitrile (40 mL) was added 1,2-bis(methylamino)ethane (1.5 g, 17 mmol), dipotassium carbonate (12.6 g, 91.4 mmol) and purged with nitrogen gas for 5 mins. copper iodide (0.995 g, 0.4 eq., 5.23 mmol) was then added and the reaction mixture was heated at 90°C for 16h in a sealed tube. Progress of the reaction was monitored through TLC & LCMS. The reaction mixture was filtered through celite bed, quenched with ice cold water (15 mL), and extracted with ethylacetate (2 X 40 mL). Combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and evaporated over vacuum to get crude product. The crude material was purified by silica gel flash column chromatography using 10% MeOH: DCM as the eluent. Compound eluted out as a mixture. Fractions pertaining to the compound were completely evaporated off to obtain tert-butyl {m- [3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl]phenyl}carbamate (4 g) as an off-white solid. LCMS (ESI)m / z=343.2[M+H]+,1H NMR (400 MHz, DMSO- d6) δ 8.30 (s, 1H), 7.44 (s, 1H), 7.34 – 7.33 (m, 2H), 7.22 (t, J = 8.0 Hz, 1H), 6.89 (d, J = 7.6 Hz, 1H), 3.19 (s, 3H), 2.75 – 2.73 (m, 2H), 2.50 – 2.48 (m, 2H), 2.18 (m, 1H), 1.46 (s, 9H), 1.07 (d, J = 6.0 Hz, 3H).

[0065] Synthesis of tert-butyl {m-[3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl) cyclobutyl] phenyl} carbamate (Intermediate-12)To a stirred solution of tert-butyl {m-[3-methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl]phenyl}carbamate (11) (1 g, 2.92 mmol) in 1,4-dioxane (10 mL) was added 1,4-dioxane—hydrogen chloride (1 / 1) (5 mL, 29.2 mmol) . The reaction mixture was stirred for 16h at RT. Progress of the reaction was monitored by LCMS. After completion of the reaction, the solvents were completely evaporated under vacuum to obtain the crude compound which was triturated with pentane to get crude oily compound which was purified by Prep HPLC purification [Prep- HPLC Conditions: Column: Sunfire- C18(19 mm X 250 mm X 5 mic), Mobile phase (A): 5mM Ammonium bicarbonate in Water, Mobile phase(B): Acetonitrile: Methanol (1:1), Flow rate: 19 ml / min]. Pure fractions were evaporated off to obtain m-[3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl]aniline, Intermediate- 12 (0.6 g, 85 %) as an off-white solid. LCMS (ESI) m / z = 243.2[M+H]+, 1H NMR (400 MHz, DMSO-d6) δ 8.26 (s, 1H), 6.99 (t, J = 8.0 Hz, 1H), 6.48 – 6.46 (m, 2H),6.42 (d, J = 8.8 Hz, 1H), 5.05 (s, 2H), 3.15 (s, 3H), 2.73 – 2.69 (m, 2H), 2.46 – 2.42 (m, 2H), 1.05 (d, J = 6.0 Hz, 3H).

[0066] Synthesis of intermediate-14: potassium—{[(S)-3-methyl-1-piperidyl] methyl} tris(fluoro)-λ⁴-boraneTo a stirred solution of (S)-3-methylpiperidine-hydrogen chloride (2 g, 14.7 mmol) and potassium-(bromomethyl)tris(fluoro)-λ⁴-borane (14) (3.55 g, 17.7 mmol, 1:1) in tetrahydrofuran was added potassium hydrogen carbonate (4.43 g, 44.2 mmol) followed by potassium iodide (1.22 g, 7.37 mmol) at 0°C and the reaction mixture was stirred at 80°C for 4 h in a sealed tube. Progress of the reaction was monitored through TLC. The reaction mixture was evaporated under vacuum to obtain crude which was taken in acetone and stirred at room temperature for 15 minutes. The reaction mixture was filtered and the filtrate was completely evaporated off to obtain potassium{[(S)-3-methyl-1-piperidyl]methyl}tris(fluoro)- λ⁴-borane (1:1) (4 g) as a colorless solid. LCMS (ESI) m / z= 181.1 [M+H]+.

[0067] Synthesis of intermediate-16: 6-{[(S)-3-methyl-1-piperidyl] methyl}-1,2- dihydro- 1λ⁶,2-benzisothiazole-1,1(3H)-dioneTo a stirred solution of 6-bromo-2,3-dihydro-1H-1λ⁶,2-benzisothiazole-1,1-dione, (16) (0.250 g, 1.01 mmol) and potassium (S)-trifluoro((3-methylpiperidin-1-yl)methyl)borate, (14) (0.265 g, 1.21 mmol) in 1,4-dioxane (6 mL) and water (2 mL) was purged with Argon for 5 minutes. Dicaesium carbonate (0.985 g, 3.02 mmol) and dicyclohexyl[2',4',6'-tris(isopropyl)-2-biphenylyl]phosphine (0.0961 g, 0.202 mmol) were added followed by (2-Dicyclohexylphosphino-2′,4′,6′- triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methane sulfonate (0.0853 g, 0.101 mmol) and heated at 100°C for 16h in a sealed tube. Progress of the reaction was monitored through TLC. After completion of the reaction, the reaction mixture was cooled to room temperature and water (10 mL) was added to it. Extraction was carried out using EtOAc (20 mL x 3). The combined organic extracts were washed with water (10 mL x 2), brine (10 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude was purified by silica gel flash column chromatography. The compound eluted out as a mixture in 0 - 3 % MeOH in DCM. The fractions pertaining to the compound were collected and evaporated to obtain 6-{[(S)-3-methyl-1- piperidyl]methyl}-1,2-dihydro-1λ⁶,2-benzisothiazole-1,1(3H)-dione, intermediate-16 (0.2 g) as a white solid. The compound was taken over to the next step without any further purification. LCMS (ESI) m / z= 281.1 [M+H]+.

[0068] Synthesis of example-1: 6-{[(S)-3-methyl-1-piperidyl]methyl}-2-{3-[3- methyl-1-(4- methyl-4H-1,2,4-triazol-3-yl)cyclobutyl]-5- (trifluoromethyl)phenyl}-2,3-dihydro- 1λ⁶,2-benzisothiazole-1,1(1H)-dione

[0069] Synthesis of intermediate 16: 6-{[(S) -3-methyl-1-piperidyl] methyl}-1,2- dihydro- 1λ⁶,2-benzisothiazole-1,1(3H)-dione:

[0070] To a stirred solution of 6-bromo-2,3-dihydro-1H-1λ⁶,2-benzisothiazole-1,1- dione (70) (0.250 g, 1.01 mmol) and potassium (S)-trifluoro((3-methylpiperidin-1- yl)methyl)borate (51) (0.265 g, 1.21 mmol) in 1,4-dioxane (6 mL) and water (2 mL) was purged with Argon for 5 minutes. Dichasium carbonate (0.985 g, 3.02 mmol) and dicyclohexyl[2',4',6'-tris(isopropyl)-2-biphenylyl]phosphine (0.0961 g, 0.202 mmol) were added followed by (2-Dicyclohexylphosphino-2′,4′,6′-triisopropyl- 1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methane sulfonate (0.0853 g, 0.101 mmol) and heated at 100°C for 16h in a sealed tube. Progress of the reaction was monitored through TLC. After completion of the reaction, the reaction mixture was cooled to room temperature and water (10 mL) was added to it. Extraction was carried out using EtOAc (20 mL x 3). The combined organic extracts were washed with water (10 mL x 2), brine (10 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude was purified by silica gel flash column chromatography. The compound eluted out as a mixture in 0 - 3 % MeOH in DCM. The fractions pertaining to the compound were collected and evaporated to obtain 6-{[(S)-3-methyl-1-piperidyl]methyl}-1,2-dihydro-1λ⁶,2- benzisothiazole-1,1(3H)-dione (0.2 g) as a white solid. The compound was taken over to the next step without any further purification. LCMS (ESI) m / z= 281.1 [M+H]+.

[0071] To a stirred solution of 6-{[(S)-3-methyl-1-piperidyl]methyl}-2,3-dihydro- 1λ⁶,2-benzisothiazole-1,1(1H)-dione (0.160 g, 0.571 mmol), 3-{1-[3-bromo-5- (trifluoromethyl)phenyl]-3-methylcyclobutyl}-4-methyl-4H-1,2,4-triazole (0.235 g, 0.628 mmol) in acetonitrile (4 mL) was added 1,2-bis(methylamino)ethane (0.0654 mg, 0.742 mmol), dipotassium carbonate (0.552 g, 3.99 mmol) and was purged with nitrogen gas for 5 mins. Copper iodide (0.0435 g, 0.228 mmol) was added and the reaction mixture was heated at 80°C for 16h in a sealed tube. Progressof the reaction was monitored through TLC & LCMS. The reaction mixture was filtered through celite bed, quenched with ice cold water (15 mL), and extracted with ethyl acetate (2 X 20 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and evaporated over vacuum to get crude product. The crude was purified by Prep-HPLC [Prep-HPLC Conditions: Column: Zorbax Eclipse C18 (150 x 21.2) mm x 7 µm, Flow rate: 19.0mL / min, Mobile phase A: 0.1% Ammonia in Water, Mobile phase B: Acetonitrile]. The pure fractions were evaporated off to obtain 6-{[(S)-3-methyl-1-piperidyl]methyl}-2-{3- [3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl]-5- (trifluoromethyl)phenyl}-2,3-dihydro-1λ⁶,2-benzisothiazole-1,1(1H)-dione (10 mg, 3 %) as an off-white solid. LCMS (ESI) m / z= 574.5 [M+H]+ 1H NMR (400 MHz, DMSO d6) δ 8.33 (s, 1H), 7.86 (s, 1H), 7.77 - 7.75 (m, 1H), 7.68 (s, 2H), 7.63 (s, 1H),7.34 (s, 1H), 5.19 (s, 2H), 3.54 (s, 2H), 3.27 (s, 3H), 3.18 - 3.16 (m, 1H), 2.92 - 2.88 (m, 2H), 2.70 - 2.67 (m, 3H), 2.63 - 2.58 (m, 2H), 1.91 - 1.88 (m, 1H), 1.63 - 1.61 (m, 4H), 1.48 - 1.45 (m, 1H), 1.11 (d, J = 6 Hz, 3H), 0.819 (d, J = 5.6 Hz, 3H).

[0072] Synthesis of Example-2: (S)-2-(3-(3-methyl-1-(4-methyl-4H-1,2,4-triazol- 3-yl)cyclobutyl)phenyl)-6-((3-methylpiperidin-1-yl)methyl)-2,3- dihydrobenzo[d]isothiazole 1,1-dioxide Scheme of synthesis6-{[(S)-3-methyl-1-piperidyl]methyl}-1,2-dihydro-1λ⁶,2-benzisothiazole-1,1(3H)- dione (16)(150 mg, 0.54 mmol), 3-[1-(m-bromophenyl)-3-methylcyclobutyl]-4- methyl-4H-1,2,4-triazole (9) (180 mg, 0.59 mmol) were dissolved in acetonitrile (20 mL) and purged with nitrogen gas. Then 1,2-bis(methylamino)ethane (61.3 mg, 0.67 mmol), dipotassium carbonate (518 mg, 3.74 mmol) were added followed bycopper iodide (40.8 mg, 0.21 mmol) and heated at 80°C for 16h in a sealed tube. Progress of the reaction was monitored through TLC & LCMS. The reaction mixture was filtered through celite bed. The filtrate was quenched with ice-cold water (15 mL), and extracted with ethyl acetate (2 X 50 mL). Combined organic layers were washed with brine (25 mL), dried over sodium sulfate, filtered and evaporated over vacuum to get crude product. The crude product was purified by Prep-HPLC using prep conditions [Prep-HPLC conditions: Column: Zorbax Eclipse C18(150 x 21.2) mm x 7 µm, Mobile phase A: 0.1% Ammonia in Water, Mobile phase B: Acetonitrile, Flow: 19.0mL / min]. Pure fractions were evaporated off to obtain (S)-2-(3-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)phenyl)-6-((3-methylpiperidin-1-yl)methyl)-2,3- dihydrobenzo[d]isothiazole 1,1-dioxide (0.018 g, 7 %) as an off-white solid. LCMS (ESI) m / z= 506.5 [M+H]+.1H NMR (400 MHz, DMSO d6): δ 8.29 (s, 1H), 7.82 (br. s, 1H), 7.74 - 7.65 (m, 2H), 7.47- 7.31 (m, 3H), 7.10 (d, 2H, J = 7.6 Hz), 5.5 (s, 2H), 3.58 (s, 2H), 3.2 (s, 3H), 2.84 (s, 2H), 2.71 - 2.67 (m, 3H), 2.56 - 2.54 (m, 3H),1.91 (br. s, 1H), 1.67 - 1.46 (m, 5H),1.11 - 1.08 (m, 3H), 0.82 - 0.813 (m, 4H).

[0073] Synthesis of Example-3: (S)-2-(3-(3-methyl-1-(4-methyl-4H-1,2,4-triazol- 3-yl)cyclobutyl)phenyl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)- 2,3-dihydrobenzo[d]isothiazole 1,1-dioxide. Scheme of synthesis

[0074] Synthesis of 2-methyl-3-(trifluoromethyl)benzenesulfonamide (18)A stirred solution of 2-(chlorosulfonyl)-6-(trifluoromethyl)toluene(17) (1 g, 3.87 mmol) in tetrahydrofuran (15 mL, 184 mmol) was cooled to 0°C and NH3 gas was purged for 10 min at 0°C. The Progress of the reaction was monitored through TLC. After completion, the reaction mixture was poured to crushed ice and extracted with ethyl acetate (50 mL X 2). The combined organic extracts were washed with brine solution (10 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced vacuum to afford product as an off white solid (0.7 g, 76%). LCMS (ESI) m / z = 237.5 [M-H]+.1HNMR (400 MHz, DMSO-d6): δ 8.18 (d, J = 8.0 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.69 (s, 2H), 7.6 (t, J = 8.0 Hz, 1H), 2.71 (s, 3H).

[0075] Step-2: Synthesis of 5-bromo-2-methyl-3- (trifluoromethyl)benzenesulfonamide (19)A stirred solution of 6-(trifluoromethyl)-2-toluenesulfonamide (18) (0.7 g, 2.93 mmol) in sulfuric acid (143 mg, 1.46 mmol) was heated to 60°C. After attaining the desired temperature, 1-bromo-2,5-pyrrolidinedione (573 mg, 3.22 mmol) was added to it and continued heating at 60° for 2 h. The reaction was monitored through TLC and LCMS. After the completion of the reaction, it was poured into crushed ice and the formed precipitates were filtered and dried over vacuum to get the product 4-bromo-6-(trifluoromethyl)-2-toluenesulfonamide (0.8 g, 86 %) as an off white solid. LCMS (ESI) m / z = 318.8 [M+H]-.1HNMR (400 MHz, DMSO-d6): δ 8.27 (d, J = 1.6 Hz, 1H), 8.13 (d, J = 1.6 Hz, 1H), 7.85 (s, 2H), 2.64 (s, 3H).

[0076] Synthesis of 6-bromo-4-(trifluoromethyl)benzo[d]isothiazol-3(2H)-one 1,1-dioxide(20)A mixture of periodic acid (2.41 g, 12.6 mmol), chromium trioxide (15.7 mg, 15.7 mmol) and 4-bromo-6-(trifluoromethyl)-2-toluenesulfonamide (19) (0.5 g, 1.57 mmol) was dissolved in acetonitrile (10 mL) and heated to 80°C for 16 h. After completion of the reaction, the reaction mixture was quenched with isopropanol (5 mL) and heated for 15 mins. The reaction mixture was filtered through celite bed and filtrate was evaporated under vacuum to obtain crude. Water was added to it which resulted in the precipitates which were filtered and dried over vacuum to get the product 6-bromo-4-(trifluoromethyl)benzo[d]isothiazol-3(2H)-one 1,1-dioxide (0.3 g, 58 %) as an off white solid. LCMS (ESI) m / z = 327 [M-H]+.1HNMR (400 MHz, DMSO-d6): δ 8.3 (s, 1H), 8.04 (s, 1H).

[0077] Synthesis of 6-bromo-4-(trifluoromethyl)-2,3- dihydrobenzo[d]isothiazole 1,1-dioxide (21)6-bromo-3-oxo-4-(trifluoromethyl)-1,2-dihydro-3H,1H,1H-1λ⁶,2-benzisothiazole- 1,1-dione (20) (230 mg, 69.7 mmol) was dissolved in tetrahydrofuran (10 mL) and cooled to 0°C. (methylthio)methane—boron (1 / 1) (3 mL, 36.6 mmol) (neat solution) was added to it in a dropwise manner and heated at 75°C for 16h under inert atmosphere. Progress of the reaction was monitored through TLC and LCMS. The reaction mixture was quenched with dilute HCl which was added dropwise over 30 minutes till all the effervescence ceased out. The crude was quenched withwater and extracted with ethyl acetate (2X 20 mL) and washed with brine solution (5 mL). Combined organic layers were dried over sodium sulfate, filtered and evaporated under vacuum to get crude product. The crude was purified through silica gel flash column chromatography using 4g column as EtOAc / Heptane as eluents (17%). The pure fractions were evaporated off to get product 6-bromo-4- (trifluoromethyl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (90 mg, 41%) as an off white solid. LCMS (ESI) m / z = 314.1 [M-H]-.1HNMR (400 MHz, DMSO-d6): δ 8.5 (s, 1H), 8.29 (s, 1H), 8.2(s, 1H), 4.52 (s, 2H).

[0078] Synthesis of (S)-6-((3-methylpiperidin-1-yl)methyl)-4- (trifluoromethyl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide(22)6-bromo-4-(trifluoromethyl)-2,3-dihydro-1H-1λ⁶,2-benzisothiazole-1,1-dione (21) (170 mg, 53.8 mmol), potassium (S)-trifluoro((3-methylpiperidin-1- yl)methyl)borate (14) (589 mg, 2.69 mmol) were dissolved in 1,4-dioxane (5 mL): water (1 ml). The reaction mixture was purged with Nitrogen gas for 5 minutes and dicaesium carbonate (526 mg, 1.61 mmol), dicyclohexyl[2',4',6'-tris(isopropyl)-2- biphenylyl]phosphine (51.3 mg, 10.8 mmol) and chloridopalladium(1+) 2- biphenylid-2'-amine—dicyclohexyl[2',4',6'-tris(isopropyl)-3-biphenylyl]phosphine (1 / 1) (42.3 mg, 5.38 mmol) were added and heated at 100°C for 16h. Progress of the reaction was monitored through TLC. The reaction mixture was quenched with ice cold water (20 mL), and extracted with ethyl acetate (2 X 50 mL). The combined organic layers were washed with brine (5 mL), dried over sodium sulfate, filtered and evaporated over vacuum and concentrated to get crude. The crude was purified by silica gel flash column chromatography. Th compound eluted out in 15% -20% Ethyl acetate: Hexane. The pure fractions were concentrated to get 6-{[(S)-3- methyl-1-piperidyl]methyl}-4-(trifluoromethyl)-1,2-dihydro-1λ⁶,2- benzisothiazole-1,1(3H)-dione (0.1 g, 53.4 %) as an off white solid. LCMS (ESI)m / z = 349.0 [M+H]+.1HNMR (400 MHz, DMSO-d6): δ 8.10 (s, 1H), 8.04 (s, 1H), 7.95(s, 1H), 4.52 (s, 2H), 3.63 (s, 2H), 2.68 (m, 2H), 1.96 – 1.93 (m, 1H), 1.65 - 1.57 (m, 4H),1.51 -1.4 (m, 1H), 0.9 - 0.87 (m, 1H), 0.81 (d, J = 6 Hz, 3H).

[0079] Synthesis of 6-{[(S)-3-methyl-1-piperidyl]methyl}-2-{m-[3-methyl-1-(4- methyl-4H-1,2,4-triazol-3-yl)cyclobutyl]phenyl}-4-(trifluoromethyl)-1,2- dihydro-1λ⁶,2-benzisothiazole-1,1(3H)-dione6-{[(S)-3-methyl-1-piperidyl]methyl}-4-(trifluoromethyl)-1,2-dihydro-1λ⁶,2- benzisothiazole-1,1(3H)-dione (22) (60 mg, 0.172 mmol), 3-[1-(m-bromophenyl)- 3-methylcyclobutyl]-4-methyl-4H-1,2,4-triazole (9) (58 mg, 0.189 mmol) were dissolved in acetonitrile (5 mL) and 1,2-bis(methylamino)ethane (19.7 mg, 0.224 mmol), dipotassium carbonate (167 mg, 1.21 mmol) were added to it and purged with nitrogen gas for 5 min. Copper iodide (13.1 mg, 0.0689 mmol) was added to it and was heated at 80°C for 16h in a sealed tube. Progress of the reaction was monitored through TLC and LCMS. The reaction mixture was filtered through celite bed, quenched with ice-cold water (5 mL), and extracted with ethyl acetate (2 X 50 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and evaporated over vacuum to get crude product. The crude was purified through silica gel flash column chromatography by using DCM and MeOH as Eluents (5%) to obtain product. The obtained product was once again purified through Prep HPLC [Column: X-Select CSH C18 (250 mm x 19 mm x 5 µm), Mobile phase (A): 0.1%Ammonia in Water, Mobile phase (B): Acetonitrile, Flow rate: 19.0 mL / min]. The pure fractions were evaporated off to obtain 6- {[(S)-3-methyl-1-piperidyl]methyl}-2-{m-[3-methyl-1-(4-methyl-4H-1,2,4- triazol-3-yl)cyclobutyl]phenyl}-4-(trifluoromethyl)-1,2-dihydro-1λ⁶,2-benzisothiazole-1,1(3H)-dione (12 mg, 12 %) as an off white solid. LCMS (ESI) m / z = 574.32 [M+H]+.1HNMR (400 MHz, DMSO-d6): δ 8.29 (s, 1H), 8.20 (s, 1H), 8.07 (s, 1H), 7.5 -7.34 (m, 3H), 7.19 (d, J =7.6Hz, 1H), 5.24 (s, 2H), 3.68 (s, 2H), 3.20 (s, 3H), 3.15 -3.10 (m, 1H), 2.84 - 2.83 (m, 2H), 2.70-2.67 (m, 2H), 2.56 - 2.55 (m, 2H), 2.27 - 2.22 (m, 1H), 1.70 - 1.59 (m, 4H), 1.52 - 1.46 (m, 1H), 1.11 -1.08 (m, 3H), 0.88 - 0.86 (m, 1H), 0.82 (d, J = 6 Hz, 3H

[0080] Synthesis of Example-4

[0081] Synthesis of (5-bromo-3-pyridyl) methanol (24):To a stirred solution of 5-bromonicotinaldehyde (23) (13 g, 69.9 mmol) in methanol (100 mL) was added sodium borohydride (3.17 g, 83.9 mmol) at 0 °C. The mixture was stirred at 0 °C for 30 minutes. Progress of the reaction was monitored through TLC & LCMS. After completion, the reaction was evaporated under reduced vacuum then quenched ice cold water (100 mL) and extracted into ethyl acetate (100 mL X 4), brine solution (100 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced vacuum to afford (5-bromo-3-pyridyl)methanol (13 g, 99 %) as a colourless liquid. LCMS (ESI) m / z = 190 [M+H]+.1HNMR (400 MHz, DMSO-d6): δ 8.58 (s, 1H); 8.51 (s, 1H); 7.96 (s, 1H); 5.45 (s, 1H); 4.54 (s, 2H).

[0082] Synthesis of 3-bromo-5-(chloromethyl)pyridine (25):

[0083] To a stirred solution of (5-bromo-3-pyridyl)methanol (24) (13 g, 69.1 mmol) in dichloromethane (50 mL) was added thionyl dichloride (5.52 mL, 76.1 mmol) at 0 °C. The mixture stirred at RT for 6h. Progress of the reaction monitored through TLC & LCMS. After completion, the reaction was quenched ice cold water (100 mL) and extracted into DCM (100 mL X 2). The combined organic layers were washed with NaHCO3solution (100 mL) and brine solution (25 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced vacuum to afford compound of 3-bromo-5-(chloromethyl)pyridine (12.5 g, 88%) as white solid. LCMS (ESI) m / z = 206 [M+H]+.1HNMR (400 MHz, DMSO-d6): δ 8.72 (d, J = 2 Hz, 1H); 8.68 (d, J = 1.6 Hz, 1H); 8.22 (t, J = 2 Hz, 1H); 4.83 (s, 2H).

[0084] Synthesis of (5-bromo-3-pyridyl)acetonitrile (26):To a stirred solution of trimethylsilanecarbonitrile (9.09 mL,72.6 mmol) and 3- bromo-5-(chloromethyl)pyridine (25) (12.5 g, 60.5 mmol) in acetonitrile (128 mL) was added tetrabutylammonium fluoride (19 g,72.6 mmol) at RT, then continued for 16 h at RT. Progress of the reaction was monitored through TLC. After completion of the reaction, the reaction mixture was evaporated under reduced pressure to result in crude compound which was purified by Combiflash chromatography using ethyl acetate-hexane gradient over a period of 45 min (Column size 80 g). Required product elutes at around 30 % ethyl acetate-hexane. Pure fractions collected and concentrated to afford (5-bromo-3-pyridyl) acetonitrile(7.5 g, 63 %) as brown liquid. LCMS (ESI) m / z = 199 [M+H]+.1HNMR (400 MHz, DMSO-d6): δ 8.69 (d, J = 1.6 Hz, 1H), 8.58 (d, J = 1.2 Hz, 1H), 8.09 (s, 1H), 4.13 (s, 2H).

[0085] Synthesis of 1-(5-bromo-3-pyridyl)-3-methylcyclobutanecarbonitrile (27):To a stirred solution of (5-bromo-3-pyridyl)acetonitrile (26) (6 g, 30.5 mmol) in dimethylformamide (50 mL) was added sodium hydride (2.44 g, 60.9 mmol) in a portion wise manner at 0°C and was allowed to continue to stirred at 0° for 30 minutes. After 30 minutes 1,3-dibromo-2-methylpropane (2) (7.89 g, 1.2 eq., 36.5 mmol) was added to the reaction mixture and the reaction mixture was allowed to stirred at RT for 2 h. Progress of the reaction was monitored through TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with ice cold water (50 mL) and extracted with ethyl acetate (2 X 50 mL). Combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and evaporated over vacuum to get crude product. The crude was purified through (40g) silica gel purifier by using EtOAc and Hexane as the eluent to afford 1-(5- bromo-3-pyridyl)-3-methylcyclobutanecarbonitrile (7 g, 92 %) as yellow liquid. LCMS (ESI) m / z = 253 [M+H]+.1HNMR (400 MHz, DMSO-d6): δ 8.75 (d, J = 2 Hz, 1H), 8.73 (d, J = 2 Hz, 1H), 8.25 (t, J = 2 Hz, 1H), 2.90 – 2.86 (m, 2H), 2.50 – 2.46 (m, 2H), 2.32 – 2.26 (m, 1H), 1.21 (d, J = 6.0 Hz, 3H).

[0086] Synthesis of 1-(5-bromo-3-pyridyl)-3-methylcyclobutanecarboxylic acid (28):To a stirred solution of 1-(5-bromo-3-pyridyl)-3-methylcyclobutanecarbonitrile (27) (7 g, 27.9 mmol) in ethanol (17.4 mL) was added potassium hydroxide (23.5 g, 418 mmol) in water (17.4 mL, 968 mmol) at RT and was allowed to continue to stir at 110°C for 24h. Progress of the reaction was monitored through TLC (10% EA / Hex). The reaction mixture was evaporated under vacuum then acidified with Potassium bisulfite (KHSO3) solutions to pH= 3 - 5. After quenching the reaction mixture, the water (100 mL) layer was extracted with ethyl acetate (2 X 100 mL). Combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and evaporated over vacuum to get product 27. The compound was forward to next step without purification. LCMS (ESI) m / z = 270 [M+H]+.1HNMR (400 MHz, DMSO-d6): δ 12.67 (s, 1H), 8.61 (d, J = 2 Hz, 1H), 8.58 (d, J = 2 Hz, 1H), 8.01 (t, J = 2 Hz, 1H), 2.92 – 2.87 (m, 2H), 2.37 – 2.32 (m, 2H), 2.23 – 2.19 (m, 1H), 1.06 (d, J = 6.4 Hz, 3H).

[0087] Synthesis of [1-(5-bromo-3-pyridyl)-3-methylcyclobutyl](4- methylthiosemi carbazido)methanone (29):

[0088] To a stirred solution of 1-(5-bromo-3-pyridyl)-3- methylcyclobutanecarboxylic acid (28) (4 g, 14.8 mmol) in tetrahydrofuran (30 mL) was added bis(1-imidazolyl)methanone (4.8 g, 29.6 mmol) and triethylamine(6.19 mL, 44.4 mmol) at RT and stirred for 1 hour at 60°C. After 1 hour, 4-methylthiosemicarbazide (6) (1.87 g, 1.2 eq., 17.8 mmol) was added to thereaction mixture and stirred for 16 h at 60°C. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was poured into water (30mL) and extracted with ethyl acetate (2x50). The organic phase was washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The material (4g) was forward to next step without purification. LCMS (ESI) m / z = 357 [M+H]+.

[0089] Synthesis of 5-[1-(5-bromo-3-pyridyl)-3-methylcyclobutyl]-4-methyl- 4H-1,2,4-triazole-3-thiol (30):

[0090] To a stirred solution of [1-(5-bromo-3-pyridyl)-3-methylcyclobutyl](4- methylthiosemicarbazido)methanone (29) (4 g, 11.2 mmol) in methanol (9.97 mL, 246 mmol) was added potassium hydroxide (2.51 g, 44.8 mmol) dissolved in minimum water (2.4 mL, 133 mmol). The reaction mixture was allowed to stirred at 80°C for TLC and LCMS monitored 16 h. Progress of the reaction. After completion of the reaction, the reaction mixture was slightly acidified with potassium bisulfite (KHSO3) solution. After acidified the reaction mixture was extracted with EtOAc (50 X 2 mL). The organic phase was washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to get crude product. The crude was purified through (24g) silica gel purifier by using EtOAc and Hexane as the eluent to afford 5-[1-(5-bromo-3-pyridyl)-3- methylcyclobutyl]-4-methyl-4H-1,2,4-triazole-3-thiol (3 g, 79 %) as brown solid. LCMS (ESI) m / z = 339 [M+H]+.1HNMR (400 MHz, DMSO-d6): δ 13.75 (s, 1H), 8.66 (d, J = 2 Hz, 1H), 8.63 (d, J = 2 Hz, 1H), 8.04 (t, J = 2 Hz, 1H), 3.07 (s, 3H), 2.97 – 2.94 (m, 2H), 2.50 – 2.46 (m, 2H), 2.35 – 2.29 (m, 1H), 1.067 (d, J = 6.0 Hz, 3H).

[0091] Synthesis of 3-[1-(5-bromo-3-pyridyl)-3-methylcyclobutyl]-4-methyl- 4H-1,2,4-triazolel (31):

[0092] To a stirred solution of 5-[1-(5-bromo-3-pyridyl)-3-methylcyclobutyl]-4- methyl-4H-1,2,4-triazole-3-thiol (30) (3 g, 8.84 mmol) in dichloromethane (12 mL, 187 mmol)was cooled to 0°C and then added acetic acid (3 mL) and hydrogen peroxide (1.5 mL) then allowed to stirred at RT for 1 h. The reaction was monitored by TLC. The reaction mixture was poured into ice-cold water and extracted with DCM. The organic phase was washed with sodium bicarbonate, brine and dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to get as 3-[1- (5-bromo-3-pyridyl)-3- methylcyclobutyl]-4-methyl-4H-1,2,4-triazole (2 g, 74 %). LCMS (ESI) m / z = 309.1 [M+H]+.1HNMR (400 MHz, DMSO-d6): δ 8.62 (d, J = 2 Hz, 1H), 8.52 (d, J = 2 Hz, 1H), 8.33 (s, 1H), 7.81 (t, J = 2 Hz, 1H), 3.20 (s, 3H), 2.92 – 2.88 (m, 2H), 2.54 – 2.50 (m, 2H), 2.33 – 2.30 (m, 1H), 1.067 (d, J = 6.0 Hz, 3H).

[0093] Synthesis of 6-{[(S)-3-methyl-1-piperidyl]methyl}-2-{5-[3-methyl-1-(4- methyl- 4H-1,2,4-triazol-3-yl)cyclobutyl]-3-pyridyl}-4-(trifluoromethyl)-1,2- dihydro- 1λ⁶,2-benzisothiazole-1,1(3H)-dione

[0094] To a stirred solution of 6-{[(S)-3-methyl-1-piperidyl]methyl}-4- (trifluoromethyl)-1,2-dihydro-1λ⁶,2-benzisothiazole-1,1(3H)-dione (22) (0.030 g,0.0861 mmol), 3-[1-(5-bromo-3-pyridyl)-3-methylcyclobutyl]-4-methyl-4H-1,2,4- triazole (31) (0.0265 g, 0.0861 mmol) in acetonitrile (3.62 mL, 69.3 mmol) added dipotassium carbonate (0.0595 g, 0.431 mmol). The reaction mixture was purged with nitrogen gas for 5 minutes then copper iodide (0.00656 g, 0.0344 mmol) was added then followed by 1,2-bis(methylamino)ethane (0.0098g, 0.011 mmol) was added to the reaction mixture and was heated to 85°C for 16h in a sealed tube. Progress of the reaction was monitored through TLC & LCMS. The reaction mixture was filtered through celite bed, quenched with ice-cold water (10 mL), and extracted with ethyl acetate (2 X 10 mL). Combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and evaporated under reduced vacuum to afford crude compound, which was purified by Prep-HPLC [Column: X-Select CSH C-18(250 mm X 4.6 mm X 5 µ), Mobile phase (A):0.1%Ammonia in water, Mobile phase (B): Acetonitrile, Flow rate: 1.0 ml / min]. Pure fractions were evaporated off to obtain 6-{[(S)-3-methyl-1- piperidyl]methyl}-2-{5-[3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl]- 3-pyridyl}-4-(trifluoromethyl)-1,2-dihydro-1λ⁶,2-benzisothiazole-1,1(3H)-dione as an off-white solid (8 mg, 16 %). LCMS (ESI) m / z = 575.1 [M+H]+.1HNMR (400 MHz, DMSO-d6): δ 8.66 (d, J = 2.4 Hz, 1H), 8.46 (s, 1H), 8.34 (s, 1H), 8.24 (s, 1H), 8.10 (s, 1H), 7.83 (s, 1H), 5.35 (s, 2H), 3.68 (s, 2H), 3.32 - 3.29 (m, 1H), 3.24 (s, 3H), 2.92 – 2.88 (m, 2H), 2.70 – 2.67 (m, 2H), 2.60 – 2.58 (m, 2H), 1.96 - 1.94 (m, 1H), 1.67 - 1.59 (m, 6H), 1.09 (d, J = 5.2 Hz, 3H), 0.82 (d, J = 6.0 Hz, 3H

[0095] Synthesis of Example-5

[0096] Synthesis of 3-(3-bromophenyl)-3-methylbutanoic acid (34):

[0097] To a stirred solution of 3-methylbut-2-enoic acid (33) (1.0 g, 9.99 mmol) in tetrahydrofuran (10 mL) and water (3 mL) was added (3- bromophenyl)boronic acid (32) (4.01 g, 20 mmol), palladium acetate (112 mg, 0.499 mmol), 2,2'-bipyridyl (156 mg, 0.999 mmol) and acetic acid (2.5 mL, 43.7 mmol). The reaction mixture allowed to stir at 80°C for 16h under air atmosphere. Progress of the reaction was monitored through TLC (10% Ethyl Acetate / Hexane). Then cooled the reaction mixture and evaporated over vacuum to get crude product. The crude material was purified by flash column chromatography using 10% Ethyl acetate: Hexane as the eluent to afford 3-(3-bromophenyl)-3-methylbutanoic acid (2.15 g, 83.7%) as white solid. LCMS (ESI) m / z = 257.01[M-H]+.1H NMR (400 MHz, DMSO d6): δ 11.88 (s, 1H), 7.52 (s, 1H), 7.40 - 7.35 (m, 2H), 7.25 (t, J = 8 Hz, 1H), 2.59 (s, 2H), 1.35 (s, 6H).

[0098] Synthesis of 2-(3-(3-bromophenyl)-3-methylbutanoyl)-N- methylhydrazine-1-carbothioamide (35):

[0099] To a stirred solution of in 3-(m-bromophenyl)-3-methylbutyric acid (34) (2.15 g, 8.36 mmol) in tetrahydrofuran (17.2 mL) added CDI (2.71 g, 16.7 mmol) and triethylamine (3.5 mL, 25.1 mmol). The reaction mixture allowed to stir at 60 °C for 1 hour. After 1 hour, 4-methylthiosemicarbazide (6) (1.32 g, 12.5 mmol) added to the reaction mixture and stirred at 60 °C for 16 h. Progress of the reaction monitored by TLC and LCMS. After completion of the reaction, the reaction mixture poured into water (40mL) and extracted with ethyl acetate (100mL). The organic phase was washed with water, brine and dried over anhydrous sodium sulfate, filtered and concentrated in vacuumed to get the 2-(3-(3-bromophenyl)-3-methylbutanoyl)-N-methylhydrazine-1-carbothioamide (2.5 g) as brown liquid. LCMS (ESI) m / z = 344.1 [M+H]+.

[0100] Synthesis of 5-(2-(3-bromophenyl)-2-methylpropyl)-4-methyl-4H- 1,2,4-triazole-3-thiol (36):

[0101] To a stirred solution of 2-(3-(3-bromophenyl)-3-methylbutanoyl)-N- methylhydrazine-1-carbothioamide (35) (2.5 g, 7.26 mmol) in methanol (6 mL) added potassium hydroxide (1.63 g, 29.00 mmol) dissolved in water (1.5 mL). The reaction mixture allowed to stir at 70°C for 2 h. Progress of the reaction monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was slightly acidified by using dilute HCl and precipitate was filtered to get 5-(2-(3- bromophenyl)-2-methylpropyl)-4-methyl-4H-1,2,4-triazole-3-thiol (1.8 g, 76 %) as pale brown solid. LCMS (ESI) m / z = 325.9 [M+H]+.1H NMR (400 MHz, DMSO- d6): δ 13.43 (s, 1H), 7.54 (s,1H), 7.40 - 7.35 (m, 2H), 7.25 (t, J = 8 Hz, 1H), 3.02 (s, 2H), 1.35 (s, 6H).

[0102] Synthesis of 3-(2-(3-bromophenyl)-2-methylpropyl)-4-methyl-4H- 1,2,4-triazole (37)

[0103] 5-(2-(3-bromophenyl)-2-methylpropyl)-4-methyl-4H-1,2,4-triazole-3-thiol (36) (625.00 mg, 1.92 mmol) dissolved in dichloromethane (5 mL) and cooled to 0°C, then acetic acid (0.8 mL) was added and stir at same temperature for 5 minutes. After 5 minutes, hydrogen peroxide (0.4 mL) added then allowed to stir at same temperature for 1 hour. The reaction monitored by TLC. The reaction mixturepoured into ice-cold water and extracted with DCM. The organic phase washed with sodium bicarbonate, brine and dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to get 3-(2-(3-bromophenyl)-2-methylpropyl)-4- methyl-4H-1,2,4-triazole (420 mg) as brown solid. LCMS (ESI) m / z = 296.0 [M+H]+.

[0104] Synthesis of (S)-2-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)propan-2-yl)phenyl)-6-((3-methylpiperidin-1-yl)methyl)-4- (trifluoromethyl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide

[0105] 3-(2-(3-bromophenyl)-2-methylpropyl)-4-methyl-4H-1,2,4-triazole (37) (33.8 mg, 0.115 mmol) and (S)-6-((3-methylpiperidin-1-yl)methyl)-4- (trifluoromethyl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (22) (40 mg, 0.12 mmol) were dissolved in acetonitrile (4.83 mL) and potassium carbonate (111 mg, 0.8 mmol) added to it. The reaction mixture purged with nitrogen gas for 5 min. Then copper iodide (8.75 mg, 0.04 mmol) and 1,2-bis(methylamino)ethane (13.2 mg, 0.15 mmol) added and heated at 85 °C for 16 h in a sealed tube. Progress of the reaction monitored through TLC & LCMS. The reaction mixture filtered through celite bed, quenched with ice-cold water (5 mL), and extracted with ethyl acetate (2 X 20 mL). Combined organic layers washed with brine (10 mL), dried over sodium sulfate, filtered and evaporated over vacuum to get crude product. The crude purified through prep-HPLC [Column: Sun fire C18 (250 mm x 19 mm x 5µm), Mobile phase (A): 0.1% Ammonia in water, Mobile phase (B): Acetonitrile, Flow rate: 19.0 mL / min]. Pure fractions were collected and concentrated to afford (S)-2- (3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)-2,3-dihydrobenz o[d]isothiazole 1,1-dioxide (10.0 mg, 15%) as off-white solid. LCMS (ESI) m / z = 562.3 [M+H]+. 1H NMR (400 MHz, DMSO d6): δ 8.20 (s, 2H), 8.07 (s, 1H), 7.44 (s, 1H), 7.41 – 7.37 (m, 2H), 7.18 (d, J = 6.8 Hz, 1H), 5.19 (s, 2H), 3.678 (s, 2H), 3.11 (s, 3H), 3.00 (s, 2H), 2.70 (t, J = 7.6 Hz, 2H), 1.96 (t, J = 10.8 Hz, 1H), 1.70-1.59 (m, 5H), 1.45 (s, 6H),0.92 - 0.88 (m, 1H), 0.827 (d, J = 6.0 Hz, 3H).

[0106] Synthesis of Example-6 & 7

[0107] Synthesis of ethyl (E)-3-(3-bromophenyl)but-2-enoate(40):

[0108] To a stirred solution of ethyl (diethoxyphosphoryl)acetate (39) (5 g, 22.3 mmol) in tetrahydrofuran (50 mL) was added lithium 1-butanide (1.57 g, 24.5 mmol) at -78°C and stirred at same temperature for 30 min then 1-(m-bromophenyl)-1-ethanone (38) (4.44 g, 22.3 mmol) was added at same temperature. The reaction mixture allowed to stir at RT for 16h. After reaction completion, the reaction mixture was quenched with saturated ammonium chloride solution till the effervescence ceases, and extracted with ethyl acetate (50 mL X 2). The combined organic extracts were washed with brine solution (10 mL), dried over anhydrous sodium sulfate, filtered and evaporated over reduced vacuum to afford product as ethyl (E)-3-(3-bromophenyl)but-2-enoate (6 g, 99%). LCMS (ESI) m / z = 270.9 [M+H]+.1HNMR (400 MHz, DMSO-d6): δ 7.76 (s, 1H), 7.64 (d, J = 1.6 Hz, 2H), 7.35 - 7.41 (m, 1H), 6.17 (d, J = 1.2 Hz, 1H), 4.17 - 4.09 (m, 2H), 2.49 (s, 3H), 1.24 (t, J = 7.2 Hz, 3H).

[0109] Synthesis of (E)-3-(3-bromophenyl)but-2-enoic acid (41):

[0110] To a stirred solution of ethyl (E)-3-(m-bromophenyl)-2-butenoate (40) (5.8 g, 21.6 mmol) in ethanol (35 mL) was added with sodium hydroxide (2.59 g, 64.7 mmol) dissolved in water (20 mL, 1.11 mol) under nitrogen atmosphere and allowed to stir at room temperature for 16 h. After completion, the reaction mixture was concentrated under reduced vacuum to afford solid, which was dissolved in minimum quantity of water and acidified with HCl (pH=7), obtained solid was filtered off and dried under reduced vacuum to get (E)-3-(3-bromophenyl)but-2- enoic acid (4 g, 77%) as an off white solid. LCMS (ESI) m / z = 239.5 [M-H]+.1HNMR (400 MHz, DMSO-d6) δ 12.31 (s, 1H), 7.72 (s, 1H), 7.54 - 7.60 (m, 2H), 7.37 - 7.49 (m, 1H), 6.12 (d, J = 1.2 Hz, 1H), 2.50 (s, 3H).

[0111] Synthesis of (E)-2-(3-(3-bromophenyl)but-2-enoyl)-N- methylhydrazine-1-carbothioamide (42):

[0112] To a stirred solution of (E)-3-(m-bromophenyl)-2-butenoic acid (41) (2.2 g, 9.13 mmol) in dimethylformamide (22 mL) was added with N- ethylbis(isopropyl)amine (4.77 mL, 27.4 mmol) and 1,1,3,3-tetramethyl-2-(3H- 1,2,3,4-tetraazainden-3-yl)-3-isoureaium hexafluoridophosphate (4.16 g, 11 mmol) under nitrogen atmosphere and allowed to stir at room temperature for 30 minutes, followed by the addition of 4-methylthiosemicarbazide (6) (1.15 g, 11 mmol) and continued to stir for an hour at same temperature. After completion, the reaction mixture was poured into ice-cold water (30 mL) and extracted with ethyl acetate (2 X 50 mL). The combined organic extracts were washed with water (15 mL), brine solution (10 mL) and dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford (E)-2-(3-(3-bromophenyl)but-2-enoyl)-N- methylhydrazine-1-carbothioamideone (3 g) as a brown colour compound. LCMS (ESI) m / z = 328.0 [M+H]+.

[0113] Synthesis of (E)-5-(2-(3-bromophenyl)prop-1-en-1-yl)-4-methyl-4H- 1,2,4-triazole-3-thiol (43):

[0114] To a stirred solution of (E)-3-(m-bromophenyl)-1-(4- methylthiosemicarbazido)-2-buten-1-one (42) (3 g, 9.14 mmol) in methanol (30 mL) was added with potassium hydroxide (5.13 g, 91.4 mmol), dissolved in water (5 mL) under nitrogen atmosphere and allowed the reaction mixture to stir at 80 °C for 1 hour. After completion, the reaction mixture was evaporated under reducedvacuum and dissolved with minimum quantity of water, acidified with HCl (pH=7) and extracted with ethyl acetate (2 X 50 mL). The combined organic extracts washed with water (15 mL), brine solution (10 mL) and dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford crude. The crude material was purified by silica gel flash column chromatography using 50% EtOAc / Hexane gradient (column size 24 g), desired product was eluted around 75% EtOAc / Hexane gradient. Collected fractions were judged by TLC, pure fractions were combined together and concentrated under reduced vacuum to get 5- (E)-5- (2-(3-bromophenyl)prop-1-en-1-yl)-4-methyl-4H-1,2,4-triazole-3-thiol (2.5 g, 88%) as an off white solid. LCMS (ESI) m / z = 310.0 [M+H]+.1HNMR (400 MHz, DMSO-d6): δ 13.8 (s, 1H), 7.87 (s, 1H), 7.67 (d, J = 8 Hz, 1H), 7.59 (d, J = 8 Hz, 1H), 7.46 - 7.36 (m, 1H), 6.63 (s, 1H), 3.55 (s, 3H), 2.44 (s, 3H).

[0115] Step-5: Synthesis of (E)-3-(2-(3-bromophenyl)prop-1-en-1-yl)-4- methyl-4H-1,2,4-triazole (44):

[0116] To a stirred solution of 5-[(E)-2-(m-bromophenyl)-1-propenyl]-4-methyl- 4H-1,2,4-triazole-3-thiol (43) (0.2 g, 0. 645 mmol) in dichloromethane (2.56 mL, 40.1 mmol) was added with acetic acid(1.5mL) at 0 °C under nitrogen atmosphere and allowed to stir at same temperature for 20 minutes, followed by the addition of hydrogen peroxide (30% w / w, 0.8 mL) continued to stir for 30 minutes at 0 °C. After completion, the reaction mixture was basified with saturated sodium bicarbonate solution (pH=8) and extracted with DCM (2 X 20 mL). The combined organic phase was washed with water (5 mL), brine solution (3 mL) and dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford (E)-3-(2-(3- bromophenyl)prop-1-en-1-yl)-4-methyl-4H-1,2,4-triazole (0.150 g) as off yellow solid. LCMS (ESI) m / z = 280.0 [M+H]+.

[0117] Step-6: Synthesis of (S,E)-2-(3-(1-(4-methyl-4H-1,2,4-triazol-3-yl)prop- 1-en-2-yl)phenyl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)-2,3- dihydrobenzo[d]isothiazole 1,1-dioxide

[0118] To a stirred solution of 6-{[(S)-3-methyl-1-piperidyl]methyl}-4- (trifluoromethyl)-1,2-dihydro-1λ⁶,2-benzisothiazole-1,1(3H)-dione (22) (0.08 g, 0.24 mmol) and 3-[(E)-2-(m-bromophenyl)-1-propenyl]-4-methyl-4H-1,2,4- triazole (44) (0.08 g, 0.26 mmol) in acetonitrile (5 mL) was degassed under nitrogen atmosphere for 15 minutes, followed by the addition of dipotassium carbonate (0.23 g, 1.69 mmol), 1,2-bis(methylamino)ethane (0.03 mL, 0.31 mmol) and copper iodide (0.02 g, 0.09 mmol) at room temperature and allowed to stir at 85 °C for 16 h in a sealed tube. After completion, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (2 X 20 mL). The Combined organic extracts were washed with water (7 mL), brine solution (5 mL), dried over anhydrous sodium sulfate, filtered and evaporated over vacuum to afford crude product. The crude material was purified through flash column chromatography using 5% MeOH / DCM gradient (column size 12 g), desired product was eluted around 7.6% MeOH / DCM gradient. Collected fractions were judged by TLC, pure fractions combined together and evaporated under reduced vacuum to get (S,E)-2- (3-(1-(4-methyl-4H-1,2,4-triazol-3-yl)prop-1-en-2-yl)phenyl)-6-((3- methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (70 mg, 9.16 µmol) as a pale yellow solid. This material was purified through prep HPLC. [Column: Xbridge C18 (250 mm x 19 mm x 5 μm), Mobile phase (A): 0.1% Ammonia in water, Mobile phase (B): Acetonitrile, Flow rate: 19.0 mL / min] Pure fractions were concentrated and lyophilized to get (S,E)-2-(3-(1-(4-methyl-4H-1,2,4-triazol-3-yl)prop-1-en-2-yl)phenyl)-6-((3-methylpiperidin-1- yl)methyl)-4-(trifluoromethyl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (0.005 g, 4%) as an off white solid. LCMS (ESI) m / z = 546.3 [M+H]+.1HNMR (400 MHz, DMSO-d6): δ 8.48 (s, 1H), 8.23 (s, 1H), 8.09 (s,1H), 7.71 (s, 1H), 7.57-7.54 (m, 3H), 6.69 (s, 1H), 5.32 (s, 2H), 3.70 (s, 3H), 3.69 (s, 1H), 3.17-3.16 (m, 1H), 2.71- 2.67 (m, 3H), 2.61 (s, 3H), 1.99-1.94 (m, 1H), 1.70-1.60 (m, 4H), 1.50-1.46 (m, 1H), 0.82 (d, J = 6 Hz, 3H).

[0119] Synthesis of 2-(3-(1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2- yl)phenyl)-6-(((S)-3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)-2,3- dihydrobenzo[d] isothiazole 1,1-dioxide formate

[0120] To a Stirred solution of 2-{m-[(E)-1-methyl-2-(4-methyl-4H-1,2,4-triazol- 3-yl)ethenyl]phenyl}-6-{[(S)-3-methyl-1-piperidyl]methyl}-4-(trifluoromethyl)- 1,2-dihydro-1λ⁶,2-benzisothiazole-1,1(3H)-dione (0.04 g, 0.07 mmol) in methanol (5 mL, 123 mmol) was added with nickel dichloride (0.01 g, 0.07 mmol) and sodium borohydride (0.05 g, 1.47 mmol) was added portion wise till the effervescence ceases under nitrogen atmosphere for 30 minutes at room temperature. After completion, the reaction mixture was evaporated under reduced vacuum, added with ethyl acetate (5 mL) and filtered off through celite bed, the filtrate was extracted with ethyl acetate (10 mL X 2) and water (5 mL), the combined organic extracts were washed with water (5 mL), brine solution (3 mL) and dried over anhydrous sodium sulfate, filtered and evaporated under reduced vacuum to afford crude, the crude material was purified through prep HPLC [Column: Sunfire C18 (250 mm x 19 mm x 5 μm), Mobile phase (A): 0.1% Formic acid in water, Mobile phase (B): Acetonitrile, Flow rate: 19.0 mL / min]. Purefractions were concentrated in vacuo and lyophilized to get 2-(3-(1-(4-methyl-4H- 1,2,4-triazol-3-yl)propan-2-yl)phenyl)-6-(((S)-3-methylpiperidin-1-yl)methyl)-4- (trifluoromethyl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide formate (0.008 g, 20%) as an off white solid. LCMS (ESI) m / z = 592.3 [M+H]+.1HNMR (400 MHz, DMSO-d6): δ 8.27 (s, 1H), 8.21 (s, 1H), 8.15 (s,1H), 8.08 (s, 1H), 7.40 - 7.36 (m, 3H), 7.16 - 7.15 (m, 1H), 5.20 (s, 2H), 3.68 (s, 2H), 3.43 (s, 1H), 3.34 - 3.29 (m, 2H), 3.05 - 2.97 (m, 2H), 2.73 - 2.67 (m, 2H), 1.99 - 1.94 (m, 1H), 1.70 - 1.59 (m, 5H), 1.50 - 1.47 (m, 1H), 1.30 (d, J = 6.8 Hz, 3H), 0.88 (br.s, 1H), 0.82 (d, J = 6.4Hz, 3H).

[0121] Synthesis of Example-8

[0122] Synthesis of 2-amino-5-methyl-3-(trifluoromethyl) benzene sulfonyl chloride (46):

[0123] A stirred solution of 4-methyl-2-(trifluoromethyl)aniline (45) (5 g, 28.5 mmol) in DCE (10 mL) was cooled to 0 °C and chlorosulphonic acid (28.5 mL, 428 mmol) was added under nitrogen atmosphere and allowed to stir at 90 °C for 20 h. The progress of the reaction was monitored through TLC and LCMS. The reaction mixture was poured into crushed ice slowly and extracted with ethyl acetate (500 mL X 2). The combined organic layer was washed with brine solution (5 mL) and dried over anhydrous sodium sulfate, filtered and evaporated under reduced vacuum to afford crude. The crude material was purified through silica gel flash column chromatography using 5% ethylaceatate / hexane gradient (column size 12 g). The desired product was eluted around 2.5% ethyl acetate / hexane gradient and pure fractions were combined together and evaporated under reduced vacuum to get 2- amino-5-methyl-3-(trifluoromethyl)benzene sulfonyl chloride (2 g, 25.6 %) as a light yellow coloured(400 MHz, DMSO-d6): δ 7.95 (s, 1H), 7.66 (s, 1H), 2.34 (s, 3H).

[0124] Synthesis of 2-amino-5-methyl-3-(trifluoromethyl) benzene sulfonic acid (47):

[0125] A stirred solution of 2-amino-5-methyl-3-(trifluoromethyl)benzene sulfonyl chloride (46) (2.5 g, 9.14 mmol) in 1,4-dioxane (40 mL), water (40 mL) was allowed to stir at 100°C for 1 h. The progress of the reaction was monitored by TLC and LCMS. The reaction mixture was concentrated to get 2-amino-5-methyl-3- (trifluoromethyl) benzene sulfonic acid (2.3 g) and the material was as such taken for the next step. LCMS (ESI) m / z= 256 [M+H]+.

[0126] Synthesis of 2-iodo-5-methyl-3-(trifluoromethyl) benzene sulfonic acid (48):

[0127] To a stirred solution of 2-amino-5-methyl-3-(trifluoromethyl) benzene sulfonic acid (47) (2.3 g, 9.01 mmol) in water (8 mL) was added disodium carbonate (0.478 g, 4.51 mmol) and stirred for 15 min till effervescence reduced. The reaction mixture was then cooled to 0°C. Sodium nitrite (0.684 g, 9.91 mmol) was added in portions and stirred for 0.5 h at the same temperature. Hydrogen chloride (0.811 mL, 18 mmol) was added to the reaction mixture and allowed to stir at the same temperature for 0.5 h. Potassium iodide (2.24 g, 13.5 mmol) was added in portions and refluxed for 2 h. After the completion of the reaction, sodium sulfate was added and concentrated under vacuum to obtain crude which was then recrystallized with water to get solid. The obtained solid was filtered and dried under vacuum to obtain 2-iodo-5-methyl-3-(trifluoromethyl)benzene sulfonic acid (2.3 g, 70%) as an off white solid. LCMS (ESI) m / z= 364.9 [M+H]+.1H NMR (400 MHz, DMSO-d6): δ 8.05 (s, 1H), 7.48 (s, 1H), 2.33 (s, 3H).

[0128] Synthesis of 2-iodo-5-methyl-3-(trifluoromethyl) benzene sulfonyl chloride (49):

[0129] 2-iodo-5-methyl-3-(trifluoromethyl)benzene sulfonic acid (48) (2.2 g, 6.01 mmol) was taken in a round bottomed flask and cooled to 0°C. Thionyl dichloride (15 mL), DMF (1 mL) were added to the reaction mixture and heated at 100°C for 2 h. The progress of the reaction was monitored by TLC. After completion of the starting material, the crude was concentrated under vacuum and then washed withDCM to get crude 2-iodo-5-methyl-3-(trifluoromethyl)benzene sulfonyl chloride (2.5 g) as an off white solid. The obtained material was taken to the next step without any further purification.1H NMR (400 MHz, DMSO-d6): δ 8.02 (s, 1H), 7.66 (d, J = 1.2 Hz, 1H), 2.33 (s, 3H).

[0130] Synthesis of 2-iodo-5-methyl-3-(trifluoromethyl) benzene sulfonamide (50):

[0131] To a stirred solution of 2-iodo-5-methyl-3-(trifluoromethyl) benzene sulfonyl chloride (49) (2.5 g, 6.5 mmol) in tetrahydrofuran (30 mL) was purged ammonia gas at 0°C for 20 min. After completion of the reaction, the mixture was concentrated and dried to get 2-iodo-5-methyl-3-(trifluoromethyl) benzene sulfonamide (2.5 g) as a light brown solid.1H NMR (400 MHz, DMSO-d6): δ 8.11 (s, 1H), 7.76 (s, 1H), 2.40 (s, 3H).

[0132] Synthesis of 5-(bromomethyl)-2-iodo-3-(trifluoromethyl) benzene sulphonamide (51):

[0133] To a stirred solution of 2-iodo-5-methyl-3-(trifluoromethyl)benzene sulphonamide (50) (2.5 g, 6.85 mmol) in benzene (160 mL) was added 1-bromo- 2,5-pyrrolidinedione (2.44 g, 13.7 mmol) and 2-(1-cyano-1-methylethylazo)-2- methylpropiononitrile (1.12 g, 6.85 mmol). The reaction mixture was heated at 100°C for 4 h. The progress of the reaction was monitored by TLC. The reaction mixture was poured into water (500 mL) and extracted with ethyl acetate(300mL*3). The organic phase was washed with water, brine and dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel flash column chromatography using 50% EtOAc: Hexane as the eluent to afford 5-(bromomethyl)-2-iodo-3-(trifluoromethyl) benzene sulfonamide (1.8 g, 59 %) as an off-white solid. LCMS (ESI) m / z= 441.1[M+H]+.1H NMR (400 MHz, DMSO-d6): δ 8.11 (s, 1H), 7.76 (s, 1H), 4.86 (s, 2H), 2.40 (s, 3H).

[0134] Synthesis of (S)-3-((3-methylpiperidin-1-yl) methyl)-5- (trifluoromethyl) benzene sulfonamide (52):

[0135] To a stirred solution of 5-(bromomethyl)-2-iodo-3-(trifluoromethyl) benzene sulphonamide (51) (1.8 g, 4.05 mmol) in DMF (10 ml) was added (S)-3- methylpiperidine (0.442 g, 4.46 mmol) and dipotassium carbonate (1.68 g, 12.2 mmol). The reaction vial was sealed and heated at 100°C for 3 h. The reaction mixture was cooled to room temperature and poured into water (40 mL) and extracted with ethyl acetate (30 mL*3). The organic phase was washed with water, brine and dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel flash column chromatography using 10% DCM: MeOH as the eluent. The compound eluted out as a mixture. The fractions were evaporated to afford (S)-3-((3-methylpiperidin-1-yl) methyl)-5- (trifluoromethyl) benzene sulfonamide (0.5 g) as a brown liquid. LCMS (ESI) m / z= 463[M+H]+.

[0136] Synthesis of (S)-7-((3-methylpiperidin-1-yl) methyl)-5- (trifluoromethyl)-2H-benzo[e][1, 2] thiazine 1, 1-dioxide (55):

[0137] To a stirred solution of (S)-3-((3-methylpiperidin-1-yl)methyl)-5- (trifluoromethyl)benzenesulfonamide (52) (0.5 g, 1.08 mmol) in 1,4-dioxane (8 mL), water (0.8 mL) was added 2-[(E)-2-ethoxyethenyl]-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (53) (0.428 g, 2.16 mmol), dipotassium carbonate (0.448 g, 3.24 mmol) and then degassed for 10 min under N2 gas. [1, 1′-Bis (diphenylphosphino) ferrocene] dichloropalladium (II), complex with dichloromethane (0.089 g, 0.108 mmol) was added to the reaction mixture and stirred at 100°C for 2 h. The reaction mixture was filtered over celite and the filtrate was concentrated to obtain crude compound which was purified by silica gel flash column chromatography using 10% DCM: MeOH as the eluent. The pure fractions were evaporated off to afford (S)-7-((3-methylpiperidin-1-yl) methyl)-5-(trifluoromethyl)-2H- benzo[e][1,2]thiazine 1,1-dioxide (0.280 g, 71.8%) as a colourless liquid. LCMS (ESI) m / z= 463[M+H]+.1H NMR (400 MHz, DMSO-d6): δ 7.68 (s, 1H), 7.53 (d, J = 8 Hz, 1H), (d, J =6.8 Hz, 1H),5.75 (s, 1H), 5.62 (d, J = 4Hz, 1H), 3.50 (s, 2H), 1.66 (t, J= 12.4 Hz, 4H), 1.49 (s, 2H), 1.30 (t, J= 7.2 Hz, 1H), 1.25(t, J= 7.6 Hz, 2H), 0.87 (s, 3H).

[0138] Synthesis of (S)-2-(3-(3-methyl-1-(1-methyl-1H-1, 2, 4-triazol-5-yl) cyclobutyl) phenyl)-7-((3-methylpiperidin-1-yl)methyl)-5-(trifluoromethyl)- 2H-benzo[e] [1,2]thiazine 1,1-dioxide

[0139] To a stirred solution of (S)-7-((3-methylpiperidin-1-yl) methyl)-5- (trifluoromethyl)-2H-benzo[e][1,2] thiazine 1,1-dioxide (55) (0.035 g, 0.097 mmol) in toluene (2 ml) was added tripotassium phosphate (0.062 g, 0.291 mmol).3-[1- (m-bromophenyl)-3-methylcyclobutyl]-4-methyl-4H-1,2,4-triazole (9) (0.033 g, 0.107 mmol) and 1,2-bis(methyl amino)ethane (0.02 g, 0.0194 mmol) were added and degassed with N2 gas for 10 min. Copper oxide (0.0154 g, 0.0194 mmol) and iron trichloride (0.016 g, 0.0971 mmol) were added to the reaction mixture and heated at 100°C for 16h in a sealed tube. Progress of the reaction was monitored through TLC and LCMS. The reaction mixture was quenched with cool water (5 mL), and extracted with ethyl acetate (2 X 50 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and evaporated over vacuum to obtain crude which was purified by Prep HPLC [Column: Sunfire C18 (250 mm x 19 mm x 5 μm), Mobile phase (A): 0.1% Formic acid in water, Mobile phase (B): Acetonitrile, Flow rate: 18.0 mL / min]. The pure fractions were collected and lyophilized to get (S)-2-(3-(3-methyl-1-(1-methyl-1H-1,2,4-triazol- 5-yl)cyclobutyl)phenyl)-7-((3-methylpiperidin-1-yl)methyl)-5-(trifluoromethyl)- 2H-benzo[e][1,2]thiazine 1,1-dioxide (6 mg, 10 % yield) as an off white solid. LCMS (ESI) m / z= 586.4[M+H]+.1H NMR (400 MHz, DMSO-d6): δ 8.29 (s, 1H), 8.13 (d, J=17.6 Hz, 2H), 7.56 - 7.51 (m, 1H), 7.44 (d, J = 8 Hz, 1H), 7.32 – 7.30 (m, 3H), 6.59 (d, J = 7.2 Hz, 1H), 3.67 (s, 2H), 3.19 (s, 3H), 3.23 (s, 1H), 3.08 (t, J = 13.2 Hz, 1H), 2.83 (s, 2H), 2.71 (d, J = 18.8 Hz, 2H), 2.50 (s, 2H), 2.27 (t, J = 10.8 Hz, 1H), 1.63 (t, J = 14 Hz, 4H), 1.48 (d, J = 12 Hz, 1H), 1.07 (t, J = 11.2 Hz, 3H), 0.83 (d, J = 6 Hz, 3H).

[0140] Synthesis of Example-9

[0141] Synthesis of 4-bromo-2-(chlorosulfonyl)-6-(trifluoromethyl)aniline (57): -

[0142] A stirred solution of 4-bromo-2-(trifluoromethyl)aniline (56) (3 g, 12.5 mmol) in (Z)-1,2-dichloroethene (20 mL) was cooled to 0°C and chlorosulfonic acid (12.5 mL, 187 mmol) was added to it under nitrogen atmosphere. The reaction mixture was gradually allowed to warm to room temperature and then heated at 90 °C for 16 h. The Progress of the reaction was monitored through TLC. After completion of the reaction, the reaction mixture was poured into crushed ice and extracted with ethyl acetate (50 mL X 2). The combined organic extracts were washed with brine solution (10 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced vacuum to afford crude which was purified by silica gel flash column chromatography using 20 % ethyl acetate / hexane gradient over a period of 30 min (Column size 24 g). The desired product eluted around 15 % ethyl acetate / hexane gradient. Pure fractions were combined together and evaporated under reduced vacuum to get 4-bromo-2-(chlorosulfonyl)-6-(trifluoromethyl)aniline (1.2 g, 28 % ) as a needle shaped crystals.1H NMR (400 MHz, DMSO d6) δ 7.77 (d, J = 2.0 Hz, 1H); 7.48 (d, J = 3.0 Hz, 1H).

[0143] Synthesis of 4-bromo-2-{m-[3-methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl) cyclobutyl] phenylaminosulfonyl}-6-(trifluoromethyl)aniline (58): -

[0144] To a stirred solution of m-[3-methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl]aniline (Intermediate-12) (0.140 g, 0.578 mmol) in pyridine (5 mL) was added 4-bromo-2-(chlorosulfonyl)-6-(trifluoromethyl)aniline (57) (0.215 g, 0.636 mmol) under nitrogen atmosphere and allowed to stir at 50°C temperature for 2 h . The Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was evaporated under reduced vacuum, quenched with cold water (10 mL) and extracted into ethyl acetate (10 mL X 2). The combined organic layers were washed with brine solution (5 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced vacuum to afford crude compound which was purified by silica gel flash column chromatography using 10 % MeOH / DCM gradient (Column size 24 g). The desired product eluted around 7.5 % MeOH / DCM gradient. Pure fractions were combined together and evaporated under reduced vacuum to get 4-bromo-2-{m-[3-methyl-1- (4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl]phenylaminosulfonyl}-6- (trifluoromethyl)aniline (0.1 g) as a pale-yellow coloured compound. LCMS (ESI) m / z= 544.1 [M+H]+.1H NMR (400 MHz, DMSO d6) δ 10.63 (s, 1H), 8.32 (s, 1H), 7.72 (d, J = 2 Hz, 2H), 7.79 (d, J = 7.2 Hz, 2H), 7.003 – 6.960 (m, 2H); 6.36 (s, 1H), 3.00 (s, 3H), 2.63 – 2.59 (m, 3H), 2.49 – 2.44 (m, 2H), 2.37 – 2.33 (m, 1H), 1.04 (d, J = 6.4. Hz, 3H).

[0145] Synthesis of 4-{[(S)-3-methyl-1-piperidyl]methyl}-2-{m-[3-methyl-1-(4- methyl-4H-1,2,4-triazol-3-yl)cyclobutyl]phenylaminosulfonyl}-6- (trifluoromethyl)aniline (59): -

[0146] To a stirred solution of 4-bromo-2-{m-[3-methyl-1-(4-methyl-4H-1,2,4- triazol-3-yl)cyclobutyl]phenylaminosulfonyl}-6-(trifluoromethyl)aniline (58) (0.080 g, 0.147 mmol) in 1,4-dioxane (6.00 mL) and water (2.00 mL) was added {[(S)-3-methyl-1-piperidyl]methyl}tris(fluoro)-λ⁴-borane (14) (0.0529 g, 0.294 mmol) and purged with Argon for 5 minutes. dicaesium carbonate (0.144 g, 0.441 mmol), dicyclohexyl[2',4',6'-tris(isopropyl)-2-biphenylyl]phosphine (0.014 g, 0.0294 mmol) were added followed by Chloro(2-dicyclohexylphosphino-2′,4′,6′- triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (0.01.6 g, 0.0147 mmol) and the reaction mixture was heated at 100°C for 16 h in a sealed tube . Progress of the reaction was monitored through TLC. After completion of the reaction, the reaction mixture was cooled to room temperature and water (10 mL) was added to it and extracted in EtOAc (10 mL x 3). The combined organic extracts were washed with water (10 mL x 2), brine (10 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica gel flash column chromatography. The compound eluted out as a mixture in 0 – 5 % MeOH: DCM gradient. The fractions pertaining to the compound were completely evaporated off to afford 4-{[(S)-3-methyl-1-piperidyl]methyl}-2-{m- [3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl]phenylaminosulfonyl}-6- (trifluoromethyl)aniline (0.050 g) as an off-white solid. LCMS (ESI) m / z= 577.2 [M+H]+.

[0147] Synthesis of 2-{m-[3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl) cyclobutyl] phenyl}-7-[(3-methyl-1-piperidyl) methyl]-5-(trifluoromethyl)-1,2- dihydro-1H,1H-1λ⁶,2,4-benzothiadiazine-1,1-dione

[0148] To a stirred solution of 2-{m-[3-methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl]phenylaminosulfonyl}-4-[(3-methyl-1-piperidyl)methyl]-6- (trifluoromethyl)aniline (59) (0.04 g, 0.069 mmol) in diethoxymethoxyethane (3 mL) was added acetic acid (0.1 mL) under nitrogen atmosphere and heated at 130°C temperature for 16 h . The Progress of the reaction was monitored by TLC & LCMS. After completion of the reaction, the reaction mixture was evaporated under reduced vacuum to afford crude compound which was purified by Prep-HPLC [ Column: Inertsil ODS C18(250 mm x 30 mm x 5 µm), Mobile phase A: 0.1%Formic acid in water, Mobile phase B: Acetonitrile, Flow rate:30ml / min]. Pure fractions were evaporated off to obtain 2-{m-[3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl) cyclobutyl] phenyl}-7-[(3-methyl-1-piperidyl) methyl]-5-(trifluoromethyl)-1,2- dihydro-1H,1H-1λ⁶,2,4-benzothiadiazine-1,1-dione (3 mg) as an off-white solid. LCMS (ESI) m / z= 577.2 [M+H]+.1H NMR (400 MHz, DMSO d6) δ 8.30 (s, 1H), 8.23 - 8.18 (m, 2H), 8.14 (s, 1H), 7.63 – 7.60 (m, 2H), 7.58 – 7.53 (m, 2H), 3.70 (s, 2H), 3.23 – 3.21 (m, 2H), 3.19 (s, 3H), 2.87 – 2.85 (m, 2H), 2.71 – 2.69 (m, 2H), 2.59 – 2.56 (m, 2H), 2.33 – 2.27 (m, 1H), 1.70 - 1.68 (m, 1H), 1.65 – 1.63 (m, 2H), 1.49 – 1.47 (m, 2H), 1.07 (d, J = 5.6 Hz, 3H), 0.82 (d, J = 6.4 Hz, 3H).

[0149] Synthesis of Example-10

[0150] Synthesis of 2-amino-5-bromo-3-(trifluoromethyl)benzenesulfonyl chloride (61)

[0151] A stirred solution of 4-bromo-2-(trifluoromethyl)aniline (60) (2 g, 8.33 mmol) in 1,2-dichloroethene (20 mL) was cooled to 0°C and added chlorosulfonic acid (8.31 mL, 125 mmol) under nitrogen atmosphere. The reaction mixture was heated at 90 °C for 16 h. After completion of the reaction, the reaction mixture was poured into crushed ice, stirred for 20 minutes and extracted with ethyl acetate (50 mL X 2). The combined organic extracts were washed with brine solution (10 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced vacuum to afford crude compound which was purified by silica gel flash column chromatography using 20% ethyl acetate / hexane gradient over a period of 30 min (Column size 24 g). Required product was eluted around 15% ethyl acetate / hexane gradient. Collected fractions were judged by TLC, pure fractions were combined together and evaporated under reduced vacuum to get 2-amino-5-bromo-3-(trifluoromethyl)benzenesulfonyl chloride (2 g, 70.9%) as a needle shaped crystals.1H NMR (400 MHz, DMSO d6) δ 7.77 (d, J = 2 Hz, 1H), 7.47 (d, J = 2.4Hz, 1H).

[0152] Synthesis of 3-(3-methyl-1-(1-methyl-1H-1,2,4-triazol-5-yl)cyclobutyl)- 5-(trifluoromethyl)aniline (62)

[0153] To a stirred solution of m-[3-methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl]aniline (Intermediate 12) (0.2 g, 0.825 mmol) in pyridine (5 mL) was added 4-bromo-2-(chlorosulfonyl)-6-(trifluoromethyl)aniline (61) (279 mg, 0.825 mmol) under nitrogen atmosphere and allowed stir at 50 °C for 1 hour. After completion of the reaction, the reaction mixture was evaporated under reduced vacuum to afford crude material which was purified through silica gel flash column chromatography using 10 % MeOH / DCM gradient (Column size 12 g). The desired product was eluted around 7.5 % MeOH / DCM gradient. The fractions pertaining to the compound were combined together and evaporated under reduced vacuum to get 2-amino-5-bromo-N-(3-(3-methyl-1-(1-methyl-1H-1,2,4-triazol-5- yl)cyclobutyl)phenyl)-3-(trifluoromethyl)benzenesulfonamide (0.2 g) as a pale- yellow coloured compound. LCMS (ESI) m / z= 544.0 [M+H]+.

[0154] Synthesis of 7-bromo-2-(3-(3-methyl-1-(1-methyl-1H-1,2,4-triazol-5- yl)cyclobutyl)phenyl)-5-(trifluoromethyl)-3,4-dihydro-2H-benzo[e][1,2,4] thiadiazine1,1-dioxide (63)

[0155] To a stirred solution of 4-bromo-2-{m-[3-methyl-1-(4-methyl-4H-1,2,4- triazol-3-yl)cyclobutyl]phenylaminosulfonyl}-6-(trifluoromethyl)aniline (62) (90 mg, 0.165 mmol) in water (3 mL) was added formaldehyde (7.45 mg, 0.248 mmol) and iron trichloride (53.6 mg, 0.331 mmol) under nitrogen atmosphere and allowed to stir at 100 °C for 16 h in a sealed tube. After completion of the reaction, the reaction mixture was concentrated under reduced vacuum to afford solid, which was triturated with 5% MeOH / DCM (3 mL X 3). The precipitated solid was filtered off. The filtrate was concentrated under reduced vacuum to get 7-bromo-2-(3-(3- methyl-1-(1-methyl-1H-1,2,4-triazol-5-yl)cyclobutyl) phenyl)-5-(trifluoromethyl)- 3,4-dihydro-2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (90 mg) as a dark brown solid. LCMS (ESI) m / z= 556.1 [M+H]+.

[0156] Synthesis of (S)-2-(3-(3-methyl-1-(1-methyl-1H-1,2,4-triazol-5- yl)cyclobutyl) phenyl)-7-((3-methylpiperidin-1-yl)methyl)-5- (trifluoromethyl)-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide

[0157] A stirred solution of 2-{5-bromo-3-[3-methyl-1-(4-methyl-4H-1,2,4- triazol-3-yl)cyclobutyl]phenyl}-5-(trifluoromethyl)-1,2,3,4-tetrahydro-1H,1H- 1λ⁶,2,4-benzothiadiazine-1,1-dione (63) (58.2 mg, 0.105 mmol) in 1,4-dioxane (3 mL) and water (1 mL) was degassed with nitrogen for 5 minutes. potassium—{[(S)- 3-methyl-1-piperidyl] methyl} tris(fluoro)-λ⁴-borane (1 / 1) (14) (114 mg, 0.523mmol), dicaesium carbonate (102 mg, 0.314 mmol), dicyclohexyl[2',4',6'- tris(isopropyl)-2-biphenylyl] phosphine (9.97 mg, 0.02 mmol) and chloridopalladium 2-biphenylid-2'-amine—dicyclohexyl[2',4',6'-tris(isopropyl)-3- biphenylyl] phosphine (1 / 1) (8.23 mg, 0.01 mmol) were added to the reaction mixture and further degassed with nitrogen for 5 minutes. The reaction mixture was then heated at 100 °C for 16 h in a sealed tube. After completion of the reaction, the reaction mixture was quenched with water and extracted with ethyl acetate (20 mL X 2). The combined organic extracts were washed with water (5 mL), brine solution (3 mL) and dried over anhydrous sodium sulfate and evaporated under reduced vacuum to afford crude. The crude material was purified through prep- HPLC purification. [Column: Xselect CSH C18 (250 mm x 20 mm x 5 µm), Mobile phase A: 0.1% Ammonia in water, Mobile phase B: Acetonitrile, Flow rate: 17.0 mL / min]. The pure fractions were combined together, concentrated and lyophilized to get (S)-2-(3-(3-methyl-1-(1-methyl-1H-1,2,4-triazol-5-yl)cyclobutyl)phenyl)-7- ((3-methylpiperidin-1-yl)methyl)-5-(trifluoromethyl)-3,4-dihydro-2H- benzo[e][1,2,4]thiadiazine 1,1-dioxide (2 mg, 3.3 %) as an off white solid. LCMS (ESI) m / z= 589.5 [M+H]+.1H NMR (400 MHz, DMSO d6) δ 8.22 (s, 1H), 7.69 (d, J = 10.8 Hz, 2H), 7.38 - 7.34 (m, 2H), 7.28 (s, 1H), 7.21 (d, J = 8 Hz, 1H), 7.07 (d, J = 6.8 Hz, 1H), 5.30 (d, J = 2.4 Hz, 2H), 3.40-3.35 (m, 2H), 3.02 (s, 3H), 2.67 - 2.60 (m, 4H), 2.45 – 2.42 (m, 1H), 2.32 - 2.29 (m, 1H), 1.88 - 1.84 (m, 1H), 1.65 - 1.55 (m, 5H), 1.43 – 1.35 (m, 1H), 1.23 (s, 1H), 1.00 (d, J = 6.4 Hz, 3H), 0.79 (d, J = 4.8 Hz, 3H).

[0158] Synthesis of Example-11

[0159] 5-bromo-2-(isopropylamino)benzenesulfonamide (65)

[0160] To a stirred solution of 5-bromo-2-fluorobenzenesulfonamide (64) (3.5 g, 13.8 mmol) in 1,4-dioxane (35 mL) was added isopropyl amine (11.7 mL, 138 mmol) and triethylamine (0.96 mL, 6.89 mmol).The reaction mixture was heated at 110°C for 16 h. Progress of reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched by ice cold water and extracted with ethyl acetate. Then organic layer was dried over sodium sulfate, filtered, concentrated under reduced pressure to get 5-bromo-2- (isopropylamino)benzenesulfonamide (4 g) as an off-white solid. LCMS (ESI) m / z= 293.0 [M+H]+.1H NMR (400 MHz, DMSO d6) δ 7.88 (d, J = 5.2 Hz, 1H), 7.69 (d, J=2.4 Hz, 1H), 7.51(s, 2H), 6.77 (d, J=9.2 Hz, 1H), 5.76 (d, J= 7.6 Hz, 1H), 3.74 - 3.66 (m, 1H), 1.18 (d, J = 6.4 Hz, 6H).

[0161] 7-bromo-4-isopropyl-1,4-dihydro-1λ⁶,2,4-benzothiadiazine-1,1-dione (66)

[0162] To 5-bromo-2-(isopropylamino)benzenesulfonamide (65) (3.9 g, 13.3 mmol) was added trimethoxymethane (10 mL) and the reaction mixture was heated at 130°C for 16 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with water and extracted with DCM. The organic layer was dried over sodium sulfate, filtered, concentrated under reduced pressure to get crude compound which was triturated by 5 % MeOH in DCM. The obtained solid was dried under vacuum to yield 7- bromo-4-isopropyl-1,4-dihydro-1λ⁶,2,4-benzothiadiazine-1,1-dione (1.1 g, 28 %). LCMS (ESI) m / z= 303.0 [M+H]+.1H NMR (400 MHz, DMSO d6): δ 8.24 (s, 1H), 8.02 (d, J = 2.4Hz, 1H), 7.96 (dd, J= 2.4 Hz, J = 9.2 Hz, 1H), 7.70 (d, J= 9.2 Hz, 1H), 4.82 - 4.75 (m, 1H), 1.47 (d, J = 6.8 Hz, 6H).

[0163] Synthesis of 7-bromo-4-isopropyl-1,2,3,4-tetrahydro-1H,1H-1λ⁶,2,4- benzothiadiazine-1,1-dione (67)

[0164] To a stirred solution of sodium boranuide (187 mg, 4.95 mmol) in isopropanol (5 mL) was added 7-bromo-4-isopropyl-1,4-dihydro-1λ⁶,2,4- benzothiadiazine-1,1-dione (66) (0.5 g, 1.65 mmol) at 0°C. The reaction mixture was gradually allowed to warm to room temperature and stirred for 1 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was completely evaporated off to obtain solid. Solid was dissolved in water and quenched with dil. HCl and extracted with DCM. The organic layer was dried over sodium sulfate, filtered, concentrated under reducedpressure to obtain 7-bromo-4-isopropyl-1,2,3,4-tetrahydro-1H,1H-1λ⁶,2,4- benzothiadiazine-1,1-dione (0.5 g). LCMS (ESI) m / z= 305.0 [M+H]+.1H NMR (400 MHz, DMSO d6): δ 7.92(t, J = 7.2 Hz, 1H), 7.61(d, J= 2.4 Hz, 1H), 7.51(dd, J1= 2.4Hz & J2= 9.2Hz, 1H), 7.02(d, J= 9.6 Hz, 1H), 4.64 (d, J = 7.2 Hz, 2H), 4.20 – 4.11 (m, 1H), 1.16 (d, J = 6.8 Hz,6H).

[0165] 7-{[(S)-3-methyl-1-piperidyl]methyl}-4-isopropyl-1,2,3,4-tetrahydro- 1H,1H-1λ⁶,2,4-benzothiadiazine-1,1-dione (68)

[0166] To a stirred solution of 7-bromo-4-isopropyl-1,2,3,4-tetrahydro-1H,1H- 1λ⁶,2,4-benzothiadiazine-1,1-dione (67) (0.5 g, 1.64 mmol) in 1,4-dioxane (6 mL) and water (2 mL) was added potassium—{[(S)-3-methyl-1- piperidyl]methyl}tris(fluoro)-λ⁴-borane (1 / 1) (14) (718 mg, 3.28 mmol) . The reaction mixture was purged with N2 for 10 min. dicaesium carbonate (1.6 g, 3 eq., 4.91 mmol) followed by dicyclohexyl[2',4',6'-tris(isopropyl)-2- biphenylyl]phosphine (156 mg, 0.2 eq., 328 µmol) and chloridopalladium(1+)2- biphenylid-2'-amine—dicyclohexyl[2',4',6'-tris(isopropyl)-3-biphenylyl]phosphine (1 / 1) (129 mg, 0.1 eq., 164 µmol) were added to it. The reaction mixture was heated at 100°C for 16h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was filtered through celite bed and the filtrate was concentrated under reduced pressure to get crude compound. The crude was purified by silica gel flash column chromatography using ethyl acetate- hexane gradient over a period of 30 min (Column size 40 g). The desired product eluted out at around 3 % - 4 % ethyl acetate-hexane as a mixture. Fractions pertaining to the compound were collected and concentrated to afford 7-{[(S)-3- methyl-1-piperidyl]methyl}-4-isopropyl-1,2,3,4-tetrahydro-1H,1H-1λ⁶,2,4- benzothiadiazine-1,1-dione (0.2 g). LCMS (ESI) m / z= 338.2 [M+H]+.

[0167] Synthesis of 4-{[(S)-3-methyl-1-piperidyl]methyl}-1-(isopropylamino)- 2-{3-[3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl]-5- (trifluoromethyl)phenyl aminosulfonyl} benzene (69):

[0168] To a stirred solution of 7-{[(S)-3-methyl-1-piperidyl]methyl}-4-isopropyl- 1,2,3,4-tetrahydro-1H,1H-1λ⁶,2,4-benzothiadiazine-1,1-dione (68) (55 mg, 0.163 mmol) in acetonitrile (2 mL) was added 3-{1-[3-bromo-5-(trifluoromethyl)phenyl]- 3-methylcyclobutyl}-4-methyl-4H-1,2,4-triazole (17) (61 mg, 0.163 mmol) and the reaction mixture was purged with N2gas for 5 min. dipotassium carbonate (158 mg, 1.14 mmol), copper diiodide (20.7 mg, 0.065 mmol) and 1,2- bis(methylamino)ethane (18.7 mg, 0.02 mmol) were added and the reaction mixture was heated at 80°C for 6 h. Progress of the reaction was monitored by TLC and LCMS. LCMS indicated the formation of ring opened Compound 69. The reaction mixture was quenched by water and extracted with ethyl acetate. Then organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to get 4-{[(S)-3-methyl-1-piperidyl]methyl}-1-(isopropylamino)-2-{3-[3-methyl-1- (4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl]-5- (trifluoromethyl)phenylaminosulfonyl}benzene (60 mg). LCMS (ESI) m / z= 619.3 [M+H]+.

[0169] Synthesis of 7-{[(S)-3-methyl-1-piperidyl]methyl}-4-isopropyl-2-{3-[3- methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl]-5- (trifluoromethyl)phenyl}-1,2,3,4-tetrahydro-1H,1H-1λ⁶,2,4-benzothiadiazine- 1,1-dione

[0170] To a stirred solution of 4-{[(S)-3-methyl-1-piperidyl]methyl}-1- (isopropylamino)-2-{3-[3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl]- 5-(trifluoromethyl)phenyl aminosulfonyl}benzene (69) (55 mg, 0.089 mmol) in water (1 mL) were added formaldehyde (4 mg, 0.013 mmol), iron trichloride (28.8 mg, 0.018 mmol) at 0°C and the reaction mixture was heated at 100°C for 1 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was filtered and concentrated to get crude compound which was purified by Prep-HPLC [Column: X select CSH C18 (250 mm x 20 mm x 5 µm), Mobile phase A: 0.1% Ammonia in water, Mobile phase B: Acetonitrile, Flow rate: 17.0 mL / min]. The pure fractions were evaporated off to obtain 7-{[(S)-3-methyl-1-piperidyl]methyl}-4-isopropyl-2-{3-[3-methyl-1-(4- methyl-4H-1,2,4-triazol-3-yl)cyclobutyl]-5-(trifluoromethyl)phenyl}-1,2,3,4- tetrahydro-1H,1H-1λ⁶,2,4-benzothiadiazine-1,1-dione (10 mg, 18%) as an off- white solid. LCMS (ESI) m / z= 631.6 [M+H]+.1H NMR (400 MHz, DMSO d6) δ 8.25(s, 1H), 7.34 - 7.51 (m, 5H), 7.11 (d, J = 8.4 Hz, 1H), 5.29 (s, 2H), 4.22 - 4.19 (m, 1H), 3.3 (s, 2H), 3.02 (s, 3H), 2.71 - 2.68 (m, 5H), 2.43 - 2.32 (m, 2H), 1.63 - 1.57 (m, 6H), 1.23(s, 1H), 1.1 – 0.98 (m, 9H), 0.80 (d, J = 6.4 Hz, 3H).

[0171] Synthesis of Example-12

[0172] Synthesis of 2-bromo-6-(chlorosulfonyl)-4-toluic acid (71)

[0173] To a stirred solution of 2-bromo-4-toluic acid (15 g, 69.8 mmol) was cooled to 0°C then was added chloro (hydroxy)-λ⁶-sulfanedione (20 mL) under nitrogen atmosphere and allowed to stir at 110°C for 16 h. The progress of the reaction was monitored through TLC and LCMS. After completion, the reaction mixture was poured to crushed ice and extracted with DCM (50 mL X 2), the combined organic extracts were washed with brine solution (10 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced vacuum to afford crude as 2-bromo- 6-(chlorosulfonyl)-4-toluic acid (16.5 g, 75.44%) as an off white solid.1H NMR (400 MHz, DMSO-d6) δ 8.35 (d, J = 1.6 Hz, 1H), 8.02 (d, J = 1.6 Hz, 1H), 2.67 (s, 3H). LCMS (ESI)m / z=310.4[M-H]+.

[0174] Synthesis of 2-aminosulfonyl-6-bromo-4-toluic acid (72)

[0175] A stirred solution of 2-bromo-6-(chlorosulfonyl)-4-toluic acid (16 g, 51 mmol) in tetrahydrofuran (15 mL) was cooled to 0°C then NH3 gas was purged for 10 min at 0°C. The progress of the reaction was monitored through TLC. After completion, the reaction mixture was evaporated under reduced vacuum to afford crude material which was forwarded to the next step without any purification. LCMS (ESI) m / z = 294 [M+H]+

[0176] Synthesis of 6-bromo-4-methoxycarbonyl-2-toluenesulfonamide (73)

[0177] To a stirred solution of 2-aminosulfonyl-6-bromo-4-toluic acid (12 g, 40.8 mmol) in methanol (167 mL, 4.13 mol) was added thionyl dichloride (15 mL) at 0°C. Then reaction mixture was stirred at 60°C for 16 h. The progress of reaction was monitored by TLC and LCMS. After completion of starting material, reaction mixture was quenched by cold water, extracted with ethyl acetate and washed with cold saturated NaHCO3 solution. The organic layer was dried over sodium sulphate, filtered and the filtrate was concentrated under reduced pressure to get 6-bromo-4- methoxycarbonyl-2-toluenesulfonamide (10 g, 79.54%) as an oil.1HNMR (400 MHz, DMSO-d6) δ 8.44 (d, J = 1.6 Hz, 1H), 8.29 (d, J = 1.6 Hz, 1H), 7.79 (s, 2H), 3.90 (s, 3H), 2.73 (s, 3H). LCMS (ESI) m / z = 306 [M+H]-

[0178] Synthesis of methyl 4-bromo-1,1-dioxo-3-oxo-2,3-dihydro-1H-1λ⁶,2- benzisothiazole-6-carboxylate (74)

[0179] A mixture of hydroxyiodanetriiumtriolate (62.3 g, 325 mmol), chromium trioxide (0.324 g, 3.25 mmol) and 6-bromo-4-methoxycarbonyl-2- toluenesulfonamide (10 g, 32.5 mmol) was dissolved in acetonitrile (200 mL) and heated to 80°C for 16 h. After completion of the reaction, the reaction mixture was quenched with isopropanol (15 mL) and heated for 15 mins, then reaction was filtered through celite bed and the filtrate was evaporated under vacuum and dried to get the product as methyl 4-bromo-1,1-dioxo-3-oxo-2,3-dihydro-1H-1λ⁶,2- benzisothiazole-6-carboxylate (6.1 g, 58.72%) as an off white solid.1HNMR (400 MHz, DMSO-d6) δ 8.44 (dd, J1 = 3.6 Hz, J2 = 1.2 Hz, 2H), 7.79 (s, 1H), 3.90 (s, 3H). LCMS (ESI) m / z = 318 [M+H]+

[0180] Synthesis of 4-bromo-6-(hydroxymethyl)-2,3-dihydro-1H-1λ⁶,2- benzisothiazole-1,1-dione (75)

[0181] Methyl 4-bromo-1,1-dioxo-3-oxo-2,3-dihydro-1H-1λ⁶,2-benzisothiazole- 6-carboxylate (3 g, 9.37 mmol) was dissolved in tetrahydrofuran (30 mL) and cooled to 0°C. (methylthio)methane—boron (1 / 1) (20.3 mL, 247 mmol) (neat solution) was added at 0°C and heated at 75°C for 16h under inert atmosphere. Progress of the reaction was monitored through TLC & LCMS. The reaction mixture was quenched with dilute HCl dropwise over 30 minutes till all the effervescence ceases out. The reaction mixture was quenched with water and extracted with ethyl acetate (2X 20 mL) and washed with brine solution (15 mL). Combined organic layers were dried over sodium sulfate, filtered and evaporatedunder vacuum to get crude product. The crude was purified by combi flash (using gradient elution 35-40% EtOAc in heptane) to afford 4-bromo-6-(hydroxymethyl)- 2,3-dihydro-1H-1λ⁶,2-benzisothiazole-1,1-dione (1.8 g, 69.06%) as a white solid.1HNMR (400 MHz, DMSO-d6) δ 8.04 (t, J = 4.4 Hz, 1H), 7.86 (s, 1H), 7.76 (s, 1H), 5.54 (t, J = 5.6 Hz, 1H), 4.61 (d, J = 5.6 Hz, 2H), 4.28 (d, J = 3.2 Hz, 2H). LCMS (ESI) m / z = 278 [M+H]+

[0182] Synthesis of 4-bromo-6-(chloromethyl)-2,3-dihydro-1H-1λ⁶,2- benzisothiazole-1,1-dione (76)

[0183] To a stirred solution of 4-bromo-6-(hydroxymethyl)-2,3-dihydro-1H-1λ⁶,2- benzisothiazole-1,1-dione (3 g, 10.8 mmol) in dichloromethane (30 mL) was added thionyl dichloride (5 ml, 75.5 mmol) at 0 °C. After 5 minutes, catalytic amount of dimethylformamide (0.5 ml, 6.46 mmol) was added to the reaction mixture. The mixture was stirred at room temperature for 6 h. Progress of the reaction was monitored through TLC and LCMS. After completion, the reaction was quenched with ice cold water (40 mL) and extracted into DCM (20 mL X 2), NaHCO3solution (15 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced vacuum to afford crude product. The crude was purified through (24 g) silica gel purifier by using EtOAc and Hexane as the eluent to afford of 4-bromo- 6-(chloromethyl)-2,3-dihydro-1H-1λ⁶,2-benzisothiazole-1,1-dione (2 g, 62.52%) as off white solid.1HNMR (400 MHz, DMSO-d6) δ 9.07 (brs, 1H), 8.23 (s, 1H), 8.09 (s, 1H), 4.98 (br.s, 2H), 4.89 (s, 2H).

[0184] Synthesis of 4-bromo-6-{[(S)-3-methyl-1-piperidyl]methyl}-2,3- dihydro-1H-1λ⁶,2-benzisothiazole-1,1-dione (77)

[0185] To a stirred solution of 4-bromo-6-(chloromethyl)-2,3-dihydro-1H-1λ⁶,2- benzisothiazole-1,1-dione (0.2 g, 6.74 mmol) and (S)-3-methylpiperidine— hydrogen chloride (1 / 1) (183 mg, 1.35 mmol) in dimethylformamide (3 mL) was added dipotassium carbonate (280 mg, 2.02 mmol) at room temperature. The reaction mixture was stirred at the same temperature for 6 h. Progress of the reaction was monitored through TLC & LCMS. After completion, the reaction was quenched with ice-cold water (10 mL) and extracted into EtOAc (10 mL X 2). The combined organic layers were washed with NaHCO3solution (10 mL) and brine solution (25 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced vacuum to afford crude product. The crude was purified through (12g) silica gel purifier by using EtOAc and Hexane as the eluent to afford 4-bromo- 6-{[(S)-3-methyl-1-piperidyl]methyl}-2,3-dihydro-1H-1λ⁶,2-benzisothiazole-1,1- dione (0.230 g, 94.93%) as colorless gummy liquid.1HNMR (400 MHz, DMSO- d6) δ 8.04 (brs, 1H), 7.86 (s, 1H), 7.75 (s, 1H), 4.28 (s, 2H), 3.58 (s, 2H), 2.73 – 2.68 (m, 2H), 1.96 – 1.90 (m, 1H), 1.65 – 1.58 (m, 4H), 1.45 – 1.42 (m, 1H), 0.88 – 0.86 (m, 1H), 0.81 (d, J = 6.4 Hz, 3H). LCMS (ESI) m / z = 359.0 [M+H]+

[0186] Synthesis of 4-cyclopropyl-6-{[(S)-3-methyl-1-piperidyl]methyl}-2,3- dihydro-1H-1λ⁶,2-benzisothiazole-1,1-dione(78)

[0187] Argon gas was purged through a stirred suspension of 4-bromo-6-{[(S)-3- methyl-1-piperidyl]methyl}-2,3-dihydro-1H-1λ⁶,2-benzisothiazole-1,1-dione (0.2 g, 0.557 mmol), cyclopropylboranediol (0.143 g, 1.67 mmol) and caesium fluoride(0.169 g, 1.11 mmol) in 1,4-dioxane (2 mL) for 5min. PdCl2(dppf).DCM (0.045 g, 0.055 mmol) was added, sealed and stirred at 100 °C for 16 h. Progress of the reaction was monitored through TLC. After completion of starting material, reaction mixture was extracted with ethyl acetate (2* 25 mL), and water (20 ml). The combined organic layer was dried over sodium sulfate, filtered and dried under vacuum to afford crude. The crude was purified by combi flash (using gradient elution 60-70% EtOAc in heptane) to afford 4-cyclopropyl-6-{[(S)-3-methyl-1- piperidyl] methyl}-2,3-dihydro-1H-1λ⁶,2-benzisothiazole-1,1-dione (0.070 g, 39.24%) as colorless liquid.1HNMR (400 MHz, DMSO-d6) δ 7.79 (s, 1H), 7.45 (s, 1H), 7.12 (s, 1H), 4.45 (d, J = 3.2 Hz, 2H), 3.48 (s, 2H), 2.65 – 2.63 (m, 2H), 1.93 – 1.89 (m, 2H), 1.65 – 1.58 (m, 4H), 1.52 – 1.46 (m, 1H), 1.25 – 1.23 (m, 1H), 1.008 – 0.98 (m, 2H), 0.97 (d, J = 4.0 Hz, 3H), 0.74 – 0.72 (m, 2H). LCMS (ESI) m / z = 321.2 [M+H]+

[0188] Synthesis of 4-cyclopropyl-2-{m-[3-methyl-1-(4-methyl-4H-1,2,4- triazol-3-yl)cyclobutyl]phenyl}-6-{[(S)-3-methyl-1-piperidyl]methyl}-2,3- dihydro-1H-1λ⁶,2-benzisothiazole-1,1-dione (Example 12)

[0189] To a stirred solution of 4-cyclopropyl-6-{[(S)-3-methyl-1- piperidyl]methyl}-2,3-dihydro-1H-1λ⁶,2-benzisothiazole-1,1-dione (0.060 g, 0.187 mmol) and 3-[1-(m-bromophenyl)-3-methylcyclobutyl]-4-methyl-4H-1,2,4- triazole (0.063 g, 0.206 mmol) in acetonitrile (2 mL) was added dipotassium carbonate (0.129 g, 0.936 mmol) and was purged with nitrogen gas for 5 mins. Copper iodide (0.015 g, 0.075 mmol) was added followed by 1,2- bis(methylamino)ethane (0.022 g, 0.243 mmol) to the reaction mixture and was heated at 85°C for 16 h in a sealed tube. Progress of the reaction was monitoredthrough TLC and LCMS. The reaction mixture was filtered through celite bed, quenched with ice-cold water (10 mL), and extracted with ethyl acetate (2 X 10 mL). Combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and evaporated under reduced vacuum to afford crude compound, which was purified by Prep-HPLC [Column Name: X-SELECT-C18-CSH (250 mm x 19 mm x 5 µm), Mobile phase (A): 0.1%Ammonia in water, Mobile phase (B): ACN, Flow rate: 18 mL / min]. Pure fractions were evaporated off to obtain isomer- 1(Example 12) 4-cyclopropyl-2-{m-[3-methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl]phenyl}-6-{[(S)-3-methyl-1-piperidyl]methyl}-2,3-dihydro-1H- 1λ⁶,2-benzisothiazole-1,1-dione (0.0154 g,15.07 %) and isomer-02 (Example-13) 4-cyclopropyl-2-{m-[3-methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl]phenyl}-6-{[(S)-3-methyl-1-piperidyl]methyl}-2,3-dihydro-1H- 1λ⁶,2-benzisothiazole-1,1-dione (0.026 g, 2.54 %) as an off-white solid.

[0190] Example 12:1HNMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 7.59 (s, 1H), 7.52 (s, 1H), 7.47 - 7.43 (m, 1H), 7.41 - 7.39 (m, 1H), 7.22 (s, 1H),7.10 (d, J = 7.2 Hz, 1H), 5.12 (s, 2H), 3.53 (s, 2H), 3.22 (s, 3H), 2.89 - 2.85 (m, 2H), 2.70 - 2.67 (m, 2H), 2.57 - 2.53 (m, 3H), 2.08 - 2.04 (m, 1H), 1.89 - 1.87 (m, 1H), 1.62 - 1.60 (m, 4H), 1.49 - 1.47 (m, 1H), 1.09 - 1.08 (m, 6H), 0.85 - 0.81 (m, 5H).LCMS (ESI) m / z = 546.3[M+H]+

[0191] Example 13:1HNMR (400 MHz, DMSO-d6) δ 8.36 (s, 1H), 7.59 (s, 1H), 7.52 (s, 1H), 7.45 - 7.40 (m, 1H), 7.36 (d, J = 2.0 Hz, 1H), 7.22 (s, 1H), 6.95 (d, J = 7.6 Hz, 1H), 5.11 (s, 2H), 3.53 (s, 2H), 3.25 (s, 3H), 3.15 - 3.11 (m, 2H), 2.70 - 2.67 (m, 2H), 2.37 - 2.35 (m, 1H), 2.27 - 2.23 (m, 2H), 2.04 - 2.03 (m, 1H), 1.92 - 1.87 (m, 1H), 1.66 - 1.60 (m, 4H), 1.50 - 1.47 (m, 1H), 1.27 - 1.22 (m, 2H), 1.10 (d, J = 6.4 Hz, 3H),1.07 - 1.05 (m, 2H), 0.87 - 0.85 (m, 2H), 0.81 (d, J = 5.6 Hz, 2H). LCMS (ESI) m / z = 546.3[M+H]+.

[0192] Synthesis of Example 14

[0193] 4-cyclopropyl-2-{m-[1,1-dimethyl-2-(4-methyl-4H-1,2,4-triazol-3- yl)ethyl] phenyl}-6-{[(S)-3-methyl-1-piperidyl]methyl}-2,3-dihydro-1H-1λ⁶,2- benzisothiazole-1,1-dione (Example 14)

[0194] 4-cyclopropyl-6-{[(S)-3-methyl-1-piperidyl]methyl}-2,3-dihydro-1H- 1λ⁶,2-benzisothiazole-1,1-dione (57 mg, 17.8 mmol) and 3-[2-(m-bromophenyl)-2- methylpropyl]-4-methyl-4H-1,2,4-triazole (57.6 mg, 1.1 eq., 19.6 mmol) was dissolved in acetonitrile (2 mL, 38.3 mmol), then it was purged with N2 gas for 5 min. Potassium carbonate (123 mg, 5 eq., 889 µmol), copper iodide (22.6 mg, 0.4 eq., 7.11 mmol) followed by 1,2-bis(methylamino)ethane (20.4 mg, 1.3 eq., 23.1 mmol) were added to the reaction mixture and heated to 85°C for 16 h. The progress of reaction was monitored by TLC and LCMS. After completion of starting material, reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to get crude. The crude compound was purified by prep HPLC [Column Name: Xbridge C18(250 mm x 19 mm x 5 µm), Mobile phase (A): 0.1%Ammonia in water, Mobile phase (B): ACN, Flow rate: 18 mL / min].The pure fractions were lyophilized to afford a 4-cyclopropyl-2-{m-[1,1-dimethyl-2-(4- methyl-4H-1,2,4-triazol-3-yl)ethyl]phenyl}-6-{[(S)-3-methyl-1- piperidyl]methyl}-2,3-dihydro-1H-1λ⁶,2-benzisothiazole-1,1-dione (40 mg, 42%) as off white solid.1HNMR (400 MHz, DMSO-d6) δ 8.22(s, 1H), 7.59(s, 1H), 7.40-7.33(m, 3H), 7.22(s, 1H), 7.12(d, J =7.2Hz, 1H), 5.06(s, 2H), 3.53(s, 2H ), 3.11(s, 3H), 3.00(s, 2H), 2.69-2.67(m, 2H), 2.05(m, 1H), 1.92 – 1.87 (m, 1H), 1.66-1.59(m, 4H), 1.45(s, 6H), 1.07(d, 2H), 0.82-0.81(m, 6H). LCMS (ESI) m / z = 534.3[M+H]+

[0195] Synthesis of Example 15

[0196] Synthesis of (S,E)-4-cyclopropyl-2-(3-(1-(4-methyl-4H-1,2,4-triazol-3- yl)prop-1-en-2-yl)phenyl)-6-((3-methylpiperidin-1-yl)methyl)-2,3- dihydrobenzo[d]isothiazole 1,1-dioxide (79)

[0197] A stirred solution of 4-cyclopropyl-6-{[(S)-3-methyl-1-piperidyl]methyl}- 2,3-dihydro-1H-1λ⁶,2-benzisothiazole-1,1-dione (90 mg, 0.281 mmol), 3-[(E)-2- (m-bromophenyl)-1-propenyl]-4-methyl-4H-1,2,4-triazole (85.9 mg, 0.31 mmol) in acetonitrile (2 mL) was degassed under nitrogen atmosphere for 5 minutes, followed by the addition of dipotassium carbonate (194 mg, 1.4 mmol), 1,2-bis(methylamino)ethane (0.039 mL, 0.365 mmol) and copper iodide (21.4 mg, 0.112 mmol) and the reaction mixture and was heated at 90°C for 16 h in a sealed tube. After completion, the reaction mixture was filtered through celite bed, ice cold water (10 mL) was added to the filtrate and extracted with ethyl acetate (2 X 20 mL). Combined organic extracts were washed with brine solution (5 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced vacuum to afford crude compound, which was purified by flash column chromatography using 5% MeOH / DCM gradient (column size 12g), desired product was eluted around 7.5% MeOH / DCM gradient. Collected fractions were judged by TLC, purefractions were combined together and evaporated under reduced vacuum to afford (S,E)-4-cyclopropyl-2-(3-(1-(4-methyl-4H-1,2,4-triazol-3-yl)prop-1-en-2- yl)phenyl)-6-((3-methylpiperidin-1-yl)methyl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (75 mg, 51.6% yield) as a pale yellow solid.1HNMR (400 MHz, DMSO-d6) δ 8.48 (s, 1H), 7.86 (s, 1H), 7.67–7.38 (m, 6H), 7.23 (s, 1H), 6.69 (bs, 1H), 5.20 (s, 1H), 3.70 (s, 3H), 3.53-3.50 (m, 2H), 3.17-3.16 (m, 1H), 2.69-2.57 (m, 6H), 2.07 (m, 1H), 1.61 (m, 3H), 1.23 (s, 1H), 1.08 (m, 1H), 0.82 (s, 6H). LCMS (ESI) m / z = 518.0[M+H]+

[0198] Synthesis of 4-cyclopropyl-2-(3-(1-(4-methyl-4H-1,2,4-triazol-3- yl)propan-2-yl)phenyl)-6-(((S)-3-methylpiperidin-1-yl)methyl)-2,3- dihydrobenzo[d]isothiazole 1,1-dioxide (Example 15)

[0199] To a stirred solution of 4-cyclopropyl-2-{m-[(E)-1-methyl-2-(4-methyl-4H- 1,2,4-triazol-3-yl)ethenyl]phenyl}-6-{[(S)-3-methyl-1-piperidyl]methyl}-2,3- dihydro-1H-1λ⁶,2-benzisothiazole-1,1-dione (62 mg, 0.12 mmol) in methanol (2 mL) was added nickel dichloride (15.5 mg, 0.12 mmol) followed by addition of sodium boranuide (22.7 mg, 0.6 mmol) portion wise till the effervescence ceased and the reaction mixture was stirred at room temperature for 20 mins. After the completion of the reaction, the reaction mixture was concentrated under reduced vacuum to afford solid, which was dissolved with ethyl acetate and filtered through celite bed. The filtrate was extracted with water (20 mL X 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered and evaporated under reduced vacuum to afford crude. The crude material was purified through prep- purification [Column Name: X-SELECT-C18-CSH (250 mm x 19 mm x 5 µm), Mobile phase (A): 0.1%Ammonia in water, Mobile phase (B): ACN, Flow rate: 18 mL / min]. The collected pure fractions were evaporated under reduced vacuum andlyophilized to get 4-cyclopropyl-2-(3-(1-(4-methyl-4H-1,2,4-triazol-3-yl)propan- 2-yl)phenyl)-6-(((S)-3-methylpiperidin-1-yl)methyl)-2,3- dihydrobenzo[d]isothiazole 1,1-dioxide (9 mg, 14.5%) as a white solid.1HNMR (400 MHz, DMSO-d6) δ 8.28 (s, 1H), 7.63–7.57 (m, 1H), 7.41–7.34 (m, 3H), 7.25 (s, 1H), 7.11 (d, J = 6.6 Hz, 1H), 5.10 (s, 2H), 3.56 (s, 1H), 3.45 (s, 3H), 3.04–2.97 (m, 2H), 2.68 (s, 2H), 2.08–2.02 (m, 1H), 1.93–1.85 (m, 1H), 1.69–1.44 (m, 6H), 1.31 (d, J = 6.9 Hz, 3H), 1.08 (d, J= 7.4 Hz, 2H), 0.84 (s, 6H). LCMS (ESI) m / z = 520.4[M+H]+

[0200] Synthesis of Example 16

[0201] Synthesis of 4-cyclopropyl-2-{5-[3-methyl-1-(4-methyl-4H-1,2,4- triazol-3-yl)cyclobutyl]-3-pyridyl}-6-{[(S)-3-methyl-1-piperidyl]methyl}-2,3- dihydro-1H-1λ⁶,2-benzisothiazole-1,1-dione

[0202] To a stirred solution of 4-cyclopropyl-6-{[(S)-3-methyl-1- piperidyl]methyl}-2,3-dihydro-1H-1λ⁶,2-benzisothiazole-1,1-dione (50 mg, 15.6 mmol) and 3-[1-(5-bromo-3-pyridyl)-3-methylcyclobutyl]-4-methyl-4H-1,2,4- triazole (47.9 mg, 15.6 mmol) in acetonitrile (5 mL) was added dipotassium carbonate (108 mg, 5 eq., 78 mmol) and was purged with nitrogen gas for 5 mins, copper iodide (11.9 mg, 0.4 eq., 6.24 mmol) was added followed by 1,2-bis(methylamino)ethane (17.9 mg, 2.03 mmol) was added to the reaction mixture and was heated at 90°C for 16h in a sealed tube. Progress of the reaction was monitored through TLC & LCMS. The reaction mixture was filtered through celite bed, quenched with ice cold water (10 mL), extracted with ethyl acetate (2 X 10 mL). Combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and evaporated under reduced vacuum to afford crude compound, which was purified by Prep-HPLC [Column Name: X-SELECT-C18-CSH (250 mm x 19 mm x 5 µm), Mobile phase (A): 0.1%Ammonia in water, Mobile phase (B): ACN, Flow rate: 18 mL / min]. Pure fractions were evaporated off to obtain 4- cyclopropyl-2-{5-[3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl]-3- pyridyl}-6-{[(S)-3-methyl-1-piperidyl]methyl}-2,3-dihydro-1H-1λ⁶,2- benzisothiazole-1,1-dione (10 mg) as an off-white solid.1HNMR (400 MHz, DMSO-d6) δ 8.67 (s, 1H), 8.39 (d, J = 6Hz,1H), 8.33 (s, 1H), 7.81 (s, 1H), 7.64 (d, J = 9.2 Hz, 1H), 7.22 (s, 1H), 5.22 (s, 2H), 3.53 (s, 2H), 3.25 (s, 3H), 2.93 - 2.92 (m, 2H), 2.67 - 2.63 (m, 2H), 2.61 - 2.59 (m, 3H), 2.08 - 2.04 (m, 1H), 1.89 - 1.87 (m, 1H), 1.62 - 1.60 (m, 4H), 1.49 - 1.47 (m, 1H), 1.09 - 1.08 (m, 6H), 0.85 - 0.81 (m, 6H). LCMS (ESI) m / z = 547.4[M+H]+

[0203] Synthesis of Example 17

[0204] Synthesis of ethyl 2-(3-(3-bromophenyl)oxetan-3-yl)acetate(80): To a stirred solution of dichloride—(Z)-1,5-cyclooctadiene—1,5-cyclooctadiene— rhodium (1 / 1 / 1 / 2) (69.4 mg, 0.141 mmol) in 1,4-dioxane (5 mL) was addedpotassium hydroxide (592 mg, 10.6 mmol) dissolved in water (1 mL) at room temperature and stirred for 30 mins in open air. Ethyl 2-(oxetan-3-ylidene)acetate (1 g, 7.03 mmol) and (3-bromophenyl)boronic acid (2.83 g,14.1 mmol) were added portion wise at room temperature under air atmosphere and stirred for 16 h. Progress of the reaction was monitored through TLC (30% Ethyl acetate / Hexane) and LCMS. The reaction mixture was filtered through celite bed and filtrate was evaporated over vacuum to get crude product. The crude material was purified by flash column chromatography using 30% Ethylacetate / Hexane as the eluent to afford ethyl 2-(3-(3-bromophenyl)oxetan-3-yl)acetate (1.9 g, crude) as a brown oil. LCMS (ESI) m / z = 299.0[M+H]+

[0205] Synthesis of 2-(3-(3-bromophenyl)oxetan-3-yl)acetohydrazide (81): To a stirred solution of ethyl 2-(3-(3-bromophenyl)oxetan-3-yl)acetate (75.0 mg, 0.25 mmol) in n-butanol (1 mL, 10.9 mmol) was added hydrazine hydrate (1 / 1) (0.1 mL,2.01 mmol) and the reaction mixture was allowed to stirred at 110°C for 24 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with water (1.0 mL) and distilled the solvent under vacuum then added (5.0 ml) water and extracted with ethyl acetate (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to afford crude 2-[3-(m-bromophenyl)-3-oxetanyl]-1- hydrazino-1-ethanone (50.0 mg) as a gummy liquid. LCMS (ESI) m / z = 286.9[M+H]+

[0206] 5-((3-(3-bromophenyl)oxetan-3-yl)methyl)-4-methyl-4H-1,2,4-triazole- 3-thiol (82):To a stirred solution of 2-(3-(3-bromophenyl)oxetan-3- yl)acetohydrazide (6.8 g, 23.8 mmol) in methanol (72 mL) was added isothiocyanatomethane (3.49 g, 47.7 mmol) at room temperature, increased the temperature to 70°C and stirred for 16 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the starting material, added potassium hydroxide (2.68 g,47.7 mmol) dissolved in water (6.63 mL) and continued the reaction at 70°C for 2 h. Progress of the reaction was monitored by TLC and LCMS. The solvents were evaporated under vacuum, added water (10 ml) and neutralizedby dilute HCL. The precipitated solid was filtered and dried under vacuum to get 5-((3-(3-bromophenyl)oxetan-3-yl)methyl)-4-methyl-4H-1,2,4-triazole-3-thiol (6.1 g, crude) as a pale brown solid. LCMS (ESI) m / z = 342.0 [M+H]+

[0207] Synthesis of 3-((3-(3-bromophenyl)oxetan-3-yl)methyl)-4-methyl-4H- 1,2,4-triazole (83):To the stirred solution of 5-((3-(3-bromophenyl)oxetan-3- yl)methyl)-4-methyl-4H-1,2,4-triazole-3-thiol (1.1 g, 3.23 mmol) in ethyl acetate (5.5 mL) was added sodium nitrite (2.23 g,32.3 mmol) dissolved in water (17.6 mL) and (1M), nitric acid (32.3 ml, 32.3 mmol) drop-wise at 0°C. The resulting mixture was stirred at room temperature for 16 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched by addition of NaHCO3 and extracted with ethyl acetate (2 x 60 mL), dried over sodium sulfate, filtered and evaporated over vacuum to get crude 3-{[3- (m-bromophenyl)-3-oxetanyl]methyl}-4-methyl-4H-1,2,4-triazole (840 mg) as a brown solid. LCMS (ESI) m / z = 309.9[M+H]+

[0208] Synthesis of (S)-4-cyclopropyl-2-(3-(3-((4-methyl-4H-1,2,4-triazol-3- yl)methyl) oxetan-3-yl)phenyl)-6-((3-methylpiperidin-1-yl)methyl)-2,3- dihydrobenzo[d] isothiazole 1,1-dioxide (Example 17)

[0209] To a stirred solution of (S)-4-cyclopropyl-6-((3-methylpiperidin-1- yl)methyl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (57 mg, 0.178 mmol) and 3-((3-(3-bromophenyl)oxetan-3-yl)methyl)-4-methyl-4H-1,2,4-triazole (49.3 mg, 0.160 mmol) in acetonitrile (7.13 mL) was added potassium carbonate (172 mg, 1.25 mmol) and was purged with nitrogen gas for 5 mins. N,N'-Dimethyl ethylenediamine (20.4 mg, 0.231 mmol) and copper iodide (13.6 mg, 0.071mmol) was added and was heated at 90°C for 16 h in a sealed tube. Progress of the reaction was monitored through TLC and LCMS. The reaction mixture was filtered through celite bed, quenched with ice cold water (5 mL), and extracted with ethyl acetate (2 X 50 mL). Combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and evaporated over vacuum to get crude product and submitted for prep purification. [Column Name: X-SELECT-C18-CSH (250 mm x 19 mm x 5 µm), Mobile phase (A): 0.1%Ammonia in water, Mobile phase (B): ACN, Flow rate: 18 mL / min] Pure fractions were collected and concentrated to afford pure (S)-4-cyclopropyl-2-(3-(3-((4-methyl-4H-1,2,4-triazol-3- yl)methyl)oxetan-3-yl)phenyl)-6-((3-methylpiperidin-1-yl)methyl)-2,3- dihydrobenzo[d]isothiazole 1,1-dioxide (25.0 mg, 25.6%) as an off-white solid.1HNMR (400 MHz, DMSO-d6) δ 8.19 (s, 1H), 7.59 (s, 1H), 7.45 (d, J =8 Hz, 1H), 7.36 (t, J = 7.6 Hz, 1H), 7.22 (s, 1H), 6.97 (s, 1H), 6.76 (d, J = 7.6 Hz, 1H), 5.0- 4.87 (m, 6H), 3.51 (m, 4H), 2.89 (s, 3H), 2.67 (m, 2H), 2.07 (m, 1H), 1.87 (m, 1H), 1.6-1.4 (m, 5H), 1.08 (m, 2H), 0.8 (m, 6H). LCMS (ESI) m / z = 548.4[M+H]+

[0210] Synthesis of Example 18

[0211] potassium—trifluoro[(4-methyl-1-piperazinyl)methyl]-λ⁴-borane (85)

[0212] To a stirred solution of 1-methylpiperazine (0.5 g, 4.99 mmol) and potassium—(bromomethyl)tris(fluoro)-λ⁴-borane (1 / 1) (3.55 g, 17.7 mmol) in tetrahydrofuran (20 mL) was added potassium hydrogencarbonate (4.43 g, 44.2 mmol) followed by potassium iodide (1.22 g, 7.37 mmol) at 0°C and the reactionmixture was stirred at 90°C for 16 h. The Progress of the reaction was monitored through TLC and LCMS. After completion, the reaction mixture was evaporated under reduced vacuum to get solid. Acetone (20 mL) was added to it and stirred for a half an hour, filtered through sintered funnel and the filtrate was concentrated under reduced vacuum to afford crude potassium—trifluoro[(4-methyl-1- piperazinyl)methyl]-λ⁴-borane (1 / 1) (1 g, crude) as a yellow liquid. LCMS (ESI) m / z = 181[M+H]+

[0213] 6-[(4-methyl-1-piperazinyl)methyl]-4-(trifluoromethyl)-2,3-dihydro- 1H-1λ⁶,2-benzisothiazole-1,1-dione (86)

[0214] 6-bromo-4-(trifluoromethyl)-2,3-dihydro-1H-1λ⁶,2-benzisothiazole-1,1- dione (0.080 g, 0.253 mmol), trifluoro[(4-methyl-1-piperazinyl)methyl]-λ⁴-borane (0.045 g, 0.253 mmol) was dissolved in 1,4-dioxane (3 mL) : H2O(1 ml), purged with N2gas and dicaesium carbonate (0.247 g, 0.759 mmol), dicyclohexyl(2',4',6'- triisopropyl-2-biphenylyl)phosphine (0.024 g, 0.050 mmol), chloridopalladium(1+) 2-biphenylid-2'-amine—dicyclohexyl(2',4',6'-triisopropyl-3-biphenylyl)phosphine (1 / 1) (0.019 g, 0.025 mmol) were added and was heated at 100°C for 16 h. Progress of the reaction was monitored through TLC. The reaction mixture was quenched with ice cold water (20 mL), and extracted with ethyl acetate (2 X 50 mL). Combined organic layers were washed with brine (5 mL), dried over sodium sulfate, filtered and evaporated over vacuum and concentrated to get crude. The crude was purified by silica gel flash column chromatography. The compound eluted out in 15% -20% Ethyl acetate :Hexane. The pure fractions were collected and concentrated to get 6-[(4-methyl-1-piperazinyl)methyl]-4-(trifluoromethyl)-2,3-dihydro-1H-1λ⁶,2-benzisothiazole-1,1-dione (0.060 g, 68%) as a pale brown colour solid.1HNMR (400 MHz, DMSO-d6) δ 8.11 (s, 1H), 8.06 (s, 1H), 7.98 (s, 1H), 4.52 (s, 2H), 3.68 (s, 2H), 3.66 (s, 2H), 3.54 – 3.50 (m, 2H), 2.68 – 2.58 (m, 2H), 2.09 (t, J = 8Hz, 1H), 1.79 (m, 1H), 1.02 (d, 3H, J = 6.4Hz). LCMS (ESI) m / z = 350[M+H]+

[0215] 2-{m-[3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl]phenyl}- 6-[(4-methyl-1-piperazinyl)methyl]-4-(trifluoromethyl)-2,3-dihydro-1H-1λ⁶,2- benzisothiazole-1,1-dione (Example 18)

[0216] To a stirred solution of 6-[(4-methyl-1-piperazinyl)methyl]-4- (trifluoromethyl)-2,3-dihydro-1H-1λ⁶,2-benzisothiazole-1,1-dione (0.060 g, 0.172 mmol), 3-[1-(m-bromophenyl)-3-methylcyclobutyl]-4-methyl-4H-1,2,4-triazole (0.063 g, 0.206 mmol) in acetonitrile (3 mL) was added DMEDA (0.0018 mL, 0.017 mmol), dipotassium carbonate (0.166 g, 1.2 mmol) and was purged with nitrogen gas for 5 mins then copper iodide (0.013 g, 0.068 mmol) was added and was heated at 90°C for 16h in a sealed tube. Progress of the reaction was monitored through TLC and LCMS. The reaction mixture was filtered through celite bed, quenched with ice cold water (5 mL), and extracted with ethyl acetate (2 X 50 mL). Combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and evaporated over vacuum and concentrated to get crude product. The crude was purified through silica gel flash column chromatography by using DCM and MeOH as Eluents (5%) to obtain product. The obtained product was once again purified through Prep HPLC [Column Name: Kinetex EVO C18(250 mm x 19 mm x 5 µm), Mobile phase (A): 0.1%Ammonia in water, Mobile phase (B): ACN, Flow rate: 18 mL / min] The pure fractions were evaporated to get purecompound 2-{m-[3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl]phenyl}- 6-[(4-methyl-1-piperazinyl)methyl]-4 (trifluoromethyl)-2,3-dihydro-1H-1λ⁶,2- benzisothiazole-1,1-dione (0.006 g, 6% yield) as an off white solid.1HNMR (400 MHz, DMSO-d6) δ 8.33 (s, 1H), 8.20 (s, 1H), 8.07 (s, 1H), 7.49 - 7.42 (m, 3H), 7.02 (d, J = 7.6 Hz, 1H), 5.23 (s, 2H), 3.71(s, 2H), 3.20 (s, 2H), 3.15 (s, 1H), 2.84 (s, 2H), 2.56 (m, 2H ), 2.42 (m, 3H), 2.32 (m,3H), 2.27 (m, 1H), 3.15 (s,3H), 1.23 (s, 1H ), 1.09 (t, J = 5.6 Hz, 3H). LCMS (ESI) m / z = 575.3[M+H]+

[0217] Synthesis of Example 19

[0218] Synthesis of potassium—trifluoro[(4-methyl-1-piperazinyl)methyl]-λ⁴- borane (1 / 1) (88)

[0219] To a stirred solution of (S)-2-methylmorpholine (0.5 g, 4.94 mmol) and potassium—(bromomethyl)tris(fluoro)-λ⁴-borane (1 / 1) (1.19 g, 5.93 mmol) in tetrahydrofuran (6.7 mL, 82.4 mmol) was added potassium hydrogen carbonate(1.48 g, 14.8 mmol) followed by potassium iodide (0.41g, 2.47 mmol) at 0°C and the reaction mixture was stirred at 90°C for 16 h. The Progress of the reaction was monitored through TLC and LCMS. After completion of the reaction, the reaction mixture was evaporated under reduced vacuum to get solid. Acetone (20 mL) was added to it and stirred for a half an hour, filtered through sintered funnel and the filtrate was concentrated under reduced vacuum to afford crude potassium— trifluoro{[(S)-2-methyl-4-morpholinyl]methyl}-λ⁴-borane (1 / 1) (1 g, crude) as a yellow liquid. LCMS (ESI) m / z = 182[M+H]+

[0220] 6-{[(S)-2-methyl-4-morpholinyl]methyl}-4-(trifluoromethyl)-2,3- dihydro-1H-1λ⁶,2-benzisothiazole-1,1-dione (89)

[0221] 6-bromo-4-(trifluoromethyl)-2,3-dihydro-1H-1λ⁶,2-benzisothiazole-1,1- dione (0.16 g, 0.50 mmol), trifluoro{[(S)-2-methyl-4- morpholinyl]methyl}boranuide (0.46 g, 2.53 mmol) was dissolved in 1,4-dioxane (3 mL) : H2O (1 ml), purged with N2gas and dicaesium carbonate (0.49 g, 1.52 mmol), dicyclohexyl(2',4',6'-triisopropyl-2-biphenylyl)phosphine (0.048 g, 0.10 mmol), chloridopalladium(1+) 2-biphenylid-2'-amine—dicyclohexyl(2',4',6'- triisopropyl-3-biphenylyl)phosphine (1 / 1) (0.039 g, 0.50 mmol) were added and was heated at 100°C for 16 h. Progress of the reaction was monitored through TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with ice cold water (20 mL), and extracted with ethyl acetate (2 X 50 mL). The combined organic layers were washed with brine (5 mL), dried over sodium sulfate, filtered and evaporated over vacuum and concentrated to get crude compound. The crude was purified by silica gel flash column chromatography. The compoundeluted out in 15% -20% Ethyl acetate: Hexane. Pure fractions were collected and evaporated off to get 6-{[(S)-2-methyl-4-morpholinyl]methyl}-4- (trifluoromethyl)-2,3-dihydro-1H-1λ⁶,2-benzisothiazole-1,1-dione (0.15 g, 84% yield) as pale brown colour solid.1HNMR (400 MHz, DMSO-d6) δ 8.11 (s, 1H); 8.07 (s, 1H); 7.92 (s, 1H); 4.52 (s, 2H); 3.73 (d, J = 10Hz, 1H); 3.66 (s, 2H); 3.54 – 3.50 (m, 2H); 2.68 – 2.58 (m, 2H); 2.09 (t, J = 8Hz, 1H); 1.79 (m, 1H); 1.02 (d, J = 6.4Hz, 3H). LCMS (ESI) m / z = 351[M+H]+

[0222] 2-{5-[3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl]-3- pyridyl}-6-{[(S)-2-methyl-4-morpholinyl]methyl}-4-(trifluoromethyl)-2,3- dihydro-1H-1λ⁶,2-benzisothiazole-1,1-dione (Example 19)

[0223] To a stirred solution of 6-{[(S)-2-methyl-4-morpholinyl]methyl}-4- (trifluoromethyl)-2,3-dihydro-1H-1λ⁶,2-benzisothiazole-1,1-dione (0.04 g, 0.11 mmol), 3-[1-(5-bromo-3-pyridyl)-3-methylcyclobutyl]-4-methyl-4H-1,2,4-triazole (0.033 g, 0.10 mmol) in acetonitrile (2 mL, 38.3 mmol) was added DMEDA (0.001 mL,0.011 mmol), dipotassium carbonate (0.11 g, 0.799 mmol), purged with nitrogen gas for 5 mins and then copper iodide (0.008 g, 0.045 mmol) was added and heated at 90°C for 16 h in a sealed tube. Progress of the reaction was monitored through TLC & LCMS. The reaction mixture was filtered through celite bed, quenched with ice cold water (5 mL), and extracted with ethyl acetate (2 X 50 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and evaporated over vacuum and concentrated to get crude product. The crude was purified through Prep HPLC. [Column Name: BEH C18(250 mm x 19 mm x 5 µm), Mobile phase (A): 0.1% Formic acid in water, Mobilephase (B): ACN, Flow rate: 18 mL / min].The pure fractions were collected and evaporated to get pure compound 2-{5-[3-methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl]-3-pyridyl}-6-{[(S)-2-methyl-4-morpholinyl]methyl}-4- (trifluoromethyl)-2,3-dihydro-1H-1λ⁶,2-benzisothiazole-1,1-dione (0.005 g, 7.6% yield) as an off white solid.1HNMR (400 MHz, DMSO-d6) δ 8.67 (s, 1H), 8.47 (s, 1H), 8.33 (s, 1H), 8.27 (s, 1H), 8.12 (s, 1H), 7.82 (s, 1H), 5.35 (s, 2H), 3.71 (s, 3H), 3.54 - 3.49 (m, 2H), 3.24 (s, 3H), 2.92 - 2.91 (m, 2H ), 2.70 (s, 1H), 2.63 - 2.58 (m, 4H), 2.14 - 2.09 (m, 1H), 1.82 (t, J = 10.4 Hz, 1H), 1.09 (d, J = 5.2 Hz, 3H ), 1.03 (d, J = 6.4Hz, 3H). LCMS (ESI) m / z = 577.4[M+H]+

[0224] Synthesis of Example 20

[0225] Synthesis of 2-{m-[3-methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl] phenyl}-6-{[(S)-2-methyl-4-morpholinyl]methyl}-4- (trifluoromethyl)-2,3-dihydro-1H-1λ⁶,2-benzisothiazole-1,1-dione (03): -

[0226] To a stirred solution of 6-{[(S)-2-methyl-4-morpholinyl]methyl}-4- (trifluoromethyl)-2,3-dihydro-1H-1λ⁶,2-benzisothiazole-1,1-dione (0.04 g, 0.11 mmol), 3-[1-(m-bromophenyl)-3-methylcyclobutyl]-4-methyl-4H-1,2,4-triazole (0.033 g, 0.18 mmol) in acetonitrile (2 mL, 38.3 mmol) was added DMEDA(0.001mL, 0.01.4 mmol), dipotassium carbonate (0.11 g, 0. 79 mmol) and was purged with nitrogen gas for 5 mins. Copper iodide (0.008 g, 0.045 mmol) was added to it and heated at 90°C for 16 h in a sealed tube. Progress of the reaction was monitored through TLC and LCMS. The reaction mixture was filtered through celite bed, quenched with ice cold water (5 mL), and extracted with ethyl acetate (2 X 50 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and evaporated over vacuum and concentrated to get crude product. The crude was purified through silica gel flash column chromatography. The compound eluted out in DCM and MeOH as Eluents (5%). The fractions were evaporated off to obtain crude product. The obtained product was once again purified through Prep HPLC [Column Name: BEH C18 (250 mm x 19 mm x 5 µm), Mobile phase (A): 0.1% Formic acid in water, Mobile phase (B): ACN, Flow rate: 18 mL / min].The fractions were evaporated off to obtain 2-{m-[3- methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl]phenyl}-6-{[(S)-2-methyl-4- morpholinyl]methyl}-4-(trifluoromethyl)-2,3-dihydro-1H-1λ⁶,2-benzisothiazole- 1,1-dione ( 0.004 g, 6% yield) as an off white solid.1HNMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 8.23 (s, 1H), 8.09 (s, 1H), 7.49 - 7.40 (m, 3H), 7.19 (d, J = 8.4Hz, 1H), 5.24 (s, 2H), 3.75-3.71(m, 3H), 3.49 (d, J = 11.5Hz, 2H), 2.84 (s, 3H), 2.68 (s, 3H), 2.62 (s, 1H ),2.62 (s, 2H), 2.14 - 2.07 (m,1H), 1.84 - 1.79 (m, 1H), 1.23 (s,1H), 1.08 (d, J = 5.2Hz, 3H ), 1.03 (d, J = 6.4Hz, 3H). LCMS (ESI) m / z = 576.4[M+H]+

[0227] Synthesis of Example 21

[0228] Synthesis of (S)-2-(3-(3-((4-methyl-4H-1,2,4-triazol-3- yl)methyl)oxetan-3-yl)phenyl)-6-((2-methylmorpholino)methyl)-4- (trifluoromethyl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (Example 21)

[0229] To a stirred solution of (S)-6-((2-methylmorpholino)methyl)-4- (trifluoromethyl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (64.0 mg, 0.18 mmol) and 3-((3-(3-bromophenyl)oxetan-3-yl)methyl)-4-methyl-4H-1,2,4-triazole (50.7 mg, 0.16 mmol) in acetonitrile (6.0 mL) was added potassium carbonate (177.0 mg, 1.28 mmol) and was purged with nitrogen gas for 5 mins. N,N'- Dimethyl ethylenediamine (20.9 mg, 0.23 mmol) and copper iodide (13.9 mg, 0.07 mmol) were added and was heated at 90°C for 16 h in a sealed tube. Progress of the reaction was monitored through TLC and LCMS. The reaction mixture was filtered through celite bed, quenched with ice cold water (5 mL), and extracted with ethyl acetate (2 X 50 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and evaporated over vacuum to get crude product and submitted for prep purification. [Column Name: X-SELECT-C18-CSH (250 mm x 19 mm x 5 µm), Mobile phase (A): 0.1%Ammonia in water, Mobile phase (B): ACN, Flow rate: 18 mL / min].The pure fractions were collected and concentrated to afford pure (S)-2-(3-(3-((4-methyl-4H-1,2,4-triazol-3- yl)methyl)oxetan-3-yl)phenyl)-6-((2-methylmorpholino)methyl)-4- (trifluoromethyl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (18.0 mg, 17%) as an off-white solid.1HNMR (400 MHz, DMSO-d6) δ 8.23 (s, 1H), 8.17 (s, 1H), 8.09 (s, 1H), 7.46 (d, J = 8.4 Hz, 1H), 7.38 (t, J = 7.6 Hz, 1H), 7.03 (s, 1H), 6.82 (d, J = 7.6 Hz, 1H), 5.13(s, 2H), 4.96 (d, J = 5.6 Hz, 2H), 4.87 (d, J = 6.0 Hz, 2H), 3.71 (m, 3H), 3.52 (m, 4H), 2.89 (s, 3H), 2.70-2.60 (m, 2H), 2.11 (m, 1H), 1.82 (t, J = 10.4 Hz, 1H), 1.03 (d, J = 6.0 Hz, 3H). LCMS (ESI) m / z = 578.4[M+H]+

[0230] Synthesis of Example 22

[0231] Synthesis of 6-bromo-2-methyl-1-((4-methyl-4H-1,2,4-triazol-3- yl)methyl)-1H-indole (92)

[0232] A stirred solution of 6-bromo-2-methyl-1H-indole (0.5 g, 2.38 mmol) in DMSO (2 mL) was added to a solution of potassium hydroxide (0.33 g, 5.95 mmol) in dimethyl sulfoxide (1 mL) and stirred for 5 min.3-(chloromethyl)-4-methyl-4H- 1,2,4-triazole (0.42 g, 3.09 mmol) was added in a single portion and the reaction mixture was stirred for 2 h at room temperature. Progress of the reaction was monitored by TLC and LCMS. The reaction mixture was quenched with ice cold water (10 mL) and extracted with ethyl acetate (2 X 10 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and evaporated over vacuum to get 6-bromo-2-methyl-1-((4-methyl-4H-1,2,4-triazol- 3-yl)methyl)-1H-indole (0.3 g, crude) as a yellow gummy solid. LCMS (ESI) m / z = 306.4[M+H]+

[0233] 2-{2-methyl-1-[(4-methyl-4H-1,2,4-triazol-3-yl)methyl]-6-indolyl}-6- {[(S)-3-methyl-1-piperidyl]methyl}-4-(trifluoromethyl)-2,3-dihydro-1H-1λ⁶,2- benzisothiazole-1,1-dione (Example 22)

[0234] To a stirred solution of 6-{[(S)-3-methyl-1-piperidyl]methyl}-4- (trifluoromethyl)-2,3-dihydro-1H-1λ⁶,2-benzisothiazole-1,1-dione (0.050 g, 0.144 mmol), 3-[(6-bromo-2-methyl-1-indolyl)methyl]-4-methyl-4H-1,2,4-triazole (0.039 g, 0.129 mmol) in acetonitrile (2.5 mL) was added DMEDA (0.020 mL, 0.187 mmol), dipotassium carbonate (0.139 g, 1 mmol), purged with nitrogen gas for 5 mins, copper iodide (0.010 g, 0.057 mmol) was added and heated at 90°C for 16 h in a sealed tube. Progress of the reaction was monitored through TLC and LCMS. The reaction mixture was filtered through celite bed, quenched with ice cold water (5 mL) and extracted with ethyl acetate (2 X 50 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and evaporated over vacuum and concentrated to get crude product. The crude was purified through silica gel flash column chromatography by using DCM and MeOH as Eluents (5%) to obtain product. The obtained product was once again purified through Prep HPLC [Column Name: BEH C18 (250 mm x 19 mm x 5 µm), Mobile phase (A): 0.1% Formic in water, Mobile phase (B): ACN, Flow rate: 18 mL / min]. Pure fractions were evaporated off to obtain 2-{2-methyl-1-[(4-methyl-4H-1,2,4- triazol-3-yl)methyl]-6-indolyl}-6-{[(S)-3-methyl-1-piperidyl]methyl}-4- (trifluoromethyl)-2,3-dihydro-1H-1λ⁶,2-benzisothiazole-1,1-dione (0.010 g, 12% yield) as an off white solid.1HNMR (400 MHz, DMSO-d6) δ 8.41 (s, 1H), 8.19 (s, 1H), 8.06 (s, 1H), 7.67 (s, 1H), 7.54 (d, J = 8Hz, 1H), 7.28 - 7.25 (m, 1H), 6.34 (s, 1H), 5.62 (s, 2H), 5.16 (s, 2H), 3.69 (s, 2H), 3.57 (s, 3H ), 2.74 - 2.67 (m, 2H), 2.33 (s, 3H), 1.97 - 1.94 (m, 1H), 1.71 - 1.59 (m, 4H), 1.50 - 1.47 (m, 1H ), 0.88 (s, 1H), 0.83 (d, J = 8 Hz, 3H). LCMS (ESI) m / z = 573.0[M+H]+

[0235] Synthesis of Example 23

[0236] Synthesis of (S)-2-(3-(3-((4-methyl-4H-1,2,4-triazol-3- yl)methyl)oxetan-3-yl)phenyl)-6-((3-methylpiperidin-1-yl)methyl)-4- (trifluoromethyl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (Example 23) :To a stirred solution of (S)-6-((3-methylpiperidin-1-yl)methyl)-4- (trifluoromethyl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (50.0 mg, 0.14 mmol) and 3-((3-(3-bromophenyl)oxetan-3-yl)methyl)-4-methyl-4H-1,2,4-triazole (39.8 mg, 0.129 mmol) in acetonitrile (5.0 mL) was added potassium carbonate (139.0 mg, 1.0 mmol) and was purged with nitrogen gas for 5 mins. N,N'-Dimethyl ethylenediamine, (16.4 mg, 0.18 mmol), copper iodide (10.9 mg, 0.57 mmol) were added and was heated at 90°C for 16 h in a sealed tube. Progress of the reaction was monitored through TLC and LCMS. The reaction mixture was filtered through celite bed, quenched with ice cold water (5.0 mL), and extracted with ethyl acetate (2 X 50 mL). The combined organic layers were washed with brine (10.0 mL), dried over sodium sulfate, filtered and evaporated over vacuum to get crude product and submitted for prep purification[Column Name: X-SELECT-C18-CSH (250 mm x 19 mm x 5 µm), Mobile phase (A): 0.1%Ammonia in water, Mobile phase (B): ACN, Flow rate: 18 mL / min]. Pure fractions were collected and concentrated to afford pure (S)-2-(3-(3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3- yl)phenyl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)-2,3- dihydrobenzo[d]isothiazole 1,1-dioxide (22.0 mg, 26.6%) as an off-white solid.1HNMR (400 MHz, DMSO-d6) δ 8.20 (s, 1H), 8.18 (s, 1H), 8.08 (s, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.38 (t, J = 8.0 Hz, 1H), 7.03 (s, 1H), 6.82 (d, J = 7.2 Hz, 1H), 5.13 (s, 2H), 4.96 (d, J = 6.0 Hz, 2H), 4.87 (d, J = 6.0 Hz, 2H), 3.71 (s, 2H), 3.50 (s, 2H), 2.89 (s, 3H), 2.69 (m, 2H), 1.96 (m, 1H), 1.67 (m, 4H), 1.49 (m, 1H), 0.83 (m, 4H). LCMS (ESI) m / z = 576.0[M+H]+

[0237] Synthesis of Example 24

[0238] Synthesis of 6-bromo-1-methyl-2,3-dihydro-1H-indene-1-carbonitrile (94)

[0239] To a stirred solution of 6-bromo-1-indancarbonitrile (1.8 g, 8.11 mmol) in THF (20 ml) was added sodium hydride (486 mg, 12.2 mmol) in portions at 0oC. The reaction mixture was stirred at the same temperature for 10 minutes and iodomethane (0.8 mL, 12.2 mmol) was added to it in a dropwise manner. The reaction mixture was gradually warmed to room temperature and stirred for 2 h. The reaction mixture was quenched with ice water and extracted in ethyl acetate. The organic layer was dried over sodium sulfate and completely evaporated off to obtain 6-bromo-1-methyl-1-indancarbonitrile (1.8 g, 94%) as an oily compound.1HNMR (400 MHz, DMSO-d6) δ 7.69 (d, J = 1.6 Hz, 1H), 7.50 – 7.48 (m, 1H), 7.29 (d, J = 8 Hz, 1H), 2.97 – 2.89 (m, 2H), 2.6 – 2.55 (m, 1H), 2.21 – 2.14 (m, 1H), 1.64 (s, 3H).

[0240] Synthesis of 6-bromo-1-methyl-2,3-dihydro-1H-indene-1-carboxylic acid (95)

[0241] To a stirred solution of 6-bromo-1-methyl-1-indancarbonitrile (1.8 g, 7.62 mmol) in ethylene glycol (45 ml) was added potassium hydroxide (3.42 g, 61 mmol). The reaction mixture was heated to 90oC for 16 h. The reaction mixture was cooled to room temperature and completely evaporated off to obtain crude compound which was acidified using 1N HCl. The crude was extracted in ethyl acetate. The organic layer was dried over sodium sulfate and completely evaporated off to obtain 6-bromo-1-methyl-2,3-dihydro-1H-indene-1-carboxylic acid (1.8 g, crude) as an oily compound.1HNMR (400 MHz, DMSO-d6) δ 12.45 (br.s, 1H), 7.42 (s, 1H), 7.37 – 7.35 (m, 1H), 7.19 (d, J = 8 Hz, 1H), 2.93 – 2.80 (m, 2H), 2.59 – 2.50 (m, 1H), 1.93 – 1.86 (m, 1H), 1.44 (s, 3H). LCMS (ESI) m / z = 256[M+H]+

[0242] Synthesis of methyl 6-bromo-1-methyl-2,3-dihydro-1H-indene-1- carboxylate (96)

[0243] To a stirred solution of 6-bromo-1-methyl-1-indancarboxylic acid (1.8 g, 7.06 mmol) in DMF (30 ml) was added dipotassium carbonate (1.95 g, 14.1 mmol) and iodomethane (0.7 mL, 1.61 mol) at 0°C was then heated to 80°C for 5h. Progress of the reaction was monitored through TLC. The reaction mixture was evaporated under vacuum, quenched with ice cold water (20 mL), extracted with ethyl acetate (2 X 50 mL). Combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and evaporated over vacuum to get crude product as a colorless oil (2 g crude).1HNMR (400 MHz, DMSO-d6): δ 7.42 (d, J= 1.6 Hz, 1H), 7.39 – 7.36 (m, 1H), 7.21 (d, J = 8 Hz, 1H), 3.61 (s, 3H), 2.90 – 2.86 (m, 2H), 2.59 – 2.54 (m, 1H), 1.98 – 1.91 (m, 1H), 1.46 (s, 3H).

[0244] Synthesis of 6-bromo-1-methyl-2,3-dihydro-1H-indene-1- carbohydrazide (97)

[0245] To a stirred solution of methyl 6-bromo-1-methyl-1-indancarboxylate (1 g, 3.72 mmol) in n-butanol (15 ml) was added Hydrazine hydrate (1.5 mL, 29.7 mmol) and the RM was allowed to stir at 110°C for 30 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with water (10.0 mL) and distilled the solvent under vacuum then added (50.0 ml) water and extracted with ethyl acetate (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to afford crude 6-bromo-1-methyl-2,3-dihydro-1H-indene-1-carbohydrazide as a gummy liquid and directly used for the next step.1HNMR (400 MHz, DMSO-d6): δ 8.90 (s, 1H), 7.51 (d, J = 1.6 Hz, 1H), 7.36 – 7.31 (m, 1H), 7.16 (d, J = 8 Hz, 1H), 4.14 (br.s, 2H), 2.92 – 2.76 (m, 2H), 2.62 – 2.57 (m, 1H), 1.87 – 1.80 (m, 1H), 1.43 (s, 3H).

[0246] 5-(6-bromo-1-methyl-2,3-dihydro-1H-inden-1-yl)-4-methyl-4H-1,2,4- triazole-3-thiol (98)

[0247] To a stirred solution of (6-bromo-1-methyl-1-indanyl)hydrazinomethanone (2 g, 7.43 mmol) in methanol (20 mL) was added isothiocyanatomethane (1.09 g, 14.9 mmol) and the resulting reaction mixture was stirred at 80 °C for 1 hour.Potassium hydroxide (14.9 g, 265 mmol) in water was added and was heated to 80 °C for 16 h. The progress of the reaction was monitored through TLC and LCMS. The reaction mixture was evaporated to remove methanol and was neutralized to pH=7 using dilute HCl, precipitated solid was filtered and dried to obtain (6-bromo- 1-methyl-1-indanyl)(4-methylthiosemicarbazido)methanone (2 g,crude) as a crude off-white solid.1HNMR (400 MHz, DMSO-d6): δ 13.66 (s, 1H), 7.45 – 7.42 (m, 1H), 7.30 – 7.20 (m, 2H), 3.07 (s, 3H), 3.03 – 2.98 (m, 2H), 2.55 – 2.50 (m, 1H), 2.17 – 2.11 (m, 1H), 1.59 (s, 3H). LCMS (ESI) m / z = 324[M+H]+

[0248] Synthesis of 3-(6-bromo-1-methyl-2,3-dihydro-1H-inden-1-yl)-4- methyl-4H-1,2,4-triazole (99)

[0249] A stirred solution of 5-(6-bromo-1-methyl-1-indanyl)-4-methyl-4H-1,2,4- triazole-3-thiol (1.8 g, 5.55 mmol) in DCM (10 ml) was cooled to 0°C and hydrogen peroxide (8 mL, 11.1 mmol) and acetic acid (16 ml) were added, allowed to stir at room temperature for 1 h. The reaction was monitored by TLC. The reaction mixture was poured into ice-cold water and extracted with DCM. The organic phase was washed with sodium bicarbonate, brine and dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to get crude 3-(6-bromo-1-methyl-1- indanyl)-4-methyl-4H-1,2,4-triazole (1.5 g, crude).1HNMR (400 MHz, DMSO-d6): δ 8.37 (s, 1H), 7.43 – 7.40 (m, 1H), 7.28 (d, J = 8.0 Hz, 1H), 7.15 (d, J = 1.6 Hz, 1H), 3.28 (s, 3H), 3.18 – 2.94 (m, 2H), 2.52 – 2.44 (m, 1H), 2.20 – 2.13 (m, 1H), 1.66 (s, 3H). LCMS (ESI) m / z = 294.1[M+H]+

[0250] Synthesis of 2-(3-methyl-3-(4-methyl-4H-1,2,4-triazol-3-yl)-2,3- dihydro-1H-inden-5-yl)-6-(((S)-3-methylpiperidin-1-yl)methyl)-4- (trifluoromethyl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (Example 24)

[0251] To a stirred solution of (S)-6-((3-methylpiperidin-1-yl)methyl)-4- (trifluoromethyl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (0.05 g, 0.144 mmol) in acetonitrile (5 mL) was added 3-(6-bromo-1-methyl-1-indanyl)-4-methyl-4H- 1,2,4-triazole (0.038 g, 0.13 mmol), DMEDA (0.15 mL, 0.144 mmol), potassium carbonate (0.14 g, 1 mmol), copper iodide (0.011 g, 0.057 mmol) and was heated at 90°C for 16h in a sealed tube. Progress of the reaction was monitored through TLC and LCMS. The reaction mixture was filtered through celite bed, quenched with ice-cold water (5 mL), and extracted with ethyl acetate (2 X 50 mL). Combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and evaporated over vacuum and concentrated to get crude product. The crude was purified through silica gel purifier by using DCM and MeOH as Eluents (5%) to obtain crude product, which was further purified through Prep HPLC [Column Name: X-SELECT-C18-CSH (250 mm x 19 mm x 5 µm), Mobile phase (A): 0.1%Ammonia in water, Mobile phase (B): ACN, Flow rate: 18 mL / min] to obtain the desired product as an off-white solid.1HNMR (400 MHz, DMSO-d6): δ 8.39 (s, 1H), 8.17 (s, 1H), 8.05 (s, 1H), 7.43 (s, 2H), 7.13 (s, 1H), 5.17 (s, 2H), 3.66 (s, 2H), 3.17 (s, 3H), 3.15 – 3.03 (m, 3H), 2.71 – 2.67 (m, 2H), 2.20 – 2.15 (m, 1H), 1.97 – 1.92 (m, 1H), 1.72 (s, 3H), 1.69 – 1.58 (m, 5H), 0.91 – 0.87 (m, 1H), 0.82 (d, J = 3.6 Hz, 3H), LCMS (ESI) m / z = 560.1[M+H]+

[0252] Synthesis of Example 25

[0253] Synthesis of (S)-(4-amino-3-(trifluoromethyl)phenyl)(3- methylpiperidin-1-yl)methanone (101)

[0254] To a stirred solution of 4-amino-3-(trifluoromethyl)benzoic acid (16 g, 78 mmol) in dimethylformamide (160 mL) was added DIPEA (40.8 mL, 234 mmol) followed by HATU (35.6 g, 93.6 mmol) under nitrogen atmosphere and allowed to stir at room temperature for 30 minutes. (S)-3-methylpiperidine (8.51 g, 85.8 mmol) was added to the reaction mixture and continued to stir at same temperature for 2 h. After completion, the reaction mixture was poured into ice cold water (50mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic phase was washed with water (25 mL), brine solution (20 mL) and dried over anhydrous sodium sulfate, filtered and concentrated under reduced vacuum to afford crude compound. The crude material was purified through silica gel flash column chromatography using 30% ethylacetate / hexane gradient (column size 80g). The desired product eluted around 28% ethylacetate / hexane gradient. The collected fractions were judged by TLC, pure fractions were combined together and evaporated under reduced vacuum to get (S)-(4-amino-3-(trifluoromethyl)phenyl)(3-methylpiperidin-1-yl)methanone (20 g, ) as a pale yellow semi solid.1HNMR (400 MHz, DMSO-d6): δ 7.35 - 7.31 (m, 1H), 7.16 (br.s, 1H), 6.83 (d, J = 8.4 Hz, 1H), 5.75 (s, 2H), 4.11 - 4.02 (m, 1H), 3.17 - 3.11 ( m, 1H), 2.88 (br.s, 1H), 2.69 (s, 1H), 2.56 (br.s, 1H), 1.99 - 1.91 (m, 1H), 1.78 - 1.55 (m, 1H), 1.54 - 1.521 (m, 1H), 1.45 - 1.35 (m, 1H), 0.83 (d, J = 4 Hz, 3H). LCMS (ESI) m / z = 287.1[M+H]+

[0255] Synthesis of (S)-2-amino-5-(3-methylpiperidine-1-carbonyl)-3- (trifluoromethyl)benzenesulfonyl chloride (102)

[0256] To [4-amino-3-(trifluoromethyl)phenyl][(S)-3-methyl-1- piperidyl]methanone (24 g, 83.8 mmol) was added chloro(hydroxy)-λ⁶- sulfanedione (33.5 mL, 503 mmol) at 0 °C under nitrogen atmosphere and allowed to stir at 130°C for 3 h. After completion of the reaction, the reaction mixture was poured to crushed ice and extracted with DCM (300 mL X 2). The combined organic extracts were washed with water (50 mL) and brine solution (25 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced vacuum to afford crude (S)-2-amino-5-(3-methylpiperidine-1-carbonyl)-3-(trifluoromethyl) benzenesulfonyl chloride (22 g, crude) as a dark yellow colored compound. LCMS (ESI) m / z = 385.1[M+H]+

[0257] Synthesis of (S)-2-amino-5-(3-methylpiperidine-1-carbonyl)-3- (trifluoromethyl) benzenesulfonic acid (103)

[0258] A stirred solution of [4-amino-3-(chlorosulfonyl)-5- (trifluoromethyl)phenyl][(S)-3-methyl-1-piperidyl]methanone (20 g, 52 mmol) in 1,4-dioxane (50 mL) and water (50 mL) was refluxed to 100°C for 2 h under nitrogen atmosphere. After completion of the reaction, the reaction mixture was concentrated under reduced vacuum to afford crude (S)-2-amino-5-(3- methylpiperidine-1-carbonyl)-3-(trifluoromethyl)benzenesulfonic acids (19 g, crude) as a yellow solid. LCMS (ESI) m / z = 367.2[M+H]+

[0259] Synthesis of (S)-2-iodo-5-(3-methylpiperidine-1-carbonyl)-3- (trifluoromethyl) benzenesulfonic acid (104)

[0260] To a stirred solution of 2-amino-5-{[(S)-3-methyl-1-piperidyl]carbonyl}-3- (trifluoromethyl)benzenesulfonic acid (16.5 g, 45 mmol) in water (160 mL) was added disodium carbonate (2.39 g, 22.5 mmol) slowly until no further evolution of gas was observed. The solution was cooled to 0 °C and sodium nitrite (3.42 g, 49.5 mmol) was added over a period of 15 min. After stirring for 30 min, hydrogen chloride (4.05 mL, 90.1 mmol) was added dropwise. Stirring was continued at 0 °C for 30 min and then potassium iodide (11.2 g, 67.6 mmol) dissolved in minimum quantity of water was added slowly. The solution was gradually allowed to warm to room temperature and then refluxed for 1 hour at 100 °C. After completion of the reaction, the reaction mixture was cooled to room temperature and sodium thiosulphate solution was added to reduce residual iodine. The reaction mixture was concentrated under reduced vacuum to afford solid, to which water (100 mL) was added and extracted with ethyl acetate (300 mL X 2). The combined organic extracts were washed with water (50 mL) and brine solution (25 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced vacuum to afford crude (S)-2-iodo-5-(3-methylpiperidine-1-carbonyl)-3-(trifluoromethyl)benzenesulfonic acid (9 g, crude) as a dark brown colored crystalline solid. LCMS (ESI) m / z = 477.2[M+H]+

[0261] Synthesis of (S)-2-iodo-5-(3-methylpiperidine-1-carbonyl)-3- (trifluoromethyl) benzenesulfonyl chloride (105)

[0262] To 2-iodo-5-{[(S)-3-methyl-1-piperidyl]carbonyl}-3- (trifluoromethyl)benzene sulfonic acid (6 g, 12.6 mmol), was added phosphoryl trichloride (8 mL) under nitrogen atmosphere at 0 °C and it was refluxed at 60 °C for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced vacuum to afford crude (S)-2-iodo-5-(3-methylpiperidine-1- carbonyl)-3-(trifluoromethyl)benzenesulfonyl chloride (6 g, crude) as brown colored gummy compound. LCMS (ESI) m / z = 495.7[M+H]+

[0263] Synthesis of (S)-2-iodo-5-(3-methylpiperidine-1-carbonyl)-3- (trifluoromethyl) benzenesulfonamide (106)

[0264] A stirred solution of [3-(chlorosulfonyl)-4-iodo-5- (trifluoromethyl)phenyl][(S)-3-methyl-1-piperidyl]methanone (6 g, 12.1 mmol) in dichloromethane (60 mL) was purged with ammonia gas at 0 °C for 30 minutes. After completion, the reaction mixture was concentrated under reduced vacuum to afford solid, to which water (50 mL) was added and extracted with ethyl acetate (100 mL X 2). The combined organic extracts were washed with water (25 mL), brine solution (15 mL) and dried over anhydrous sodium sulfate, filtered andevaporated under reduced vacuum to afford crude compound. The crude material was purified through silica gel flash column chromatography using 50% Ethyl acetate / hexane gradient (column size 40 g). The desired product eluted around 48% ethyl acetate / hexane gradient. The collected fractions were judged by TLC, pure fractions were combined together and evaporated under reduced vacuum to obtain crude (S)-2-iodo-5-(3-methylpiperidine-1-carbonyl)-3- (trifluoromethyl)benzenesulfonamide(3 g, 52%) as an off yellow crystalline solid. LCMS (ESI) m / z = 477.7[M+H]+.1HNMR (400 MHz, DMSO-d6): δ 8.19 (d, J = 1.6 Hz, 1H), 7.86 (d, J = 1.2 Hz, 1H), 7.82 (s, 2H), 3.41 - 3.35 (m, 1H), 3.04 - 2.78 (m, 2H), 1.98 - 1.39 (m, 4H), 1.29 - 1.31 (m, 1H), 1.10 - 1.07 (m, 1H), 0.92 (br.s, 1H), 0.87 - 0.84 (m, 1H), 0.83 - 0.80 (m, 1H).

[0265] Synthesis of (S)-(1,1-dioxido-5-(trifluoromethyl)-2H- benzo[e][1,2]thiazin-7-yl)(3-methylpiperidin-1-yl)methanone (107)

[0266] To a stirred solution of 2-iodo-5-{[(S)-3-methyl-1-piperidyl]carbonyl}-3- (trifluoromethyl)benzenesulfonamide (0.5 g, 1.05 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was added dipotassium carbonate (261 mg, 1.89 mmol) and 2-[(E)-2-ethoxyethenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (250 mg, 1.26 mmol), purged with nitrogen gas for 5 min, followed by the addition of [1,1′- Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (85.7 mg, 0.105 mmol) and stirred at 90°C for 16 h. After completion of the reaction, the reaction mixture was filtered through celite bed and then filtrate was concentrated under vacuum to afford crude material, which was purified through silica gel flash column chromatography using 0-10% MeOH: DCM gradient (column size 24 g). The desired product eluted out in 8% MeOH:DCM gradient. The collected fractions were judged by TLC and the purefractions were combined together and evaporated under reduced vacuum to get (S)- (1,1-dioxido-5-(trifluoromethyl)-2H-benzo[e][1,2]thiazin-7-yl)(3- methylpiperidin-1-yl)methanone (350 mg, crude) as a dark brown colored gummy compound. LCMS (ESI) m / z = 375.0[M+H]+.

[0267] Synthesis of (S)-7-((3-methylpiperidin-1-yl)methyl)-5- (trifluoromethyl)-3,4-dihydro-2H-benzo[e][1,2]thiazine 1,1-dioxide (108)

[0268] To a stirred solution of 7-{[(S)-3-methyl-1-piperidyl]carbonyl}-5- (trifluoromethyl)-1λ⁶,2-benzothiazine-1,1(2H)-dione (250 mg, 0.668 mmol) in tetrahydrofuran (3 mL) was added (methylthio)methane—boron (1 / 1) (487 mg, 6.68 mmol) at 0 °C under nitrogen atmosphere and allowed to stir at 75 °C for 1 hour. After completion of the reaction, methanol was added to the reaction mixture dropwise at 0 °C till the effervescence ceases. The reaction mixture was concentrated under reduced vacuum to afford solid. Water (15 mL) was added to it and extracted with ethyl acetate (30 mL X 2). The combined organic extracts were washed with water (5 mL), brine solution (3 mL) and dried over anhydrous sodium sulfate, filtered and evaporated under reduced vacuum to get crude (S)-7-((3- methylpiperidin-1-yl)methyl)-5-(trifluoromethyl)-3,4-dihydro-2H- benzo[e][1,2]thiazine 1,1-dioxide (0.2 g, crude) as brown colored gummy compound. LCMS (ESI) m / z = 363.2[M+H]+.

[0269] 7-{[(S)-3-methyl-1-piperidyl]methyl}-2-(m-{3-[(4-methyl-4H-1,2,4- triazol-3-yl)methyl]-3-oxetanyl}phenyl)-5-(trifluoromethyl)-3,4-dihydro- 1λ⁶,2-benzothiazine-1,1(2H)-dione (Example 25)

[0270] To a stirred solution of 7-{[(S)-3-methyl-1-piperidyl]methyl}-5- (trifluoromethyl)-3,4-dihydro-1λ⁶,2-benzothiazine-1,1(2H)-dione (0.07 g, 0.193 mmol), 3-{[3-(m-iodophenyl)-3-oxetanyl]methyl}-4-methyl-4H-1,2,4-triazole (0.061 g, 0.174 mmol) in acetonitrile (3 mL, 57.4 mmol) was added dipotassium carbonate (0.187 g, 1.35 mmol) and was purged with nitrogen gas for 5 mins.1,2- bis(methylamino)ethane (0.027 mL, 0.251 mmol), copper iodide (0.012 g, 0.038 mmol) were added and was heated at 90°C for 16 h in a sealed tube. Progress of the reaction was monitored through TLC and LCMS. The reaction mixture was filtered through celite bed, quenched with ice cold water (5 mL), and extracted with ethyl acetate (2 X 50 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and evaporated over vacuum and concentrated to get crude product. The obtained crude product was once again purified through Prep HPLC [Column Name: X-Bridge-C18(250 mm x 19 mm x 5 µm), Mobile phase (A): 0.1%Ammonia in water, Mobile phase (B): ACN, Flow rate: 18 mL / min]. The pure fractions were evaporated off to obtain 7-{[(S)-3-methyl-1-piperidyl]methyl}- 2-(m-{3-[(4-methyl-4H-1,2,4-triazol-3-yl)methyl]-3-oxetanyl}phenyl)-5- (trifluoromethyl)-3,4-dihydro-1λ⁶,2-benzothiazine-1,1(2H)-dione (0.015 g, 13% yield) as an off white solid.1HNMR (400 MHz, DMSO-d6): δ 8.15 (s, 1H), 8.00 (s, 1H), 7.94 (s, 1H), 7.67 (s, 1H), 7.30 (d, J = 8Hz, 1H), 7.10 (d, J = 8Hz, 1H), 6.88 (d, J = 8Hz, 1H), 6.81 (s,1H), 4.89 (d, J = 4Hz, 2H), 4.77 (d, J = 8Hz, 2H), 3.12 (t, J = 8Hz, 2H ), 3.60 (s, 2H), 3.44 (s, 2H), 3.22 (t, J = 8Hz, 2H), 2.82 (s,3H), 2.67 (s, 2H ), 1.96 - 1.87 (m, 1H), 1.65 - 1.58 (m, 3H), 1.47 - 1.44 (m, 1H), 0.87 (s, 1H), 0.81(d, J = 4Hz, 3H). LCMS (ESI) m / z = 590.4[M+H]+

[0271] Synthesis of Example 26

[0272] 2-{m-[1,1-dimethyl-2-(4-methyl-4H-1,2,4-triazol-3-yl)ethyl]phenyl}-7- {[(S)-3-methyl-1-piperidyl]methyl}-5-(trifluoromethyl)-3,4-dihydro-1λ⁶,2- benzothiazine-1,1(2H)-dione(Example 26)

[0273] A stirred solution of 7-{[(S)-3-methyl-1-piperidyl]methyl}-5- (trifluoromethyl)-3,4-dihydro-1λ⁶,2-benzothiazine-1,1(2H)-dione (0.07 g, 0.193 mmol), 3-[2-(m-bromophenyl)-2-methylpropyl]-4-methyl-4H-1,2,4-triazole (0.051 g, 0.174 mmol) in acetonitrile (3 mL, 57.4 mmol) was purged with nitrogen gas for 5 mins. Potassium carbonate (0.187 g, 1.35 mmol), copper iodide (0.012 g, 0.038 mmol) and 1,2-bis(methylamino)ethane (0.027 mL, 0.251 mmol) were added and heated at 90°C for 16 h in a sealed tube. Progress of the reaction was monitored through TLC and LCMS. The reaction mixture was filtered through celite bed, quenched with ice cold water (5 mL), and extracted with ethyl acetate (2 X 50 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and evaporated over vacuum and concentrated to get crude product. The obtained crude product was once again purified through Prep HPLC [Column Name: BEH C18 (250 mm x 19 mm x 5 µm), Mobile phase (A): 0.1%Formic acid in water, Mobile phase (B): ACN, Flow rate: 18 mL / min].The pure fractions were evaporated off to obtain 2-{m-[1,1-dimethyl-2-(4-methyl-4H-1,2,4-triazol-3-yl)ethyl]phenyl}-7-{[(S)-3-methyl-1-piperidyl]methyl}-5- (trifluoromethyl)-3,4-dihydro-1λ⁶,2-benzothiazine-1,1(2H)-dione (0.006 g, 5% yield) as an off white solid. LCMS (ESI) m / z = 576.1 [M+H]+1HNMR (400 MHz, DMSO-d6): δ 8.18 (s, 1H), 8.01 (s, 1H), 7.96 (s, 1H), 7.30 (t, J = 8Hz, 1H), 7.21 (d, J = 8Hz, 1H), 7.06 (d, J = 8Hz, 2H), 4.15 (t, J = 4Hz, 2H ), 3.60 (s, 2H), 3.22 (t, J = 8Hz, 2H), 2.98 (s, 3H), 2.90 (s, 2H), 2.67 (s, 2H), 1.95 - 1.90 (m,1H), 1.65 - 1.57 (m, 4H), 1.35 (s, 6H ), 0.81 (d, J = 8Hz, 3H).

[0274] Synthesis of Example 27

[0275] Synthesis of 2-[3-methyl-3-(4-methyl-4H-1,2,4-triazol-3-yl)-5-indanyl]- 7-{[(S)-3-methyl-1-piperidyl]methyl}-5-(trifluoromethyl)-3,4-dihydro-1λ⁶,2- benzothiazine-1,1(2H)-dione (Example 27)

[0276] 7-{[(S)-3-methyl-1-piperidyl]methyl}-5-(trifluoromethyl)-3,4-dihydro- 1λ⁶,2-benzothiazine-1,1(2H)-dione (17.7 mg, 4.89 mmol) and 3-(6-bromo-1- methyl-1-indanyl)-4-methyl-4H-1,2,4-triazole (14.3 mg, 4.89 mmol) was dissolved in acetonitrile (2 mL) and purged with N2gas for 5 min, dipotassium carbonate (47.3 mg, 34.2 mmol), copper iodide (3.72 mg, 1.96 mmol) followed by 1,2- bis(methylamino)ethane (5.6 mg, 6.36 mmol) were added to the reaction mixture and heated at 90°C for 16 h. The progress of reaction was monitored by TLC and LCMS. After completion of starting material, the reaction mixture was diluted withwater and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to get crude compound. The crude was purified by prep HPLC [Column Name: X-SELECT-C18-CSH (250 mm x 19 mm x 5 µm), Mobile phase (A): 0.1%Ammonia in water, Mobile phase (B): ACN, Flow rate: 18 mL / min].The pure fraction was lyophilized to afford a 2- [3-methyl-3-(4-methyl-4H-1,2,4-triazol-3-yl)-5-indanyl]-7-{[(S)-3-methyl-1- piperidyl]methyl}-5-(trifluoromethyl)-3,4-dihydro-1λ⁶,2-benzothiazine-1,1(2H)- dione (4 mg, 14.2%) as an off white solid.1HNMR (400 MHz, DMSO-d6): δ 8.33 (s, 1H), 7.97 (s, 1H), 7.91 (s, 1H), 7.35 (d, 1H, J = 8 Hz), 7.13 (d, J = 8 Hz, 1H,), 6.76 (d, , J = 8 Hz, 1H), 4.13 (t, J = 6 Hz, 2H), 3.58(s, 2H), 3.23 (s, 3H), 3.10 (s, 3H), 3.07 - 3.02 (m, 2H), 2.65 (m, 2H), 2.46 (s, 1H), 2.17 - 2.11 (m, 1H), 1.92 (m, 1H), 1.67 - 1.63 (m, 7H), 1.45 (m, 1H), 0.81 (d, J = 4 Hz ,3H). LCMS (ESI) m / z = 574.1 [M+H]+

[0277] Synthesis of Example 28

[0278] Synthesis of 2-{5-[3-methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl]-3-pyridyl}-7-{[(S)-3-methyl-1-piperidyl]methyl}-5- (trifluoromethyl)-3,4-dihydro-1λ⁶,2-benzothiazine-1,1(2H)-dione (Example 28)

[0279] 7-{[(S)-3-methyl-1-piperidyl]methyl}-5-(trifluoromethyl)-3,4-dihydro- 1λ⁶,2-benzothiazine-1,1(2H)-dione (65.5 mg, 0.181 mmol) and 3-[1-(5-bromo-3- pyridyl)-3-methylcyclobutyl]-4-methyl-4H-1,2,4-triazole (38.9 mg, 0.127 mmol) were dissolved in acetonitrile (2 mL) and the reaction mixture was purged with N2 gas for 5 min. Potassium carbonate (175 mg, 1.27 mmol), copper iodide (11.5 mg, 0.036 mmol) followed by 1,2-bis(methylamino)ethane (0.039 mL, 0.036 mmol) were added to the reaction mixture and heated at 90°C for 16 h. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to get crude compound. The crude compound was purified by prep HPLC [Column Name: X-SELECT-C18-CSH (250 mm x 19 mm x 5 µm), Mobile phase (A): 0.1%Ammonia in water, Mobile phase (B): ACN, Flow rate: 18 mL / min]. The pure fraction was lyophilized to afford a 2-{5-[3-methyl-1-(4- methyl-4H-1,2,4-triazol-3-yl)cyclobutyl]-3-pyridyl}-7-{[(S)-3-methyl-1- piperidyl]methyl}-5-(trifluoromethyl)-3,4-dihydro-1λ⁶,2-benzothiazine-1,1(2H)- dione (10 mg, 9.4% yield) as an off white solid.1HNMR (400 MHz, DMSO-d6): δ 8.47 (d, 1H), 8.43 (d, 1H), 8.28 (s, 1H), 8.02 (s, 1H), 7.96 (s, 1H), 7.48 (s, 1H), 4.27 (m, 2H), 3.60 (s, 2H), 3.17 (s, 1H), 3.15 (s, 3H), 2.80 - 2.77 (m, 2H), 2.67 (m, 5H), 1.93 (m, 1H), 1.65 - 1.57 (m, 4H), 1.43 (m, 1H), 1.24 (s, 1H), 1.045 (d, J = 4Hz , 3H), 0.87 (m, 1H), 0.81 (d, J = 8Hz , 3H). LCMS (ESI) m / z = 589.1 [M+H]+

[0280] Synthesis of Example 29

[0281] Synthesis of (S)-2-(2-methyl-1-((4-methyl-4H-1,2,4-triazol-3- yl)methyl)-1H-indol-6-yl)-7-((3-methylpiperidin-1-yl)methyl)-5-(trifluoromethyl)-3,4-dihydro-2H-benzo[e][1,2]thiazine 1,1-dioxide (Example 29)

[0282] To a stirred solution of 7-{[(S)-3-methyl-1-piperidyl]methyl}-5- (trifluoromethyl)-3,4-dihydro-1λ⁶,2-benzothiazine-1,1(2H)-dione (50 mg, 0.138 mmol) in acetonitrile (5 mL, 95.7 mmol) was added dipotassium carbonate (133 mg, 0.966 mmol) and 3-[(6-bromo-2-methyl-1-indolyl)methyl]-4-methyl-4H- 1,2,4-triazole (42.1 mg, 0.138 mmol), degassed for 10 min, added 1,2- bis(methylamino)ethane (0.003 mL, 0.0276 mmol) and copper iodide (8.76 mg, 0.0276 mmol). The reaction mixture was heated at 90°C for 16 h. The progress of the reaction was monitored by TLC and LCMS. The reaction mixture was filtered over celite and the filtrate was concentrated under vacuum to obtain the crude material which was purified by silica gel flash column chromatography using 10% MeOH:DCM as the eluent to afford the product as a mixture. The obtained crude compound was further purified using Prep HPLC. [Column Name: X-SELECT- C18-CSH (250 mm x 19 mm x 5 µm), Mobile phase (A): 0.1%Ammonia in water, Mobile phase (B): ACN, Flow rate: 18 mL / min]. Pure fractions were collected and evaporated under vacuum to get (S)-2-(2-methyl-1-((4-methyl-4H-1,2,4-triazol-3- yl)methyl)-1H-indol-6-yl)-7-((3-methylpiperidin-1-yl)methyl)-5- (trifluoromethyl)-3,4-dihydro-2H-benzo[e][1,2]thiazine 1,1-dioxide as an off white solid (4 mg, 4%).1HNMR (400 MHz, DMSO-d6): δ 8.39 (s,1H), 8.01 (s,1H), 7.46 (s, 1H), 7.42 (d, J = 8Hz, 1H), 6.81 (d, J = 8Hz, 1H), 5.57 (s, 2H), 4.15 (t, J = 6Hz, 2H), 6.34 (s, 2H), 3.53 (s, 3H), 3.26 (t, J = 6Hz, 2H), 2.69 - 2.67 (m, 2H), 2.40 (s, 3H), 1.96 -1.9 (m, 1H), 1.66 -1.58(m, 4H), 1.48 -1.45 (m, 1H), 0.87 - 0.83 (m, 1H), 0.81 (d, J = 6Hz, 3H). LCMS (ESI) m / z = 587.1 [M+H]+

[0283] Synthesis of Example 30

[0284] Synthesis of (S)-2-(3-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)phenyl)-7-((3-methylpiperidin-1-yl)methyl)-5-(trifluoromethyl)- 3,4-dihydro-2H-benzo[e][1,2]thiazine 1,1-dioxide (Example 30)

[0285] A stirred solution of 7-{[(S)-3-methyl-1-piperidyl]methyl}-5- (trifluoromethyl)-3,4-dihydro-1λ⁶,2-benzothiazine-1,1(2H)-dione (65.5 mg, 0.181 mmol) and 3-[1-(m-bromophenyl)-3-methylcyclobutyl]-4-methyl-4H-1,2,4- triazole (38.7 mg, 0.127 mmol) in acetonitrile (2 mL) was degassed under nitrogen atmosphere for 5 minutes, followed by the addition of dipotassium carbonate (175 mg, 1.27 mmol), 1,2-bis(methylamino)ethane (0.039 mL, 0.361 mmol) and copper diiodide (11.5 mg, 0.036 mmol). The reaction mixture and was heated at 90°C for 16 h in a sealed tube. After completion of the reaction, the reaction mixture was filtered through celite bed. Ice cold water (10 mL) was added to the filtrate and extracted with ethyl acetate (2 X 20 mL).The Combined organic extracts were washed with brine solution (5 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced vacuum to afford crude compound, The crude material was purified through prep-purification[Column Name: X-SELECT-C18- CSH (250 mm x 19 mm x 5 µm), Mobile phase (A): 0.1%Ammonia in water, Mobile phase (B): ACN, Flow rate: 18 mL / min]. The pure fractions were collected, evaporated under reduced vacuum and lyophilized to obtain (S)-2-(3-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-7-((3-methylpiperidin-1- yl)methyl)-5-(trifluoromethyl)-3,4-dihydro-2H-benzo[e][1,2]thiazine 1,1-dioxide (5 mg, 5%) as a white solid.1HNMR (400 MHz, DMSO-d6): δ 8.25 (s, 1H), 8.01 (s, 1H), 7.95 (s, 1H), 7.43-7.39 (m, 1H), 7.23 (d, J = 8 Hz, 1H), 7.17 (d, J = 8 Hz, 1H), 7.11 (s, 1H), 4.22 (m, 2H), 3.59 (s, 2H), 3.23 (m, 3H), 3.10 (s, 3H), 2..67 (m, 4H), 1.93 (m, 1H), 1.65 - 1.57 (m, 5H), 1.47 (m, 1H), 1.24 (m, 1H), 1.03 (d, J = 8 Hz, 3H), 0.90 (m, 1H), 0.81 (d, J = 8 Hz, 3H). LCMS (ESI) m / z = 588.1 [M+H]+

[0286] Synthesis of Example 31 and 32

[0287] Synthesis of 6-{[(S)-3-methyl-1-piperidyl]methyl}-4-phenyl-2,3- dihydro-1H-1λ⁶,2-benzisothiazole-1,1-dione (110)

[0288] Argon gas was purged through a stirred suspension of 4-bromo-6-{[(S)-3- methyl-1-piperidyl]methyl}-2,3-dihydro-1H-1λ⁶,2-benzisothiazole-1,1-dione (0.4 g, 1.11 mmol), phenylboranediol (0.163 g, 1.34 mmol) and cesium fluoride (0.338 g, 2.23 mmol) in 1,4-dioxane (2.0 mL) for 5 minutes. PdCl2(dppf).DCM (0.09 g, 0.0111 mmol) was added to the reaction mixture and stirred at 100 °C for 16 h in a sealed tube. Progress of the reaction was monitored through TLC. After completion of starting material, reaction mixture was extracted with ethyl acetate (2* 25 mL), and water (20 ml). The combined organic layer was dried over sodium sulfate, filtered and dried under vacuum to afford crude compound which was purified bysilica gel flash column chromatography (using gradient elution 35-40% EtOAc in heptane). The fractions were evaporated off to afford 6-{[(S)-3-methyl-1- piperidyl]methyl}-4-phenyl-2,3-dihydro-1H-1λ⁶,2-benzisothiazole-1,1-dione (0.250 g, crude) as a brown colour liquid. LCMS (ESI) m / z = 357.0 [M+H]+

[0289] Synthesis of (S)-2-(3-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl) phenyl)-6-((3-methylpiperidin-1-yl)methyl)-4-phenyl-2,3- dihydrobenzo[d]isothiazole 1,1-dioxide

[0290] To a stirred solution of 6-{[(S)-3-methyl-1-piperidyl]methyl}-4-phenyl- 2,3-dihydro-1H-1λ⁶,2-benzisothiazole-1,1-dione (55 mg, 0.154 mmol) and 3-[1- (m-bromophenyl)-3-methylcyclobutyl]-4-methyl-4H-1,2,4-triazole (42.5 mg, 0.139 mmol) in acetonitrile (2 mL, 38.3 mmol) was added dipotassium carbonate (149 mg, 1.08 mmol) and purged with nitrogen gas for 5 mins. Copper iodide (19.6 mg, 0.62 mmol) was added followed by the addition of 1,2-bis(methylamino)ethane (0.02 mL, 0.201 µmol). The reaction mixture was heated to 85°C and stirred for 16 h in a sealed tube. Progress of the reaction was monitored through TLC and LCMS. The reaction mixture was filtered through celite bed, quenched with ice-cold water (10 mL), and extracted with ethyl acetate (2 X 10 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and evaporated under reduced vacuum to afford crude compound which was purified by Prep- HPLC[Column Name: X-Bridge C18(250 mm x 19 mm x 5 µm), Mobile phase (A): 0.1%Ammonia in water, Mobile phase (B): ACN, Flow rate: 18 mL / min]. The pure fractions were collected and lyophilized to obtain Isomer-1 (Major peak) 2-{m- [(1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl]phenyl}-6-{[(S)-3-methyl-1-piperidyl]methyl}-4-phenyl-2,3-dihydro-1H-1λ⁶,2-benzisothiazole- 1,1-dione (Example 31, 10 mg, 11.1%) as a white solid.

[0291] 1HNMR (400 MHz, DMSO-d6): δ 8.28 (s, 1H), 7.84 (s, 1H), 7.70 (s, 1H), 7.64 (d, J = 7.2 Hz, 2H), 7.56–7.41 (m, 5H), 7.32 (d, J = 8.0 Hz, 1H), 7.14 (d, J = 7.6 Hz, 1H), 5.08 (s, 2H), 3.65 (s, 2H), 3.19 (s, 3H), 2.82-2.73 (m, 4H), 2.57 - 2.50 (m, 3H), 1.94 (t, J = 10.8 Hz, 1H), 1.69 - 1.58 (m, 4H), 1.49 -1.46 ((m, 1H), 1.07 (d, J = 5.2 Hz, 3H), 0.87-0.81 (m, 4H). LCMS (ESI) m / z = 582.5 [M+H]+

[0292] Isomer-2 (minor peak) 2-{m-[(1r,3S)-3-methyl-1-(4-methyl-4H-1,2,4- triazol-3-yl)cyclobutyl]phenyl}-6-{[(S)-3-methyl-1-piperidyl]methyl}-4- phenyl-2,3-dihydro-1H-1λ⁶,2-benzisothiazole-1,1-dione (Example 32, 4 mg, 4.5%) as a white solid.1HNMR (400 MHz, DMSO-d6): δ 8.35 (s, 1H), 7.84 (s, 1H), 7.70 (s, 1H), 7.64 (d, J = 7.2 Hz, 2H), 7.56 – 7.38 (m, 4H), 7.32 - 7.27 (m, 2H), 6.97 (d, J = 7.6 Hz, 1H), 5.08 (s, 2H), 3.65 (s, 2H), 3.23 (s, 3H), 3.13 - 3.09 (m, 2H), 2.77 - 2.73 (m, 2H), 2.27 - 2.33 (m, 1H), 2.24 - 2.19 (m, 2H), 1.94 (t, J = 10.8 Hz, 1H), 1.69 - 1.52 (m, 4H), 1.48 - 1.46 ((m, 1H), 1.09 (d, J = 6.8 Hz, 3H), 0.87 - 0.81 (m, 4H). LCMS (ESI) m / z = 582.5 [M+H]+

[0293] Synthesis of Example 33 and 34

[0294] Synthesis of (S)-2-(5-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)pyridin-3-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-phenyl-2,3- dihydrobenzo[d]isothiazole 1,1-dioxide (Example 33 & 34)

[0295] To a stirred solution of 6-{[(S)-3-methyl-1-piperidyl]methyl}-4-phenyl- 2,3-dihydro-1H-1λ⁶,2-benzisothiazole-1,1-dione (65 mg, 0.182 mmol) and 3-[1-(5- bromo-3-pyridyl)-3-methylcyclobutyl]-4-methyl-4H-1,2,4-triazole (50.4 mg, 0.164 mmol) in acetonitrile (5 mL) was added potassium carbonate (176 mg, 1.28 mmol) and was purged with nitrogen gas for 5 mins. Copper diiodide (23.1 mg, 0.07 mmol) was added followed by 1,2-bis(methylamino)ethane (39.4 µL, 0.037 mmol) was added to the reaction mixture and was heated at 85°C for 16 h in a sealed tube. Progress of the reaction was monitored through TLC and LCMS. The reaction mixture was filtered through celite bed, quenched with ice-cold water (10 mL), and extracted with ethyl acetate (2 X 10 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and evaporated under reduced vacuum to afford crude compound, which was purified by Prep- HPLC[Column Name: Atlantis C18 (250 mm x 19 mm x 5 µm), Mobile phase (A): 0.1%Ammonia in water, Mobile phase (B): ACN, Flow rate: 18 mL / min]. Pure fractions were evaporated off to obtain Isomer-01-(S)-2-(5-(3-methyl-1-(4-methyl- 4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-3-yl)-6-((3-methylpiperidin-1- yl)methyl)-4-phenyl-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (20 mg, 19% yield) as a white solid.1HNMR (400 MHz, DMSO-d6): δ 8.59 (d, J = 2 Hz, 1H), 8.43 (d, J = 2 Hz, 1H), 8.32 (s, 1H), 7.88 (s, 1H), 7.77 – 7.72 (m, 2H), 7.65 - 7.63 (m, 2H), 7.5 – 7.49 (m, 3H), 5.21 (s, 2H), 3.65 (s, 2 H), 3.22 (s, 3H), 2.90 - 2.88 (m, 2H), 2.75 (m, 2H), 2.67 - 2.57 (m, 3H), 1.95 (m, 1H), 1.66 - 1.58 (m, 4H), 1.49 (m, 1H), 1.09 - 1.07 (d, J = 5.6 Hz, 3H), 0.87 (m,1H), 0.83 - 0.81 (d, J = 6 Hz, 3H). LCMS (ESI) m / z = 583.5 [M+H]+Isomer-02-(S)-2-(5-(3-methyl-1-(4-methyl-4H- 1,2,4-triazol-3-yl)cyclobutyl)pyridin-3-yl)-6-((3-methylpiperidin-1-yl)methyl)-4- phenyl-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (3 mg, 3% yield) as a whitesolid.1HNMR (400 MHz, DMSO-d6): δ 8.56 (d, J = 2 Hz, 1H), 8.40 (d, J = 2 Hz, 1H), 8.27 (s, 1H), 7.87 (s, 1H), 7.72 (s, 1H), 7.65 - 7.63 (m, 3H), 7.5 – 7.49 (m, 3H), 5.2 (s, 2H), 3.65 (s, 2 H), 3.26 (s, 3H), 3.17 - 3.13 (m, 2H), 2.74 (m, 2H), 2.39 - 2.27 (m, 3H), 1.97 - 1.92 (m, 1H), 1.66 - 1.56 (m, 5H), 1.11 - 1.09 (d, J = 6.4 Hz, 3H), 0.87 (m, 1H), 0.83 - 0.81 (d, J = 6 Hz, 3H). LCMS (ESI) m / z = 583.5 [M+H]+

[0296] Synthesis of Example 35

[0297] Synthesis of 2-{m-[1,1-dimethyl-2-(4-methyl-4H-1,2,4-triazol-3- yl)ethyl]phenyl}-6-{[(S)-3-methyl-1-piperidyl]methyl}-4-phenyl-2,3-dihydro- 1H-1λ⁶,2-benzisothiazole-1,1-dione: To a stirred solution of 6-{[(S)-3-methyl-1- piperidyl]methyl}-4-phenyl-2,3-dihydro-1H-1λ⁶,2-benzisothiazole-1,1-dione (60 mg, 0.168 mmol), 3-[2-(m-bromophenyl)-2-methylpropyl]-4-methyl-4H-1,2,4- triazole (47 mg, 0.16 mmol) in acetonitrile (3 mL) was added DMEDA (1.81 µL, 0.02 mmol), potassium carbonate (163 mg, 1.18 mmol) and was purged with nitrogen gas for 5 mins. Copper iodide (12.8 mg, 0.067 mmol) was added and was heated at 90°C for 16 h in a sealed tube. Progress of the reaction was monitored through TLC and LCMS. The reaction mixture was filtered through celite bed, quenched with ice cold water (5 mL), and extracted with ethyl acetate (2 X 50 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and evaporated over vacuum and concentrated to get crude product. The crude was purified through silica gel flash column chromatography using DCM and MeOH as Eluents (5%) to obtain product. The obtained product was once again purified through Prep HPLC[Column Name: BEH C18(250 mm x 19 mm x 5 µm), Mobile phase (A): 0.1%Ammonia in water, Mobile phase (B): ACN, Flow rate: 18mL / min]. Pure fractions were evaporated off to obtain 2-{m-[1,1-dimethyl-2-(4- methyl-4H-1,2,4-triazol-3-yl)ethyl]phenyl}-6-{[(S)-3-methyl-1- piperidyl]methyl}-4-phenyl-2,3-dihydro-1H-1λ⁶,2-benzisothiazole-1,1-dione (20 mg, 21%) as an off white solid.1HNMR (400 MHz, DMSO-d6): δ 8.19 (s, 1H), 7.84 (s, 1H), 7.70 (s, 1H), 7.66 (d, J = 7.2 Hz, 2H), 7.57 - 7.53 (m, 2H), 7.50 - 7.49 (m, 1H), 7.40 (s, 1H), 7.34 (d, J = 4.4 Hz, 2H), 7.13 (s, 1H), 5.04 (s, 2H ), 3.65 (s, 2H ), 3.08 (s, 3H), 2.97 (s, 3H), 2.75 - 2.67 (t, J = 8 Hz, 1H), 1.92 (t, J = 5.2 Hz, 1H), 1.67 - 1.59 (m, 4H), 1.50 (s, 1H), 1.42 (s, 6H), 0.87 ( s, 1H), 0.82 (d, J = 6Hz, 3H). LCMS (ESI) m / z = 570.48 [M+H]+

[0298] Synthesis of Example 36 & 37

[0299] Synthesis of 3-chloro-2-methylbenzenesulfonamide (112)

[0300] A stirred solution of 3-chloro-2-methylbenzenesulfonyl chloride (5 g, 22.2 mmol) in tetrahydrofuran (50 mL) was cooled to 0°C and NH3gas was purged for 10 min at 0°C. The progress of the reaction was monitored through TLC. Aftercompletion of the reaction, the reaction mixture was poured to crushed ice and extracted with ethyl acetate (150 mL X 2). The combined organic extracts were washed with brine solution (10 mL), dried over anhydrous sodium sulphate, filtered and evaporated under reduced vacuum to afford crude material 3-chloro-2- methylbenzenesulfonamide (4.1 g, crude) which was taken to the next step without any further purification.1HNMR (400 MHz, DMSO-d6): δ 7.8 (d, J = 8.0 Hz, 1H), 7.6 (d, J = 8.0 Hz, 1H), 7.3 (t, J = 7.6 Hz, 1H), 2.6 (s, 3H). LCMS (ESI) m / z = 204 [M-H]+

[0301] Synthesis of 5-bromo-3-chloro-2-methylbenzenesulfonamide (113)

[0302] A stirred solution of 3-chloro-2-methylbenzenesulfonamide (1 g, 4.86 mmol) in sulphuric acid (8 mL) was heated to 40°C.1-bromo-2,5-pyrrolidinedione (0.779 g, 4.38 mmol) was added to it at 40°C was continued for 2h. Progress of the reaction was monitored through TLC. The reaction mixture was quenched with ice cold water (10 mL), and extracted with ethyl acetate (2 X 100 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and evaporated over vacuum to get crude material which was purified by silica gel flash column chromatography using 30% EA / Hex as the eluent to afford 5-bromo- 3-chloro-2-methylbenzenesulfonamide (0.520 g, 37.57 %) as an off white solid.1HNMR (400 MHz, DMSO-d6): δ 8.01 (d, J = 1.6 Hz, 1H), 7.97 (d, J = 1.6 Hz, 1H), 7.77 (s, 2H), 2.57 (s, 3H). LCMS (ESI) m / z = 281.8 [M-H]+

[0303] Synthesis of 6-bromo-4-chlorobenzo[d]isothiazol-3(2H)-one 1,1-dioxide (114)

[0304] To a stirred solution of 5-bromo-3-chloro-2-methylbenzenesulfonamide (0.4 g, 1.41 mmol) in acetonitrile (11.8 mL) was added periodic acid (2.56 g, 11.2 mmol) and chromium trioxide (14.1 mg, 0.141 mmol) and was heated to 80°C for 16 h. After completion of the reaction, the reaction mixture was quenched with isopropanol (5 mL) and heated for 15 mins, then reaction mixture was filtered through celite bed and the filtrate was evaporated under vacuum. Water was added to it which resulted in the formation of precipitates which was filtered and dried over vacuum to get the product 6-bromo-4-chlorobenzo[d]isothiazol-3(2H)-one 1, 1-dioxide (0.2 g, 47.98 %) as an off white solid.1HNMR (400 MHz, DMSO-d6): δ 8.34 (s, 1H), 8.12 (s, 1H). LCMS (ESI) m / z = 293.9 [M-H]+

[0305] Synthesis of 6-bromo-4-chloro-2, 3-dihydrobenzo[d]isothiazole 1, 1- dioxide(115)

[0306] 6-bromo-4-chlorobenzo[d]isothiazol-3(2H)-one 1,1-dioxide (0.3 g, 1.01 mmol) was dissolved in tetrahydrofuran (10 mL) and cooled to 0°C. (methylthio)methane—boron (1 / 1) (7.5 mL, 82.2 mmol) was added at 0°C and heated at 75°C for 16h under inert atmosphere. Progress of the reaction monitored through TLC and LCMS. The reaction mixture was quenched with dilute HCL dropwise over 30 minutes till all the effervescence ceased out. The crude was quenched with water and extracted with ethyl acetate (100 mL) and washed with brine solution (5 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated under vacuum to get crude product. The crude compoundwas purified through silica gel flash column chromatography using 4g column as EtOAc / Heptane as eluents (17%) to get product 6-bromo-4-chloro-2, 3- dihydrobenzo[d]isothiazole 1, 1-dioxide (0.1 g, 69.97 %) as an off white solid.1HNMR (400 MHz, DMSO-d6): δ 8.2 (s, 1H), 8.11 (d, J =1.2 Hz, 1H), 4.52 (d, J=4.8 Hz, 2H). LCMS (ESI) m / z = 281.9 [M-H]+

[0307] Synthesis of (S)-4-chloro-6-((3-methylpiperidin-1-yl)methyl)-2,3- dihydrobenzo [d]isothiazole 1,1-dioxide (116)

[0308] 6-bromo-4-chloro-2, 3-dihydrobenzo[d]isothiazole 1, 1-dioxide (0.1 g, 0.354 mmol), (S)-3-methyl-1-((trifluoro-l4-boraneyl) methyl) piperidine, potassium salt (1 / 1) (0.233 g, 1.06 mmol) dissolved in 1, 4-dioxane (5 mL), water (1 mL) was purged with Nitrogen gas. Cesium carbonate (0.346 g, 1.06 mmol), XPhos Pd G2 (0.014 g, 0.0177 mmol) and dicyclohexyl(2',4',6'-triisopropyl-2- biphenylyl)phosphine (0.017 g, 0.035 mmol) were added and heated at 100°C for 16h. Progress of the reaction was monitored through TLC. The reaction mixture was quenched with ice cold water (20 mL), and extracted with ethyl acetate (2 X 50 mL). The combined organic layers were washed with brine (5 mL), dried over sodium sulphate, filtered and evaporated over vacuum and concentrated to get crude compound. The crude was purified by silica gel flash column chromatography. The compound eluted out in 15% -20% Ethyl acetate :Hexane. The pure fractions were evaporated and concentrated to get (S)-4-chloro-6-((3-methylpiperidin-1- yl)methyl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (0.050 g, 44.87 %) as an off white solid.1HNMR (400 MHz, DMSO-d6): δ 8.04 (s, 1H), 7.70 (s, 1H), 4.35 (d, J= 4 Hz, 2H), 3.55 (s, 1H), 2.68 (m, 2H), 1.99 – 1.88 (m, 1H), 1.62 - 1.58 (m,5H), 1.24 (d, J= 28 Hz, 2H), 0.83(d, J= 12 Hz, 2H), 0.81 (d, J = 6 Hz, 3H). LCMS (ESI) m / z = 315.1 [M+H]+

[0309] Synthesis of 4-chloro-2-(5-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl) cyclobutyl)pyridin-3-yl)-6-(((S)-3-methylpiperidin-1-yl)methyl)-2,3- dihydrobenzo[d]isothiazole 1,1-dioxide (Example 36 & 37)

[0310] To a stirred solution of (S)-4-chloro-6-((3-methylpiperidin-1-yl)methyl)- 2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (0.050 g, 0.159 mmol), 3-[1-(5-bromo- 3-pyridyl)-3-methylcyclobutyl]-4-methyl-4H-1,2,4-triazole (0.044 g, 0.143 mmol) in acetonitrile (3 mL) was added dipotassium carbonate (0.110 g, 0.794 mmol) and was purged with nitrogen gas for 5 mins. Copper iodide (0.012 g, 0.0635 mmol) followed by 1,2-bis(methyl amino)ethane (0.22.2 mL, 0.206 mmol) was added to the reaction mixture and was heated at 90°C for 16 h in a sealed tube. Progress of the reaction was monitored through TLC and LCMS. The reaction mixture was filtered through celite bed, quenched with ice cold water (10 mL), and extracted with ethyl acetate (2 X 10 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulphate, filtered and evaporated under reduced vacuum to afford crude compound, which was purified by Prep-HPLC [Column Name: X-SELECT-C18-CSH (250 mm x 19 mm x 5 µm), Mobile phase (A): 0.1%Ammonia in water, Mobile phase (B): ACN, Flow rate: 18 mL / min]. Pure fractions were evaporated off to obtain 4-chloro-2-(5-(3-methyl-1-(4-methyl-4H- 1,2,4-triazol-3-yl)cyclobutyl)pyridin-3-yl)-6-(((S)-3-methylpiperidin-1- yl)methyl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (0.05 g, 5.82 %) as an off white solid. Isomer-01:1HNMR (400 MHz, DMSO-d6): δ 8.66 (d, J = 2 Hz, 1H),8.42 (s, 1H), 8.33 (s, 1H), 7.90 (s, 1H), 7.85 (s, 1H), 7.80 (s, 1H), 5.17 (s, 2H), 3.60 (s, 2H), 3.24 (s, 3H), 2.93 (d, J = 3.6 Hz, 2H), 2.70 (t, J = 7.2 Hz, 2H), 2.60 (d, J = 40.4 Hz, 3H), 1.93 – 1.89 (m, 1H), 1.67 - 1.43 (m, 6H), 1.10 (d, J = 5.2 Hz, 3H), 0.90 - 0.81 (m, 3H). LCMS (ESI) m / z =541.3[M+H]+. Isomer-02: 4-chloro-2-(5- (3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-3-yl)-6-(((S)-3- methylpiperidin-1-yl)methyl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (0.002 g, 2.33 %) as an off-white solid.1HNMR (400 MHz, DMSO-d6): δ 8.62 (d, J = 2 Hz, 1H), 8.40 (s, 1H), 8.26 (s, 1H), 7.90 (s, 1H), 7.85 (s, 1H), 7.65 (s, 1H), 5.16 (s, 2H), 3.60 (s, 2H), 3.27 (s, 3H), 3.18 -3.14 (m, 2H), 2.96 (s, 1H), 2.70 – 2.68 (m, 3H), 2.40- 2.30 (m, 4H), 1.95 – 1.93 (m, 1H), 1.67 - 1.46 (m, 3H), 1.12 (d, J = 6 Hz, 3H), 0.91 - 0.82 (m, 3H). LCMS (ESI) m / z = 541.3[M+H]+

[0311] Synthesis of Example 38

[0312] Synthesis of (S)-4-chloro-2-(3-(3-methyl-1-(4-methyl-4H-1, 2, 4-triazol- 3-yl) cyclobutyl)phenyl)-6-((3-methylpiperidin-1-yl)methyl)-2,3- dihydrobenzo[d] isothiazole 1, 1-dioxide (Example 38)

[0313] To a stirred solution of (S)-4-chloro-6-((3-methylpiperidin-1-yl)methyl)- 2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (0.040 g, 0.127 mmol), 3-[1-(m-bromophenyl)-3-methylcyclobutyl]-4-methyl-4H-1,2,4-triazole (0.117 g, 0.381 mmol) in acetonitrile (2.5 mL) was added potassium carbonate (0.88 g, 0.635 mmol) and was purged with nitrogen gas for 5 mins. Copper iodide (0.010 g, 0.0508 mmol) followed by 1,2-bis(methylamino)ethane (0.018 mL, 0.165 mmol) was added to the reaction mixture and was heated at 90°C for 16 h in a sealed tube. Progress of the reaction was monitored through TLC and LCMS. The reaction mixture was filtered through celite bed, quenched with ice cold water (20 mL), and extracted with ethyl acetate (2 X 20 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulphate, filtered and evaporated under reduced vacuum to afford crude compound, which was purified by Prep-HPLC [Column Name: X-Bridge C18 (250 mm x 19 mm x 5 µm), Mobile phase (A): 0.1%Ammonia in water, Mobile phase (B): ACN, Flow rate: 18 mL / min]. Pure fractions were evaporated off to obtain (S)-4-chloro-2-(3-(3- methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-6-((3- methylpiperidin-1-yl)methyl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (0.002 mg, 2.91 %) as an off-white solid.1HNMR (400 MHz, DMSO-d6): δ 8.29 (s, 1H), 7.84 (d, J = 15.2 Hz, 2H), 7.47-7.39 (m, 3H), 7.14 (d, J= 7.6 Hz,1H), 5.07 (s, 2H), 3.59 (s, 2H),3.20 (s, 3H), 2.85 (s, 2H), 2.70 (t, J = 8 Hz, 3H), 2.56 (d, J= 7.2 Hz, 3H), 1.93 (d, J = 10.4 Hz,1H), 1.67 - 1.58 (m, 4H), 1.49 (d, J = 7.6 Hz, 1H), 1.09 (d, J= 5.2 Hz, 3H), 0.83 (d, J= 6 Hz, 3H). LCMS (ESI) m / z = 540.1[M+H]+

[0314] Synthesis of Example 39

[0315] Synthesis of (S)-4-chloro-2-(3-(3-((4-methyl-4H-1,2,4-triazol-3- yl)methyl)oxetan-3-yl)phenyl)-6-((3-methylpiperidin-1-yl)methyl)-2,3- dihydrobenzo[d]isothiazole 1,1-dioxide (Example 39) :To a stirred solutionof (S)-4-chloro-6-((3-methylpiperidin-1-yl)methyl)-2,3- dihydrobenzo[d]isothiazole 1,1-dioxide (25 mg, 0.79 mmol) and 3-((3-(3- bromophenyl)oxetan-3-yl)methyl)-4-methyl-4H-1,2,4-triazole (22 mg, 0.71 mmol) in acetonitrile (3.5 mL) was added potassium carbonate (76.8 mg, 0.55 mmol) and was purged with nitrogen gas for 5 mins. N,N'-Dimethyl ethylenediamine (9.1 mg, 0.10 mmol) and copper iodide (6.05 mg, 0.03 mmol) were added and was heated at 90°C for 16 h in a sealed tube. Progress of the reaction was monitored through TLC and LCMS. The reaction mixture was filtered through celite bed, quenched with ice cold water (5 mL), and extracted with ethyl acetate (2 X 50 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and evaporated over vacuum to get crude product and submitted for prep purification[Column Name: X-SELECT-C18-CSH (250 mm x 19 mm x 5 µm), Mobile phase (A): 0.1%Ammonia in water, Mobile phase (B): ACN, Flow rate: 18 mL / min].Pure fractions were collected and concentrated to afford pure (S)-4-chloro-2-(3-(3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan- 3-yl)phenyl)-6-((3-methylpiperidin-1-yl)methyl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (7.0 mg, 16.2%) as an off-white solid.1HNMR (400 MHz, DMSO-d6): δ 8.18 (s, 1H), 7.87 (s, 1H), 7.83(s, 1H), 7.44 (d, J = 7.2 Hz, 1H), 7.36 (t, J = 8.0 Hz, 1H), 7.01 (s, 1H), 6.77 (d, J = 7.2 Hz, 1H), 4.96 (m, 4H), 4.88 (d, J = 6.0 Hz, 2H), 3.59 (s, 2H), 3.50 (s, 2H), 2.89 (s, 3H), 2.69 (m, 2H), 1.93 (m, 1H), 1.64 (m, 4H), 1.49(m, 1H), 0.83 (m, 4H). LCMS (ESI) m / z = 542.0[M+H]+

[0316] Synthesis of Example 40

[0317] Synthesis of (S)-4-chloro-2-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol- 3-yl)propan-2-yl)phenyl)-6-((3-methylpiperidin-1-yl)methyl)-2,3- dihydrobenzo[d]isothiazole 1,1-dioxide (Example 40)

[0318] To a stirred solution of (S)-4-chloro-6-((3-methylpiperidin-1-yl)methyl)- 2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (35.0 mg, 0.11 mmol) and 3-(2-(3- bromophenyl)-2-methylpropyl)-4-methyl-4H-1,2,4-triazole (29.4 mg, 0.1 mmol) in acetonitrile (4.0 mL) was added dipotassium carbonate (108.0 mg, 0.77 mmol) and was purged with nitrogen gas for 5 mins. N,N'-Dimethyl ethylenediamine (12.7 mg, 0.14 mmol) and copper iodide (8.47 mg, 0.44 mmol) were added and was heated at 90°C for 16 h in a sealed tube. Progress of the reaction was monitored through TLC and LCMS. The reaction mixture was filtered through celite bed, quenched with ice cold water (5.0 mL), and extracted with ethyl acetate (2 X 50 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and evaporated over vacuum to get crude product and submitted for prep purification. [Column Name: X-SELECT-C18-CSH (250 mm x 19 mm x 5 µm), Mobile phase (A): 0.1%Ammonia in water, Mobile phase (B): ACN, Flow rate: 18 mL / min]. Pure fractions were collected and concentrated to afford pure (S)-4- chloro-2-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-6- ((3-methylpiperidin-1-yl)methyl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (3.3 mg, 5.6%) as an off-white solid.1HNMR (400 MHz, DMSO-d6): δ 8.21 (s, 1H), 7.87 (s, 1H), 7.83 (s, 1H), 7.42-7.34 (s, 3H), 7.15 (d, J = 8.0 Hz , 1H), 5.02 (s, 2H), 3.60 (s, 2H), 3.11 (s, 4H), 3.01 (s, 2H), 2.71 (m, 2H), 1.93(m , 1H), 1.67-1.59 (m, 6H), 1.45 (s, 6H), 0.83 (m, 4H). LCMS (ESI) m / z = 528.1[M+H]+

[0319] Synthesis of Example 41

[0320] Synthesis of (S)-4-chloro-2-(2-methyl-1-((4-methyl-4H-1,2,4-triazol-3- yl)methyl)-1H-indol-6-yl)-6-((3-methylpiperidin-1-yl)methyl)-2,3- dihydrobenzo[d]isothiazole 1,1-dioxide (Example 41)

[0321] A stirred solution of 4-chloro-6-{[(S)-3-methyl-1-piperidyl]methyl}-2,3- dihydro-1H-1λ⁶,2-benzisothiazole-1,1-dione (50 mg, 0.159 mmol) and 3-[(6- bromo-2-methyl-1-indolyl)methyl]-4-methyl-4H-1,2,4-triazole (43.6 mg, 0.143 mmol) in acetonitrile (2 mL) was degassed under nitrogen atmosphere for 5 minutes, followed by the addition of dipotassium carbonate (154 mg, 1.11 mmol), 1,2-bis(methylamino)ethane (0.22 mL,0.206 mmol) and copper iodide (12.1 mg, 0.063 mmol). The reaction mixture and was heated at 90°C for 16 h in a sealed tube. After completion of the reaction, the reaction mixture was filtered through celite bed. The filtrate was treated with ice cold water (10 mL) and extracted with ethyl acetate (2 X 20 mL). The combined organic extracts were washed with brine solution (5 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced vacuum to afford crude compound. The crude material was purified through prep-purification [Column Name: X-SELECT-C18-CSH (250 mm x 19 mm x 5 µm), Mobile phase (A): 0.1%Ammonia in water, Mobile phase (B): ACN, Flow rate: 18 mL / min].The pure fractions were evaporated under reduced vacuum and lyophilized to get (S)-4-chloro-2-(2-methyl-1-((4-methyl-4H-1,2,4-triazol-3- yl)methyl)-1H-indol-6-yl)-6-((3-methylpiperidin-1-yl)methyl)-2,3- dihydrobenzo[d]isothiazole 1,1-dioxide (9 mg, 10.51%) as a white solid.1HNMR (400 MHz, DMSO-d6): δ 8.42 (s, 1H), 7.85 (s, 1H), 7.81 (s, 1H), 7.66 (s, 1H), 7.53 (d, J = 8 Hz, 1H), 7.25 (d, J = 12 Hz, 1H), 6.33 (s, 1H), 5.62 (s, 2H), 4.99 (s, 2H), 3.60 (s, 2H), 3.57 (s, 3H), 2.74 - 2.67 (m, 2H), 2.40 (s, 3H), 1.96 - 1.91 (m, 1H),1.67 - 1.53 (m, 4H), 1.50 - 1.47 (m, 1H), 0.87 (br.s, 1H) 0.82 (d, J = 4 Hz, 3H). LCMS (ESI) m / z = 539.0[M+H]+

[0322] Synthesis of Example 42

[0323] Synthesis of 4-chloro-2-[3-methyl-3-(4-methyl-4H-1,2,4-triazol-3-yl)-5- indanyl]-6-{[(S)-3-methyl-1-piperidyl]methyl}-2,3-dihydro-1H-1λ⁶,2- benzisothiazole-1,1-dione (3)

[0324] A stirred solution of 4-chloro-6-{[(S)-3-methyl-1-piperidyl]methyl}-2,3- dihydro-1H-1λ⁶,2-benzisothiazole-1,1-dione (44 mg, 0.14 mmol) and 3-(6-bromo- 1-methyl-1-indanyl)-4-methyl-4H-1,2,4-triazole (40.8 mg, 0.140 mmol) in acetonitrile (2 mL) was purged with N2 gas for 5 min. dipotassium carbonate (135 mg, 0.98 mmol), copper iodide (10.6 mg, 0.56 mmol) followed by 1,2- bis(methylamino)ethane (16 mg, 0.19 mmol) were added to it. The reaction mixture was stirred at 95°C for 16 h. The progress of reaction was monitored by TLC and LCMS. After completion of starting material, reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to get crude compound which was purified by prep HPLC[Column Name: Xtimate C18 (250 mm x 19 mm x 5 µm), Mobile phase (A): 0.1%Ammonia in water, Mobile phase (B): ACN, Flowrate: 18 mL / min]. The pure fractions were lyophilized to afford a 4-chloro-2-[3- methyl-3-(4-methyl-4H-1,2,4-triazol-3-yl)-5-indanyl]-6-{[(S)-3-methyl-1- piperidyl]methyl}-2,3-dihydro-1H-1λ⁶,2-benzisothiazole-1,1-dione (4 mg, 5 %) as an off white solid.1HNMR (400 MHz, DMSO-d6): δ 8.39 (s, 1H), 7.81 (d, 2H, J =1.2 Hz), 7.42 (s, 2H), 7.08 (s, 1H), 5.0 (s, 2H), 3.58 (s, 2H), 3.17 (s, 3H), 3.14 - 3.06 (m, 2H), 2.72 - 2.66 (m, 3H), 2.20 - 2.15 (m, 1H), 1.94 - 1.89 (m, 1H), 1.72 (s, 3H), 1.61 - 1.57 (m, 4H), 1.48 - 1.45 (m, 1H), 0.86 - 0.81 (m, 4H). LCMS (ESI) m / z = 526.0[M+H]+

[0325] Synthesis of Example 43

[0326] 4-chloro-2-(3-(1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)- 6-(((S)-3-methylpiperidin-1-yl)methyl)-2,3-dihydrobenzo[d]isothiazole 1,1- dioxide (Example 43)

[0327] To a stirred solution of (S)-4-chloro-6-((3-methylpiperidin-1-yl)methyl)- 2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (0.05 g, 0.159 mmol) and 3-(2-(3- bromophenyl)propyl)-4-methyl-4H-1,2,4-triazole (0.044 g, 0.159 mmol) in acetonitrile (2 mL) was added dipotassium carbonate (0.15 g, 1.11 mmol) and was purged with nitrogen gas for 5 minutes. 1,2-bis(methylamino)ethane (0.022 mL, 0.20 mmol) followed by copper iodide (0.012 g, 0.63 mmol) were added to thereaction mixture and heated to 90 °C for 16 h. Progress of the reaction was monitored through TLC and LCMS. After completion of the reaction, the reaction mixture was filtered through celite bed. The filtrate was quenched with ice cold water (10 mL) and extracted using ethyl acetate (2 X 25 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and evaporated over vacuum to get crude product which was purified by prep purification. [Column Name: X-Bridge-RP-C18 (250 mm x 19 mm x 5 µm), Mobile phase (A): 0.1%Ammonia in water, Mobile phase (B): ACN, Flow rate: 18 mL / min]. Pure fractions were collected and concentrated to afford 4-chloro-2-(3- (1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-6-(((S)-3- methylpiperidin-1-yl)methyl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (0.01 g, 12.16 % yield) as an off-white solid.1HNMR (400 MHz, DMSO-d6): δ 8.28 (s, 1H), 7.8 (s, 1H), 7.83 (s, 1H), 7.39-7.35 (m, 3H), 7.13 (d, J = 8.0 Hz, 1H), 5.04 (s, 2H), 3.60 (s, 2H), 3.44 (s, 3H), 3.27 (s, 1H), 3.06 - 2.95 (m, 2H), 2.74 - 2.69 (m, 2H), 1.94 – 1.92 (m, 1H), 1.68 - 1.44 (m, 5H), 1.31 – 1.29 (m, 3H), 0.90 - 0.87 (m, 1H), 0.83 (d, J = 4.0 Hz, 3H). LCMS (ESI) m / z = 516.0[M+H]+

[0328] Synthesis of Example 44

[0329] 4-chloro-6-(1-methyl-5-imidazolyl)-2,3-dihydro-1H-1λ⁶,2- benzisothiazole-1,1-dione (117)

[0330] To a stirred solution of 6-bromo-4-chloro-2,3-dihydro-1H-1λ⁶,2- benzisothiazole-1,1-dione (0.2 g, 0.708 mmol) and 4,4,5,5-tetramethyl-2-(1- methyl-5-imidazolyl)-1,3,2-dioxaborolane (0.13 g, 0.637 mmol) in 1,4-dioxane (5 mL), water (0.5 mL) was added dipotassium carbonate (0.29 g, 2.12 mmol) at room temperature and the resulting reaction mixture was degassed for 5 min with nitrogen gas. [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium (II), complex with dichloromethane (0.028 g, 0.035 mmol) was added and the reaction mixture was stirred at 100°C for 16 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was filtered over celite, washed with ethyl acetate. The filtrate was treated with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to get crude compound. The crude was purified by silica gel flash column chromatography. The compound eluted out in 5- 7% Methanol in DCM. The fractions were evaporated off to afford crude 4-chloro- 6-(1-methyl-5-imidazolyl)-2,3-dihydro-1H-1λ⁶,2-benzisothiazole-1,1-dione (50 mg, crude) as a brown liquid. LCMS (ESI) m / z = 184[M+H]+

[0331] 4-chloro-6-(1-methyl-5-imidazolyl)-2-{m-[3-methyl-1-(4-methyl-4H- 1,2,4-triazol-3-yl)cyclobutyl]phenyl}-2,3-dihydro-1H-1λ⁶,2-benzisothiazole- 1,1-dione (Example 44)

[0332] To a stirred solution of 4-chloro-6-(1-methyl-5-imidazolyl)-2,3-dihydro- 1H-1λ⁶,2-benzisothiazole-1,1-dione (0.05 g, 0.176 mmol), 3-[1-(m-bromophenyl)- 3-methylcyclobutyl]-4-methyl-4H-1,2,4-triazole (0.048 g, 0.159 mmol) in acetonitrile (4 mL) was added dipotassium carbonate (0.17 g, 1.23 mmol) and was purged with nitrogen gas for 5 mins. 1,2-bis(methylamino)ethane (0.0024 mL,0.229 mmol) and copper iodide (0.006 g, 0.035 mmol) were added and the reaction mixture was heated at 90°C for 16 h in a sealed tube. Progress of the reaction was monitored through TLC and LCMS. The reaction mixture was filtered through celite bed, quenched with ice cold water (5 mL), and extracted with ethyl acetate (2 X 50 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and evaporated over vacuum and concentrated to get crude product. The crude was purified through silica gel flash column chromatography by using DCM and MeOH as Eluents (5%) to obtain the product. The product was once again purified through Prep HPLC[Column Name: X- Bridge-C18 (250 mm x 19 mm x 5 µm), Mobile phase (A): 0.1%Ammonia in water, Mobile phase (B): ACN, Flow rate: 18 mL / min]. Pure fractions were evaporated to obtain 4-chloro-6-(1-methyl-5-imidazolyl)-2-{m-[3-methyl-1-(4-methyl-4H-1,2,4- triazol-3-yl)cyclobutyl]phenyl}-2,3-dihydro-1H-1λ⁶,2-benzisothiazole-1,1-dione (0.002 g, 2.2% yield) as an off white solid.1HNMR (400 MHz, DMSO-d6): δ 8.30 (s, 1H), 8.15 (s, 1H), 8.06 (d, J = 1.2 Hz, 1H), 7.81 (s, 1H), 7.49 - 7.41 (m, 3H), 7.34 (s, 1H), 7.16 (d, J = 7.6 Hz, 1H), 5.12 (s, 2H), 3.77 (s, 3H), 3.21 (s, 3H), 2.86 - 2.84 (m, 2H), 2.57 - 2.55 (m, 2H), 1.23 (s,1H), 1.09 (d, J = 5.2 Hz, 3H). LCMS (ESI) m / z = 509.4[M+H]+

[0333] Synthesis of Example 45

[0334] 4-chloro-6-(1-methyl-5-imidazolyl)-2-(m-{[3-(4-methyl-4H-1,2,4- triazol-3-yl)-3-oxetanyl]methyl}phenyl)-2,3-dihydro-1H-1λ⁶,2- benzisothiazole-1,1-dione (Example 45)

[0335] To a stirred solution of 4-chloro-6-(1-methyl-5-imidazolyl)-2,3-dihydro- 1H-1λ⁶,2-benzisothiazole-1,1-dione (0.050 g, 0.176 mmol), 3-{[3-(m- bromophenyl)-3-oxetanyl]methyl}-4-methyl-4H-1,2,4-triazole (0.038 g, 0.123 mmol) in acetonitrile (4 mL) was added dipotassium carbonate (170 mg, 1.23 mmol) and was purged with nitrogen gas for 5 mins. 1,2-bis(methylamino)ethane (24.9 µL, 0.23 mmol) and copper iodide (0.006 g, 0.035 mmol) was added and was heated at 90°C for 16 h in a sealed tube. Progress of the reaction was monitored through TLC and LCMS. The reaction mixture was filtered through celite bed, quenched with ice cold water (5 mL), and extracted with ethyl acetate (2 X 50 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and evaporated over vacuum and concentrated to get crude product. The obtained crude product was purified by Prep HPLC [Column Name: X-Bridge-C18 (250 mm x 19 mm x 5 µm), Mobile phase (A): 0.1%Ammonia in water, Mobile phase (B): ACN, Flow rate: 18 mL / min]. The pure fractions were evaporated off to obtain 4-chloro-6-(1-methyl-5-imidazolyl)-2-(m-{[3-(4-methyl- 4H-1,2,4-triazol-3-yl)-3-oxetanyl]methyl}phenyl)-2,3-dihydro-1H-1λ⁶,2- benzisothiazole-1,1-dione (0.006 g, 7% yield) as an off white solid.1HNMR (400 MHz, DMSO-d6): δ 8.19 (s, 1H), 8.15 (s, 1H), 8.06 (s, 1H), 7.81 (s, 1H), 7.47 (d, J = 9.6Hz, 1H), 7.39 - 7.34 (m, 2H), 7.04 (s, 1H), 6.80 (d, J = 7.2Hz, 1H), 5.02 (s, 2H), 4.96 (d, J = 6Hz, 2H), 4.88 (d, J = 6.4Hz, 2H), 3.77 (s, 3H), 3.51(s, 2H), 2.91 (s, 3H). LCMS (ESI) m / z = 511[M+H]+

[0336] Methods and materials: Cbl-b and C-Cbl protein expression and purification: Biophysical and assay experiments were carried out using two different proteins CBl-b and c-Cbl: the CBl-b (36-427aa), the N-terminal Glutathione S- transferase(GST-tag) followed by a TEV protease cleavage site and the E3 ligase fragment consisting of TKBD-LHR-RING (36–427aa). Similarly, c-Cbl protein (47-435aa) which has N-terminal GST and TEV; both were constructed and cloned into pGEX4T-1 expression vector. These clones were procured from GenScript Biotech (Singapore) PTE.LTD. These proteins were expressed E. coli BL21 (DE3) Gold cells using 2YT media. All the proteins were started to purify using GST affinity chromatography, followed by TEV digestion; Then, Nickel sepharose affinity chromatography, further purified by size exclusion chromatography using a HiLoadTM16 / 600 SuperdexTMS75 gel filtration column (Cytiva). In every purification steps, protein purity and quantity were checked by SDS-PAGE and western analysis.

[0337] Thermal shift assay The purified Cbl-b protein’s stability and its binding property with compounds were analyzed by thermal shift assay. This assay is conducted in protein storage buffer which is 20 mM HEPES pH 7.5, 100mM KCl, 1mM DTT, 5mM MgCl2. 150 μl reaction mixture was prepared in a 96-well real-time PCR plates by combining the test protein 1 μM, test compounds (respective concentrations) with thermal shift dye (5x Sypro Orange, Invitrogen / Thermo Fisher Scientific) and buffer. Then, it is dispensed 50 μl in each well. The plates were sealed with Microseal ‘B’ Plate Sealing Film (Bio-Rad; catalogue no. MSB1001) and spun to collect the reaction mix at the bottom of the plate. The plates were analysed at 15°C – 95 °C temperature gradient (temperature increase of 1 °C / 30 sec) using a CFX-96 real-time PCR instrument (Bio-Rad). The calculation of the midpoint of the curves (Tm) was performed using the software package CFX-Maestro (Bio-Rad). All the test compounds were spotted at four different concentrations and experiments were performed in triplicate.

[0338] Biochemical assay protocol: Effect of Cbl-b inhibitors on the Cbl-b mediated ubiquitination was assessed using a TR-FRET kit (Cat# - 79575, BPS Bioscience). Assay was performed following manufactures instructions. Briefly, UBE1 (E1), UBCH5b (E2) and Human CBL-B(E3), enzymes given in the kit were diluted to working concentrations (E1 – 25ng / ml, E2 – 220ng / ml and E3 – 3ng / ml) in assay buffer. Master enzyme mix was prepared by mixing required volumes diluted E1, E2, E3 and Biotin-Ubiquitin given in kit (10 reactions mix 10µl of 25ng / ml E1, 10µl of 220ng / ml E2, 2.5µl of 3ng / ml E3 and 10µl of Biotin-Ubiquitin). Furthermore, 5.5µl of this master mix was added to each well. Assays were performed in a 384 well opti-plate. 2µl of diluted test compounds (final concentrations ranging from 0.0015µM to 30µM in wells) were added to each well containing master enzyme mix (final DMSO concentration was maintained at 1% in each well). Plates were incubated at 370C for 1h. Ubiquitination reaction was started by adding 2.5µl of 40µM ATP to all the wells. Following that plates were incubated at 370C for 4h. Manufactures provided labeled donor and acceptor, that were diluted according to kit protocol and 10µl of it was added to each well. Fluorescence intensity was measured in a microplate reader capable of measuring TR-FRET (PHERAstar, BMG LABTECH). For measuring TR-FRET two sequential measurement was taken. Excitation wavelength of 340±20 nm was fixed and emission was measured at 620±10, 665±10 nm (lag time and Integration time of 60µs and 500µs respectively for both the measurements) respectively. Blank (reaction without E3), substrate control (reaction without ATP) and positive control (reaction with all the required components) were used as controls. Readings were normalized by calculating a ratio of emission at 665nm to emission at 620nm (em 665nm / 620nm).

[0339] Cytokine release assay from human PBMCs. PBMC isolation. Blood from healthy human donor was collected in heparin coated vacuum sealed blood collection tubes. Blood was then diluted with phosphate buffered saline (PBS) in 1:1 ratio and layered carefully on histopaque (cat#, 10771) in a centrifuge tubes in 1:2 ratio (2 volume of diluted blood to 1 volume of histopaque). Tubes were centrifuged at 1800rpm for 20 minutes with lowest break and acceleration settings. Buffy coat layer formed between serum and histopaque was carefully transferred to separate centrifuge tube and tubes were further centrifuged at1800rpm for 10 min. Cell pellet was then washed with sufficient volume of PBS and again centrifuged at 1800rpm for 10min. Cell pellet was then re-suspended in X-vivo medium (cat#, BE02-060F) and taken for cell count.

[0340] PBMC seeding, treatment and supernatant collection. PBMCs were seeded in 96 well U-bottom plate (0.2 million cells / well in 100 µl of X-vivo medium). Seeded cells were stimulated by anti-human CD3 (cat#, 317302) and CD28 (cat#, 377804) cocktail (50µl) prepared in X-vivo medium (CD3 and CD28 were used at 0.1µg / ml and 0.25µg / ml final concentrations respectively). For unstimulated samples 50 µl of X-vivo medium was added, and incubated at 370C and 5% CO2 for 30 minutes. Compounds were serially diluted in DMSO and further diluted in X-vivo medium (ranging from 0.00032 µM to 5 µM final concentration in well), 50 µl of diluted compound was added to each well and incubated at 370C and 5% CO2 for 72 h (final DMSO concentration of 0.5% was maintained in each well). 0.5% DMSO treated PBMCs were kept as untreated controls. After 72 h, plates were centrifuged at 1500 rpm for 10 min and supernatant from each well was transferred to fresh plate and stored at -800C.

[0341] ELISA to Quantify the amount of IFN-γ, TNF-α and IL-2 secreted by PBMCs. Cytokine secretion from compound treated PBMCs was measured by commercially available ELISA kits [IFN-γ (Cat#, DY285B), TNF-α (cat#, DY210) and IL-2 (cat#, DY202)]. Supernatant collected from PBMCs as mentioned in section above, was thawed on ice and diluted as per assay requirement. ELISA was performed and amount of cytokines was quantified as per kit protocol.

[0342] Table-2 shows results of biological activity of selected compounds. The binding of compounds was evaluated using the thermal shift assay. Biochemical evaluation was done using TR-FRET based assay and the results shown in the table is the Emax at 30 uM. Compounds were designated as “A” having an Emax of ≥ 45% and “B” having an Emax of ≥35%-45% and “C” having an Emax of <35%. Cytokine release in response to compounds were performed in PBMC cells and thecompounds were designated as “A” having an EC50 of ≤ 2µM and “B” having an EC50between 2µM - 10 µM. “ND” refers to compounds data was not determined.

[0343] Table-2: Biological activity of selected compounds on Cbl-b Compound (ΔTm - °C) T Emax EC50 from stimulated PBMC ID SA (%) ELISA (nM) CBL-b C-CBL IFN γ TNFα IL-2 Example-03 5 1 B A A A Example-04 4 1 A B B AExample-052 0 C A A AExample-071 0 B B A BExample-087 -1 A A A AExample-09 6 1 B A A BExample-181 0 A ND ND NDExample-365 1 BA B AExample-201 0 BND ND NDExample-211 0 AND ND NDExample-284 0 CA B A

Claims

CLAIMS 1. A compound of Formula-1:their pharmaceutically acceptable salt, solvate, hydrate, clathrate, polymorph or stereoisomer thereof, wherein: A is selected fromE and D is selected from alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl and their derivatives; R is selected from alkyl, branched alkyl, alkynyl, alkoxy, cyanoalkyl, halogen substituted alkyls, hydroxyalkyl, haloalkoxy, alkoxyalkyl, heteroalkyls, cycloalkyls, multicyclic cycloalkyl, heterocycloalkyls, substituted heterocycloalkyls, aryl, substituted aryl, heteroaryl, their deuterated analogs, and their substitutions.The term “alkyl” refers to a hydrocarbon chain radical that includes solely carbon and hydrogen atoms in the backbone, containing no unsaturation, having from one to eight carbon atoms (i.e. C1-8alkyl), and which is attached to the rest of the molecule by a single bond, such as, but not limited to, methyl, ethyl, n- propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, and 1,1-dimethylethyl (t-butyl);W, X and Y is selected from CH, C, N, NH, O, S; Z1, Z2& Z3is selected from CH, C, N, NH, S, O or suitably substituted; m= 0,1, 2 or 3; n= 0, 1, 2 or 3.

2. A compound of Formula-2their pharmaceutically acceptable salt, solvate, hydrate, clathrate, polymorph or stereoisomer thereof, wherein: A is selected fromE and D is selected from alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl and their derivatives; R is selected from alkyl, branched alkyl, alkynyl, alkoxy, cyanoalkyl, halogen substituted alkyls, hydroxyalkyl, haloalkoxy, alkoxyalkyl, heteroalkyls, cycloalkyls, multicyclic cycloalkyl, heterocycloalkyls, substituted heterocycloalkyls, aryl, substituted aryl, heteroaryl, their deuterated analogs, and their substitutions. The term “alkyl” refers to a hydrocarbon chain radical that includes solely carbon and hydrogen atoms in the backbone, containing no unsaturation, having from one to eight carbon atoms (i.e. C1-8alkyl), and which is attached to the rest of the molecule by a single bond, such as, but not limited to, methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, and 1,1-dimethylethyl (t-butyl); X and Y is selected from CH, C, N, NH, O, S; Z1, Z2 & Z3 is selected from CH, C, N, NH, S, O or suitably substituted; m= 0,1, 2 or 3.

3. The compound as claimed in claim 2, wherein the compound is4. The compound as claimed in claim 2, wherein the compound is5. The compound as claimed in claim 2, wherein the compound is6. The compound as claimed in claim 2, wherein the compound is7. The compound as claimed in claim 2, wherein the compound is8. The compound as claimed in claim 2, wherein the compound is9. The compound as claimed in claim 2, wherein the compound is10. The compound as claimed in claim 2, wherein the compound is11. The compound as claimed in claim 2, wherein the compound is12. The compound as claimed in claim 2, wherein the compound is13. The compound as claimed in claim 2, wherein the compound is14. The compound as claimed in claim 2, wherein the compound is15. The compound as claimed in claim 2, wherein the compound is16. The compound as claimed in claim 2, wherein the compound is17. The compound as claimed in claim 2, wherein the compound is18. The compound as claimed in claim 2, wherein the compound is19. The compound as claimed in claim 2, wherein the compound is20. The compound as claimed in claim 2, wherein the compound is21. The compound as claimed in claim 2, wherein the compound is22. The compound as claimed in claim 2, wherein the compound is23. The compound as claimed in claim 2, wherein the compound is24. The compound as claimed in claim 2, wherein the compound is25. The compound as claimed in claim 2, wherein the compound is26. The compound as claimed in claim 2, wherein the compound is27. The compound as claimed in claim 2, wherein the compound is28. The compound as claimed in claim 2, wherein the compound is29. The compound as claimed in claim 2, wherein the compound is30. The compound as claimed in claim 2, wherein the compound is31. The compound as claimed in claim 2, wherein the compound is32. The compound as claimed in claim 2, wherein the compound is33. The compound as claimed in claim 2, wherein the compound is34. The compound of Formula 3a and 3b as claimed in claim 1their pharmaceutically acceptable salt, solvate, hydrate, clathrate, polymorph or stereoisomer thereof, wherein: A is selected fromE and D is selected from alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl and their derivatives; R is selected from alkyl, branched alkyl, alkynyl, alkoxy, cyanoalkyl, halogen substituted alkyls, hydroxyalkyl, haloalkoxy, alkoxyalkyl, heteroalkyls, cycloalkyls, multicyclic cycloalkyl, heterocycloalkyls, substituted heterocycloalkyls, aryl, substituted aryl, heteroaryl, their deuterated analogs, and their substitutions.The term “alkyl” refers to a hydrocarbon chain radical that includes solely carbon and hydrogen atoms in the backbone, containing no unsaturation, having from one to eightcarbon atoms (i.e. C1-8alkyl), and which is attached to the rest of the molecule by a single bond, such as, but not limited to, methyl, ethyl, n- propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, and 1,1-dimethylethyl (t-butyl); X and Y is selected from CH, C, N, NH, O, S; Z1, Z2& Z3is selected from CH, C, N, NH, S, O or suitably substituted; m= 0,1, 2 or 3.

35. The compound of Formula 3c and 3d as claimed in claim 1their pharmaceutically acceptable salt, solvate, hydrate, clathrate, polymorph or stereoisomer thereof, wherein: A is selected fromE and D is selected from alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl and their derivatives; R is selected from alkyl, branched alkyl, alkynyl, alkoxy, cyanoalkyl, halogen substituted alkyls, hydroxyalkyl, haloalkoxy, alkoxyalkyl, heteroalkyls, cycloalkyls, multicyclic cycloalkyl, heterocycloalkyls, substituted heterocycloalkyls, aryl, substituted aryl, heteroaryl, their deuterated analogs, and their substitutions.The term “alkyl” refers to ahydrocarbon chain radical that includes solely carbon and hydrogen atoms in the backbone, containing no unsaturation, having from one to eight carbon atoms (i.e. C1-8alkyl), and which is attached to the rest of the molecule by a single bond, such as, but not limited to, methyl, ethyl, n- propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, and 1,1-dimethylethyl (t-butyl); X and Y is selected from CH, C, N, NH, O, S; Z2& Z3is selected from CH, C, N, NH, S, O or suitably substituted; m= 0,1, 2 or 3.

36. The compound as claimed in claim 34, wherein the compound is37. The compound as claimed in claim 34, wherein the compound is38. The compound as claimed in claim 34, wherein the compound is39. The compound as claimed in claim 34, wherein the compound is40. The compound as claimed in claim 34, wherein the compound is41. The compound as claimed in claim 34, wherein the compound is42. The compound as claimed in claim 34, wherein the compound is43. The compound as claimed in claim 34, wherein the compound is44. The compound as claimed in claim 34, wherein the compound is45. The compound as claimed in claim 34, wherein the compound is46. A method of treatment in a human subject in need thereof comprising administering a therapeutically effective amount of a compound of structural Formula-1 or Formula-2 or their pharmaceutically acceptable salt as modulators of E3 ligase CBL-B.

47. A method of treatment in claim 46, wherein a compound of structural Formula-1 or Formula-2 or their pharmaceutically acceptable salt is used for T cell activation and differentiation.

48. A method of treatment in claim 46, wherein a compound of structural Formula-1 or Formula-2 or their pharmaceutically acceptable salt is used in modulating immune responses.

49. A method of treatment in claim 46, wherein a compound of structural Formula-1 or Formula-2 or their pharmaceutically acceptable salt is used in modulating immune responses in cancer immunotherapy.

50. A method of treatment in claim 46, wherein a compound of structural Formula-1 or Formula-2 or their pharmaceutically acceptable salt is used in treatment of autoimmune conditions.

51. A method of treatment in claim 46, wherein a compound of structural Formula-1 or Formula-2 or their pharmaceutically acceptable salt is used in treatment of immune dysregulation conditions.

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