WO2018163077A1 - Indanyl compounds as voltage gated sodium channel modulators - Google Patents

Indanyl compounds as voltage gated sodium channel modulators Download PDF

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WO2018163077A1
WO2018163077A1 PCT/IB2018/051464 IB2018051464W WO2018163077A1 WO 2018163077 A1 WO2018163077 A1 WO 2018163077A1 IB 2018051464 W IB2018051464 W IB 2018051464W WO 2018163077 A1 WO2018163077 A1 WO 2018163077A1
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Vidya Ramdas
Rajeshkumar Maganlal LORIYA
Moloy BANERJEE
Ganesh Shankar Chaure
Amit Kumar DAS
Advait Arun JOSHI
Deepak Sahebrao WALKE
Laxmikant Shamlal DATRANGE
Pradeep Rangrao PATIL
Venkata P. Palle
Rajender Kumar Kamboj
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Lupin Limited
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    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D213/00Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with heteroatoms or with carbon atoms having three bonds to hetero atoms, with at the most one to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72Nitrogen atoms
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    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D239/00Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32One oxygen, sulfur or nitrogen atom
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    • C07D277/02Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D401/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D405/02Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
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    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
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    • C07D413/12Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D417/00Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Abstract

The invention relates to indanyl compounds, their pharmaceutically acceptable salts thereof, processes for their preparation and pharmaceutical compositions comprising the same for the treatment, management and /or lessening severity of diseases, disorders, syndromes or conditions which are associated with the voltage-gated sodium channels (VGSC). More specifically the present invention provides compounds having the structure of Formula (I).

Description

INDANYL COMPOUNDS AS VOLTAGE GATED SODIUM CHANNEL

MODULATORS

Field of the Invention

The invention relates to indanyl compounds their pharmaceutically acceptable salts thereof, and pharmaceutical compositions for the treatment, management and /or lessening severity of diseases, disorders, syndromes or conditions which are associated with the voltage-gated sodium channels (VGSC). The invention also relates to processes for the preparation of the compounds of the invention and to methods of treating, managing and/or lessening the severity of the diseases disorders, syndromes or conditions associated with voltage-gated sodium channels.

Background of the Invention

Voltage-gated sodium channels play a crucial role in maintaining a specific membrane potential (intra- and extracellular ionic environments) across the mammalian cell membrane. The intracellular concentration of Na+ is kept low relative to the extracellular by active sodium pumps that eject three Na+ ions for every two K+ ions taken in. This generates a negative membrane potential (since more positive charge is pumped out and less taken in) and maintains the Na+ concentration of 6 and 140 mM in the intra and extracellular milieu. On opening of the voltage-gated sodium channels (VGSC), Na+ rushes in and leads to depolarization of the membrane because of the associated positive charge. The entry of Na+ via VGSC's occurs in cells of the heart, central and peripheral nervous system and is essential to initiate the firing of an action potential.

VGSCs consist of a pore-forming alpha subunit and a stabilizing beta subunit, 9 isoforms of the alpha subunit have been identified till date (Navl. l to Navl .9). All nine members of the family have >50% identity in the amino acid sequence in the extracellular and transmembrane domain. The channels have also been further classified based on their sensitivity to the puffer fish toxin (tetrodotoxin, TTX). Channels Navl .8, Navl.9 and Navl.5 are TTX resistant (TTX-R) whereas the remaining channels are sensitive to TTX (TTX-S). (England and Rawson. Future Med. Chem. (2010), 2, 775-790). However, Navl .7 gene is prominently responsible to cause pain. Loss of function mutations in the human Navl.7 gene lead to congenital insensitivity to pain which was observed for the first time in certain Pakistani families. Affected individuals displayed painless burns, fractures, and injuries of the lips and tongue. The patients did not have any autonomic or motor abnormalities, and reportedly had normal tear formation, sweating ability, reflexes, and intelligence. This genetic evidence clearly indicates that gain or loss of Navl.7 function can lead to exacerbation or loss of pain sensation respectively. Thus, it may be possible to treat chronic pain by pharmacologically blocking Navl .7. Moreover, Navl .7 has also been implicated in epilepsy. Small molecule Navl.7 blockers showed efficacy in in vivo epilepsy models. It has therefore been proposed that selective Navl .7 blockers may lead to therapeutic benefit in epilepsy (Hoyt et al. Bioorganic & Medicinal Chemistry Letters (2008), 18, 1963-1966).

Genetic evidence stems from the human gain of function as well as loss of function mutations that lead to inherited pain disorders and insensitivity to pain respectively. Non selective VGSC blockers have been shown to alleviate pain in animal models as well as in humans {e.g., Carbamazepine). Ralfinamide, another non-selective sodium channel blocker, is also being developed for the treatment of neuropathic pain.

Vagal sensory neurons expressing Nav channels are known to regulate cough reflex in mammalian airways. Vagal cough receptors and neurons innervating the respiratory tract have been shown to express Navl .7, Navl.8, and Navl .9 channels in guinea pigs. Knock down of Navl .7 in vagal in the vagal sensory ganglion of guinea pigs significantly suppressed cough induced by citric acid suggesting a direct benefit of modulation of Nav 1.7 for treatment of cough (Pulm. Pharmacol. Ther. 2013, 26 (5), 508-509.)

Voltage-gated sodium channels are implicated in various diseases and disease conditions, including but not limited to chronic pain, visceral pain, cough, pruritus, diabetes (Int. J. Mol. Sci. 2016, 17, 1479), arrhythmia, multiple sclerosis, epilepsy and related disorders as well as cancer (Scientific Reports, 2015 Jun 22; 5: 11541 ; Journal of Cell Science, 2013, 126 (21), 4939-4949). Thus, small molecules targeting one or more of the relevant VGSCs is likely to alleviate the suffering from these conditions.

International publication numbers WO 2006/1 10917, WO 2007/109324, WO 2008/046049, WO 2008/046084, WO 2008/046087, WO 2008/060789, WO 2009/012242, WO 2010/035166, WO 2010/045197, WO 2010/045251, WO 2010/053998, WO 2010/078307, WO2010/151595, WO2010/151597, WO 201 1/002708, WO 201 1/026240, WO 2011/103196, WO 2011/056985, WO 201 1/058766, WO 201 1/088201, WO201 1/140425 and Bioorganic & Medicinal Chemistry Letters (201 1), 21, 3676-681 disclose compounds related to voltage-gated sodium channel (VGSC) modulators for the treatment of various diseases mediated by VGSC modulation.

Summary of the Invention

In accordance with one aspect, the invention provides compounds having the structure of Formula (I),

Figure imgf000004_0001
wherein, ring A is five or six membered monocyclic heteroaryl;

Ri is selected from the group consisting of hydrogen, halogen, cyano, substituted or unsubstituted alkyl and substituted or unsubstituted alkoxy; R2, which may be same or different at each occurrence, is independently selected from the group consisting of halogen, cyano, substituted or unsubstituted alkyl, haloalkyl, -(CH2)(M-S(0)2-alkyl, -OR6, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted monocyclic heterocyclyl, -COOH, -COO-alkyl and

R3, which may be same or different at each occurrence, is independently selected from the group consisting of halogen, cyano, substituted or unsubstituted alkyl and substituted or unsubstituted alkoxy; R4 and R5 are independently hydrogen or substituted or unsubstituted alkyl; or R4 and R5 together with the nitrogen atom to which they are attached, form a substituted or unsubstituted 5- to 6- membered heterocyclic ring;

R6 is selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted monocyclic heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted monocyclic heteroaryl;

'm' is an integer ranging from 1 to 3, both inclusive;

'n' is an integer ranging from 0 to 3, both inclusive; wherein the substituents on alkyl, alkoxy, cycloalkyl, aryl, heteroaryl, heterocyclyl, heterocyclic ring, alkoxyalkyl are one or more, same or different and independently selected from the group consisting of halogen, cyano, nitro, oxo (=0), alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclic ring, heterocyclylalkyl, heteroarylalkyl, -C(0)ORx, -C(0)Ry, - C(S)Ry, -C(0)NRxRz, -NRxC(0)NRxRz, -NRx-S(0)2Ry, -NRXRZ, -NRxC(0)Ry, - NRxC(S)Ry, -NRxC(S)NRxRz, -S(0)2NRxRz, -OR*, -OC(0)Ry, -(CRaRb)i-3C(0)ORx, - (CRaRb)i-3C(0)NRxRz, -0-(CRaRb)i-3-ORx, -0-(CRaRb)i-3-NRxRz, -0-(CRaRb)i-3-S(0)o-

2Ry, -(CRaRb)l-3-NRxRz, -(CRaRb)l-3-S(O)0-2Ry, -0(CRaRb)l-3-C(0)NRxRz, -0(CRaRb)l-3-

C(0)ORx and -S(0)o-2Ry; each Rx independently is selected from the group consisting of hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic ring, heterocyclylalkyl and heteroarylalkyl; each Ry independently is selected from the group consisting of alkyl, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic ring, heterocyclylalkyl and heteroarylalkyl; each Rz independently is selected from the group consisting of hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic ring, heterocyclylalkyl and heteroarylalkyl; or Rx and Rz together with the nitrogen atom to which they are attached form a substituted or unsubstituted, saturated or unsaturated 4- to 8- membered cyclic ring, wherein the unsaturated cyclic ring may have one or two double bonds; and each of Ra and Rb are independently selected individually from the group consisting of hydrogen, halogen and alkyl; or N-oxides thereof or a pharmaceutically acceptable salt thereof or stereoisomer thereof.

According to one embodiment, the invention provides compounds having the structure of Formula (II)

Figure imgf000006_0001
or N-oxides thereof or a pharmaceutically acceptable salt thereof or stereoisomer thereof; wherein, R2a is halogen, cyano, substituted or unsubstituted alkyl, haloalkyl and substituted or unsubstituted cycloalkyl;

R2b is selected from the group consisting of halogen, cyano, substituted or unsubstituted alkyl, haloalkyl, -(CH2)o -S(0)2-alkyl, -OR6, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted monocyclic heterocyclyl, -COOH, -COO-alkyl and -CONR4R5; ring A, R3, R4, R5, R6 and 'n' are as defined herein above. According to another embodiment of compound of Formula (I) wherein ring A is selected from thiazole, pyridine, pyrimidine, pyridazine, oxazole, isoxazole and thiadiazole.

According to another embodiment of compound of Formula (I) wherein ring A is pyridine.

According to another embodiment of compound of Formula (I) wherein ring A is pyrimidine.

According to another embodiment of compound of Formula (I) wherein ring A is thiazole. According to another embodiment of compound of Formula (I) wherein ring A is pyridazine.

According to another embodiment of compound of Formula (I) wherein ring A is oxazole.

According to another embodiment of compound of Formula (I) wherein ring A is, isoxazole.

According to another embodiment of compound of Formula (I) wherein ring A is thiadiazole.

According to another embodiment of compound of Formula (I) wherein R2 is selected from group consisting of halogen, substituted or unsubstituted alkyl, haloalkyl, - COOH, -COO-alkyl, substituted or unsubstituted aryl, substituted or unsubstituted monocyclic heterocyclyl, substituted or unsubstituted heteroaryl, -(CH2)o-4-S(0)2-alkyl and -OR6; wherein R& is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted monocyclic heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl.

According to another embodiment of compound of Formula (I) wherein R2 is selected from group consisting of halogen, haloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted monocyclic heterocyclyl, substituted or unsubstituted heteroaryl, -(CH2)o-4-S(0)2-alkyl and -OR6'; wherein R6' is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted monocyclic heterocyclyl,

According to another embodiment of compound of Formula (I) wherein R2 is selected from chlorine, CF3, CH(CH3)2, C(CH3)3, fluoropropane, -(CH2)2-S(0)2-methyl,

Figure imgf000008_0001

It should be understood that the Formula (I) and (II) structurally encompasses all tautomers, stereoisomers, enantiomers and diastereomers, including isotopes wherever applicable and pharmaceutically acceptable salts that may be contemplated from the chemical structures generally described herein.

Below compound of formula (I), their stereoisomers, or a pharmaceutically acceptable salt thereof, are representative compounds, which are only illustrative in nature and are not intended to limit to the scope of the invention: l-(2-(6-Fluoropyridin-3-yl)-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)-2,3-dihydro- 1H- indene-5-sulfonamide; l-(2-(6-Methylpyridin-3-yl)-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)-2,3-dihydro- 1 H-indene-5-sulfonamide; l-(2-(6-Fluoropyridin-3-yl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-2-yl)-2,3- dihydro- lH-indene-5-sulfonamide; l-(2-(6-Methylpyridin-3-yl)-4-(trifluoro

dihydro- lH-indene-5-sulfonamide;

1 -(2-( 1 -Methyl- 1 H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-2-yl)-2,3- dihydro- lH-indene-5-sulfonamide;

N-(6-Fluoropyridin-2-yl)-l-(2-(6-fluoropyridin-3-yl)-4-(trifluoro methyl)phenyl)-2,3- dihydro- lH-indene-5-sulfonamide;

N-(6-Fluoropyridin-2-yl)-l-(2-(6-methylpyridin-3-yl)-4-(trifluoro methyl)phenyl)- 2,3-dihydro-lH-indene-5-sulfonamide;

N-(6-Fluoropyridin-2-yl)- 1 -(2-( 1 -methyl- 1 H-pyrazol-5-yl)-4-(trifluoro

methyl)phenyl)-2,3-dihydro- lH-indene-5-sulfonamide;

2'-(5-(N-(6-Fluoropyridin-2-yl)sulfamoyl)-2,3-dihydro- 1 H-inden- 1 -yl)-5'- (trifluoromethyl)- [ 1 , 1 '-biphenyl] -4-carboxylic acid;

2'-(5-(N-(pyrimidin-2-yl)sulfamoyl)-2,3-dihydro- 1 H-inden- 1 -yl)-5'-(trifluoromethyl)- [1, 1 '-biphenyl] -4-carboxylic acid;

1 -(2-(2-oxopyrrolidin- 1 -yl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-2-yl)-2,3- dihydro- lH-indene-5-sulfonamide;

N-(6-fluoropyridin-2-yl)- 1 -(2-(2-oxopyrrolidin- 1 -yl)-4-(trifluoromethyl)phenyl)-2,3- dihydro- lH-indene-5-sulfonamide; l-(2-(2-oxooxazolidin-3-yl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-2-yl)-2,3- dihydro- lH-indene-5-sulfonamide;

N-(6-fluoropyridin-2-yl)-l-(2-(2-oxooxazolidin-3-yl)-4-(trifluoromethyl)phenyl)-2,3- dihydro- lH-indene-5-sulfonamide;

N-(6-fluoropyridin-2-yl)-l-(2-(2-(methylsulfonyl)ethyl)-4-(trifluoromethyl)phenyl)- 2,3-dihydro-lH-indene-5-sulfonamide;

1- (2-(3-fluoro- l-methylazetidin-3-yl)-4-(trifluoromethyl)phenyl)-N-(6-fluoropyridin-

2- yl)-2,3-dihydro- 1 H-indene-5-sulfonamide hydrochloride; l-(2-(3-fluoro- l-methylazetidin-3-yl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-2-yl)- 2,3-dihydro-lH-indene-5-sulfonamide hydrochloride;

N-(6-fluoropyridin-2-yl)-l-(2-((tetrahydrofuran-3-yl)oxy)-4-(trifluoromethyl)phenyl)- 2,3-dihydro-lH-indene-5-sulfonamide;

N-(pyrimidin-2-yl)- l-(2-((tetrahydrofuran-3-yl)oxy)-4-(trifluoromethyl)phenyl)-2,3- dihydro- lH-indene-5-sulfonamide;

1 -(2-(4-methylpiperazin- 1 -yl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-2-yl)-2,3- dihydro- lH-indene-5-sulfonamide;

N-(6-fluoropyridin-2-yl)- 1 -(2-(4-methylpiperazin- 1 -yl)-4-(trifluoromethyl)phenyl)- 2,3-dihydro-lH-indene-5-sulfonamide; l-(2-Mo^holino-4-(trifluoromethyl)phenyl)-N-(pyrimidin-2-yl)-2,3-dihydro-lH- indene-5-sulfonamide;

N-(6-Fluoropyridin-2-yl)-l-(2-morpholino-4-(trifluoromethyl) phenyl)-2,3-dihydro- 1 H-indene-5-sulfonamide; l-(2-(Oxetan-3-yloxy)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-2-yl)-2,3-dihydro- 1 H-indene-5-sulfonamide;

1 -(2-( 1 -methyl- 1 H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)-2,3- dihydro- lH-indene-5-sulfonamide;

N-(isoxazol-3-yl)- 1 -(2-( 1 -methyl- 1 H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-2,3- dihydro- lH-indene-5-sulfonamide;

1 -(2-( 1 -methyl- lH-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N-(pyridazin-3-yl)-2,3- dihydro- lH-indene-5-sulfonamide; l-(4-isopropyl-2-(l-methyl-lH-pyrazol-5-yl)phenyl)-N-(pyrimidin-2-yl)-2,3-dihydro- 1 H-indene-5-sulfonamide;

N-(6-fluoropyridin-2-yl)- 1 -(4-isopropyl-2-( 1 -methyl- 1 H-pyrazol-5-yl)phenyl)-2,3- dihydro- lH-indene-5-sulfonamide; 1 -(4-(tert-butyl)-2-( 1 -methyl- 1 H-pyrazol-5-yl)phenyl)-N-(pyrimidin-2-yl)-2,3- dihydro- lH-indene-5-sulfonamide;

1 -(4-(tert-butyl)-2-( 1 -methyl- 1 H-pyrazol-5-yl)phenyl)-N-(6-fluoropyridin-2-yl)-2,3- dihydro- lH-indene-5-sulfonamide;

1 -(2-(oxazol-2-yl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-2-yl)-2,3-dihydro- 1 H- indene-5-sulfonamide;

N-(6-fluoropyridin-2-yl)-l-(2-(oxazol-2-yl)-4-(trifluoromethyl)phenyl)-2,3-dihydro- 1 H-indene-5-sulfonamide;

N-(6-fluoropyridin-2-yl)-l-(4'-isopropyl-5-(trifluoromethyl)-[l,r-biphenyl]-2-yl)-2,3- dihydro- lH-indene-5-sulfonamide; l-(3'-chloro-4'-fluoro-5-(trifluoromethyl)-[l,r-biphenyl]-2-yl)-N-(6-fluoropyridin-2- yl)-2,3-dihydro-lH-indene-5-sulfonamide;

N-(6-fluoropyridin-2-yl)- 1 -(4'-methoxy-5-(trifluoromethyl)-[l , 1 '-biphenyl]-2-yl)-2,3- dihydro- lH-indene-5-sulfonamide;

1 -(2',4'-difluoro-5-(trifluoromethyl)-[ 1 , 1 '-biphenyl] -2-yl)-N-(6-fluoropyridin-2-yl)- 2,3-dihydro-lH-indene-5-sulfonamide;

N-(2,4-dimethoxybenzyl)-N-(6-fluoropyridin-2-yl)-l-(2-(pyridin-3-yl)-4- (trifluoromethyl)phenyl)-2,3-dihydro-lH-indene-5-sulfonamide;

N-(6-fluoropyridin-2-yl)-l-(2-(pyridin-4-yl)-4-(trifluoromethyl)phenyl)-2,3-dihydro- 1 H-indene-5-sulfonamide;

N-(6-fluoropyridin-2-yl)-l-(2-(l -methyl- lH-indol-5-yl)-4-(trifluoromethyl)phenyl)- 2,3-dihydro-lH-indene-5-sulfonamide; l-(2-(pyridin-3-yl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-2-yl)-2,3-dihydro-lH- indene-5-sulfonamide; l-(2-(6-ethoxypyridin-3-yl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-2-yl)-2,3- dihydro- lH-indene-5-sulfonamide; l-(2-(pyridin-4-yl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-2-yl)-2,3-dihydro-lH- indene-5-sulfonamide;

1 -(2-( 1 -methyl- 1 H-indol-5-yl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-2-yl)-2,3- dihydro- lH-indene-5-sulfonamide;

1 -(2-( 1 -methyl- 1 H-indazol-5-yl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-2-yl)-2,3- dihydro- lH-indene-5-sulfonamide; l-(3'-chloro-4'-fluoro-5-(trifluoromethyl)-[l, r-biphenyl]-2-yl)-N-(pyrimidin-2-yl)- 2,3-dihydro-lH-indene-5-sulfonamide;

1 -(4'-chloro-5-(trifluoromethyl)-[ 1 , 1 '-biphenyl]-2-yl)-N-(pyrimidin-2-yl)-2,3-dihydro- 1 H-indene-5-sulfonamide;

1 -(4'-methoxy-5-(trifluoromethyl)- [1, 1 '-biphenyl] -2-yl)-N-(pyrimidin-2-yl)-2,3- dihydro- lH-indene-5-sulfonamide;

1 -(4'-(dimethylamino)-5-(trifluoromethyl)-[ 1 , 1 '-biphenyl] -2-yl)-N-(pyrimidin-2-yl)- 2,3-dihydro-lH-indene-5-sulfonamide;

1 -(4'-fluoro-2'-methoxy-5-(trifluoromethyl)-[ 1 , l'-biphenyl] -2-yl)-N-(pyrimidin-2-yl)- 2,3-dihydro-lH-indene-5-sulfonamide; l-(4'-isopropoxy-5-(trifluoromethyl)-[l, r-biphenyl]-2-yl)-N-(pyrimidin-2-yl)-2,3- dihydro- lH-indene-5-sulfonamide;

1 -(4'-isopropyl-5-(trifluoromethyl)- [1,1 '-biphenyl]-2-yl)-N-(pyrimidin-2-yl)-2,3- dihydro- lH-indene-5-sulfonamide; l-(2',4'-difluoro-5-(trifluoromethyl)-[l, l'-biphenyl]-2-yl)-N-(pyrimidin-2-yl)-2,3- dihydro- lH-indene-5-sulfonamide; l-(2',4'-difluoro-5-(trifluoromethyl)-[l, l'-biphenyl]-2-yl)-N-(pyrimidin-2-yl)-2,3- dihydro- lH-indene-5-sulfonamide;

N-(3,5-difluoropyridin-2-yl)- 1 -(2-( 1 -methyl- 1 H-pyrazol-5-yl)-4- (trifluoromethyl)phenyl) -2,3-dihydro- 1 H-indene-5-sulfonamide; 1 -(2-( 1 -methyl- 1 H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N-(oxazol-2-yl)-2,3- dihydro- lH-indene-5-sulfonamide;

1 -(2-( 1 -methyl- 1 H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N-(pyridin-2-yl)-2,3- dihydro- lH-indene-5-sulfonamide;

N-(4-fluoropyridin-2-yl)-l-(2-(l -methyl- lH-pyrazol-5-yl)-4-(trifluoromethyl)phenyl) -2,3-dihydro-lH-indene-5-sulfonamide;

N-(5-fluoropyridin-2-yl)-l-(2-(l -methyl- lH-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)- 2,3-dihydro-lH-indene-5-sulfonamide;

1 -(4'-fluoro-5-(trifluoromethyl)-[ 1 , 1 '-biphenyl] -2-yl)-N-(pyrimidin-2-yl)-2,3-dihydro - 1 H-indene-5-sulfonamide;

1 -(4'-fluoro-5-(trifluoromethyl)-[ 1 , 1 '-biphenyl] -2-yl)-N-(6-fluoropyridin-2-yl)-2,3- dihydro- lH-indene-5-sulfonamide;

1 -(4'-fluoro-5-(trifluoromethyl)-[ 1 , 1 '-biphenyl]-2-yl)-N-(thiazol-2-yl)-2,3-dihydro- 1 H-indene-5-sulfonamide;

1 -(4'-fluoro-5-(trifluoromethyl)-[ 1 , 1 '-biphenyl] -2-yl)-N-(oxazol-2-yl)-2,3-dihydro- 1 H-indene-5-sulfonamide;

1 -(2-chloro-4-(trifluoromethyl)phenyl)-N-(4-fluoropyridin-2-yl)-2,3-dihydro- 1 H- indene-5-sulfonamide; l-(2-chloro-4-(trifluoromethyl)phenyl)-N-(pyrimidin-2-yl)-2,3-dihydro- lH-indene-5- sulfonamide;

1 -(2-chloro-4-(trifluoromethyl)phenyl)-N-(6-fluoropyridin-2-yl)-2,3-dihydro- 1 H- indene-5-sulfonamide; l-(2-(2-fluoroethyl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-2-yl)-2,3-dihydro-lH- indene-5-sulfonamide and l-(2-(2-fluoroethyl)-4-(trifluoromethyl)phenyl)-N-(6-fluoropyridin-2-yl)-2,3-dihydro- 1 H-indene-5-sulfonamide. In another embodiment, the invention provides a compound of Formulae (I) and (II) wherein the compound is in free base form.

In another embodiment, the invention provides a compound of Formulae (I) and (II) wherein the compound is pharmaceutically acceptable salt.

In another embodiment, the invention provides compounds of Formulae (I) and (II) structurally encompass stereoisomers including enantiomers or diastereomers.

In another embodiment, the invention provides a compound of Formulae (I) and (II) wherein the compound is racemic mixture containing 'R' isomer and 'S' isomer.

In another embodiment, the invention provides a compound of Formulae (I) and (II) wherein the compound is 'R' isomer.

In another embodiment, the invention provides a compound of Formulae (I) and (II) wherein the compound is 'S' isomer.

In another aspect of the invention, there is provided a compound of Formulae (I) and (II) or a pharmaceutically acceptable salt thereof for use as a medicament.

In another aspect of the invention, there is provided a compound of Formulae (I) and (II), or a pharmaceutically acceptable salt thereof, for use in treating the diseases, disorders, syndromes or conditions associated with VGSC particularly Navl .7.

In another aspect, the invention provides a pharmaceutical composition comprising at least one compound of Formulae (I) and (II), or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

In another aspect, the invention provides a pharmaceutical composition comprising a compound of Formulae (I) and (II), or a pharmaceutically acceptable salt thereof, for use in treating, the diseases disorders, syndromes or conditions associated with VGSC particularly Navl .7 in a subject, in need thereof by administering to the subject, one or more compounds described herein in a therapeutically effective amount to cause modulation of such receptor. In another aspect, the invention provides a pharmaceutical composition comprising a compound of Formulae (I) and (II), or a pharmaceutically acceptable salt thereof, N-oxide thereof, or a pharmaceutically acceptable stereoisomer thereof, together with a pharmaceutically acceptable excipient. In another aspect of the invention, the compounds of the present invention can be used in combination with one or more other compounds of the invention or one or more other therapeutic agent other used to treat pain such as nonsteroidal anti-inflammatory compounds (NSAIDs), steroidal compounds, cyclooxygenase inhibitors and opioid analgesics.

In another aspect of the invention, the composition is suitable for topical, oral, subcutaneous or intravenous administration.

In another aspect of the invention, there is provided use of a compound of Formulae (I) and (II), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating, the diseases, disorders, syndromes or conditions associated with VGSC, particularly Navl.7.

Detailed description of the invention

Definitions and Abbreviations:

Unless otherwise stated, the following terms used in the specification and the claims have the meanings given below.

For purposes of interpreting the specification, the following definitions will apply and whenever appropriate, terms used in the singular will also include the plural and vice versa.

The terms "halogen" or "halo" means fluorine, chlorine, bromine, or iodine.

Unless otherwise stated, in the present application "oxo" means C(=0) group. Such an oxo group may be a part of either a cycle or a chain in the compounds of the present invention. The term "alkyl" refers to an alkane derived hydrocarbon radical that includes solely carbon and hydrogen atoms in the backbone, contains no unsaturation, has from one to six carbon atoms, and is attached to the remainder of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1, 1 - dimethylethyl (t- butyl) and the like. Unless set forth or recited to the contrary, all alkyl groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.

The term "alkenyl" refers to a hydrocarbon radical containing from 2 to 10 carbon atoms and including at least one carbon-carbon double bond. Non-limiting examples of alkenyl groups include ethenyl, 1-propenyl, 2-propenyl (allyl), z'so-propenyl, 2 -methyl- 1- propenyl, 1 -butenyl, 2-butenyl and the like. Unless set forth or recited to the contrary, all alkenyl groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.

The term "alkynyl" refers to a hydrocarbon radical containing 2 to 10 carbon atoms and including at least one carbon- carbon triple bond. Non- limiting examples of alkynyl groups include ethynyl, propynyl, butynyl and the like. Unless set forth or recited to the contrary, all alkynyl groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.

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. Unless set forth or recited to the contrary, all alkoxy groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.

The term "alkoxyalkyl" refers to an alkoxy group as defined above directly bonded to an alkyl group as defined above, e.g., -CH2-O-CH3, -CH2-O-CH2CH3, - CH2CH2-O-CH3 and the like. Unless set forth or recited to the contrary, all alkoxyalkyl groups described or claimed herein may be substituted or unsubstituted.

The term "hydroxyalkyl" refers to an alkyl group, as defined above that is substituted by one or more hydroxy groups. Preferably, the hydroxyalkyl is monohydroxyalkyl or dihydroxyalkyl. Non-limiting examples of a hydroxyalkyl include 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, and the like. The term "haloalkyl" refers to an alkyl group as defined above that is substituted by one or more halogen atoms as defined above. Preferably, the haloalkyl may be monohaloalkyl, dihaloalkyl or polyhaloalkyl including perhaloalkyl. A monohaloalkyl can have one iodine, bromine, chlorine or fluorine atom. Dihaloalkyl and polyhaloalkyl groups can be substituted with two or more of the same halogen atoms or a combination of different halogen atoms. Preferably, a polyhaloalkyl is substituted with up to 12 halogen atoms. Non-limiting examples of a haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl and the like. A perhaloalkyl refers to an alkyl having all hydrogen atoms replaced with halogen atoms. Unless set forth or recited to the contrary, all haloalkyl groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.

The term "cycloalkyl" refers to a non-aromatic mono or multicyclic ring system having 3 to 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. Examples of multicyclic cycloalkyl groups include, but are not limited to, perhydronapththyl, adamantyl and norbornyl groups, bridged cyclic groups or spirobicyclic groups, e.g., spiro(4,4)non-2-yl and the like. Unless set forth or recited to the contrary, all cycloalkyl groups described or claimed herein may be substituted or unsubstituted. The term "cycloalkenyl" refers to a non-aromatic mono or multicyclic ring system having 3 to 12 carbon atoms and including at least one carbon-carbon double bond, such as cyclopentenyl, cyclohexenyl, cycloheptenyl and the like. Unless set forth or recited to the contrary, all cycloalkenyl groups described or claimed herein may be substituted or unsubstituted. The term "cycloalkylalkyl" refers to a cycloalkyl group as defined above, directly bonded to an alkyl group as defined above, e.g., cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclohexylethyl, etc. Unless set forth or recited to the contrary, all cycloalkylalkyl groups described or claimed herein may be substituted or unsubstituted. The term "aryl" refers to an aromatic radical having 6- to 14- carbon atoms, including monocyclic, bicyclic and tricyclic aromatic systems, such as phenyl, naphthyl, tetrahydronaphthyl, indanyl, and biphenyl and the like. Unless set forth or recited to the contrary, all aryl groups described or claimed herein may be substituted or unsubstituted. The term "arylalkyl" refers to an aryl group as defined above directly bonded to an alkyl group as defined above, e.g., -CH2C6H5 and -C2H4C6H5. Unless set forth or recited to the contrary, all arylalkyl groups described or claimed herein may be substituted or unsubstituted.

A "4 to 8" membered cyclic ring" as used herein refers to a monocyclic or bicyclic heteroaryl or heterocyclic ring systems.

The term "heterocyclic ring" or "heterocyclyl ring" or "heterocyclyl", unless otherwise specified, refers to substituted or unsubstituted non-aromatic 3- to 15- membered ring which consists of carbon atoms and with one or more (e.g., 2 or 3) heteroatom(s) independently selected from N, O or S. The heterocyclic ring may be a mono-, bi- or tricyclic ring system, which may include fused, bridged or spiro ring systems and the nitrogen, carbon, oxygen or sulfur atoms in the heterocyclic ring may be optionally oxidized to various oxidation states. In addition, the nitrogen atom may be optionally quaternized, the heterocyclic ring or heterocyclyl may optionally contain one or more olefinic bond(s) and one or two carbon atoms(s) in the heterocyclic ring or heterocyclyl may be interrupted with -CF2-, -C(O)-, -S(O)-, S(0)2, -C(=N-alkyl)-, or -C(=N-cycloalkyl), etc. In addition heterocyclic ring may also be fused with aromatic ring. Non-limiting examples of heterocyclic rings include azetidinyl, oxetanyl, benzopyranyl, chromanyl, decahydroisoquinolyl, indolinyl, isoindolinyl, isochromanyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, oxazolinyl, oxazolidinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxooxazolidinyl, 2-oxoazepinyl, octahydroindolyl, octahydroisoindolyl, perhydroazepinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, piperidinyl, phenothiazinyl, phenoxazinyl, quinuclidinyl, tetrahydroisquinolyl, tetrahydrofuryl, tetrahydropyranyl, thiazolinyl, thiazolidinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone indoline, benzodioxole, tetrahydroquinoline, tetrahydrobenzopyran and the like. The heterocyclic ring may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure. Unless set forth or recited to the contrary, all heterocyclyl groups described or claimed herein may be substituted or unsubstituted; substituents may be on same or different ring atom. The term "heteroaryl" unless otherwise specified, refers to a substituted or unsubstituted 5- to 14- membered aromatic heterocyclic ring with one or more (e.g., 2 or 3) heteroatom(s) independently selected from N, O or S. The heteroaryl may be a mono-, bi- or tricyclic ring system. The heteroaryl ring may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure. Non- limiting examples of a heteroaryl ring include oxazolyl, pyrazolyl, isoxazolyl, imidazolyl, furyl, indolyl, isoindolyl, indazolyl, pyrrolyl, triazolyl, triazinyl, tetrazolyl, thienyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzofuranyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzothienyl, carbazolyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, naphthyridinyl, pteridinyl, purinyl, quinoxalinyl, quinolyl, isoquinolyl, thiadiazolyl, indolizinyl, acridinyl, phenazinyl, phthalazinyl and the like. Unless set forth or recited to the contrary, all heteroaryl groups described or claimed herein may be substituted or unsubstituted.

The term "heterocyclylalkyl" refers to a heterocyclic ring radical directly bonded to an alkyl group. 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. Unless set forth or recited to the contrary, all heterocyclylalkyl groups described or claimed herein may be substituted or unsubstituted.

The term "heteroarylalkyl" refers to a heteroaryl ring radical directly bonded to an alkyl group. The heteroarylalkyl 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. Unless set forth or recited to the contrary, all heteroarylalkyl groups described or claimed herein may be substituted or unsubstituted.

The compounds of the present invention may have one or more chiral centers. The absolute stereochemistry at each chiral center may be 'R' or 'S'. The compounds of the invention include all diastereomers and enantiomers and mixtures thereof. Unless specifically mentioned otherwise, reference to one stereoisomer applies to any of the possible stereoisomers. Whenever the stereoisomeric composition is unspecified, it is to be understood that all possible stereoisomers are included. The term "stereoisomer" refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures which are not interchangeable. The three-dimensional structures are called configurations. As used herein, the term "enantiomer" refers to two stereoisomers whose molecules are nonsuperimposable mirror images of one another. The term "chiral center" refers to a carbon atom to which four different groups are attached. As used herein, the term "diastereomers" refers to stereoisomers which are not enantiomers. The terms "racemate" or "racemic mixture" refer to a mixture of equal parts of enantiomers.

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

The term "modulate" or "modulating" or "modulation" refers to a decrease or inhibition in the amount, quality, or effect of a particular activity, function or molecule; by way of illustration that antagonists of a voltage-gated sodium channels are modulators of VGSC. Any such modulation, whether it is partial or complete inhibition or prevention of ion flux, is sometimes referred to herein as "blocking" and corresponding compounds as "blockers". For example, the compounds of invention are useful as modulators of the NaV1.7. In general, the compounds of the invention modulates the activity of a sodium channel downwards, inhibits the voltage-dependent activity of the sodium channel, and/or reduces or prevents sodium ion flux across a cell membrane by preventing sodium channel activity such as ion flux.

The term "subject" includes mammals, preferably humans and other animals, such as domestic animals; e.g., household pets including cats and dogs.

A "therapeutically effective amount" refers to the amount of a compound that, when administered to a subject in need thereof, is sufficient to cause a desired effect. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity, age, weight, physical condition and responsiveness of the subject to be treated. The compounds of the invention may form salts with acid or base. The compounds of invention may be sufficiently basic or acidic to form stable nontoxic acid or base salts, administration of the compound as a pharmaceutically acceptable salt may be appropriate. Non-limiting examples of pharmaceutically acceptable salts are inorganic, organic acid addition salts formed by addition of acids including hydrochloride salts. Non-limiting examples of pharmaceutically acceptable salts are inorganic, organic base addition salts formed by addition of bases. The compounds of the invention may also form salts with amino acids. Pharmaceutically acceptable salts may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion. With respect to the overall compounds described by the Formula (I), the invention extends to these stereoisomeric forms and to mixtures thereof. To the extent prior art teaches synthesis or separation of particular stereoisomers, the different stereoisomeric forms of the invention may be separated from one another by a method known in the art, or a given isomer may be obtained by stereospecific or asymmetric synthesis or chiral HPLC (high performance liquid chromatography. Tautomeric forms and mixtures of compounds described herein are also contemplated.

The screening of compounds of the invention for VGSC modulatory activity can be achieved by using various in vitro and in vivo protocols. Some of the methods include measuring current (electrophysiology), estimating membrane potential (using membrane potential dyes or voltage specific dye pairs), measuring ion flux (e.g., Sodium or Guanidium), measuring second messenger and transcription factor levels, measuring sodium concentration or by Rubidium efflux assay. These assays can be performed in tissue slices or cell lines that endogenously express sodium channels (e.g. ND7/23, SHSY- 5Y). Alternatively, one can also use cell lines stably expressing the NaV of interest (e.g., stable cell lines generated in HEK293 cells or CHO cells).

The invention relates to pharmaceutical compositions containing the compound of Formula (I). In particular, the pharmaceutical compositions contain a therapeutically effective amount of at least one compound of Formula (I) and at least one pharmaceutically acceptable excipient (such as a carrier or diluent). Preferably, the pharmaceutical compositions include the compound(s) described herein in an amount sufficient to modulate the ion flux through a voltage-dependent sodium channel to treat sodium channel mediated diseases such as pain when administered to a subject. The compound of the invention may be incorporated with a pharmaceutically acceptable excipient (such as a carrier or a diluent) or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container. The pharmaceutically acceptable excipient includes a pharmaceutical agent that does not itself induce the production of antibodies harmful to the individual receiving the composition, and which may be administered without undue toxicity.

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

The pharmaceutical composition may also include one or more pharmaceutically acceptable auxiliary agents, wetting agents, emulsifying agents, suspending agents, preserving agents, salts for influencing osmotic pressure, buffers, sweetening agents, flavoring agents, colorants, or any combination of the foregoing. The pharmaceutical composition of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the subject by employing procedures known in the art.

The pharmaceutical compositions described herein may be prepared by conventional techniques known in the art. For example, the active compound can be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier, which may be in the form of an ampoule, capsule, sachet, paper, or other container. When the carrier serves as a diluent, it may be a solid, semi-solid, or liquid material that acts as a vehicle, excipient, or medium for the active compound. The active compound can be adsorbed on a granular solid container, for example, in a sachet.

The pharmaceutical compositions may be administered in conventional forms, for example, capsules, tablets, aerosols, solutions, suspensions or products for topical application.

The route of administration may be any route which effectively transports the active compound of the invention to the appropriate or desired site of action. Suitable routes of administration include, but are not limited to, oral, nasal, pulmonary, buccal, subdermal, intradermal, transdermal, parenteral, rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic (such as with an ophthalmic solution) or topical (such as with a topical ointment).

Solid oral Formulations include, but are not limited to, tablets, capsules (soft or hard gelatin), dragees (containing the active ingredient in powder or pellet form), troches and lozenges. Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application. Liquid Formulations include, but are not limited to, syrups, emulsions, suspensions, solutions, emulsions, soft gelatin and sterile injectable liquids, such as aqueous or non-aqueous liquid suspensions or solutions. For parenteral application, particularly suitable are injectable solutions or suspensions, preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.

The pharmaceutical preparation is preferably in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form. For administration to human patients, the total daily dose of the compounds of the invention depends, of course, on the mode of administration. For example, oral administration may require a higher total daily dose, than an intravenous (direct into blood). The quantity of active component in a unit dose preparation may be varied or adjusted from 0.1 mg to 10000 mg, more typically 1.0 mg to 1000 mg, and most typically 10 mg to 500 mg, according to the potency of the active component or mode of administration.

Suitable doses of the compounds for use in treating the diseases disorders, syndromes and conditions described herein can be determined by those skilled in the relevant art. Therapeutic doses are generally identified through a dose ranging study in humans based on preliminary evidence derived from the animal studies. Doses must be sufficient to result in a desired therapeutic benefit without causing unwanted side effects for the patient. For example, the daily dosage of the Sodium channel modulator can range from about 0.1 to about 30.0 mg/kg. Mode of administration, dosage forms, suitable pharmaceutical excipients, diluents or carriers can also be well used and adjusted by those skilled in the art. All changes and modifications are envisioned within the scope of the invention.

The compounds of the invention may be combined with one or more other compounds of the invention or one or more other therapeutic agent or as any combination thereof, in the treatment of sodium channel-mediated diseases and conditions. For example, a compound of the invention may be administered simultaneously, sequentially or separately in combination with other therapeutic agents, Examples of such other therapeutic agents include, but are not limited to aspirin, celecoxib, hydrocodone, oxycodone, codeine, fentanyl, ibuprofen, ketoprofen, naproxen, acetaminophen, gabapentin and pregabalin. Examples of classes of medicines that contain compounds that can be used in combination with the compounds of the present invention include non-steroidal anti-inflammatory compounds (NSAIDS), steroidal compounds, cyclooxygenase inhibitors and opioid analgesics.

In an embodiment the invention are provided compounds and pharmaceutical compositions that are useful in the treatment of diseases, disorders, syndromes and/or conditions modulated by NaV channel. The invention further provides a method of treating a disease, condition and/or disorder modulated by NaV channel in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound or a pharmaceutical composition of the invention.

One aspect of the invention provides methods for decreasing ion flow through voltage-gated sodium channels in a cell, comprising contacting a cell containing the target ion channels with a compound, associated to voltage-dependent gated ion channel, described herein.

In another aspect of the invention, the methods are also useful for the diagnosis of conditions that can be treated by acting on ion flux through voltage-dependent gated ion channel, for determining if a patient will be responsible to therapeutic agents.

In still another aspect of the invention provides a method for the treatment of a disorder or condition through modulating a voltage-gated sodium channel. In this method, a subject in need of such treatment is administered an effective amount of a compound described herein and/or according to Formula (I) described herein. The compound of Formula (I), being a voltage-dependent gated sodium channel modulator, is potentially useful in the treating, managing and/or lessening of diseases, disorders, syndromes or conditions including but not limited to pain, erythromyalgia, neurological disorders, cardiovascular conditions, diabetes, cough, neuromuscular conditions, multiple sclerosis, cancer, pruritus, benign prostatic hyperplasia (BPH) and the like.

Pain includes, but is not limited to, acute pain, musculoskeletal pain, post-operative pain, chronic pain, persistent pain, peripherally mediated pain, centrally mediated pain and neuropathic pain.

The compounds, compositions and methods of the invention are of particular use in treating, managing and/or lessening of pain including inflammatory, neuropathic, nociceptive and idiopathic pain.

The compounds, compositions and methods of the invention are of particular use in treating, managing and/or lessening of pain including but not limited to postoperative pain, arthritis pain, osteoarthritis pain, pain associated with cancer including chemotherapy pain, neuropathic pain secondary to metastatic inflammation, neuralgic, orofacial pain, burn pain, somatic pain, dental pain, sciatica pain, intestinal obstruction pain, visceral pain, colicky pain, myofacial pain, trauma pain, labour pain, trigeminal neuralgia, glossopharangyl neuralgia, adiposis dolorosa, acute herpetic and post-therapeutic neuralgia, diabetic neuropathy, causalgia, brachial plexus avulsion, occipital neuralgia, reflex sympathetic dystrophy, fibromyalgia, gout, phantom limb pain, pain following stroke, thalamic lesions, radiculopathy, chronic headache, migraine pain, familial hemiplegic migraine, conditions associated with cephalic pain, sinus headache, tension headache, cardiac pain arising from an ischemic myocardium, pain following stroke, neuropathy secondary to metastatic inflammation, pain due to connective tissue damage, and other forms of neuralgic, neuropathic, and idiopathic pain syndromes.

Idiopathic pain is pain of unknown origin, for example, phantom limb pain. Neuropathic pain is generally caused by injury or infection of the peripheral sensory nerves generally it includes, but is not limited to, pain from peripheral nerve trauma, herpes virus infection, diabetes mellitus, causalgia, plexus avulsion, neuroma, limb amputation, and vasculitis. Neuropathic pain is also caused by nerve damage from chronic alcoholism, human immunodeficiency virus infection, hypothyroidism, uremia, or vitamin deficiencies. The compounds of the invention may be useful for treating certain types of inflammatory disease such as pancreatitis, which includes acute pancreatitis and chronic pancreatitis, is characterized by recurring or persistent abdominal pain with or without steatorrhea or diabetes mellitus, hereditary pancreatitis, pancreatic dysfunction. And it may also useful for treating the pain associated with pancreatitis and its related disorders.

The compounds of the invention may be useful for treating cardiovascular conditions such as arrhythmias, atrial fibrillation and ventricular fibrillation.

Although no mutations in humans have been detected, Navl .6 is thought to play a role in the manifestation of the symptoms associated with multiple sclerosis and has been considered as a target for the treatment of this disease (Craner, M.J., et al. Proc. Natl. Acad. Sci. USA (2004), 101, 8168-73). Navl .7 was first cloned from the pheochromocytoma PC 12 cell line (Toledo-Aral, J. J., et al. Proc. Natl. Acad. Sci. USA (1997), 94, 1527-1532). Its presence at high levels in the growth cones of small-diameter neurons suggested that it could play a role in the transmission of nociceptive information. Although this has been challenged by experts in the field as Navl.7 is also expressed in neuroendocrine cells associated with the autonomic system (Klugbauer, N., et al. EMBO J. (1995), 14, 1084-90) and as such has been implicated in autonomic processes. The compounds of the invention may be useful for treating Crohns disease, multiple sclerosis (MS) and pain associated with multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), disseminated sclerosis, motor failure, ataxia, tremor, muscle weakness, and dystonia. Epilepsy and cardiac arrhythmias are often targets of sodium channel blockers. Recent evidence from animal models suggests that sodium channel blockers may also be useful for neuroprotection under ischemic conditions caused by stroke or neural trauma and in patients with multiple sclerosis (MS). The compounds of the invention may be useful for treating certain type of cancers for example prostate cancer, breast cancer, ovarian cancer, testicular cancer, thyroid neoplasia. The VGSC's are reported to have been expressed in prostate and breast cancer cells. Navl .5 has been identified in breast cancer cells and the enhanced expression of this isoform was associated with strong metastatic potential in vitro and breast cancer progression in vivo. (Fraser et al. Clin. Cancer Res. (2005), JJ_, 5381-5389). Expression of Navl.7 is upregulated ~20 fold in prostate cancer. Moreover, the expression correlates with high metastatic potential in vitro. {Current Pharmaceutical Design (2006), 12, 3681- 3695; Prostate Cancer and Prostatic Diseases (2005), 8, 266-273).

The compounds of invention may be useful in the treatment of epilepsy, partial and general tonic seizures, arrhythmias, fibromyalgia, neuroprotection under ischaemic conditions caused by stroke, glaucoma or neural trauma, neuromuscular conditions such as restless leg syndrome and muscle paralysis or tetanus.

The compounds of invention may be useful in the treatment of pruritus and related diseases such as psoriatic pruritus, itch due to hemodialysis, aguagenic pruritus, itching caused by skin disorders, allergic itch, insect bite itch, itch caused by hypersensitivity such as dry skin, acne, eczema, psoriasis or injury, itch caused by vulvar vestibulitis and the similar itch.

The compounds of the invention may be useful in treating the symptoms associated with BPH (benign prostate hyperplasia) including but not limited to acute urinary retention and urinary tract infection.

The compounds of the invention may be useful in treating the symptoms associated with cough reflex.

The compounds described herein may be prepared by techniques known in the art. In addition, the compounds described herein may be prepared by following the reaction sequences as depicted in Schemes- 1 & 2, wherein ring A, Ri, R2, R3, 'm' and 'n' are as described herein above. Further, in the following schemes, where specific bases, acids, reagents, solvents, coupling agents, etc. are mentioned, it is understood that other bases, acids, reagents, solvents, coupling agents etc., known in the art may also be used and are therefore included within the scope of the present invention. Variations in reaction conditions, for example, temperature and/or duration of the reaction, which may be used as known in the art, are also within the scope of the present invention. All the isomers of the compounds described in these schemes, unless otherwise specified, are also encompassed within the scope of this invention. General Scheme- 1

Figure imgf000029_0001
The compound of general formula (I) is prepared starting from formula 1 as depicted in Scheme- 1. The compound of formula 1 reacts with benzyl mercaptan under basic conditions in suitable solvent using Pd catalysts to yield compound of formula 2. The compound of formula 2 reacts with 4-methylbenzenesulfonohydrazide to give compound of formula 3, which further reacts with aryl halide 4 (where X = halogen) in presence of Pd- catalysts to give compound of formula 5. The compound of formula 5 reacts with NCS (N-chloro succinimide) in acetic acid - water leading to the formation of sulfonyl chloride which on treatment with 2,3,4,5,6 - pentafluorophenol in the presence of organic base for example triethyl amine gives compound of formula 6. This compound of formula 6 on hydrogenation gives compound of formula 7. Alternatively, compound of formula 7 can also be prepared by the reaction of compound of formula 3 with suitably substituted aryl boronic acids or boronates 8 in presence of base to yield compound 9, which on further reaction with NCS in acetic acid - water followed by 2,3,4,5,6 - pentafluorophenol will give compound of formula 7. Finally, the compound of formula 7 reacts with various heteroaryl amines 10 in presence of base and solvent to give compounds of formula (I). Alternatively compound of formula 7 reacts with protected heteroaryl amines of formula 11 in the presence of a suitable base for example LiHMDS to give the compound of formula 12 which upon deprotection of amine group gives the compound of formula (I). When one of the R2 is halogen in compound of formula (12), it can further react with various aryl or heteroaryl boronic acid or boronic ester followed by reaction with TFA to give the compound of formula (I).

General Scheme-2

Figure imgf000030_0001

i. NCS, acetic acid ii. 2,3,4,5,6- pentafluorophenol

Figure imgf000030_0002

The compounds of formula (I) can also be prepared by converting a compound of formula 1 to corresponding triflate of formula 13 by using a suitable triflating agent and base known in the literature. This can be coupled to boronic acids / esters 8 using Pd - catalyzed conditions to yield compound of formula 14 which is further reacted with benzyl mercaptan to yield compound of formula 5. Further, reacting a compound of formula 5 with NCS in acetic acid - water leads to the formation of sulfonyl chloride which on treatment with 2,3,4,5,6 - pentafluorophenol the presence of organic base gives compound of formula 6. This undergoes hydrogenation to yield compound of formula 7 which further can couple with amino compound of formula (10) to give compounds of formula (I).

General Scheme-3

Figure imgf000031_0001

The required enantiomers of formula (I) can be prepared by following a diastereomeric separation approach in which compounds of formula 5 can undergo a hydroboration-oxidation sequence to give the alcohols of formula 15 as a mixture of trans isomers. Ester formation with suitable derivatizing agents, e.g. amino acids of which Boc- L-proline is a representative example, can give compounds of formula 16 which can be separated by column chromatography or crystallization to give the individual diastereomers of formula 17. The required diastereomer can then be hydrolyzed to give the free alcohol of formula 18. The alcohol can undergo deoxygenation via a thio/xanthate derivative 19 to compounds of formula 20. The chloro substitution on 20 can be functionalized using a boronic acid to give compounds 21. Further, reacting a compound of formula 21 with NCS or SO2CI2 in acetic acid - water leads to the formation of sulfonyl chloride which on treatment with 2,3,4,5,6 - pentafluorophenol in the presence of organic base gives compound of formula 22. The reaction of pentafluoroester 22 with amino compound of formula (10) in presence of a base like LiHMDS forms sulfonamide compounds of formula (I).

General Scheme-4

Figure imgf000032_0001

The required enantiomers of compounds of formula (I) can also be prepared by following a diastereoselective 1,4-addition approach. For which Heck reaction of appropriate starting material, halo derivatives such as 23with acrylates can give cinnamic esters of formula 24 which on subsequent hydrolysis can give cinnamic acids of formula 25. The acids can be converted to acid chlorides and coupled with Evan's chiral oxazolidinones to give compounds of formula 26. These can undergo copper catalyzed 1,4- addition of Grignard reagent prepared from dihalo compounds like 1 -bromo-4-iodobenzene to give compounds of formula 27. The auxiliary can be cleaved and the acid 28 cyclized to give the indanone derivative 29. Reduction of the keto group gives compounds of formula 30 after which the bromo substitution can be converted to the thiobenzyl group as in 20. This chloro compound can then be converted to sulfonamide compounds of formula (I) by suitable transformations as outlined in the previous schemes. Experimental

The invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and do not limit the scope of the invention. The examples set forth below demonstrate the synthetic procedures for the preparation of the representative compounds. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the invention. The aforementioned patents and patent applications are incorporated herein by reference.

Unless otherwise stated, work-up implies the following operations: distribution of the reaction mixture between the organic and aqueous phase, separation of layers, drying the organic layer over sodium sulfate, filtration and evaporation of the organic solvent. Purification, unless otherwise mentioned, implies purification by silica gel chromatographic techniques, generally using ethyl acetate/petroleum ether mixture of a suitable polarity as the mobile phase.

Abbreviations Used

DCM, CH2C12: Dichloromethane; DMF: Ν,Ν-Dimethylformamide; DCE: Dichloroethane; IPA: Isopropyl Alcohol; THF: Tetrahydrofuran; TFA: Trifluoroacetic acid; NCS: N-Chlorosuccinimide; DCC: N, N'-Dicyclohexylcarbodiimide; AIBN: Azobisisobutyronitrile; LiHMDS: Lithium bis(trimethylsilyl)amide; HATU: 1- [Bis(dimethylamino)methylene] - 1 H- 1 ,2,3 -triazolo [4,5 -b]pyridinium 3 -oxid hexafluorophosphate; Deoxo-Fluor: Bis(2-methoxyethyl)aminosulfur trifluoride; EDTA: Ethylenediaminetetraacetic acid; Pd2(dba)3 : Tris(dibenzylideneacetone)dipalladium(0); PdCl2(dppf)-DCM: [l, l '-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane; TLC: Thin Layer chromatography; MeOH: Methanol; DEA: Diethanolamine; EtOAc: Ethyl acetate; H2O2: Hydrogen peroxide; DMSO: Dimethyl sulfoxide; LiOH: Lithium hydroxide: SOCb: Thionyl chloride; Me2S: Dimethyl sulphide; Na2S04: Sodium sulfate; Na2C03: Sodium carbonate; NaHCCb: Sodium bicarbonate; NH4C1: Ammonium chloride; BH3: Borane; HEX: hexane. INTERMEDIATES

Intermediate-1: (S)-benzyl(l-(2-chloro-4-(trifluoromethyl)phenyl)-2,3-dihydi inden-5-yl)sulfane

Figure imgf000034_0001

(Method 1: using the Diastereomer separation method as in General Scheme-3) Step-1 : N'-(5-(benzylthio)-2,3-dihydro- lH-inden- 1 -ylidene)-4-methylbenzene sulfonohydrazide

Figure imgf000034_0002

A stirred solution of 5-(benzylthio)-2,3-dihydro-lH-inden- l-one (400 g, 1.57 mol) [synthesized as described in Howbert et al., Synth Commun, 1990, 20 (20), 3193 - 3200] and 4-methylbenzenesulfonohydrazide (322 g, 1.73 mol) in 4.5 L MeOH was heated at 70 °C for 17 h. The reaction mixture was cooled to 0 °C and the solid formed was filtered, washed with cold methanol and dried under vacuum. The filtrate was concentrated and the solid obtained was washed with cold methanol. The combined solid was dried under vacuum to obtain off white solid. (Yield: 600 g, 90%)

!H-NMR (400 MHz, DMSO-ifc), δ 10.31 (s, 1H), 7.81 (d, J = 7.9 Hz, 2H), 7.43 - 7.34 (m, 5H), 7.33 - 7.27 (m, 3H), 7.26 - 7.19 (m, 2H), 4.28 (s, 2H), 2.99 - 2.92 (m, 2H), 2.76 - 2.67 (m, 2H), 2.37 (s, 3H). LCMS (ESI): m/z 423.01 (M+H)+.

Step 2: benzyl(3-(2-chloro-4-(trifluoromethyl)phenyl)- lH-inden-6-yl)sulfane

Figure imgf000035_0001

To a stirred solution of N'-(5-(benzylthio)-2,3-dihydro- lH-inden- l-ylidene)-4- methylbenzene sulfonohydrazide (500 g, 1.18 mol) and 1 -bromo-2-chloro-4- (trifluoromethyl)benzene (614 g, 2.37 mol) in a mixture of degassed 5.83 L Dioxane-EhO (6: 1) was added Na2C03 (314 g, 2.96 mol) followed by PdCl2(dppf)-CH2Cl2Adduct (97 g, 1 18 mmol) and the reaction mixture was heated at 80°C for 36 h. After completion of reaction, the mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure to get the crude product which was purified by column chromatography to obtain a pale yellow solid. Yield (250 g, 51% ).

¾ NMR (400 MHz, Chloroform-if) δ 7.80 (s, 1H), 7.61 (d, J = 8.1 Hz, 1H), 7.54 (s, 2H), 7.38 - 7.28 (m, 6H), 7.15 - 7.04 (m, 1H), 6.65 (d, J = 3.0 Hz, 1H), 4.17 (s, 2H), 3.58 (s, 2H). LCMS (ESI): m/z 417.18 (M+H)+.

Step 3: 5-(benzylthio)- l-(2-chloro-4-(trifluoromethyl)phenyl)-2,3-dihydro-lH-inden-2-ol

Figure imgf000035_0002

Benzyl(3-(2-chloro-4-(trifluoromethyl)phenyl)-lH-inden-6-yl)sulfane (235 g, 564 mmol) was dissolved in 2.3 L THF, and to this stirred solution was added a 1M solution of BH3.THF (1409 ml, 1409 mmol) at 0°C and after the addition, the mixture was stirred overnight at room temperature. A 2M solution of sodium hydroxide (1 127 ml, 2255 mmol) was added dropwise at 0°C to the reaction mixture over a period of 2 h, followed by the addition of 30% H2O2 (256 g, 2255 mmol) over a period of 1 h and left to stir for 30 min. The reaction mixture was poured into brine solution and extracted with ethyl acetate. The organic layer was washed with water, dried over Na2S04 and concentrated to get the crude compound which was purified by column chromatography to obtain the pure compound as a viscous liquid. Yield (146 g, 60 %)

¾ NMR (400 MHz, Chloroform-if) δ 7.74 (d, J = 1.8 Hz, 1H), 7.45 - 7.39 (m, 1H), 7.36 - 7.32 (m, 4H), 7.31 - 7.29 (m, 2H), 7.23 - 7.16 (m, 1H), 6.96 - 6.84 (m, 2H), 4.81 (d, J = 4.4 Hz, 1H), 4.56 (d, J = 6.3 Hz, 1H), 4.16 (s, 2H), 3.24 (d, J = 6.3 Hz, 1H), 2.97 (d, J = 4.7 Hz, 1H). LCMS (ESI): m/z 435.14 (M+H)+.

Step 4: 2-((l S,2R)-5-(benzylthio)-l-(2-chloro-4-(trifluoromethyl)phenyl)-2,3-dihydro- lH-inden-2-yl) l-(tert-butyl) (S)-pyrrolidine-l,2-dicarboxylate

Figure imgf000036_0001

To a solution of 5-(benzylthio)-l-(2-chloro-4-(trifluoromethyl)phenyl)-2,3- dihydro-lH-inden-2-ol (145 g, 333 mmol) in 1.5 L DCM was added (S)-l-(tert- butoxycarbonyl)pyrrolidine-2-carboxylic acid (86 g, 400 mmol) followed by DCC (83 g, 400 mmol) at room temperature The progress of the reaction was monitored by TLC and the reaction was complete in an hour. The reaction mixture was then filtered through a pad of celite to remove the urea by-product and the filtrate was concentrated to obtain the crude. The diastereomers were separated by column chromatography to obtain the required (S, R)- diastereomer as a viscous liquid. Yield (86 g, 41%, based on the separated diastereomer)

¾ NMR (400 MHz, Chloroform-if) δ 7.71 (d, J = 7.8 Hz, 1H), 7.42 (d, J = 8.3 Hz, 1H), 7.36 - 7.23 (m, 7H), 7.22 - 7.15 (m, 1H), 6.95 (d, J = 8.2 Hz, 1H), 6.91 - 6.82 (m, 1H), 5.51 - 5.39 (m, 1H), 4.98 (t, J = 7.3 Hz, 1H), 4.36 - 4.20 (m, 1H), 4.15 (s, 2H), 3.63 - 3.38 (m, 3H), 2.97 (d, J = 18.3 Hz, 1H), 2.34 - 2.11 (m, 1H), 2.02 - 1.76 (m, 3H), 1.41 (d, J = 30.6 Hz, 8H). LCMS (ESI): m/z 654.30 (M+Na)+. Step 5: (1 S,2R)-5-(benzylthio)- l-(2-chloro-4-(trifluoromethyl)phenyl)-2,3-dihydro- 1H- inden-2-ol

Figure imgf000037_0001

To a stirred solution of 2-((lS,2R)-5-(benzylthio)-l-(2-chloro-4-(trifluoromethyl)phenyl)- 2,3-dihydro-lH-inden-2-yl) 1 -(tert-butyl) (S)-pyrrolidine-l,2-dicarboxylate (80 g, 126 mmol) in a mixture of 750 mL THF - H20 (4: 1) was added LiOH-H20 (26.6 g, 632 mmol) and the reaction mixture was stirred at room temperature for 30 h, the progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was diluted with ethyl acetate and washed with brine, dried over sodium sulphate and concentrated under reduced pressure to get the crude compound which was purified by column chromatography. Yield (53 g, 95 %)

¾ NMR (400 MHz, Chloroform-if) δ 7.74 (s, 1H), 7.52 - 7.15 (m, 8H), 6.90 (t, J = 9.2 Hz, 2H), 4.81 (d, J = 4.3 Hz, 1H), 4.56 (d, J = 5.5 Hz, 1H), 4.16 (s, 2H), 3.28 - 3.25 (m, 1H), 2.95 (dd, J = 16.2, 4.7 Hz, 1H). LCMS (ESI): m/z 435.14 (M+H)+.

Step 6: 0-((lS,2R)-5-(benzylthio)-l-(2-chloro-4-(trifluoromethyl)phenyl)-2,3-dihydro- 1 H-inden-2-yl) 1 H-imidazole- 1 -carbothioate

Figure imgf000037_0002

To a stirred solution of (lS,2R)-5-(benzylthio)-l -(2-chloro-4-(trifluoromethyl)phenyl)-2,3- dihydro-lH-inden-2-ol (50 g, 115 mmol) in 500 mL DCE, di(lH-imidazol-l- yl)methanethione (41 g, 230 mmol) was added and the solution was heated at 80°C for 2 h. After completion of reaction as seen from TLC, the reaction mixture was evaporated to dryness under reduced pressure to get the crude which was purified by column chromatography to get the pure compound as a white foamy solid. Yield (53 g, 84 %) ¾ NMR (400 MHz, Chloroform-if) δ 8.43 (d, J = 6.4 Hz, 1H), 7.75 (d, J = 1.8 Hz, 1H), 7.67 (s, 1H), 7.47 (d, J = 8.1 Hz, 1H), 7.34 (d, J = 6.1 Hz, 3H), 7.26 (s, 1H), 7.23 - 7.15 (m, 3H), 7.13 - 7.07 (m, 1H), 6.99 (dd, J = 14.0, 8.1 Hz, 2H), 6.02 (dt, J = 6.6, 4.5 Hz, 1H), 5.26 (d, J = 4.5 Hz, 1H), 4.18 (s, 2H), 3.68 (dd, J = 17.1, 6.7 Hz, 1H), 3.19 (dd, J = 17.2, 4.4 Hz, 1H). LCMS (ESI) : m/z 545.11 (M+H)+.

Step 7: (S)-benzyl(l-(2-chloro-4-(trifluoromethyl)phenyl)-2,3-dihydro- lH-inden-5- yl)sulfane

Figure imgf000038_0001
To a stirred solution of 0-(( 1 S,2R)-5-(benzylthio)- 1 -(2-chloro-4-(trifluoromethyl)phenyl)- 2,3-dihydro-lH-inden-2-yl) lH-imidazole- l-carbothioate (52 g, 96 mmol) in 500 mL toluene, AIBN (3.13 g, 19 mmol) was added followed by 1, 1, 1,3,3, 3-hexamethyl-2- (trimethylsilyl)trisilane (21 g, 86 mmol) and the reaction mixture was stirred at 80°C for 40 min. After completion of the reaction, the mixture was added to ice cold water and the organic layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over sodium sulphate and concentrated under reduced pressure to get the crude compound which was purified by column chromatography. Yield (32 g, 81 %)

¾ NMR (400 MHz, Chloroform-if) δ 7.70 (s, 1H), 7.41 (d, J = 8.3 Hz, 1H), 7.36 - 7.29 (m, 5H), 7.26 (d, J = 4.1 Hz, 1H), 7.16 (d, J = 7.9 Hz, 1H), 7.05 (d, J = 8.1 Hz, 1H), 6.91 (d, J = 7.9 Hz, 1H), 4.88 (t, J = 7.9 Hz, 1H), 4.15 (s, 2H), 3.05 - 2.91 (m, 2H), 2.76 - 2.66 (m, 1H), 2.01 - 1.89 (m, 1H). Stereoselective Synthesis of Intermediate-1 using Method 2 (diastereoselective 1,4- addition method as in General Scheme-4):

Step 1: Synthesis oftert-butyl (E)-3-(2- fluoromethyl)phenyl)acrylate

Figure imgf000039_0001

Acetonitrile (5 L) was taken in a 3 -necked 10 L round bottom flask fitted with an overhead stirrer and reflux condensers. The stirred solution was degassed by passing a flow of N2 for 30 min., after which l-bromo-2-chloro-4-(trifluoromethyl)benzene (500 g, 1.93 mol), tert- butyl acrylate (395 mL, 2.70 mol), triethylamine (672 mL, 4.82 mol), tri-o-tolylphosphine (23.46 g, 77 mmol), and palladium(II) acetate (21.63 g, 96 mmol) were added and the mixture was heated for 16 h at 90 °C.

The reaction mixture was then cooled in an ice bath and filtered through a pad of celite to remove the triethylamine hydrobromide salt and the phosphine oxide. The pad was washed with minimum volume of ethyl acetate and the combined filtrate was concentrated. The residue was dissolved in ethyl acetate and washed with brine and the organic layer was dried over Na2S04 and concentrated in vacuum to obtain crude (E)-tert-butyl 3-(2-chloro- 4-(trifluoromethyl)phenyl)acrylate as a brownish yellow solid (HPLC purity: 86%) which was used as such in the next step.

¾ NMR (400 MHz, Chloroform-i/) δ 7.99 (d, J = 16.0 Hz, 1H), 7.78 - 7.64 (m, 2H), 7.60 - 7.46 (m, 1H), 6.45 (d, J = 16.0 Hz, 1H), 1.57 (s, 9H).

Step 2: Synthesis of (E)-3-(2-chloro-4- ethyl)phenyl)acrylic acid

Figure imgf000039_0002

The crude (E)-tert-butyl 3-(2-chloro-4-(trifluoromethyl)phenyl)acrylate (532 g, 1.74 mol) obtained from the previous step was dissolved in DCM (5 L) and the solution was cooled to 0°C. Trifluoroacetic acid (1.34 L, 17.3 mol) was added to it from a dropping funnel and the reaction was stirred overnight at room temperature. The reaction mixture was concentrated on rotavap and the brownish solid obtained was stirred in water for some time and then filtered. The solid was washed with water until the filtrate was neutral and the filtered solid was dissolved in ethyl acetate. The ethyl acetate layer was washed with brine and the organic layer was dried over Na2S04 and concentrated in vacuum to obtain the acid as a pale brown solid. This solid was stirred in hexane and filtered to obtain the pure (E)- 3-(2-chloro-4-(trifluoromethyl)phenyl)acrylic acid. (Yield = 400 g, 83 % over two steps). 1H NMR (400 MHz, DMSO-ifc) δ 12.85 (s, 1H), 8.14 (d, J = 8.3 Hz, 1H), 7.96 (s, 1H), 7.85 (d, J = 16.0 Hz, 1H), 7.74 (dd, J = 8.4, 1.9 Hz, 1H), 6.74 (d, J = 15.9 Hz, 1H). GCMS: m/z = 250.19 (M +)

Step 3: Synthesis of (R, E)-3-(3-(2-chloro-4-(trifluoromethyl)phenyl)acryloyl)-4- phenyloxazolidin-2-one

Figure imgf000040_0001

(E)-3-(2-chloro-4-(trifluoromethyl)phenyl)acrylic acid (150 g, 599 mmol) was dissolved in 1 L DCM and a catalytic amount of dry DMF (2.3 mL, 31 mmol) was added to it. Thionyl chloride (175 mL, 2394 mmol) was added to it dropwise and the reaction mixture was refluxed for 3 h (until a clear solution formed).The solvent and the remaining SOQ2 was removed by distillation. The crude acid chloride was co-distilled with dry toluene to remove traces of thionyl chloride. The resulting acid chloride was dissolved in 750 mL dry THF and slowly added from a dropping funnel to a precooled lithiated (R)-4-phenyloxazolidin- 2-one (97.5 g, 599 mmol) suspension, which was prepared before by adding 1.6 M solution of n-butyllithium (374 mL, 599 mmol)) into a solution of (R)-4-phenyloxazolidin-2-one (97.5 g, 599 mmol) in 1.25 L dry THF at -78 °C. The resulting reaction mixture was allowed to warm to room temperature over a period of 2 h. The reaction was quenched by the addition of saturated aqueous NFL CI solution and then extracted with ethyl acetate, washed with dilute NaHCCb solution followed by brine. The organic layer was dried over anhydrous Na2S04 and concentrated and the crude product was stirred in 1 L IPA until the product became a fine powder. The solid was filtered and dried, re-dissolved in dichloromethane (DCM) and washed with brine followed by anhydrous Na2S04 to remove traces of adsorbed IPA from the previous treatment and concentrated to obtain the pure product as a light brown solid.(Yield = 200 g, 84 %)

¾ NMR (400 MHz, DMSO-ifc) δ 8.05 - 7.80 (m, 5H), 7.46 - 7.31 (m, 5H), 5.60 (dd, J = 8.6, 4.0 Hz, 1H), 4.83 (t, J = 8.7 Hz, 1H), 4.25 (dd, J = 8.7, 4.0 Hz, 1H). LCMS: 395.93

(M+H)+

Step 4: Synthesis of (R)-3-((S)-3-(4-bromophenyl)-3-(2-chloro-4- (trifluoromethyl)phenyl)propanoyl)-4-phenyloxazolidin-2-one

Figure imgf000041_0001

1 -bromo-4-iodobenzene (222 g, 783 mmol) was dissolved in 1.7 L dry THF and the solution was cooled to 0 °C. A 2 M solution of isopropylmagnesium chloride (379 mL, 760 mmol) was added to it and the desired Grignard reagent was allowed to form over a period of 1 h. The milky solution of the Grignard reagent was added dropwise (over a period of 5 h) to a precooled (-45 °C) mixture of copper(I)bromide-dimethyl sulfide complex (78 g, 379 mmol) and (R,E)-3-(3-(2-chloro-4-(trifluoromethyl)phenyl)acryloyl)-2-phenyloxazolidin- 4-one (100 g, 253 mmol) in 1.7 L of a solvent mixture of dry THF-lVfeS (2: 1). The resulting solution was stirred at -45 °C for 30 min and slowly allowed to warm to room temperature overnight. The reaction mixture was quenched with a satd. solution of NH4C1 solution and extracted with ethyl acetate. The ethyl acetate layer was passed through a pad of Celite and the filtrate was washed with a 10% aq. solution of EDTA followed by a 10% aq. solution of sodium thiosulfate and finally brine. The organic layer was dried over anhydrous Na2S04 and concentrated to obtain the crude product, (crude diastereomeric ratio= 96:4 as seen from reverse phase HPLC).

Removal of unrequired diastereomer: The crude residue (220 g) was dissolved in 150 mL of toluene and 300 mL of hexane was added and the mixture was stirred with an overhead stirrer for 16 h. The white solid obtained was filtered and the solid was washed with a mixture of toluene-hexane (1 : 10) and dried. Recrystallization can be repeated with 7 vol of a solvent mixture of toluene-hexane ( 1 :2) until the required purity is achieved (unrequired diastereomer <0.3%). The combined filtrate can be concentrated and subjected to repeated recrystallization to get maximum recovery. (Yield = 98 g, 70 %).

¾ NMR (400 MHz, Chloroform-if) δ 7.62 (d, J = 1.8 Hz, 1H), 7.51 - 7.43 (m, 2H), 7.38 - 7.26 (m, 5H), 7.12 - 7.02 (m, 4H), 5.39 (dd, J = 8.8, 4.1 Hz, 1H), 5.1 1 (t, J = 7.8 Hz, 1H), 4.70 (t, J = 8.9 Hz, 1H), 4.28 (dd, J = 9.0, 4.1 Hz, 1H), 3.91 (dd, J = 16.9, 7.8 Hz, 1H), 3.59 (dd, J = 16.9, 7.9 Hz, 1H). LCMS: 573.88 & 575.88 (M+Na)+

Step 5: Synthesis of (S)-3-(4-bromophenyl)-3-(2-chloro-4-

(trifluoromethyl)phenyl)propanoic acid

Figure imgf000042_0001

(S)-3-((R)-3-(4-bromophenyl)-3-(2-chloro-4-(trifluoromethyl)phenyl)propanoyl)-4- phenyloxazolidin-2-one (77 g, 139 mmol) was dissolved in a mixture of 580 mL THF and 78 mL H20 and cooled to 0°C. A 30 % solution of H2O2 (1 14 mL, 1 1 14 mmol) was added to it followed by L1OH.H2O (7.79 g, 181 mmol) and the reaction mixture was stirred at that temperature. The progress of the reaction was monitored by TLC, and after 1 h, the reaction was quenched by adding an ice-cold 2 N HC1 solution. The organic layer was diluted with ethyl acetate and washed with brine, dried over anhydrous Na2S04 and concentrated. The crude product was triturated with a mixture of diethyl ether-hexane (5:95). The solids were filtered to obtain the recovered auxiliary and the filtrate was concentrated to obtain the product acid as a white sticky solid. (Yield = 52 g, 91 %)

¾ NMR (400 MHz, Chloroform-if) δ 7.69 - 7.63 (m, 1H), 7.55 - 7.49 (m, 1H), 7.49 - 7.43 (m, 2H), 7.36 (d, J = 8.2 Hz, 1H), 7.18 - 7.09 (m, 2H), 5.04 (t, J = 7.9 Hz, 1H), 3.09 (dd, J = 7.9, 4.9 Hz, 2H). LCMS: 407.89 (M+H)+

Step 6: Synthesis of (S)-6-bromo-3-(2-chloro-4-(trifluoromethyl)phenyl)-2,3-dihydro- lH- inden- 1 -one

Figure imgf000043_0001

CF3

(S)-3-(4-bromophenyl)-3-(2-chloro-4-(trifluoromethyl)phenyl)propanoic acid (56.3 g, 138 mmol) was dissolved in 550 mL DCM and the solution was cooled to 0 °C. Chlorosulfonic acid (93 mL, 1382 mmol) was added dropwise and the reaction mixture was warmed to room temperature and stirred for 2 h. After completion of reaction, the mixture was slowly poured into crushed ice. The organic layer was diluted with ethyl acetate and washed with brine, dried over anhydrous Na2S04 and concentrated and the crude product obtained was used as such in the next step. (Yield = 51 g, 94 %)

¾ NMR (400 MHz, Chloroform-if) δ 8.00 (d, J = 1.9 Hz, 1H), 7.79 - 7.70 (m, 2H), 7.51 - 7.40 (m, 1H), 7.24 (d, J = 8.2 Hz, 1H), 7.02 (s, 1H), 5.1 1 (d, J = 7.7 Hz, 1H), 3.37 (dd, J = 19.4, 8.3 Hz, 1H), 2.64 (d, J = 19.4 Hz, 1H). LCMS: 388.76 & 390.76 (M+H)+

Step 7: Synthesis of (S)-5-bromo-l-(2-chloro-4-(trifluoromethyl)phenyl)-2,3-dihydro-lH- indene

Figure imgf000043_0002

(S)-6-bromo-3-(2-chloro-4-(trifluoromethyl)phenyl)-2,3-dihydro-lH-inden-l-one (44 g, 1 13.7 mmol) was dissolved in 400 mL of trifluoroacetic acid and triethylsilane (55 mL, 341 mmol) was added to it and the reaction mixture was stirred at room temperature overnight. The progress of the reaction was monitored by TLC and after completion, the mixture was concentrated on the rotavap and the residue was quenched by pouring it in to an ice-cold satd. solution of NaHCCb. The organic layer was diluted with ethyl acetate and washed with brine, dried over anhydrous Na2S04 and concentrated and the crude product was purified by column chromatography to obtain the pure product as a white sticky liquid. (Yield = 40 g, 94 %)

¾ NMR (400 MHz, Chloroform-if) δ 7.76 - 7.64 (m, 1H), 7.49 (s, 1H), 7.42 (dd, J = 8.2, 1.9 Hz, 1H), 7.33 (dd, J = 8.0, 1.8, 1H), 7.1 1 - 7.00 (m, 1H), 6.89 (dd, J = 8.1, 1.0 Hz, 1H), 4.87 (t, J = 7.9 Hz, 1H), 3.10 - 2.94 (m, 2H), 2.72 (m, 1H), 2.04 - 1.93 (m, 1H). GCMS: m/z = 374.24 & 376.26 (M +)

Step 8: Synthesis of (S)-benzyl(l-(2-chloro-4-(trifluoromethyl)phenyl)-2,3-dihydro-lH- inden-5-yl)sulfane

Figure imgf000044_0001

(S)-5-bromo-l-(2-chloro-4-(trifluoromethyl)phenyl)-2,3-dihydro-lH-indene (30 g, 80 mmol) was dissolved in 300 mL of 1,4-Dioxane and the solution was degassed by passing nitrogen through it. Xantphos (2.31 g, 4 mmol), Pd2(dba)3 (2.20 g, 2.37 mmol), benzyl mercaptan (9.25 mL, 78.2 mmol) and Hunig's Base (28 mL, 160 mmol) were added to it and the reaction mixture was heated at 80 °C for 3 h. After completion of reaction, the reaction mixture was filtered through a pad of celite. The filtrate was diluted with ethyl acetate and washed with 2 N HC1 solution followed by brine and the organic layer was dried over Na2S04 and concentrated to obtain the crude product. This was purified by column chromatography to obtain the product as a white solid. (Yield = 31 g, 93 %). ¾ NMR (400 MHz, Chloroform-if) δ 7.70 (dd, J = 1.7, 0.8 Hz, 1H), 7.45 - 7.39 (m, 1H), 7.37 - 7.24 (m, 6H), 7.22 - 7.12 (m, 1H), 7.05 (d, J = 8.2 Hz, 1H), 6.91 (d, J = 7.9 Hz, 1H), 4.88 (t, J = 7.8 Hz, 1H), 4.15 (s, 2H), 3.04 - 2.91 (m, 2H), 2.71 (m, 1H), 2.05 - 1.90 (m, 1H).

Determination of the absolute configuration of Intermediate-1 :

To determine the absolute configuration of Intermediate 1 prepared either by Method- 1 or 2, it was converted to a primary sulfonamide derivative by methods well known in the art. Single crystals of the primary sulfonamide were obtained from a solution of chloroform. The absolute configuration of the sulfonamide derivative was determined to be 'S' by a single crystal X-ray crystallographic analysis. Intermediate-2/2a:

Figure imgf000045_0001

lnt-2 lnt-2a

Perfluorophenyl 1 -(2-chloro-4-(trifluoromethyl)phenyl)-2,3-dihydro- lH-indene-5- sulfonate (Int-2-racemic):

Step 1: Perfluorophenyl 3-(2-chloro-4-(trifluoromethyl)phenyl)-lH-indene-6-sulfonate To a cold suspension (5 °C) of benzyl(3-(2-chloro-4-(trifluoromethyl)phenyl)-lH-inden-6- yl)sulfane (1 g, 1.9 mmol) from Step 2 of Intermediate 1 (Method-1) in acetic acid (10 mL) and water (1 mL) was added NCS (0.73 g, 5.4 mmol) in two portions. After completion of the reaction as indicated by TLC, the reaction mixture was diluted with DCM. The organic layer was washed with water, followed by brine. The organic layer was dried over Na2S04 and evaporated to dryness under vacuum. This crude sulfonyl chloride was taken in DCM (10 mL) and added into a stirring solution of 2,3,4,5,6-pentafluorophenol (0.54 g, 2.9 mmol) and triethylamine (1.9 ml, 13.6 mmol) in 10 mL DCM at 0 °C. The reaction mixture was gradually warmed to room temperature and stirred for 45 min. The reaction mixture was quenched with water, followed by extraction with DCM. The organic layer was washed with brine, dried over sodium sulphate and purified by column chromatography to obtain a brown sticky mass (Yield = 700 mg, 55%).

¾-NMR (400 MHz, DMSO-ifc) δ 8.24 (s, 1H), 8.10 (s, 1H), 7.93 (d, J= 8.3 Hz, 1H), 7.88 (d, J = 8.1 Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.43 (d, J= 8.4 Hz, 1H), 7.23 (s, 1H), 3.96 - 3.83 (m, 2H). LCMS (ESI) : m/z 562.95 (M+Na)+.

Step 2: Perfluorophenyl l-(2-chloro-4-(trifluoromethyl)phenyl)-2,3-dihydro-lH-indene-5- sulfonate

To a solution of product from Step 1 (4.8 g, 8.9 mmol) in EtOAc (100 ml) was added 10% Pd-C (5.7 g) and subjected to hydrogenation at 50 psi for 5 h at room temperature. The reaction mixture was filtered through celite bed and the celite bed was washed with EtOAc. The combined filtrates were concentrated and purified by column chromatography to obtain the title compound. (Yield = 4.3 g, 91%).

¾ NMR (400 MHz, DMSO-ifc) δ 8.03 (s, 1H), 7.96 (s, 1H), 7.81 (d, J= 8.1 Hz, 1H), 7.68 (d, J = 8.2 Hz, 1H), 7.30 (d, J = 8.1 Hz, 1H), 7.24 (d, J = 8.2 Hz, 1H), 5.02 (t, J = 8.3 Hz, 1H), 3.23 - 3.07 (m, 2H), 2.77 - 2.69 (m, 1H), 2.17 - 2.08 (m, 1 H).

Perfluorophenyl (S)- 1 -(2-chloro-4-(trifluoromethyl)phenyl)-2,3-dihydro- 1 H-indene-5- sulfonate (Int-2a; S-enantiomer):

Step 1: The title compound as a single enantiomer was prepared from Intermediate 1 by following the same procedure for sulfonate ester formation as described in Step- 1 of Intermediate 2. Yield: 75%

Intermediate-3/3a: l -(2-Chloro-4-(trifluoromethyl)phenyl)-N-(2,4-dimethoxybenzyl)-N- (6-fluoropyridin-2-yl)-2,3-dihydro- lH-indene-5-sulfonamide

Figure imgf000046_0001

lnt-3 lnt-3a l -(2-Chloro-4-(trifluoromethyl)phenyl)-N-(2,4-dimethoxybenzyl)-N-(6-fluoropyridin-2- yl)-2,3-dihydro- lH-indene-5-sulfonamide (Int-3-racemic):

To a solution of N-(2,4-dimethoxybenzyl)-6-fluoropyridin-2-amine (0.26 g, 0.96 mmol), [synthesized by procedure in WO2014066490] in anhydrous THF (4 ml) was added LiHMDS (1. 16 ml, 1M in THF, 1.16 mmol) at 0 °C and stirred for 0.5 h at the same temperature. Intermediate-2 (0.45 g, 0.83 mmol) in anhydrous THF (0.8 ml) was added to the reaction mixture and stirred for 0.5 h. The reaction mixture was poured in to water and extracted with ethyl acetate, washed with brine, dried over sodium sulphate and concentrated under vacuum. The crude was purified by column chromatography to obtain a colorless solid (Yield = 422 mg, 82%).

¾ NMR (400 MHz, DMSO-ifc) δ 7.99 (t, J = 8.3 Hz, 1H), 7.95 (s, 1H), 7.71 (s, 1H), 7.67 (d, J = 8.3 Hz, 1H), 7.56 (d, J = 7.9 Hz, 1H), 7.32 (d, J= 7.9 Hz, 1H), 7.20 (d, J = 8.3 Hz, 1H), 7.15 (d, J= 8.1 Hz, 1H), 7.07 (d, J= 8.4 Hz, 1H), 6.99 (dd, J= 8.2, 2.7 Hz, 1H), 6.49 (d, J = 2.3 Hz, 1H), 6.44 (dd, J = 8.4, 6.1 Hz, 1H), 4.95 (t, J = 8.2 Hz, 1H), 4.91 (s, 2H), 3.71 (s, 3H), 3.65 (s, 3H), 3.12 - 3.01 (m, 2H), 2.47 - 2.45 (m, 1H), 2.1 1 - 2.01 (m, 1H). LCMS (ESI): m/z 643.11 (M+Na)+.

(S)-l-(2-chloro-4-(trifluoromethyl)phenyl)-N-(2,4-dimethoxybenzyl)-N-(6-fluoropyridin- 2-yl)-2,3-dihydro-lH-indene-5-sulfonamide (Int-3a; S-enantiomer):

The title compound as a single enantiomer was prepared from Intermediate 2a and N-(2,4- dimethoxybenzyl)-6-fluoropyridin-2-amine by following the same procedure as above. Yield: 78%

Intermediate-4/4a/4b: (R&S)- 1 -(2-Chloro-4-(trifluoromethyl)phenyl)-N-(2,4-dimethoxy benzyl)-N-(pyrimidin-2-yl)-2,3- fonamide

Figure imgf000047_0001

The title compound (racemic mixture) was prepared by following similar procedure as described in Intermediate-3 using Intermediate-2 and N-(2,4-dimethoxybenzyl)pyrimidin- 2-amine (synthesized as described in Sun et al., Bioorg. Med. Chem. Lett, 2014, 24(18), 4397 - 4401), Yield: 55%.

¾ NMR (400 MHz, DMSO-ifc) δ 8.60 (d, J = 4.8 Hz, 2H), 7.94 (s, 1H), 7.84 (d, J = 8.5 Hz, 1H), 7.73 (s, 1H), 7.67 (d, J = 8.1 Hz, 1H), 7.22 - 7.12 (m, 2H), 7.08 (d, J = 8.1 Hz, 1H), 6.99 (d, J = 8.3 Hz, 1H), 6.50 (d, J = 2.3 Hz, 1H), 6.48 - 6.42 (m, 1H), 5.31 (s, 2H), 4.90 (t, J = 8.2 Hz, 1H), 3.73 (s, 3H), 3.59 (s, 3H), 3.12 - 2.91 (m, 2H), 2.69 - 2.60 (m, 1H), 2.09 - 1.99 (m, 1H). LCMS (ESI): m/z 604.12 (M+H)+.

Further the enantiomers were separated using chiral preparative HPLC [Column: ChiralPak ID; Mobile phase: A = (Hexane + 0.1% DEA), B = IPA:MeOH = 1 : 1, A:B = 40:60], to afford isomer-1 and isomer-2. These isomers were obtained at retention time 6.50 min (Intermediate-4a) and retention time 7.40 min (Intermediate-4b).

Figure imgf000048_0001

The S-enantiomer was also synthesized separately from Intermediate 2a and N-(2,4- dimethoxybenzyl)pyrimidin-2-amine by following the same procedure as described for Intermediate-3. Yield: 62%

The spectral data of final sulfonamide compound obtained from S-enantiomer matches with the final compound obtained from intermediate 4b and hence intermediate 4a is assigned as R- enantiomer and intermediate 4b as S- enantiomer.

Intermediate-5: Perfluorophenyl l-(2-morpholino-4-(trifluoromethyl)phenyl)-2,3- dihydro- 1 H-indene-5-sulfonate

Figure imgf000048_0002

Step 1: 4-(2-(6-(Benzylthio)-lH-inden-3-yl)-5-(trifluoromethyl)phenyl)morpholine To a N2 purged solution of 4-(2-bromo-5-(trifluoromethyl)phenyl)morpholine (2.5 g, 8.1 mmol) (synthesized as described in WO2013134518), N'-(5-(benzylthio)-2,3-dihydro-lH- inden- 1 -ylidene)-4-methylbenzene sulfonohydrazide (Step 1, Intermediate 1, Method- 1) (3.8 g, 8.9 mmol) and Na2C03 (2.14 g, 20.2 mmol) in a mixture of dioxane (18 ml) and water (3 ml) was added PdCkidppf -CEhCk adduct (0.66 g, 0.81 mmol) and stirred in a preheated oil bath at 100 °C for 5 h. The reaction mixture was added to water and the compound was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulphate and concentrated under vacuum. The crude was purified by column chromatography to obtain dark brown sticky solid (Yield = 2.2 g, 58%).

¾ NMR (400 MHz, DMSO-ifc) δ 7.54 (s, 1H), 7.49 (d, J = 7.9 Hz, 1H), 7.40 (d, J = 8.1 Hz, 1H), 7.34 - 7.28 (m, 4H), 7.27 - 7.19 (m, 4H), 6.74 (d, J = 2.2 Hz, 1H), 4.23 (s, 2H), 3.34 (s, 2H), 3.29 (d, J = 5.2 Hz, 4H), 2.90 (t, J = 4.3 Hz, 4H). LCMS (ESI) : m/z 468.03 (M+H)+.

Step 2: Perfluorophenyl 3-(2-morpholino-4-(trifluoromethyl)phenyl)-lH-indene-6- sulfonate

The title compound was prepared by following similar procedure as described in Intermediate-2 (Step-1) using 4-(2-(6-(Benzylthio)- lH-inden-3-yl)-5-

(trifluoromethyl)phenyl) morpholine obtained above, Yield: 53%.

¾ NMR (400 MHz, DMSO-ifc) δ 8.19 (s, 1H), 7.86 (d, J = 8.3 Hz, 1H), 7.60 - 7.51 (m, 3H), 7.47 (d, J = 8.4 Hz, 1H), 7.18 (s, 1H), 3.81 (s, 2H), 3.26 (br s, 4H), 2.91 (br s, 4H). LCMS (ESI): m/z 592.03 (M+H)+.

Step 3: Perfluorophenyl l-(2-morpholino-4-(trifluoromethyl)phenyl)-2,3-dihydro-lH- indene-5-sulfonate

The title compound was prepared by following similar procedure as described in Intermediate-2 (Step-2) using perfluorophenyl 3-(2-morpholino-4- (trifluoromethyl)phenyl)-lH-indene-6-sulfonate (Step-2 above), Yield: 91%.

¾ NMR (400 MHz, Chloroform-if) δ 7.95 (s, 1H), 7.75 (d, J = 8.1 Hz, 1H), 7.48 (s, 1H), 7.37 (d, J = 8.2 Hz, 1H), 7.03 (t, J = 7.5 Hz, 2H), 5.15 (t, J = 8.9 Hz, 1H), 3.90 (d, J= 5.0 Hz, 4H), 3.30 - 3.20 (m, 1H), 3.20 - 2.96 (m, 5H), 2.79 - 2.72 (m, 1H), 2.19 - 2.05 (m, 1H). LCMS (ESI): m/z 594.00 (M+H)+. Intermediate-6: Perfluorophenyl l-(2-(oxetan-3-yloxy)-4-(trifluoromethyl)phenyl)-2,3- dihydro- 1 H-indene-5-sulfonate

Figure imgf000050_0001

Step 1: 3-(2-bromo-5-(trifluoromethyl)phenoxy)oxetane

To a stirred solution of oxetan-3-ol (4.5 g, 61.7 mmol) in THF (50 ml) was added 60 % NaH (2.5 g, 61.7 mmol) at 0 °C for 20 min and then 1 -bromo-2-fluoro-4- (trifluoromethyl)benzene (7.5 g, 30.9 mmol) was added. The resultant mixture was stirred at 50 °C for 12 h. Reaction mixture was then poured into cold water and extracted with ethyl acetate, washed with brine, dried over sodium sulphate and concentrated under reduced pressure. The crude was purified by column chromatography to obtain a white solid (Yield = 6.7g, 73%).

¾ NMR (500 MHz, DMSO-ifc) δ 7.88 (d, J= 8.2 Hz, 1H), 7.30 (dd, J = 8.3, 2.0 Hz, 1H), 7.02 (d, J = 2.0 Hz, 1H), 5.53 (ddd, J= 10.7, 6.0, 4.7 Hz, 1H), 4.98 (ddd, J = 7.2, 5.9, 1.0 Hz, 2H), 4.59 (ddd, J= 7.4, 4.7, 1.0 Hz, 2H). GCMS: m/z 296.02 & 298.10 (M +).

Step 2: 3-(2-(6-(benzylthio)-lH-inden-3-yl)-5-(trifluoromethyl)phenoxy)oxetane The title compound was prepared by following similar procedure as described in

Intermediate- l(Step-2, Method 1) using N'-(5-(benzylthio)-2,3-dihydro-lH-inden-l- ylidene)-4-methylbenzenesulfonohydrazide (Step-1, Intermediate- 1 ; Method 1) and 3-(2- bromo-5-(trifluoromethyl)phenoxy)oxetane, Yield: 30 %.

LCMS (ESI): m/z 455.10 (M+H)+.

Step 3: Perfluorophenyl 3-(2-(oxetan-3-yloxy)-4-(trifluoromethyl)phenyl)-lH-indene-6- sulfonate

The title compound was prepared by following similar procedure as described in Intermediate-2 (Step-1) using 3-(2-(6-(benzylthio)-lH-inden-3-yl)-5-(trifluoromethyl) phenoxy)oxetane, Yield: 47 %.

¾ NMR (400 MHz, DMSO-ifc) δ 8.20 (d, J= 1.8 Hz, 1H), 7.89 (dd, J = 8.2, 1.9 Hz, 1H), 7.67 (d, J= 7.9 Hz, 1H), 7.58 (d, J= 8.3 Hz, 1H), 7.48 (d, J= 7.9 Hz, 1H), 7.19 (d, J= 2.0 Hz, 1H), 7.04 (d, J = 1.6 Hz, 1H), 5.54 - 5.46 (m, 1H), 4.95 - 4.84 (m, 2H), 4.38 (dd, J = 7.4, 4.8 Hz, 2H), 3.83 (d, J= 2.1 Hz, 2H). LCMS (ESI) : m/z 579.08 (M+H)+.

Step 4: Perfluorophenyl l-(2-(oxetan-3-yloxy)-4-(trifluoromethyl)phenyl)-2,3-dihydro- 1 H-indene-5-sulfonate

The title compound was prepared by following similar procedure as described in Intermediate-2 (Step-2) using above Step-3 intermediate, Yield: 79 %.

¾ NMR (400 MHz, DMSO-ifc) δ 8.00 (s, 1H), 7.77 (d, J = 8.1 Hz, 1H), 7.38 - 7.21 (m, 3H), 6.94 (s, 1H), 5.53 - 5.39 (m, 1H), 5.02 - 4.81 (m, 3H), 4.47 (t, J = 6.2 Hz, 1H), 4.40 (t, J= 6.1 Hz, 1H), 3.24 - 3.00 (m, 2H), 2.71 - 2.60 (m, 1H), 2.29 - 2.14 (m, 1H). LCMS (ESI): m/z 603.04 (M+Na)+.

Intermediate-7: l-(2-Chloro-4-(trifluoromethyl)phenyl)-N-(2,4-dimethoxybenzyl)-N- (thiazol-2-yl)-2,3-dihydro-l

Figure imgf000051_0001

The title compound was prepared by following similar procedure as described in Intermediate-3 using Intermediate-2 and N-(2,4-dimethoxybenzyl)thiazol-2-amine, Yield: 67%.

LCMS (ESI): m/z 631.15 (M+Na)+.

Intermediate-8: perfluorophenyl (S)- l-(2-(l -methyl- 1 H-pyrazol-5-yl)-4-

(trifluoromethyl)phenyl)-2,3-dihydro-lH-indene-5-sulfonate

Figure imgf000052_0001

Step 1 : (S)-5-(2-(5-(benzylthio)-2,3-dihydro- lH-inden- 1 -yl)-5-(trifluoromethyl)phenyl)- 1 -methyl- 1 H-pyrazole

Figure imgf000052_0002

(S)-benzyl(l-(2-chloro-4-(trifluoromethyl)phenyl)-2,3-dihydro-lH-inden-5-yl)sulfane (45 g, 107 mmol) (Intermediate 1 prepared either using method A or B) was dissolved in 500 mL degassed dioxane. l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- pyrazole (46.9 g, 226 mmol), potassium phosphate, dibasic (69.2 g, 397 mmol), PdCb(dppf)-CH2Cl2Adduct (13.16 g, 16.1 1 mmol), and tritert-butylphosphanium tetrafluoroborate (4.05 g, 13.97 mmol) were added to it and the reaction mixture was heated to 1 15 °C for 16 h. After completion of the reaction, the reaction mixture was filtered through a pad of celite. The filtrate was diluted with ethyl acetate and washed with brine and the organic layer was dried over Na2S04 and concentrated to obtain the crude product which was then purified by column chromatography to obtain the product as a pale yellow sticky liquid. (Yield = 41.6 g, 83 %).

¾ NMR (400 MHz, Chloroform-if) δ 7.64 (d, J = 9.4 Hz, 2H), 7.56 (s, 1H), 7.35 - 7.22 (m, 7H), 7.12 (d, J = 7.9 Hz, 1H), 6.74 (d, J = 7.9 Hz, 1H), 6.36 (d, J = 1.9 Hz, 1H), 4.22 (t, J = 8.6 Hz, 1H), 4.13 (s, 2H), 3.79 (s, 3H), 3.04 - 2.92 (m, 1H), 2.92 - 2.76 (m, 1H), 2.52 - 2.34 (m, 1H), 2.01 - 1.84 (m, 1H). LCMS: 465.02 (M+H)+ Step 2: perfluorophenyl (S)-l-(2-(l -methyl- lH-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)- 2,3-dihydro-lH-indene-5-sulfonate

(S)-5-(2-(5-(benzylthio)-2,3 -dihydro- 1 H-inden- 1 -yl)-5-(trifluoromethyl)phenyl)- 1 - methyl- lH-pyrazole (40 g, 86 mmol) was dissolved in 400 mL DCM. Water (7.76 mL, 431 mmol) and acetic acid (24.65 mL, 431 mmol) was added to it and the solution was cooled to 0 °C. Sulfuryl chloride (19.6 mL, 241 mmol) was added dropwise into it and after the addition TLC was checked every 5 min. As soon as the starting material was consumed, the reaction was quenched by pouring it into water and the organic layer was extracted with DCM. The DCM layer was dried over sodium sulphate and concentrated under reduced pressure to get the crude sulfonyl chloride in about 100 mL of DCM. This solution of sulfonyl chloride was added dropwise to a solution of 2,3,4,5,6-pentafluorophenol (23.77 g, 129 mmol) and triethylamine (84 mL, 603 mmol) in 400 mL DCM kept at 0 °C. The reaction mixture was stirred at 0 °C for 30 min after which it was poured into an ice cold 1 N HCl solution so that the final pH becomes just acidic. The organic phase was extracted with DCM, washed with brine and dried over Na2S04 and concentrated to obtain the crude product. This was purified by column chromatography to obtain the product as a white fluffy solid. (Yield = 38 g, 75 %).

¾ NMR (400 MHz, Chloroform-d) δ 7.93 (d, J = 1.7 Hz, 1H), 7.78 (dd, J = 8.1, 1.8 Hz, 1H), 7.73 - 7.67 (m, 1H), 7.63 (d, J = 1.9 Hz, 1H), 7.63 - 7.60 (m, 1H), 7.20 (d, J = 8.2 Hz, 1H), 7.08 (d, J = 8.2 Hz, 1H), 6.37 (d, J = 1.9 Hz, 1H), 4.41 (t, J = 8.8 Hz, 1H), 3.80 (s, 3H), 3.18 (ddd, J = 16.4, 8.8, 2.9 Hz, 1H), 3.10 - 2.96 (m, 1H), 2.67 - 2.52 (m, 1H), 2.19 - 2.02 (m, 1H). LCMS: 589.21 (M+H)+

Intermediate-9: perfluorophenyl (S)- 1 -(4'-fluoro-5-(trifluoromethyl)-[ 1 , l'-biphenyl] -2- yl)-2,3-dihydro-lH-indene-5-sulfonate

Figure imgf000054_0001

Step 1 : (S)-berEyl(l -(4'-fluoro-5-(trifluoromethyl)-[ l, l '-biphenyl]-2-yl)-2,3-dihydro- lH- inden-5-yl)sulfane

Figure imgf000054_0002

The title compound was prepared by following similar procedure as described in Intermediate- 8 using Intermediate- 1 and (4-fluorophenyl)boronic acid. Yield: 81%.

¾ NMR (400 MHz, Chloroform-if) δ 7.58 - 7.49 (m, 2H), 7.39 - 7.22 (m, 10H), 7.21 - 7.09 (m, 4H), 6.76 (d, J = 7.9 Hz, 1H), 4.42 (t, J = 8.6 Hz, 1H), 4.13 (s, 2H), 3.06 - 2.94 (m, 1H), 2.92 - 2.78 (m, 1H), 2.52 - 2.38 (m, 1H), 2.1 1 - 1.94 (m, 1H).

Step 2: perfluorophenyl (S)- l -(4'-fluoro-5-(trifluoromethyl)-[ l,r-biphenyl]-2-yl)-2,3- dihydro- 1 H-indene-5-sulfonate

The title compound was prepared by following similar procedure as described in Intermediate-2 Step 1 , using above Step-1 intermediate. Yield: 79%

¾ NMR (400 MHz, Chloroform- d) δ 7.91 (s, 1H), 7.76 (dd, J = 8.1, 1.8 Hz, 1H), 7.59 (d, J = 8.3 Hz, 2H), 7.43 - 7.32 (m, 2H), 7.25 - 7.17 (m, 2H), 7.10 (dd, J = 16.9, 8.1 Hz, 2H), 4.56 (t, J = 8.8 Hz, 1H), 3.24 - 3.13 (m, 1H), 3.06 - 2.95 (m, 1H), 2.65 - 2.54 (m, 1H), 2.22 - 2.15 (m, 1H). Intermediate-10: perfluorophenyl l-(2-tosylhydrazineylidene)-2,3-dihydro-lH-indene-5- sulfonate

Figure imgf000055_0001

Step 1: 5-(benzylthio)-2,3-dihydro-lH-inden- l-one

5-bromo-2,3-dihydro-lH-inden-l-one (20 g, 95 mmol), Xantphos (2.74 g, 4.74 mmol), Hunig's Base (33.1 ml, 190 mmol), Pd2(dba)3 (2.70 g, 2.37 mmol) and phenylmethanethiol (10.57 ml, 90 mmol) were added to 150 mL of degassed dioxane and the reaction mixture heated at 90 °C for 6 h. After the starting material was consumed, the reaction mixture was cooled to 0 °C and filtered through a pad of celite and the filtrate concentrated to obtain the crude as an orange solid. The solid was triturated with methanol and filtered to obtain the product as a yellow solid. (Yield = 19.5 g, 81%).

¾ NMR (400 MHz, DMSO-ifc) δ 7.55 - 7.49 (m, 2H), 7.48 - 7.41 (m, 2H), 7.38 - 7.30 (m, 3H), 7.29 - 7.23 (m, 1H), 4.40 (s, 2H), 3.09 - 3.00 (m, 2H), 2.63 - 2.57 (m, 2H). LCMS: 255.1 1 (M+H)+

Step 2: perfluorophenyl l-oxo-2,3-dihydro-lH-indene-5-sulfonate

5-(benzylthio)-2,3-dihydro-lH-inden-l-one (9.50 g, 37.4 mmol) was added to a 1 10 mL mixture of Acetic Acid and Water (ratio 10: 1) and stirred for 10 min after which NCS (14.96 g, 1 12 mmol) was added. The reaction mixture was stirred at 10°C for 1 h. The crude product was diluted with water and extracted with diethyl ether, and the organic layer was concentrated under reduced pressure to get the crude which was dissolved in DCM and added dropwise to a mixture of 2,3,4,5, 6-pentafluorophenol (10.31 g, 56.0 mmol) and triethylamine (26.0 ml, 187 mmol) in DCM at 0-5°C temperature. The reaction mixture was stirred at 25 °C for 30 min and the reaction mixture was poured into water and extracted with DCM. The organic later was dried over Na2S04 and concentrated to dryness. The crude product was purified by column chromatography to get the pentafluoroester as a white solid. (Yield = 9.5 g, 67%).

¾ NMR (400 MHz, DMSO-ifc) δ 8.34 (d, J = 1.6 Hz, 1H), 8.03 (dd, J = 8.1, 1.7 Hz, 1H), 7.93 (d, J = 8.1 Hz, 1H), 3.29 - 3.21 (m, 2H), 2.83 - 2.75 (m, 2H). LCMS (ESI) : m/z 379.09 (M+H)+.

Step 3: perfluorophenyl l-(2-tosylhydrazineylidene)-2,3-dihydro-lH-indene-5-sulfonate

A stirred solution of perfluorophenyl l-oxo-2,3-dihydro-lH-indene-5-sulfonate (4.3 g, 11.37 mmol) and 4-methylbenzenesulfonohydrazide (2.23 g, 1 1.94 mmol) in 50 mL MeOH was heated at 70°C for 4 h. After the consumption of starting materials as seen from TLC, the reaction mixture was cooled to 0°C and the solid formed was filtered. The solid was washed with cold methanol and dried under vacuum to obtain the product as an off white solid. (Yield = 5 g, 82%).

¾ NMR (400 MHz, DMSO-i¾) δ 10.86 (s, 1H), 8.04 (s, 1H), 7.90 - 7.80 (m, 3H), 7.75 (d, J = 8.2 Hz, 1H), 7.42 (d, J = 8.0 Hz, 2H), 3.14 (t, J = 6.5 Hz, 2H), 2.84 (dd, J = 8.1, 4.7 Hz, 2H), 2.38 (s, 3H). LCMS (ESI) : m/z 547.20 (M+H)+.

Intermediate-11 : Perfluorophenyl 1 -(2-(2-oxopyrrolidin- 1 -yl)-4-

(trifluoromethyl)phenyl)-2,3-dihydro-lH-indene-5-sulfonate

Figure imgf000056_0001

Step 1: Perfluorophenyl 3-(2-(2-oxopyrrolidin- l-yl)-4-(trifluoromethyl)phenyl)-lH- indene-6-sulfonate

A stirred suspension of l-(2-bromo-5-(trifluoromethyl)phenyl)pyrrolidin-2-one (1.36 g, 4.43 mmol), [synthesized according to the procedure reported in WO 2017037682], perfluorophenyl l-(2-tosylhydrazineylidene)-2,3-dihydro-lH-indene-5-sulfonate (2.2 g, 4.03 mmol) and Na2C03 (1.28 g, 12.08 mmol) in 20 mL 1 ,4-Dioxane and 2 mL water was degassed using nitrogen for 20 min. Then PdCb (dppf -CEhCkAdduct (0.33 g, 0.403 mmol) was added and the reaction mixture was heated at 100°C for 1 h. After consumption of the pentafluoroester, starting material as seen from TLC, the reaction mixture was diluted with ethyl acetate and washed with brine. The organic layer was dried over sodium sulphate and concentrated under reduced pressure to get the crude compound which was purified by column chromatography to get the required pure compound as a yellow viscous liquid. (Yield = 900 mg, 38 %)

¾ NMR (400 MHz, Chloroform-if) δ 8. 16 (dd, J = 1.7, 0.7 Hz, 1H), 7.93 - 7.90 (m, 2H), 7.73 (d, J = 1.8 Hz, 1H), 7.61 (d, J = 3.7 Hz, 1H), 7.40 (d, J = 8.2 Hz, 1H), 6.99 (t, J = 2.1 Hz, 1H), 3.75 (d, J = 2.1 Hz, 2H), 3.45 (t, J = 6.9 Hz, 2H), 2.35 - 2.31 (m, 2H), 1.92 - 1.80 (m, 2H).

LCMS (ESI): m/z 589.99 (M+H)+.

Step 2: Perfluorophenyl l -(2-(2-oxopyrrolidin- l -yl)-4-(trifluoromethyl)phenyl)-2,3- dihydro- lH-indene-5-sulfonate

The title compound was prepared by following similar procedure as described in the synthesis of Intermediate-2 Step 2, using above Step-1 intermediate. Yield: 66%

¾ NMR (400 MHz, Chloroform-if) δ 7.94 (d, J = 1.7 Hz, 1H), 7.76 (dd, J = 8.2, 1.8 Hz, 1H), 7.60 - 7.52 (m, 2H), 7.23 (s, 1H), 7.1 1 (d, J = 8.2 Hz, 1H), 4.57 (t, J = 8.6 Hz, 1 H), 3.87 (d, J = 10.0 Hz, 2H), 3.27 - 3.03 (m, 2H), 2.86 - 2.59 (m, 3H), 2.35 (q, J = 7.5 Hz, 2H), 2.20 - 2.09 (m, 1H). LCMS (ESI): m/z 591.95 (M+H)+.

Intermediate-12: Perfluorophenyl l -(2-(2-oxooxazolidin-3-yl)-4-

(trifluoromethyl)phenyl)-2,3-dihydro- lH-indene-5-sulfonate

Figure imgf000057_0001

Step 1 : 2-hydroxyethyl (2-bromo-5-(trifluoromethyl)phenyl)carbamate 2-bromo-5-(trifluoromethyl)aniline (10 g, 41.7 mmol) was dissolved in 60 mL DCM and a 2 M solution of trimethylaluminum in toluene (29.2 ml, 58.3 mmol) was added slowly to it. After the addition the solution was stirred for 15 min after which l,3-dioxolan-2-one (5.14 g, 58.3 mmol) was added to it and the reaction mixture was stirred at room temperature overnight. The reaction was quenched by the slow addition of 1 N HC1 and the compound was extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure and the crude product obtained was purified by column chromatography to obtain the product as a colorless oil. (Yield = 8 g, 59%)

¾ NMR (400 MHz, Chloroform-d) δ 8.60 - 8.45 (m, 1H), 7.67 (dd, J = 8.4, 0.9 Hz, 1H), 7.37 (s, 1H), 7.26 - 7.15 (m, 1H), 4.45 - 4.33 (m, 2H), 3.95 (t, J = 4.5 Hz, 2H).

Step 2: 3-(2-bromo-5-(trifluoromethyl)phenyl)oxazolidin-2-one

To a stirred solution of 2-hydroxyethyl (2-bromo-5-(trifluoromethyl)phenyl)carbamate (3.7 g, 1 1.28 mmol) in 40 mL THF was added triphenylphosphine (3.55 g, 13.53 mmol) followed by the dropwise addition of diethyl azodicarboxylate (2.143 ml, 13.53 mmol) dissolved in 20 mL THF. The reaction was monitored by TLC and after completion, water was added to quench the reaction and the mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over sodium sulphate and concentrated under reduced pressure to get the crude compound which was purified by column chromatography to get the pure compound as a colorless oil. (Yield = 3.37g, 86%) ¾ NMR (400 MHz, Chloroform-if) δ 7.83 (dd, J = 8.4, 0.9 Hz, 1H), 7.70 (d, J = 2.2 Hz, 1H), 7.59 - 7.44 (m, 1H), 4.69 - 4.55 (m, 2H), 4.11 - 4.03 (m, 2H).

Step 3: Perfluorophenyl 3-(2-(2-oxooxazolidin-3-yl)-4-(trifluoromethyl)phenyl)-lH- indene-6-sulfonate

The title compound was prepared by following similar procedure as described in Intermediate- 11 Step 1, using the Step-2 intermediate obtained above and perfluorophenyl l-(2-tosylhydrazineylidene)-2,3-dihydro-lH-indene-5-sulfonate. Yield: 40%

!H NMR ^OO MHZ, Chloroforn /) δ 8.19 (d, J= 1.6 Hz, 1H), 7.97 - 7.93 (m, 1H), 7.89 - 7.81 (m, 1H), 7.72 (d, J = 7.9 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.42 (d, J= 8.1 Hz, 1H), 7.04 (s, 1H), 4.24 - 4.17 (m, 2H), 3.85 - 3.76 (m, 2H), 3.70 - 3.59 (m, 2H). LCMS (ESI): m/z 592.04 (M+H)+.

Step 4: Perfluorophenyl l-(2-(2-oxooxazolidin-3-yl)-4-(rrifluoromethyl)phenyl)-2,3- dihydro- 1 H-indene-5-sulfonate

The title compound was prepared by following similar procedure as described in Intermediate-2 Step 2, using above Step-3 intermediate. Yield: 68%

¾ NMR (400 MHz, Chloroform-if) δ 7.95 (d, J = 1.7 Hz, 1H), 7.77 (dd, J = 8.1, 1.8 Hz, 1H), 7.64 - 7.56 (m, 2H), 7.20 (d, J= 8.0 Hz, 1H), 7.15 (d, J= 8.2 Hz, 1H), 4.73 (t, J= 8.6 Hz, 1H), 4.63 (t, J = 7.8 Hz, 2H), 4.15 - 4.04 (m, 2H), 3.28 - 3.08 (m, 2H), 2.83 (d, J = 1 1.3 Hz, 1H), 2.22 - 2.10 (m, 1H). LCMS (ESI): m/z 594.06 (M+l)+.

Intermediate-13 : perfluorophenyl 1 -(2-(2-(methylsulfonyl)ethyl)-4-

(trifluoromethyl)phenyl)-2,3-dihydro-lH-indene-5-sulfonate

Figure imgf000059_0001

Step 1: Perfluorophenyl 3-(2-(2-(methylsulfonyl)ethyl)-4-(trifluoromethyl)phenyl)-lH- indene-6-sulfonate

The title compound was prepared by following similar procedure as described in Intermediate- 11 Step 1, using l-bromo-2-(2-(methylsulfonyl)ethyl)-4- (trifluoromethyl)benzene [Synthesized according to procedure reported in WO2017037682] and perfluorophenyl l-(2-tosylhydrazineylidene)-2,3-dihydro-lH- indene-5-sulfonate. Yield: 42%

¾ NMR (400 MHz, Chloroform-if) δ 8.20 (d, J = 1.6 Hz, 1H), 7.96 - 7.93 (m, 1H), 7.68 (t, J= 2.1 Hz, 1H), 7.48 (dd, J= 9.1, 5.5 Hz, 1H), 7.37 (d, J= 7.7 Hz, 1H), 7.25 (d, J= 8.1 Hz, 1H), 6.94 (d, J = 2.0 Hz, 1H), 3.81 (d, J = 1.9 Hz, 2H), 3.24 - 3.07 (m, 4H), 2.77 (s, 3H). LCMS (ESI): m/z 634.97 (M+Na)+. Step 2: perfluorophenyl l-(2-(2-(methylsulfonyl)ethyl)-4-(rrifluoromethyl)phenyl)-2,3- dihydro- 1 H-indene-5-sulfonate

The title compound was prepared by following similar procedure as described in Intermediate-2 Step 2, using above Step-1 intermediate. Yield: 50%

LCMS (ESI): m/z 637.05 (M+Na)+.

Intermediate-14: tert-butyl 3-fluoro-3-(2-(5-((perfluorophenoxy)sulfonyl)-2,3-dihydro- 1 H-inden- 1 -yl)-5-(trifluoromethyl)phenyl)azetidine- 1 -carboxylate

Figure imgf000060_0001

Step 1: tert-butyl 3-fluoro-3-(2-(6-((perfluorophenoxy)sulfonyl)-lH-inden-3-yl)-5- (trifluoromethyl)phenyl)azetidine- 1 -carboxylate

The title compound was prepared by following similar procedure as described in Intermediate- 11 Step 1, using tert-butyl 3-(2-bromo-5-(trifluoromethyl)phenyl)-3- fluoroazetidine- 1 -carboxylate [Synthesized according to procedure reported in WO2015151001] and perfluorophenyl l-(2-tosylhydrazineylidene)-2,3-dihydro-lH- indene-5-sulfonate. Yield: 39%.

¾ NMR (400 MHz, Chloroform-if) δ 8.20 (d, J = 1.7 Hz, 1H), 7.96 (dd, J = 8.2, 1.7 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.76 (d, J = 2.5 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.38 (d, J = 8.1 Hz, 1H), 7.07 - 7.01 (m, 1H), 4.60 - 3.99 (m, 4H), 3.76 (d, J = 2.0 Hz, 2H), 1.40 (s, 9H).

Step 2: tert-butyl 3-fluoro-3-(2-(5-((perfluorophenoxy)sulfonyl)-2,3-dihydro-lH-inden-l- yl)-5-(trifluoromethyl)phenyl)azetidine- 1 -carboxylate

The title compound was prepared by following similar procedure as described in Intermediate-2 Step 2, using above Step-1 intermediate. Yield: 48% ¾ NMR (400 MHz, Chloroform-if) δ 7.97 (d, J = 1.7 Hz, 1H), 7.77 (dd, J = 8.1, 1.8 Hz, 1H), 7.71 - 7.62 (m, 2H), 7.16 (d, J = 1 1.1 Hz, 1H), 7.04 (d, J = 8.0 Hz, 1H), 4.72 - 4.48 (m, 5H), 3.33 - 3.12 (m, 2H), 2.89 - 2.73 (m, 1H), 2.22 - 2.10 (m, 1H), 1.50 (s, 9H). LCMS (ESI): m/z 704 (M+Na)+.

Intermediate-15: Perfluorophenyl l-(2-(((S)-tetrahydrofuran-3-yl)oxy)-4-

(trifluoromethyl)phenyl)-2,3-dihydro-lH-indene-5-sulfonate

Figure imgf000061_0001

Step 1: Perfluorophenyl (S)-3-(2-((terrahydrofuran-3-yl)oxy)-4-(trifluoromethyl)phenyl)- lH-indene-6-sulfonate

The title compound was prepared by following similar procedure as described in the synthesis of Intermediate- 1 1 Step 1, using (S)-3-(2-bromo-5- (trifluoromethyl)phenoxy)tetrahydrofuran [Synthesized according to procedure reported in WO2017037682A1] and perfluorophenyl l-(2-tosylhydrazineylidene)-2,3-dihydro-lH- indene-5-sulfonate. Yield: 45%

LCMS (ESI): m/z 614.96 (M+Na)+.

Step 2: Perfluorophenyl l-(2-(((S)-tetrahydrofuran-3-yl)oxy)-4-(trifluoromethyl)phenyl)- 2,3-dihydro-lH-indene-5-sulfonate

The title compound was prepared by following similar procedure as described in Intermediate-2 Step 2, using above Step-1 intermediate. Yield: 58%

¾ NMR (400 MHz, Chloroform-if) δ 7.93 (d, J = 1.8 Hz, 1H), 7.85 - 7.71 (m, 1H), 7.19 (dd, J = 10.6, 8.1 Hz, 2H), 7.07 (dd, J = 8.5, 4.4 Hz, 2H), 5.04 (s, 1H), 4.85 (t, J = 8.4 Hz, 1H), 4.09 - 3.81 (m, 4H), 3.22 - 3.05 (m, 2H), 2.73 - 2.61 (m, 1H), 2.32 - 2.12 (m, 2H), 2.03 - 1.92 (m, 1H). LCMS (ESI): m/z 616.98 (M+Na)+. Intermediate-16: Tert-butyl 4-(2-(5-((perfluorophenoxy)sulfonyl)-2,3-dihydro-lH-inden- 1 -yl)-5-(trifluoromethyl)phenyl)piperazine- 1 -carboxylate

Figure imgf000062_0001

Step 1: Tert-butyl 4-(2-nitro-5-(trifluoromethyl)phenyl)piperazine-l -carboxylate To a stirred solution of 2-fluoro- 1 -nitro-4-(trifluoromethyl)benzene (25 g, 120 mmol), tert- butyl piperazine- 1 -carboxylate (22.27 g, 120 mmol) in 180 ml DMF was added CS2CO3 (1 17 g, 359 mmol). The reaction mixture was stirred at 100°C for 30 mins and the progress of the reaction was monitored by TLC. After completion of starting material, the reaction was quenched by addition of water and ethyl acetate was used for extraction of organic compound. The combined organic layer was washed with brine, dried over sodium sulphate and concentrated under reduced pressure to get the product as a yellow solid. (Yield = 30 g, 67%)

¾ NMR (400 MHz, Chloroform-if) δ 7.87 (d, J = 8.4 Hz, 1H), 7.39 - 7.23 (m, 2H), 3.62 (t, J = 5.0 Hz, 4H), 3.09 (t, J = 5.1 Hz, 4H), 1.50 (s, 9H).

Step 2: Tert-butyl 4-(2-amino-5-(trifluoromethyl)phenyl)piperazine-l -carboxylate

Iron (22.32 g, 400 mmol) was suspended in 300 mL ethanol and HC1 (3.28 ml, 40.0 mmol) was added to it. The suspension was heated at 65°C for 2 h and a solution of ammonium chloride (4.28 g, 80 mmol) in 20 mL water was added followed by tert-butyl 4-(2-nitro-5- (trifluoromethyl)phenyl)piperazine- 1 -carboxylate (30 g, 80 mmol). The reaction mixture was heated for another 2 h till the disappearance of the nitro starting compound. The reaction mixture was then filtered through a pad of celite, the filtrate was concentrated under reduced pressure and diluted with ethyl acetate. The ethyl acetate layer was washed with brine, the organic layer was dried over sodium sulphate and concentrated under reduced pressure to get the product. (Yield = 21 g, 76%).

¾ NMR (400 MHz, Chloroform-if) δ 7.24 - 7.17 (m, 2H), 6.84 - 6.66 (m, 1H), 4.00 - 3.24 (m, 4H), 2.97 - 2.80 (m, 4H), 1.51 (s, 9H). LCMS (ESI): m/z 345.93 (M+H)+.

Step 3: Tert-butyl 4-(2-bromo-5-(trifluoromethyl)phenyl)piperazine-l -carboxylate

To the stirred solution of tert-butyl 4-(2-amino-5-(trifluoromethyl)phenyl)piperazine- l- carboxylate (21 g, 60.8 mmol) in 250 mL acetonitrile, copper bromide(II) (7.47 g, 33.4 mmol) was added followed by the dropwise addition of tert-butyl nitrite (10.94 ml, 91 mmol) and the reaction was heated at 65°C for 45 min. After completion of the reaction, water was added to quench it and the compound was extracted with ethyl acetate. The organic layer was combined and dried over sodium sulphate, concentrated to get the crude compound, which was then purified by column chromatography to get the pure product as a yellow solid. (Yield = 16 g, 64%)

¾ NMR (400 MHz, DMSO-i¾) δ 7.93 - 7.74 (m, 1H), 7.42 (d, J = 2.2 Hz, 1H), 7.39 - 7.33 (m, 1H), 3.60 - 3.44 (m, 4H), 3.09 - 2.93 (m, 4H), 1.43 (s, 9H). LCMS (ESI): m/z 409.10 & 41 1.10 (M+H)+.

Step 4: Tert-butyl 4-(2-(6-((perfluorophenoxy)sulfonyl)-lH-inden-3-yl)-5- (trifluoromethyl)phenyl)piperazine- 1 -carboxylate

The title compound was prepared by following similar procedure as described in Intermediate- 11 Step 1, using tert-butyl 4-(2 -bromo-5-(trifluoromethyl)phenyl)piperazine- 1 -carboxylate obtained from Step-3 above and perfluorophenyl l-(2- tosylhydrazineylidene)-2,3-dihydro- 1 H-indene-5-sulfonate. Yield: 41 %

¾ NMR (400 MHz, DMSO-ifc) δ 8.17 (d, J = 1.8 Hz, 1H), 7.87 - 7.80 (m, 1H), 7.55 (d, J = 7.8 Hz, 1H), 7.52 - 7.44 (m, 2H), 7.43 (d, J = 1.7 Hz, 1H), 7.23 - 7.14 (m, 1H), 3.92 - 3.74 (m, 2H), 3.09 - 2.95 (m, 4H), 2.94 - 2.81 (m, 4H), 1.33 (s, 9H). LCMS (ESI): m/z 713.04 (M+Na)+.

Step 5: Tert-butyl 4-(2-(5-((perfluorophenoxy)sulfonyl)-2,3-dihydro-lH-inden-l-yl)-5- (trifluoromethyl)phenyl)piperazine- 1 -carboxylate

The title compound was prepared by following similar procedure as described in Intermediate-2 Step 2, using above Step^l intermediate. Yield: 95%

¾ NMR (400 MHz, DMSO-ifc) δ 8.00 (d, J = 1.8 Hz, 1H), 7.78 - 7.72 (m, 1H), 7.56 (d, J = 1.9 Hz, 1H), 7.47 - 7.40 (m, 1H), 7.09 (d, J = 8.1 Hz, 2H), 5.07 (t, J = 8.6 Hz, 1H), 3.46 (s, 4H), 3.25 - 3.00 (m, 2H), 2.98 - 2.83 (m, 4H), 2.77 - 2.64 (m, 1H), 2.15 - 2.02 (m, 1H), 1.42 (s, 9H). LCMS (ESI): m/z 693.13 (M+H)+.

Intermediate-17: perfluorophenyl 1 -(4-isopropyl-2-(l -methyl- lH-pyrazo l-5-yl)phenyl)- 2,3-dihydro-lH-indene-5-sulfonate

Figure imgf000064_0001

Step 1: 2-bromo-4-isopropylaniline

To a stirred solution of 4-isopropylaniline (5 g, 37.0 mmol) in 100 mL DMF, 1- bromopyrrolidine-2,5-dione (6.58 g, 37.0 mmol) was added at 0°C. The reaction mixture was allowed to warm to room temperature and stirred overnight under the exclusion of light. The reaction was quenched by the addition of water and the organic contents were extracted with ethyl acetate. The combined organic layer was washed with brine, dried over sodium sulphate and concentrated and the crude obtained was purified by column purification to give the product as a brown oil. (Yield = 5.45 g, 69%).

¾ NMR (400 MHz, Chloroform-if) δ 7.32 - 7.29 (m, 1H), 7.03 - 6.98 (m, 1H), 6.79 (d, J = 8.2 Hz, 1H), 2.81 (p, J = 6.9 Hz, 1H), 1.22 (d, J = 6.9 Hz, 6H).

Step 2: 4-isopropyl-2-(l -methyl- lH-pyrazol-5-yl)aniline

To a stirred solution of 2-bromo-4-isopropylaniline ( 5 g, 23.35 mmol) in 18 mL of degassed solvent mixture of Toluene-ethanol-water (3:2: 1), l-methyl-5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (12.15 g, 58.4 mmol), Na2C03 (2.72 g, 25.7 mmol) and Pd(PPl¾)4 (2.70 g, 2.335 mmol) were added and the reaction mixture was stirred at 70°C for 8 h. The reaction mixture was then filtered through a pad of celite and the filtrate was concentrated and then diluted with ethyl acetate. The ethyl acetate layer was washed with water dried over sodium sulphate and concentrated and the crude residue was purified by column chromatography to give the pure product. (Yield = 4 g, 80%)

¾ NMR (400 MHz, DMSO-ifc) δ 7.48 (d, J = 1.8 Hz, 1H), 7.02 (dd, J = 8.4, 2.2 Hz, 1H), 6.86 (d, J = 2.2 Hz, 1H), 6.73 (d, J = 8.3 Hz, 1H), 6.26 (d, J = 1.8 Hz, 1H), 4.66 (s, 2H), 3.65 (s, 3H), 2.76 (p, J = 6.9 Hz, 1H), 1.16 (d, J = 6.8 Hz, 6H).

Step 3: 5-(2-bromo-5-isopropylphenyl)-l -methyl- lH-pyrazole

The title compound was prepared by following similar procedure as described in Intermediate- 16 Step 3, using above Step-2 intermediate. Yield: 52%

¾ NMR (400 MHz, Chloroform-if) δ 7.64 - 7.55 (m, 3H), 7.18 (d, J = 2.3 Hz, 1H), 6.32 (s, 1H), 3.75 (s, 3H), 2.98 - 2.90 (m, 1H), 1.28 (dd, J = 6.9, 0.9 Hz, 6H). LCMS (ESI) : m/z 279.09 & 281.09 (M+H)+.

Step 4: perfluorophenyl 3 -(4-isopropyl-2-(l -methyl- lH-pyrazol-5-yl)phenyl)-lH-indene- 6-sulfonate

The title compound was prepared by following similar procedure as described in Intermediate- 11 Step 1, using 5-(2-bromo-5-isopropylphenyl)-l -methyl- lH-pyrazole obtained from Step-3 above and perfluorophenyl l-(2-tosylhydrazineylidene)-2,3-dihydro- 1 H-indene-5-sulfonate.

Yield: 60%.

LCMS (ESI) : m/z 561.20 (M+H)+.

Step 5: perfluorophenyl l-(4-isopropyl-2-(l-methyl-lH-pyrazol-5-yl)phenyl)-2,3- dihydro- 1 H-indene-5-sulfonate.

The title compound was prepared by following similar procedure as described in Intermediate-2 Step 2, using above Step^l intermediate. Yield: 50%

¾ NMR (400 MHz, Chloroform-if) δ 7.89 (d, J = 1.7 Hz, 1H), 7.75 (dd, J = 8.1, 1.9 Hz, 1H), 7.59 (d, J = 1.8 Hz, 1H), 7.31 - 7.26 (m, 1H), 7.17 (d, J = 2.0 Hz, 1H), 7.12 - 7.08 (m, 1H), 6.96 (d, J = 8.1 Hz, 1H), 6.31 (d, J = 1.9 Hz, 1H), 4.32 (t, J = 8.8 Hz, 1H), 3.78 (s, 3H), 3.16 - 3.09 (m, 1H), 3.03 - 2.92 (m, 2H), 2.59 - 2.51 (m, 1H), 2.12 - 2.07 (m, 1H), 1.30 (d, J = 6.9 Hz, 6H). LCMS (ESI) : m/z 563.04 (M+H)+. Intermediate-18 : perfluorophenyl 1 -(4-(tert-butyl)-2-( 1 -methyl- 1 H-pyrazol-5-yl)phenyl)- 2,3-dihydro-lH-indene-5-sulfonate

Figure imgf000066_0001

Step 1: 2-bromo-4-(tert-butyl)aniline

The title compound was prepared by following similar procedure as described in Intermediate- 17 Step 1. Yield: 72%

¾ NMR (400 MHz, Chloroform-if) δ 7.44 (d, J = 2.2 Hz, 1H), 7.16 (dd, J = 8.3, 2.2 Hz, 1H), 6.77 (d, J = 8.3 Hz, 1H), 1.29 (s, 9H).

Step 2: 4-(tert-butyl)-2-(l -methyl- lH-pyrazol-5-yl)aniline

The title compound was prepared by following similar procedure as described in Intermediate- 17 Step 2. Yield: 80%

¾ NMR (400 MHz, DMSO-ifc) δ 7.49 (d, J = 1.8 Hz, 1H), 7.17 (dd, J = 8.5, 2.4 Hz, 1H), 6.97 (d, J = 2.4 Hz, 1H), 6.73 (d, J = 8.4 Hz, 1H), 6.27 (d, J = 1.8 Hz, 1H), 4.68 (s, 2H), 3.65 (s, 3H), 1.23 (s, 9H).

Step 3: 5-(2-bromo-5-(tert-butyl)phenyl)- l -methyl- lH-pyrazole

The title compound was prepared by following similar procedure as described in Intermediate- 17 Step 3. Yield: 54%

LCMS (ESI) : m/z 293.27 & 295.27(M+H)+.

Step 4: perfluorophenyl 3-(4-(tert-butyl)-2-(l-methyl-lH-pyrazol-5-yl)phenyl)-lH- indene-6-sulfonate

The title compound was prepared by following similar procedure as described in Intermediate- 11 Step 1, using 5-(2-bromo-5-(tert-butyl)phenyl)- l -methyl- lH-pyrazole obtained from Step-3 above and perfluorophenyl l-(2-tosylhydrazineylidene)-2,3-dihydro- lH-indene-5-sulfonate. Yield: 78%.

LCMS (ESI) : m/z 574.95 (M+H)+. Step 5: perfluorophenyl l-(4-(tert-butyl)-2-(l-methyl- lH-pyrazol-5-yl)phenyl)-2,3- dihydro- 1 H-indene-5-sulfonate

The title compound was prepared by following similar procedure as described in Intermediate-2 Step 2, using above Step^l intermediate. Yield: 90%

LCMS (ESI) : m/z 577.25 (M+H)+.

Intermediate-19 : perfluorophenyl 1 -(2-(oxazol-2-yl)-4-(trifluoromethyl)phenyl)-2,3- dihydro- 1 H-indene-5-sulfonate

Figure imgf000067_0001

Step 1 : 2-bromo-N-(2,2-diethoxyethyl)-5-(trifluoromethyl)benzamide

To a stirred solution of 2-bromo-5-(trifluoromethyl)benzoic acid (5 g, 18.59 mmol) in 50 mL DMF at 0° C was added HATU (10.60 g, 27.9 mmol) and triethylamine (3.89 ml, 27.9 mmol). The reaction mixture was stirred for 15 min. and then 2, 2-diethoxyethanamine (4.05 ml, 27.9 mmol) was added to it and the reaction mixture was slowly warmed to room temperature and stirred for 12 h. The reaction mixture was diluted with ice cold water, and the precipitate obtained was filtered and the residue was dissolved in ethyl acetate, dried over sodium sulphate and concentrated to get the product as white solid. (Yield = 6 g, 85%). ¾ NMR (400 MHz, Chloroform-if) δ 7.82 (d, J = 2.8 Hz, 1H), 7.76 (d, J = 8.3 Hz, 1H), 7.55 (d, J = 8.3 Hz, 1H), 6.33 (s, 1H), 4.69 (dd, J = 6.0, 3.6 Hz, 1H), 3.83 - 3.72 (m, 2H), 3.68 - 3.57 (m, 4H), 1.30 - 1.18 (m, 6H). LCMS (ESI) : m/z 406.07 & 408.07(M+Na)+.

Step 2: 2-(2-bromo-5-(trifluoromethyl)phenyl)oxazole

2-bromo-N-(2,2-diethoxyethyl)-5-(trifluoromethyl)benzamide (4.7 g, 12.23 mmol) was dissolved in Eaton's Reagent [Phosphorus pentoxide, 7.7 wt. % in methanesulfonic acid ] (44.0 ml, 20.80 mmol) and the reaction mixture was stirred at 140° C for 1.5 h. The reaction mixture was then cooled and diluted with 100 mL of ice cold water and was neutralized by the addition of a satd. solution of NaHCCb. The reaction mixture was extracted with ethyl acetate and the combined organic layer was washed with brine, dried over sodium sulphate and concentrated to get the crude, which was purified by column chromatography to afford the pure title compound. (Yield = 2.5 g, 70%).

¾ NMR (400 MHz, Chloroform-if) δ 8.26 (s, 1H), 7.92 - 7.82 (m, 2H), 7.56 (d, J = 8.4 Hz, 1H), 7.39 (s, 1H). LCMS (ESI) : m/z 292.09 & 293.98 (M+H)+.

Step 3: perfluorophenyl 3-(2-(oxazol-2-yl)-4-(trifluoromethyl)phenyl)-lH-indene-6- sulfonate

The title compound was prepared by following similar procedure as described in Intermediate- 11 Step 1, using 2-(2-bromo-5-(trifluoromethyl)phenyl)oxazole obtained from Step-2 above and perfluorophenyl l-(2-tosylhydrazineylidene)-2,3-dihydro-lH- indene-5-sulfonate.Yield: 91%.

¾ NMR (400 MHz, Chloroform-if) δ 8.41 (d, J = 1.9 Hz, 1H), 8.12 (dd, J = 1.8, 0.8 Hz, 1H), 7.86 - 7.81 (m, 1H), 7.71 (dd, J = 8.2, 1.8 Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.47 (d, J = 0.8 Hz, 1H), 7.09 (d, J = 0.8 Hz, 1H), 6.99 - 6.94 (m, 2H), 3.77 (d, J = 2.1 Hz, 2H). LCMS (ESI) : m/z 574.22 (M+H)+.

Step 4: perfluorophenyl l-(2-(oxazol-2-yl)-4-(trifluoromethyl)phenyl)-2,3-dihydro-lH- indene-5-sulfonate

The title compound was prepared by following similar procedure as described in Intermediate-2 Step 2, using above Step-3 intermediate. Yield: 99%

¾ NMR (400 MHz, Chloroform-if) δ 8.32 (d, J = 2.0 Hz, 1H), 7.96 (d, J = 1.8 Hz, 1H), 7.85 (d, J = 0.9 Hz, 1H), 7.78 (dd, J = 8.1, 1.9 Hz, 1H), 7.63 (dd, J = 8.4, 2.0 Hz, 1H), 7.37 - 7.33 (m, 1H), 7.18 (t, J = 8.5 Hz, 2H), 5.88 (t, J = 8.4 Hz, 1H), 3.30 - 3.09 (m, 2H), 3.01 - 2.89 (m, 1H), 2.22 - 2.05 (m, 1H). LCMS (ESI) : m/z 576.12 (M+H)+.

Intermediate-20 : perfluorophenyl (R)- 1 -(2-(2-fluoroethyl)-4-(trifluoromethyl)phenyl)- 2,3-dihydro-lH-indene-5-sulfonate

Figure imgf000069_0001

Step 1: (S)-benzyl(l-(4-(trifluoromethyl)-2-vinylphenyl)-2,3-dihydro- lH-inden-5- yl)sulfane To a mixture of degassed DME (10 ml) and Water (3 ml) was added Intermediate 1 (S)- benzyl(l-(2-chloro-4-(trifluoromethyl)phenyl)-2,3-dihydro-lH-inden-5-yl)sulfane (500 mg, 1.19 mmol), vinylboronic anhydride pyridine complex (575 mg, 2.39 mmol), K2CO3 (495 mg, 3.58 mmol), Pd(OAc)2 (26.8 mg, 0.1 19 mmol) and tritert- butylphosphanium;tetrafluoroborate (69.3 mg, 0.24 mmol) and the contents were heated in a microwave vial for 1 h at 140°C. The reaction mixture was diluted with water and extracted with ethyl acetate and the organic layer was washed with brine, dried over sodium sulphate and concentrated to get the crude, which was purified by column chromatography to afford the pure title compound as a colorless oil. Yield 61%

¾ NMR (400 MHz, DMSO-ifc) δ 7.84 (d, J = 2.0 Hz, 1H), 7.56 (dd, J = 8.3, 2.0 Hz, 1H), 7.38 - 7.27 (m, 5H), 7.27 - 7.23 (m, 1H), 7.22 - 7.17 (m, 1H), 7.13 (dd, J = 7.9, 1.9 Hz, 1H), 7.07 (d, J = 8.1 Hz, 1H), 6.82 (d, J = 7.9 Hz, 1H), 5.90 (dd, J = 17.3, 1.1 Hz, 1H), 5.48 (dd, J = 1 1.0, 1.1 Hz, 1H), 4.75 (t, J = 8.0 Hz, 1H), 4.23 (s, 2H), 2.96 - 2.87 (m, 2H), 2.60 - 2.54 (m, 1H), 1.93 - 1.83 (m, 1H). LCMS (ESI) : m/z 41 1.06 (M+H)+.

Step 2: (R)-2-(2-(5-(benzylthio)-2,3-dihydro-lH-inden-l-yl)-5-(trifluoromethyl) phenyl) ethan-l-ol

To a stirred solution of (S)-benzyl(l-(4-(trifluoromethyl)-2-vinylphenyl)-2,3-dihydro-lH- inden-5-yl)sulfane (0.4 g, 0.97 mmol) in 20 mL THF, a 1 M solution of BH3.THF (1.95 ml, 1.95 mmol) was added at 0°C and stirred at room temperature for 4 h. A 2 M solution of NaOH (1.95 ml, 3.90 mmol) was added dropwise to the reaction mixture and after 10 min hydrogen peroxide (0.4 ml, 3.90 mmol) was added at 0°C and stirred for 30 min. The reaction mixture was quenched by the addition of a dil. aq. solution of sodium thiosulfate and was then extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulphate and concentrated to get the crude, which was purified by column chromatography to afford the pure title compound. Yield 40%. ¾ NMR (400 MHz, Chloroform-if) δ 7.53 (d, J = 2.0 Hz, 1H), 7.41 (dd, J = 8.2, 2.0 Hz, 1H), 7.36 - 7.31 (m, 4H), 7.29 (dd, J = 6.9, 2.2 Hz, 2H), 7.13 (dd, J = 7.9, 1.8 Hz, 1H), 7.06 (d, J = 8.1 Hz, 1H), 6.79 (d, J = 7.9 Hz, 1H), 4.67 (t, J = 8.3 Hz, 1H), 4.15 (s, 2H), 3.95 (t, J = 6.9 Hz, 2H), 3.22 - 2.90 (m, 4H), 2.69 - 2.59 (m, 1H), 2.04 - 1.92 (m, 1H).

Step 3: (R)-benzyl(l-(2-(2-fluoroethyl)-4-(trifluoromethyl)phenyl)-2,3-dihydro-lH-inden- 5-yl)sulfane.

To a solution of (R)-2-(2-(5-(benzylthio)-2,3-dihydro- lH-inden-l-yl)-5- (trifluoromethyl)phenyl)ethanol (0.2 g, 0.467 mmol) in 10 mL DCM was added Deoxo- Fluor (0.22 ml, 0.61 mmol) and the reaction mixture was stirred at 0°C for 2 h after which it was warmed to room temperature and stirred overnight. Water was added to quench the reaction and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulphate and concentrated to get the crude which was used as such for the next step.

Step 4: perfluorophenyl (R)-l-(2-(2-fluoroethyl)-4-(trifluoromethyl)phenyl)-2,3-dihydro- 1 H-indene-5-sulfonate

The title compound was synthesized from the compound obtained from Step 3 above by following an analogous procedure as in Step- 1 of Intermediate-2

Examples

Certain exemplified compounds were synthesized as racemic compounds and the individual enantiomers were separated using chiral preparative HPLC by varying stationary and/or mobile phases as appropriate. These enantiomers were characterized as isomer- 1 and isomer-2. However, the absolute configuration of the separated isomers was not determined. Certain other exemplified compounds were selectively synthesized starting from Intermediate-I (S-enantiomer) and using the transformations as outlined in the General Schemes. Examples-1/2: (R&S)- l-(2-(6-Fluoropyridin-3-yl)-4-(trifluoromethyl)phenyl)-N-(thiazol- 2-yl)- -dihydro-lH-indene-5-sulfonamide;

Figure imgf000071_0001

Step 1 : N-(2,4-Dimethoxybenzyl)- 1 -(2-(6-fluoropyridin-3-yl)-4-(trifluoromethyl)phenyl)- N-(thiazol-2-yl)-2,3-dihydro-lH-indene-5-sulfonamide

To a nitrogen purged solution of the Intermediate-7 (0.1 g, 0.16 mmol) in 10 mL 1,4- dioxane was added 2-fluoro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (0.1 1 g, 0.49 mmol), PdCl2(dppf)-CH2Ci2 adduct (0.034 g, 0.04 mmol), K3P04.3H20 (0.14 g, 0.49 mmol) and tritertbutylphosphin tetrafluoroborate (0.005 g, 0.016 mmol). The reaction mixture was heated at 120°C for 2 h after which it was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2S04, evaporated and purified by column chromatography to obtain the product as a colorless mass (Yield = 70 mg, 57 %).

1H NMR (400 MHz, DMSO-ifc) δ 8.35 (s, 1H), 8.1 1 (s, 1H), 7.76 (d, J= 8.7 Hz, 1H), 7.70 (d, J = 7.3 Hz, 2H), 7.60 (d, J= 8.2 Hz, 1H), 7.41 (d, J= 12.9 Hz, 2H), 7.30 (dd, J= 18.7, 8.3 Hz, 2H), 7.09 (d, J = 8.4 Hz, 1H), 7.01 (d, J = 8.5 Hz, 1H), 6.51 (s, 1H), 6.47 - 6.40 (m, 1H), 5.01 (s, 2H), 4.38 (t, 1H), 3.71 (s, 6H), 3.14 - 2.98 (m, 1H), 2.98 - 2.83 (m, 1H), 2.20 - 1.94 (m, 2H).

Step 2: (R&S)-l-(2-(6-Fluoropyridin-3-yl)-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)- 2,3-dihydro-lH-indene-5-sulfonamide

To a stirred solution of the product from Step-1 (0.060 g, 0.090 mmol) in DCM (2 ml) at 0-10 °C was added TFA (0.01 ml, 0.1 mmol) and stirred at 10 °C for 30 min. The contents were evaporated completely and diluted with MeOH (2 ml). This was evaporated again up to dryness under reduced pressure. The pink colored residue was taken up in MeOH and filtered through a membrane filter to get a sticky mass. This was dissolved in EtOAc and pentane was added to get an off white solid precipitate which was submitted for chiral preparative HPLC.

The enantiomers were separated using chiral preparative HPLC [Column: ChiralPak ID; Mobile phase: A = (Hexane + 0.1% DEA), B = (IPA: MeOH =1 : 1), A:B = 60:40] to afford isomer- 1 and isomer-2. These isomers were obtained at retention time 6.84 min (Example - 1) and 10.03 min (Example-2).

¾ NMR (400 MHz, DMSO-ifc) δ 8.35 (s, 1H), 8.1 1 (t, J = 8.3 Hz, 1H), 7.73 (d, J = 8.6 Hz, 1H), 7.68 (s, 2H), 7.56 (d, J = 7.9 Hz, 1H), 7.29 (dd, J = 16.0, 8.5 Hz, 2H), 7.16 (s, 1H), 6.97 (d, J= 8.0 Hz, 1H), 6.72 (d, J= 4.4 Hz, 1H), 4.32 (t, J= 8.8 Hz, 1H), 3.1 1 - 2.99 (m, 1H), 2.96 - 2.85 (m, 2H), 2.12 - 1.99 (m, 1H). LCMS (ESI): m/z 520.05 (M+l)+. Examples-3/4: (R&S)- 1 -(2-(6-Methylpyridin-3-yl)-4-(trifluoromethyl)phenyl)-N-

Figure imgf000072_0001

Step 1: N-(2,4-dimethoxybenzyl)-l-(2-(6-methylpyridin-3-yl)-4-(trifluoromethyl)phenyl)- N-(thiazol-2-yl)-2,3-dihydro-lH-indene-5-sulfonamide

The title compound was prepared by following similar procedure as described in Example- l/2(Step-l) using Intermediate-7 and 2-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)pyridine. Yield: 50%.

¾-NMR (400 MHz, DMSO-ifc) δ 8.54 (s, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.77 - 7.69 (m, 2H), 7.66 - 7.56 (m, 2H), 7.48 - 7.33 (m, 3H), 7.27 (d, J = 8.3 Hz, 1H), 7.07 (d, J = 8.1 Hz, 1H), 7.01 (d, J= 8.3 Hz, 1H), 6.51 (s, 1H), 6.43 (d, J= 8.6 Hz, 1H), 5.01 (s, 2H), 4.40 (t, 1H), 3.78 (s, 6H), 3.13 - 3.00 (m, 1H), 2.97 - 2.82 (m, 1H), 2.51 (s, 3H), 2.45 - 2.42 (m, 1H), 2.16 - 2.01 (m, 1H). LCMS (ESI): m/z 666.18 (M+H)+.

Step 2: (R&S)- 1 -(2-(6-methylpyridin-3-yl)-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)- 2,3-dihydro-lH-indene-5-sulfonamide The title compounds were prepared by following similar procedure as described in Example- 1/2 (Step-2) using Step-1 intermediate.

Further the enantiomers were separated using chiral preparative HPLC [Column: ChiralPak ID; Mobile phase: A = (Hexane + 0.1% DEA), B = (IPA : DCM =1 : 1), A:B = 50:50] to afford isomer- 1 and isomer-2. These isomers were obtained at retention time 5.25 min (Example-3) and 6.52 min (Example-4).

1H NMR (400 MHz, DMSO-i/e) δ 12.69 (s, 1H), 8.53 (s, 1H), 7.79 (d, J= 8.0 Hz, 1H), 7.71 (d, J= 9.6 Hz, 2H), 7.62 (s, 1H), 7.58 (d, J= 8.0 Hz, 1H), 7.38 (d, J= 8.1 Hz, 1H), 7.27 (d, J= 9.2 Hz, 2H), 6.99 (d, J= 8.0 Hz, 1H), 6.82 (s, 1H), 4.36 (t, J= 9.0 Hz, 1H), 3.13 - 3.03 (m, 1H), 2.98 - 2.88 (m, 1H), 2.51 (s, 3H), 2.45 - 2.42 (m, 1H), 2.18 - 2.00 (m, 1H). LCMS (ESI): m/z 515.94 (M+H)+.

Examples-5/6: (R&S)- l-(2-(6-Fluoropyridin-3-yl)-4-(trifluoromethyl)phenyl)-N-

Figure imgf000073_0001

Step 1: N-(2,4-Dimethoxybenzyl)-l-(2-(6-fluoropyridin-3-yl)-4-(trifluoromethyl)phenyl)- N-(pyrimidin-2-yl)-2,3-dihydro-lH-indene-5-sulfonamide

The title compound was prepared by following similar procedure as described in Example- l/2(Step-l) using Intermediate-4 and 2-fluoro-5-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan- 2-yl)pyridine. Yield: 60%.

¾ NMR (400 MHz, DMSO-ifc) δ 8.58 (dd, J = 4.9, 1.8 Hz, 2H), 8.35 (s, 1H), 8.12 (t, J = 8.4 Hz, 1H), 7.78 (dd, J= 18.4, 8.3 Hz, 2H), 7.68 (d, J = 8.0 Hz, 2H), 7.32 (d, J = 8.7 Hz, 1H), 7.22 (d, J= 8.4 Hz, 1H), 7.17 - 7.09 (m, 1H), 6.99 (dd, J= 14.3, 8.2 Hz, 2H), 6.52 - 6.40 (m, 2H), 5.29 (s, 2H), 4.34 (t, J= 8.6 Hz, 1H), 3.72 (s, 3H), 3.58 (s, 3H), 3.05 - 2.94 (m, 1H), 2.93 - 2.79 (m, 1H), 2.08 - 1.97 (m, 2H). LCMS (ESI): m/z 664.84 (M+H)+. Step 2: (R&S)-l-(2-(6-fluoropyridin-3-yl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-2- yl)-2,3-dihydro-lH-indene-5-sulfonamide The title compounds were prepared by following similar procedure as described in Example- l/2(Step-2) using Step-1 intermediate.

Further the enantiomers were separated using chiral preparative HPLC [Column: ChiralPak ID; Mobile phase: A = (Hexane + 0.1% DEA), B = (IPA : DCM =1 : 1), A:B = 35:65] to afford isomer-1 and isomer-2. These isomers were obtained at retention time 4.57 min (Example-5) and 6.02 min (Example-6).

¾ NMR (400 MHz, DMSO-i/e) δ 1 1.72 (s, 1H), 8.51 (d, J= 4.8 Hz, 2H), 8.35 (s, 1H), 8.1 1 (t, J = 8.3 Hz, 1H), 7.89 (s, 1H), 7.82 - 7.72 (m, 2H), 7.69 (s, 1H), 7.29 (dd, J= 16.3, 8.4 Hz, 2H), 7.07 (d, J= 7.4 Hz, 2H), 4.35 (t, J= 8.7 Hz, 1H), 3.18 - 3.03 (m, 1H), 2.98 - 2.87 (m, 1H), 2.49 - 2.47 (m, 1H), 2.18 - 1.98 (m, 1H). LCMS (ESI): m/z 514.99 (M+l)+.

Examples-7/8: (R&S)- 1 -(2-(6-Methylpyridin-3-yl)-4-(trifluoromethyl)phenyl)-N-

Figure imgf000074_0001

Step 1 : N-(2,4-Dimethoxybenzyl)- 1 -(2-(6-methylpyridin-3-yl)-4- (trifluoromethyl)phenyl)-N-(pyrimidin-2-yl)-2,3-dihydro- 1 H-indene-5-sulfonamide

The title compound was prepared by following similar procedure as described in Example- l/2(Step-l) using Intermediate-4 and 2-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)pyridine. Yield: 63%.

¾ NMR (400 MHz, DMSO-ifc) δ 8.61 - 8.51 (m, 3H), 7.80 (d, J = 8.1 Hz, 2H), 7.73 (d, J = 8.4 Hz, 1H), 7.65 (d, J= 14.3 Hz, 2H), 7.38 (d, J= 8.0 Hz, 1H), 7.22 (d, J= 8.3 Hz, 1H), 7.14 (t, J= 5.0 Hz, 1H), 6.98 (d, J= 8.3 Hz, 2H), 6.52 - 6.42 (m, 2H), 5.29 (s, 2H), 4.37 (t, J = 8.6 Hz, 1H), 3.72 (s, 3H), 3.58 (s, 3H), 3.06 - 2.95 (m, 1H), 2.93 - 2.80 (m, 1H), 2.48 (s, 3H), 2.12 - 1.97 (m, 2H). LCMS (ESI): m/z 660.84 (M+H)+.

Step 2: (R&S)- 1 -(2-(6-methylpyridin-3-yl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-2- yl)-2,3-dihydro- lH-indene-5-sulfonamide

The title compound was prepared by following similar procedure as described in Example- 1/2 (Step-2) using Step-1 intermediate. Further the enantiomers were separated using chiral preparative HPLC [Column: ChiralPak ID; Mobile phase: A = (Hexane + 0.1% DEA), B = (IPA: MeOH =1 : 1), A:B = 60:40] to afford isomer- 1 and isomer-2. These isomers were obtained at retention time 7.75 minutes (Example-7) and 9.91 min (Example-8).

¾ NMR (400 MHz, DMSO-i¾) δ 1 1.79 (s, 1H), 8.53 (s, 1H), 8.40 (d, J= 4.8 Hz, 2H), 7.89 - 7.75 (m, 2H), 7.71 (d, J = 8.2 Hz, 2H), 7.62 (s, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.26 (d, J = 8.3 Hz, 1H), 6.97 (d, J = 8.0 Hz, 1H), 6.88 (s, 1H), 4.35 (t, J = 8.7 Hz, 1H), 3.14 - 3.00 (m, 1H), 2.95 - 2.79 (m, 1H), 2.48 (s, 3H), 2.47 - 2.45 (m, 1H), 2.14 - 1.95 (m, 1H). LCMS (ESI) : m/z 51 1.25 (M+H)+.

Examples-9/10: (R&S)- 1 -(2-( 1 -Methyl- 1 H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N- (pyrim

Figure imgf000075_0001

The title compounds were prepared by following the similar procedure as described in Example-1/2 (Step-1&2) using l-methyl-5-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)- lH-pyrazole and Intermediated and Intermediate-4a to obtain Example-9 and 10 respectively.

¾ NMR (400 MHz, DMSO-ifc) δ 1 1.76 (s, 1H), 8.51 (d, J = 4.8 Hz, 2H), 7.89 (d, J = 1.7 Hz, 1H), 7.78 (ddd, J= 7.9, 5.9, 1.9 Hz, 2H), 7.73 (d, J= 2.0 Hz, 1H), 7.53 (d, J= 1.9 Hz, 1H), 7.29 (d, J= 8.3 Hz, 1H), 7.09 - 6.98 (m, 2H), 6.43 (d, J= 1.9 Hz, 1H), 4.24 (t, J= 8.6 Hz, 1H), 3.67 (s, 3H), 3.09 (ddd, J = 16 A, 8.9, 2.9 Hz, 1H), 3.02 - 2.88 (m, 1H), 2.50 (m, 1H) 2.11 - 1.96 (m, 1H). LCMS (ESI): m/z 500.03 (M+l)+

The S-enantiomer was also selectively synthesized using intermediate-8, pyrimidin-2- amine and LiHMDS by following the similar procedure as described for synthesis of intermediate-3.

Examples-11/12: (R&S)-N-(6-Fluoropyridin-2-yl)-l-(2-(6-fluoropyridin-3-yl)-4- (trifluoro methyl)phenyl)-2,3-dihydro- lH-indene-5-sulfonamide;

Figure imgf000076_0001

Step 1 : (R&S)-N-(2,4-dimethoxybenzyl)-N-(6-fluoropyridin-2-yl)- 1 -(2-(6-fluoropyridin- 3-yl)-4-(trifluoromethyl)phenyl)-2,3-dihydro-lH-indene-5-sulfonamide

The title compounds were prepared by following the similar procedure as described in Example- l/2(Step- l) using Intermediate-3 and 2-fluoro-5-(4,4,5,5-tetramethyl- 1,3,2- dioxaborolan-2-yl)pyridine. Yield: 70%. LCMS (ESI): m/z 704.17 (M+Na)+.

Further the enantiomers were separated using chiral preparative HPLC [Column: ChiralPak IA; Mobile phase: A = (Hexane + 0.1% DEA), B = (IPA: DCM = 1 : 1), A:B = 60:40], to afford isomer- 1 and isomer-2. These isomers were obtained at retention time 5.18 min (Isomer- 1 ) and 6.18 min (Isomer-2)

Step 2: (R&S)-N-(6-fluoropyridin-2-yl)- 1 -(2-(6-fluoropyridin-3-yl)-4-(trifluoromethyl) phenyl)-2,3-dihydro-lH-indene-5-sulfonamide

The title compounds were prepared by following similar procedure as described in Example- l/2(Step-2) using Step-1 intermediates (Isomer- 1 and 2) and TFA to obtain Example- 1 1 and 12 respectively.

¾ NMR (400 MHz, DMSO-i/e) δ 11.36 (s, 1H), 8.34 (s, 1H), 8.10 (t, J= 8.4 Hz, 1H), 7.85 (s, 2H), 7.73 (t, J = 6.3 Hz, 2H), 7.68 (s, 1H), 7.28 (dd, J = 18.3, 8.3 Hz, 2H), 7.08 (d, J = 8.0 Hz, 1H), 6.96 (d, J = 8.0 Hz, 1H), 6.74 (d, J = 8.1 Hz, 1H), 4.35 (t, J = 8.8 Hz, 1H), 3.13 - 3.00 (m, 1H), 3.00 - 2.83 (m, 1H), 2.45 - 2.43 (m, 1H), 2.12 - 2.00 (m, 1H). LCMS (ESI) : m/z 532.01 (M+H)+

Examples-13/14: (R&S)-N-(6-Fluoropyridin-2-yl)- 1 -(2-(6-methylpyridin-3-yl)-4-

(trifluoro methyl)phenyl)-2,3-dihydro- lH-indene-5-sulfonamide;

Figure imgf000077_0001

Step 1: (R & S)-N-(2,4-dimethoxybenzyl)-N-(6-fluoropyridin-2-yl)- l-(2-(6- methylpyridin-3-yl)-4-(trifluoromethyl)phenyl)-2,3-dihydro-lH-indene-5-sulfonamide The title compounds were prepared by following the similar procedure as described in Example- l/2(Step- l) using Intermediate-3 and 2-methyl-5-(4,4,5,5-tetramethyl- 1,3,2- dioxaborolan-2-yl)pyridine. Yield: 65%. LCMS (ESI): m/z 678.19 (M+H)+

Further the enantiomers were separated using chiral preparative HPLC [Column: ChiralPak ID; Mobile phase: A = (Hexane + 0.1% DEA), B = (IPA : MeOH =1 : 1), A:B = 60:40], to afford isomer-1 and isomer-2. These isomers were obtained at retention time 5.39 min (Isomer-1) and 6.46 min (Isomer-2).

Step-2: (R & S)-N-(6-fluoropyridin-2-yl)-l-(2-(6-methylpyridin-3-yl)-4-(trifluoromethyl) phenyl)-2,3-dihydro-lH-indene-5-sulfonamide

The title compounds were prepared by following similar procedure as described in Example- l/2(Step-2) using Step-1 intermediates (Isomer-1 and Isomer-2) and TFA to obtain Example- 13 and 14 respectively.

¾ NMR (400 MHz, DMSO-ifc) 8 1 1.37 (s, 1H), 8.53 (s, 1H), 7.83 (s, 1H), 7.79 (d, J= 8.2 Hz, 2H), 7.71 (d, J = 8.3 Hz, 2H), 7.63 (s, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.26 (d, J = 8.2 Hz, 1H), 7.04 (d, J= 8.1 Hz, 1H), 6.92 (d, J= 7.8 Hz, 1H), 6.66 (s, 1H), 4.37 (t, J= 8.8 Hz, 1H), 3.16 - 3.02 (m, 1H), 3.00 - 2.86 (m, 1H), 2.50 (s, 3H), 2.47 - 2.45 (m, 1H), 2.15 - 2.03 (m, 1H), LCMS (ESI) : m/z 528.03 (M+H)+

Examples-15/16: (R&S)-N-(6-Fluoropyridin-2-yl)- 1 -(2-( 1 -methyl- 1 H-pyrazol-5-yl)-4- (trifluoro methyl)phenyl)-2,3-dihydro- lH-indene-5-sulfonamide;

Figure imgf000078_0001

Step 1 : (R&S)-N-(2,4-Dimethoxybenzyl)-N-(6-fluoropyridin-2-yl)- 1 -(2-(l -methyl- 1 H- pyrazol- 5 -yl) -4- (trifluoromethyl)phenyl) -2,3- dihydro- 1 H-indene- 5- sulfonamide

The title compounds were prepared by following the similar procedure as described in Example- l/2(Step- l) using Intermediate-3 and l-methyl-5-(4,4,5,5-tetramethyl- 1,3,2- dioxaborolan-2-yl)-lH-pyrazole. Yield: 84%. LCMS (ESI): m/z 667.14 (M+H)+

Further the enantiomers were separated using chiral preparative HPLC [Column: ChiralPak IA; Mobile phase: A = (Hexane + 0.1% DEA), B = (IPA: MeOH (1 : 1), A:B = 50:50] to afford isomer-1 and isomer-2. These isomers were obtained at retention time 6.03 min (Isomer-1) and 7.18 min (Isomer-2).

Step 2: (R&S)-N-(6-Fluoropyridin-2-yl)- 1 -(2-( 1 -methyl- 1 H-pyrazol-5-yl)-4-(trifluoro methyl)phenyl)-2,3-dihydro-lH-indene-5-sulfonamide

The title compounds were prepared by following similar procedure as described in Example- 1/2 (Step-2) using Step-1 intermediates (Isomer-1 and Isomer-2) and TFA to obtain Exapmple- 15 and 16 respectively.

¾ NMR (400 MHz, DMSO-ifc) δ 1 1.37 (s, 1H), 7.85 (d, J = 7.4 Hz, 2H), 7.78 (d, J = 8.4 Hz, 1H), 7.72 (d, J = 7.6 Hz, 2H), 7.52 (s, 1H), 7.28 (d, J = 8.3 Hz, 1H), 7.06 (d, J = 8.1 Hz, 1H), 6.97 (d, J= 8.0 Hz, 1H), 6.74 (d, J= 8.0 Hz, 1H), 6.42 (s, 1H), 4.24 (t, J= 8.7 Hz, 1H), 3.67 (s, 3H), 3.13 - 3.01 (m, 1H), 2.97 - 2.89 (m, 1H), 2.45 - 2.43 (m, 1H), 2.10 - 1.96 (m, 1H). LCMS (ESI): m/z 516.93 (M+H)+.

Examples-17/18: (R&S)-2'-(5-(N-(6-Fluoropyridin-2-yl)sulfamoyl)-2,3-dihydro-lH- inden- 1 -yl)-5'-(trifluoromethyl)-[ 1 , 1 '-biphenyl] -4-carboxylic acid;

Figure imgf000079_0001

Step 1: tert-Butyl 2'-(5-(N-(2,4-dimethoxybenzyl)-N-(6-fluoropyridin-2-yl)sulfamoyl)- 2,3-dihydrc- 1 H-inden- 1 -yl)-5'-(trifluoromethyl)-[ 1 , l'-biphenyl] -4-carboxylate

The title compound was prepared by following the similar procedure as described in Example-1/2 (Step-1) using Intermediate-3 and tert-butyl 4-(4,4,5,5-tetramethyl- 1,3,2- dioxaborolan-2-yl)benzoate [synthesized described in Lee et al., J. Am. Chem. Soc, 2017, 139 (2), 976 - 989]. Yield: 80%,

¾ NMR (400 MHz, DMSO-ifc) δ 8.02 (d, J = 8.0 Hz, 2H), 7.97 (d, J = 8.2 Hz, 1H), 7.74 (d, J = 8.2 Hz, 1H), 7.65 (s, 1H), 7.60 (m, 3H), 7.52 (d, J = 8.2 Hz, 1H), 7.34 - 7.28 (m, 1H), 7.25 (d, J= 8.3 Hz, 1H), 7.04 (t, J = 8.4 Hz, 2H), 6.97 (dd, J= 8.1, 2.6 Hz, 1H), 6.48 (d, J = 2.3 Hz, 1H), 6.42 (dd, J = 8.5, 2.4 Hz, 1H), 4.89 (s, 2H), 4.41 (t, J = 8.7 Hz, 1H), 3.70 (s, 3H), 3.64 (s, 3H), 3.13 - 2.99 (m, 1H), 2.98 - 2.83 (m, 1H), 2.43 - 2.41 (m, 1H), 2.14 - 2.01 (m, 1H), 1.57 (s, 9H).

Step 2: (R&S)-2'-(5-(N-(6-Fluoropyridin-2-yl)sulfamoyl)-2,3-dihydro- lH-inden- 1 -yl)-5'- (trifluoromethyl)-[l, r-biphenyl]-4-carboxylic acid

The title compounds were prepared by following the similar procedure as described in Example- l/2(Step-2) using Step-1 intermediate and TFA.

Further the enantiomers were separated using chiral preparative HPLC [Column: ChiralPak ID; Mobile phase: A = (Hexane + 0.1% TFA), B = (IPA : MeOH =1 : 1), A:B = 50:50] to afford isomer- 1 and isomer-2. These isomers were obtained at retention time 4.19 min (Example- 17) and 4.99 min (Example- 18).

¾ NMR (400 MHz, DMSO-i/e) δ 13.0 (s, 1H), 1 1.36 (d, J= 3.6 Hz, 1H), 8.04 (s, 2H), 7.85 (s, 2H), 7.72 (s, 2H), 7.59 (d, J= 10.8 Hz, 3H), 7.25 (s, 1H), 7.05 (s, 1H), 6.96 (s, 1H), 6.73 (s, 1H), 4.40 (t, J= 8.7 Hz, 1H), 3.09 - 3.07 (m, 1H), 2.92 - 2.90 (m, 1H), 2.46 - 2.43 (m, 1H), 2.10 - 2.05 (m, 1H). LCMS (ESI): m/z 557.22 (M+H)+.

Examples-19/20: (R&S)-2'-(5-(N-(pyrimidin-2-yl)sulfamoyl)-2,3-dihydro- lH-inden- 1 - yl)-5'-(trifluoromethyl)-[ 1 , 1 '-biphenyl] -4-carboxylic acid;

Figure imgf000080_0001

Step 1: (R&S)-tert-butyl 2'-(5-(N-(2,4-dimethoxybenzyl)-N-(pyrimidin-2-yl)sulfamoyl)- 2,3-dihydro- 1 H-inden- 1 -yl)-5'-(trifluoromethyl)-[ 1 , l'-biphenyl] -4-carboxylate

The title compound was prepared by following the similar procedure as described in Example-1/2 (Step-1) using Intermediate-4 and tert-butyl 4-(4,4,5,5-tetramethyl- 1,3,2- dioxaborolan-2-yl)benzoate [synthesized described in Lee et al., J. Am. Chem. Soc, 2017, 139 (2), 976 - 989]. Yield: 71%

¾ NMR (400 MHz, DMSO-ifc) δ 8.58 (d, J = 4.9 Hz, 2H), 8.08 - 7.86 (m, 3H), 7.77 (dd, J = 22.8, 8.3 Hz, 2H), 7.71 - 7.50 (m, 3H), 7.28 - 7.07 (m, 2H), 6.97 (t, J = 6.6 Hz, 2H), 6.56 - 6.38 (m, 2H), 5.29 (s, 2H), 4.47 - 4.30 (m, 1H), 3.72 (s, 3H), 3.58 (s, 3H), 3.07 - 2.94 (m, 1H), 2.88 - 2.81 (m, 1H), 2.12 - 1.99 (m, 2H), 1.56 (s, 9H). LCMS (ESI): m/z 768.50 (M+Na)+

Step 2: (R&S)-2'-(5-(N-(pyrimidin-2-yl)sulfamoyl)-2,3-dihydro-lH-inden- l-yl)-5'- (trifluoromethyl)-[l, r-biphenyl]-4-carboxylic acid

The title compounds were prepared by following the similar procedure as described in Example- l/2(Step-2) using Step-1 intermediate and TFA.

Further the enantiomers were separated using chiral preparative HPLC [Column: ChiralPak IC; Mobile phase: A = HEX + 0.1%TFA, B = (IPA : MeOH =1 : 1), A:B = 50:50] to afford isomer- 1 and isomer-2. These isomers were obtained at retention time 5.47 min (Example - 19) and 6.75 min (Example-20)

¾ NMR (400 MHz, DMSO-ifc) δ 8.50 (d, J = 4.5 Hz, 2H), 8.05 (d, J = 7.8 Hz, 2H), 7.88 (s, 1H), 7.82 - 7.70 (m, 2H), 7.60 (d, J = 1 1.2 Hz, 3H), 7.26 (d, J = 8.4 Hz, 1H), 7.10 - 6.99 (m, 2H), 4.40 (t, J = 8.9 Hz, 1H), 3.07 (d, J = 12.8 Hz, 1H), 2.93 (s, 1H), 2.09 (d, J = 10.2 Hz, 2H). LCMS (ESI): m/z 540.32 (M+H)+

Examples-21/22: (R&S)-l-(2-(2-oxopyrrolidin-l-yl)-4-(trifluoromethyl)phenyl)-N- (pyrimidin-2-yl)-2,3-dihydro-lH-indene-5-sulfonamide;

Figure imgf000081_0001

The title compounds were prepared by following the similar procedure as described in the synthesis of Intermediate-3 using Intermediate 1 1 and pyrimidin-2-amine in presence of LiHMDS.

Further the enantiomers were separated using chiral preparative HPLC [Column: ChiralPak IA; Mobile phase: A = (Hexane + 0.1% TFA), B = (IPA:DCM = 1 : 1), A:B = 40:60] to afford isomer-1 and isomer-2. These isomers were obtained at retention time 4.58 min (Example-21) and retention time 5.09 min (Example-22)

¾ NMR (400 MHz, DMSO-ifc) δ 1 1.75 (s, 1H), 8.52 (d, J = 4.9 Hz, 2H), 7.90 (d, J = 1.7 Hz, 1H), 7.81 - 7.69 (m, 2H), 7.63 (dd, J= 8.4, 2.0 Hz, 1H), 7.21 (d, J= 8.2 Hz, 1H), 7.12 - 6.97 (m, 2H), 4.52 (t, J = 8.6 Hz, 1H), 3.74 (dd, J = 17.7, 10.2 Hz, 2H), 3.19 - 2.93 (m, 2H), 2.58 - 2.60 (m 1H), 2.44 - 2.42 (m 2H), 2.13 - 2.06 (m, 2H), 1.99 - 2.02 (m, 1H). LCMS (ESI): m/z 503.30 (M+H)+. Examples-23/24: (R&S)-N-(6-fluoropyridin-2-yl)- l-(2-(2-oxopyrrolidin- l-yl)-4- (trifluoromethyl)phenyl)-2,3-dihydro-lH-indene-5-sulfonamide;

Figure imgf000081_0002

The title compounds were prepared by following the similar procedure as described in the synthesis of Intermediate-3 using Intermediate 1 1 and 6-fluoropyridin-2-amine in presence of LiHMDS. Further the enantiomers were separated using chiral preparative HPLC [Column: ChiralPak IA; Mobile phase: A = (Hexane + 0.1% TFA), B =(IPA:DCM = 1 : 1), A:B = 40:60] to afford isomer- 1 and isomer-2. These isomers were obtained at retention time 4.90 min (Example - 23) and retention time 5.53 min (Example-24)

¾ NMR (400 MHz, DMSO-ifc) δ 1 1.37 (s, 1H), 7.93 - 7.81 (m, 2H), 7.79 - 7.68 (m, 2H), 7.63 (dd, J= 8.4, 2.0 Hz, 1H), 7.21 (d, J= 8.2 Hz, 1H), 7.04 (d, J = 8.1 Hz, 1H), 6.97 (dd, J = 7.9, 2.1 Hz, 1H), 6.74 (dd, J = 8.0, 2.5 Hz, 1H), 4.52 (t, J = 8.6 Hz, 1H), 3.73 (dd, J = 19.6, 12.3 Hz, 2H), 3.17 - 2.92 (m, 2H), 2.62 - 2.54 (m, 1H), 2.45 - 2.38 (m, 2H), 2.10 (q, J= 7.4 Hz, 2H), 2.04 - 1.97 (m, 1H). LCMS (ESI): m/z 519.88 (M+H)+

Examples-25/26: (R&S)-l-(2-(2-oxooxazolidin-3-yl)-4-(trifluoromethyl)phenyl)-N- (pyrimidin-2-yl)-2,3-dihydro-lH-indene-5-sulfonamide;

Figure imgf000082_0001

The title compounds were prepared by following the similar procedure as described in the synthesis of Intermediate-3 using Intermediate 12 and pyrimidin-2-amine in presence of LiHMDS.

Further the enantiomers were separated using chiral preparative HPLC [Column: ChiralPak ID; Mobile phase: A = (Hexane + 0.1% TFA), B = (IPA:DCM = 1 : 1), A:B = 50:50] to afford isomer- 1 and isomer-2. These isomers were obtained at retention time 1 1.47 min (Example-25) and retention time 12.58 min (Example-26).

¾ NMR (400 MHz, DMSO-ifc) δ 1 1.75 (s, 1H), 8.52 (d, J = 4.9 Hz, 2H), 8.02 - 7.88 (m, 2H), 7.83 - 7.73 (m, 1H), 7.66 (dd, J = 8.4, 2.0 Hz, 1H), 7.24 (d, J = 8.3 Hz, 1H), 7.15 - 6.95 (m, 2H), 4.70 (t, J = 8.6 Hz, 1H), 4.55 - 4.38 (m, 2H), 4.02 - 3.98 (m, 2H), 3.20 - 2.99 (m, 2H), 2.65 - 2.62 (m, 1H), 2.10 - 1.97 (m, 1H). LCMS (ESI): m/z 505.19 (M+H)+. Examples-27/28: (R&S)-N-(6-fluoropyridin-2-yl)- 1 -(2-(2-oxooxazolidin-3-yl)-4-

(trifluoromethyl)phenyl)-2,3-dihydro-lH-indene-5-sulfonamide;

Figure imgf000083_0001

The title compounds were prepared by following the similar procedure as described in the synthesis of Intermediate-3 using Intermediate 12 and 6-fluoropyridin-2-amine in presence of LiHMDS.

Further the enantiomers were separated using chiral preparative HPLC [Column: ChiralPak IG; Mobile phase: A = (Hexane + 0.1% TFA), B = (IPA:DCM = 1 : 1), A:B = 40:60] to afford isomer-1 and isomer-2. These isomers were obtained at retention time 4.99 min (Example-27) and retention time 5.66 min (Example-28)

¾ NMR (400 MHz, DMSO-ifc) δ 1 1.38 (s, 1H), 7.95 (d, J = 2.0 Hz, 1H), 7.90 - 7.80 (m, 2H), 7.70 - 7.68 (m, 2H), 7.24 (d, J = 8.2 Hz, 1H), 7.03 (d, J = 8.1 Hz, 1H), 6.97 (dd, J = 7.9, 2.1 Hz, 1H), 6.74 (dd, J = 8.0, 2.4 Hz, 1H), 4.71 (t, J = 8.6 Hz, 1H), 4.47 - 4.44 (m, 2H), 4.05 - 3.88 (m, 2H), 3.18 - 2.96 (m, 2H), 2.66 - 2.57 (m, 1H), 2.07 - 1.97 (m, 1H). LCMS (ESI): m/z 522.07 (M+H)+.

Examples-29/30: (R&S)-N-(6-fluoropyridin-2-yl)- 1 -(2-(2-(methylsulfonyl)ethyl)-4- (trifluoromethyl)phenyl)-2,3-dihydro-lH-indene-5-sulfonamide;

Figure imgf000084_0001

The title compounds were prepared by following the similar procedure as described in the synthesis of Intermediate-3 using Intermediate 13 and 6-fluoropyridin-2-amine in presence of LiHMDS.

Further the enantiomers were separated using chiral preparative HPLC [Column: ChiralPak ID; Mobile phase: A = (Hexane + 0.1% TFA), B = (IPA:MEOH = 3:2), A:B = 40:60] to afford isomer-1 and isomer-2. These isomers were obtained at retention time 6.32 min (Example-29) and retention time 7.23 min (Example-30)

¾ NMR (400 MHz, DMSO-ifc) 8 1 1.38 (s, 1H), 7.97 - 7.80 (m, 2H), 7.78 - 7.68 (m, 2H), 7.52 (dd, J= 8.3, 2.0 Hz, 1H), 7.1 1 - 6.93 (m, 3H), 6.74 (dd, J = 8.0, 2.5 Hz, 1H), 4.74 (t, J = 8.4 Hz, 1H), 3.53 - 3.42 (m, 2H), 3.25 (dd, J= 9.8, 5.4 Hz, 2H), 3.14 - 3.10 (m, 1H), 3.04 (s, 3H), 2.75 - 2.58 (m, 2H), 2.00 - 1.87 (m, 1H). LCMS (ESI): m/z 542.95 (M+H)+.

Examples-31/32: (R&S)- 1 -(2-(3-fluoro- 1 -methylazetidin-3-yl)-4- (trifluoromethyl)phenyl)-N-(6-fluoropyridin-2-yl)-2,3-dihydro-lH-indene-5-sulfonamide hydrochloride;

Figure imgf000084_0002
Step 1: tert-butyl (R&S)-3-fluoro-3-(2-(5-(N-(6-fluoropyridin-2-yl)sulfamoyl)-2,3- dihydro- 1 H-inden- 1 -yl)-5-(trifluoromethyl)phenyl)azetidine- 1 -carboxylate The title compounds were prepared by following the similar procedure as described in the synthesis of Intermediate-3 using Intermediate 14 and 6-fluoropyridin-2-amine in presence of LiHMDS.

Further the enantiomers were separated using chiral preparative HPLC [Column: ChiralPak ID; Mobile phase: A = (Hexane + 0.1% TFA), B = (IPA:DCM = 70:30), A:B = 60:40] to afford isomer- 1 and isomer-2. These isomers were obtained at retention time 6.74 min and retention time 7.56 min.

Step 2: (R&S)-l-(2-(3-fluoro-l-methylazetidin-3-yl)-4-(trifluoromethyl)phenyl)-N-(6- fluoropyridin-2-yl)-2,3-dihydro- lH-indene-5-sulfonamide hydrochloride

To a solution of the individually separated enantiomers of tert-butyl (R&S)-3-fluoro-3-(2- (5-(N-(6-fluoropyridin-2-yl)sulfamoyl)-2,3-dihydro- lH-inden- 1 -yl)-5- (trifluoromethyl)phenyl)azetidine- 1 -carboxylate (100 mg, 0.164 mmol) from Step- 1 above in 10 mL DCM was added TFA (0.253 ml, 3.28 mmol) and the mixture stirred for 1 h. After completion as shown in TLC the mixture was evaporated to dryness and triturated with ether to get the TFA salts of the individual enantiomers. The TFA salts were dissolved in 15 mL DCE and formaldehyde (0.135 ml, 4.92 mmol) was added to it followed by acetic acid (0.033 ml, 0.57 mmol) and the mixture heated at 50°C for 20 h. Sodium triacetoxyborohydride (348 mg, 1.64 mmol) was added and stirred for further 18 h. After completion the mixture was added to a satd solution of sodium bicarbonate and extracted with DCM and washed with brine, dried over sodium sulphate and purified by column to get the respective free base's which were converted to their HCl salt's by the addition of 10 ml of 2N HCl solution in ether.

¾ NMR (400 MHz, Methanol-^) δ 7.98 (d, J= 1.6 Hz, 1H), 7.91 - 7.59 (m, 4H), 7.26 (d, J = 8.5 Hz, 1H), 7.10 - 6.89 (m, 2H), 6.62 (dd, J= 7.9, 2.5 Hz, 1H), 5.44 - 4.91 (m, 4H), 4.51 - 4.34 (m, 1H), 3.29 - 2.99 (m, 5H), 2.79 - 2.66 (m, 1H), 2.21 - 2.03 (m, 1H). LCMS (ESI): m/z 524.00 (M+H)+.

Examples-33/34: (R&S)- 1 -(2-(3-fluoro- 1 -methylazetidin-3-yl)-4-

(trifluoromethyl)phenyl)-N-(pyrimidin-2-yl)-2,3-dihydro-lH-indene-5-sulfonamide hydrochloride;

Figure imgf000086_0001

Step 1: tert-butyl (R&S)-3-fluoro-3-(2-(5-(N-(pyrimidin-2-yl)sulfamoyl)-2,3-dihydro-lH- inden- 1 -yl)-5-(trifluoromethyl)phenyl)azetidine- 1 -carboxylate

The title compounds were prepared by following the similar procedure as described in the synthesis of Intermediate-3 using Intermediate 14 and pyrimidin-2-amine in presence of LiHMDS. LCMS (ESI): m/z 593.21 (M+H)+.

Further the enantiomers were separated using chiral preparative HPLC [Column: ChiralPak IA; Mobile phase: A = (Hexane + 0.1% TFA), B = (IPA:DCM = 60:40), A:B = 40:60] to afford isomer- 1 and isomer-2. These isomers were obtained at retention time 4.42 min and retention time 5.19 min.

Step 2: (R&S)- 1 -(2-(3-fluoro- l-methylazetidin-3-yl)-4-(trifluoromethyl)phenyl)-N- (pyrimidin-2-yl)-2,3-dihydro-lH-indene-5-sulfonamide hydrochloride

The title compounds were prepared using the separated enantiomers from Step-1 by following similar procedure as described in the synthesis of Examples 31/32.

¾ NMR (400 MHz, Methanol-A) δ 8.47 (d, J= 4.8 Hz, 2H), 8.05 (d, J= 1.6 Hz, 1H), 7.89 (d, J = 7.8 Hz, 1H), 7.85 - 7.70 (m, 2H), 7.29 (dd, J = 14.6, 8.2 Hz, 1H), 7.06 - 6.92 (m, 2H), 5.39 - 4.96 (m, 4H), 4.50 - 4.38 (m, 1H), 3.25 - 3.04 (m, 5H), 2.80 - 2.67 (m, 1H), 2.20 - 2.03 (m, 1H). LCMS (ESI): m/z 507.01 (M+H)+. Examples-35/36: (R&S)-N-(6-fluoropyridin-2-yl)- 1 -(2-(((S)-tetrahydrofuran-3-yl)oxy)- 4-(trifluoromethyl)phenyl)-2,3-dihydro-lH-indene-5-sulfonamide;

Figure imgf000087_0001

The title compounds were prepared by following the similar procedure as described in the synthesis of Intermediate-3 using Intermediate 15 and 6-fluoropyridin-2-amine in presence of LiHMDS.

Further the enantiomers were separated using chiral preparative HPLC [Column: CHIRALPAK OX-H; Mobile phase: A = (Hexane + 0.1% TFA), B = (IPAMEOH = 60:40), A:B = 40:60], to afford isomer-1 and isomer-2. These isomers were obtained at retention time 6.33 min (Example-35) and retention time 6.99 min (Example-36)

¾ NMR (400 MHz, DMSO-i/e) δ 1 1.34 (s, 1H), 7.94 - 7.78 (m, 2H), 7.69 (dd, J= 8.0, 1.8 Hz, 1H), 7.35 - 7.20 (m, 3H), 7.04 (d, J = 8.0 Hz, 1H), 6.97 (dd, J= 8.0, 2.1 Hz, 1H), 6.73 (dd, J= 8.0, 2.5 Hz, 1H), 5.19 - 5.08 (m, 1H), 4.68 (t, J = 8.5 Hz, 1H), 3.84 (dd, J = 10.2, 4.3 Hz, 1H), 3.68 (d, J= 10.2 Hz, 1H), 3.62 - 3.52 (m, 1H), 3.44 (q, J= 7.9 Hz, 1H), 3.13 - 2.94 (m, 2H), 2.49 - 2.41 (m, 1H), 2.25 - 2.00 (m, 2H), 1.98 - 1.88 (m, 1H) . LCMS (ESI): m/z 523.32 (M+H)+.

Examples-37/38: (R&S)-N-(pyrimidin-2-yl)- 1 -(2-(((S)-tetrahydrofuran-3-yl)oxy)-4- (trifluoromethyl)phenyl)-2,3-dihydro-lH-indene-5-sulfonamide;

Figure imgf000087_0002

The title compounds were prepared by following the similar procedure as described in the synthesis of Intermediate-3 using Intermediate 15 and pyrimidin-2-amine in presence of LiHMDS. Further the enantiomers were separated using chiral preparative HPLC [Column: CHIRALPAK OX-H; Mobile phase: A = (Hexane + 0.1% TFA), B = (IPA:MEOH = 50:50), A:B = 50:50] to afford isomer-1 and isomer-2. These isomers were obtained at retention time 9.30 min (Example-37) and retention time 10.38 min (Example-38) ¾ NMR (400 MHz, DMSO-ifc) δ 8.51 (d, J = 4.8 Hz, 2H), 7.88 (d, J = 1.7 Hz, 1H), 7.74 (dd, J = 7.9, 1.8 Hz, 1H), 7.25 (s, 3H), 7.12 - 6.96 (m, 2H), 5.20 - 5.09 (m, 1H), 4.69 (t, J = 8.4 Hz, 1H), 3.86 (dd, J = 10.2, 4.4 Hz, 1H), 3.70 (d, J = 10.2 Hz, 1H), 3.59 (m, 1H), 3.47 (q, J = 8.1 Hz, 1H), 3.15 - 2.93 (m, 2H), 2.49 - 2.41 (m, 1H), 2.15 - 2.08 (m, 2H), 1.98 - 1.89 (m, 1H). . LCMS (ESI): m/z 506.30 (M+H)+.

Examples-39/40: (R&S)- 1 -(2-(4-methylpiperazin- 1 -yl)-4-(trifluoromethyl)phenyl)-N- (pyrimidin-2-yl)-2,3-dihydro-lH-indene-5-sulfonamide;

Figure imgf000088_0001
Step 1: tert-butyl (R&S)-4-(2-(5-(N-(pyrimidin-2-yl)sulfamoyl)-2,3-dihydro- lH-inden-l- yl)-5-(trifluoromethyl)phenyl)piperazine- 1 -carboxylate

The title compounds were prepared by following the similar procedure as described in the synthesis of Intermediate-3 using Intermediate 16 and pyrimidin-2-amine in presence of

LiHMDS.

Further the enantiomers were separated using chiral preparative HPLC [Column: ChiralPak IC; Mobile phase: A = MeOH + 0.1% TFA ] to afford isomer-1 and isomer-2. These isomers were obtained at retention times of 6.89 min and 7.84 min.

Step 2 : (R&S)- 1 -(2-(4-methylpiperazin- 1 -yl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-2- yl)-2,3-dihydro-lH-indene-5-sulfonamide

The title compounds were prepared using the separated enantiomers from Step-1 by following similar procedure as described in the synthesis of Examples 31/32. ¾ NMR (400 MHz, DMSO-ifc) δ 8.51 (d, J = 4.9 Hz, 2H), 7.90 (s, 1H), 7.75 (d, J = 8.1 Hz, 1H), 7.46 (d, J = 1.9 Hz, 1H), 7.38 (d, J = 8.1 Hz, 1H), 7.11 (d, J = 8.1 Hz, 1H), 7.05 (d, J = 5.3 Hz, 1H), 6.89 (d, J = 8.0 Hz, 1H), 4.91 (t, J = 8.6 Hz, 1H), 3.53 - 3.21 (m, 2H), 3.21 - 2.80 (m, 7H), 2.67 - 2.52 (m, 2H), 2.23 (s, 3H), 2.09 - 1.92 (m, 1H). LCMS (ESI): m/z 517.97 (M+H)+.

Examples-41/42: (R&S)-N-(6-fluoropyridin-2-yl)-l-(2-(4-methylpiperazin- l-yl)-4- (trifluoromethyl)phenyl)-2,3-dihydro-lH-indene-5-sulfonamide;

Figure imgf000089_0001

Step 1: (R & S)-tert-butyl 4-(2-(5-(N-(6-fluoropyridin-2-yl)sulfamoyl)-2,3-dihydro-lH- inden- 1 -yl)-5-(trifluoromethyl)phenyl)piperazine- 1 -carboxylate

The title compounds were prepared by following the similar procedure as described in the synthesis of Intermediate-3 using Intermediate 16 and 6-fluoropyridin-2-amine in presence of LiHMDS. LCMS (ESI): m/z 621.21 (M+H)+

Further the enantiomers were separated using chiral preparative HPLC [Column: ChiralPak IC; Mobile phase: A = (HEX 0.1%TFA), B = IPA ] to afford isomer-1 and isomer-2. These isomers were obtained at retention time 6.06 min and 6.80 min. Step 2: (R&S)-N-(6-fluoropyridin-2-yl)-l-(2-(4-methylpiperazin- l-yl)-4-

(trifluoromethyl)phenyl)-2,3-dihydro-lH-indene-5-sulfonamide

The title compounds were prepared using the separated enantiomers from Step-1 by following similar procedure as described in the synthesis of Examples 31/32.

¾ NMR (400 MHz, DMSO-ifc) δ 1 1.37 (s, 1H), 10.25 (s, 1H), 7.91 - 7.82 (m, 2H), 7.71 (dd, J = 8.0, 1.8 Hz, 1H), 7.50 (s, 1H), 7.45 (d, J = 8.1 Hz, 1H), 7.14 (d, J = 8.1 Hz, 1H), 6.98 (dd, J = 7.9, 2.1 Hz, 1H), 6.94 (d, J = 8.0 Hz, 1H), 6.75 (dd, J = 8.0, 2.5 Hz, 1H), 4.94 (t, J = 8.8 Hz, 1H), 3.46 (d, J = 10.6 Hz, 2H), 3.30 - 3.09 (m, 6H), 3.05 - 2.09 (m, 2H), 2.83 (s, 3H), 2.71 - 2.62 (m, 2H), 2.08 - 1.97 (m, 1H). LCMS (ESI): m/z 534.97 (M+H)+

Examples-43/44: (R&S)- 1 -(2-Morpholino-4-(trifluoromethyl)phenyl)-N-(pyrimidin-2- yl)- -dihydrc- lH-indene-5-sulfonamide;

Figure imgf000090_0001

The title compounds were prepared by following similar procedure as described in Intermediate-3 using Intermediate-5 and pyrimidin-2-amine in presence of LiHMDS. Further the enantiomers were separated using chiral preparative HPLC [Column: ChiralPak ID; Mobile phase: A = (Hexane + 0.1% TFA), B = (IPA: MeOH =1 : 1), A:B = 50:50] to afford isomer- 1 and isomer-2. These isomers were obtained at retention time 7.48 min (Example-43) and 9.48 min (Example-44).

¾NMR (400 MHz, DMSO-i/e) δ 1 1.72 (s, 1H), 8.52 (d, J= 4.9 Hz, 2H), 7.91 (s, 1H), 7.75 (d, J= 8.0 Hz, 1H), 7.50 (s, 1H), 7.40 (d, J= 8.2 Hz, 1H), 7.13 (d, J= 8.1 Hz, 1H), 7.07 (t, J= 4.9 Hz, 1H), 6.91 (d, J= 8.0 Hz, 1H), 4.96 (t, J= 8.7 Hz, 1H), 3.77 - 3.57 (m, 4H), 3.20 - 3.1 1 (m, 1H), 3.1 1 - 3.00 (m, 1H), 2.97 - 2.86 (m, 4H), 2.71 - 2.57 (m, 1H), 2.1 1 - 1.95 (m, 1H). LCMS (ESI): m/z 505.00 (M+H)+.

Examples-45/46: (R&S)-N-(6-Fluoropyridin-2-yl)- 1 -(2-morpholino-4-(trifluoromethyl)

Figure imgf000090_0002

The title compounds were prepared by following similar procedure as described in Intermediate-3 using Intermediate-5 and 6-fluoropyridin-2-amine in presence of LiHMDS. Further the enantiomers were separated using chiral preparative HPLC [Column: ChiralPak ID; Mobile phase: A = (Hexane + 0.1% TFA), B = (IPA : DCM =1 : 1), A:B = 50:50] to afford Isomer- 1 and Isomer-2. These isomers were obtained at retention time 7.79 min (Example-45) and 8.63 min (Example-46).

¾ NMR (400 MHz, DMSO-ifc) δ 1 1.37 (s, 1H), 7.92 - 7.81 (m, 2H), 7.71 (d, J = 8.0 Hz, 1H), 7.51 (s, 1H), 7.40 (d, J = 8.2 Hz, 1H), 7.13 (d, J = 8.2 Hz, 1H), 6.98 (d, J = 8.0 Hz, 1H), 6.93 (d, J = 8.0 Hz, 1H), 6.75 (d, J = 8.1 Hz, 1H), 4.96 (t, J = 8.8 Hz, 1H), 3.67 (s, 4H), 3.22 - 3.12 (m, 1H), 3.10 - 3.00 (m, 1H), 2.90 (s, 4H), 2.70 - 2.58 (m, 2H). LCMS (ESI) : m/z 522.07 (M+H)+.

Examples-47/48: (R&S)- 1 -(2-(Oxetan-3-yloxy)-4-(trifluoromethyl)phenyl)-N-

(pyrimidin-2-yl)-2,3-dihydro-lH-indene-5-sulfonamide;

Figure imgf000091_0001

The title compounds were prepared by following similar procedure as described in Intermediate-3 using Intermediate-6 and pyrimidin-2-amine.

Further the enantiomers were separated using chiral preparative HPLC [Column: ChiralPak ID; Mobile phase: A = (Hexane + 0.1% TFA), B = (IPA : MeOH =1 : 1), A:B = 60:40] to afford isomer- 1 and isomer-2. These isomers were obtained at retention time 1 1.70 min (Example-47) and 13.84 min (Example-48)

¾ NMR (400 MHz, DMSO-i/e) δ 1 1.69 (s, 1H), 8.51 (d, J= 4.9 Hz, 2H), 7.91 (s, 1H), 7.83 - 7.72 (m, 1H), 7.29 (d, J= 8.0 Hz, 1H), 7.23 (d, J= 8.0 Hz, 1H), 7.15 - 7.01 (m, 2H), 6.90 (s, 1H), 5.41 (t, J = 5.4 Hz, 1H), 4.87 (t, J = 6.6 Hz, 1H), 4.85 - 4.76 (m, 2H), 4.42 (dd, J = 7.2, 4.9 Hz, 1H), 4.32 (dd, J= 7.2, 4.9 Hz, 1H), 3.16 - 3.01 (m, 2H), 2.64 - 2.55 (m, 1H), 2.20 - 2.06 (m, 1H). LCMS (ESI): m/z 491.98 (M+H)+.

Examples 49/50: (R&S)- 1 -(2-( 1 -methyl- 1 H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N- (thiazol-2-yl)-2,3-dihydro-lH-indene-5-sulfonamide;

Figure imgf000092_0001

Step 1: (R&S) perfluorophenyl l-(2-(l-methyl-lH-pyrazol-5-yl)-4- (trifluoromethyl)phenyl)-2,3-dihydro-lH-indene-5-sulfonate

The title compounds were prepared by Suzuki coupling of Intermediate 2 and l-methyl-5- (4,4,5, 5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole by following similar procedure as described for the synthesis of Example: 1/2.

Step 2: (R&S)- 1 -(2-( 1 -methyl- 1 H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N-(thiazol-2- yl)-2,3-dihydro-lH-indene-5-sulfonamide

The title compounds were prepared by following similar procedure as described in the synthesis of Intermediate-3 using Step 1 compound obtained above and thiazol-2-amine in presence of LiHMDS.

Further the enantiomers were separated using chiral preparative HPLC [Column: ChiralPak IC; Mobile phase: A = HEX_0.1%TFA, B = IPA DCM] to afford isomer- 1 and isomer-2. These isomers were obtained at retention time 10.05 min (Example-49) and 1 1.21 min (Example-50).

¾ NMR (400 MHz, DMSO-ifc) δ 12.70 (s, 1H), 7.79 (dd, J = 8.3, 2.0 Hz, 1H), 7.72 (dd, J = 8.9, 1.9 Hz, 2H), 7.62 - 7.57 (m, 1H), 7.54 (d, J = 1.9 Hz, 1H), 7.30 (d, J = 8.3 Hz, 1H), 7.26 (d, J = 4.6 Hz, 1H), 6.99 (d, J = 8.0 Hz, 1H), 6.83 (d, J = 4.6 Hz, 1H), 6.45 (d, J = 1.9 Hz, 1H), 4.22 (t, J = 8.6 Hz, 1H), 3.68 (s, 3H), 3.13 - 3.02 (m, 1H), 2.92 (q, J = 8.4, 7.9 Hz, 1H), 2.50 (m, 1H) 2.01 (dd, J = 12.6, 9.0 Hz, 1H). LCMS (ESI): m/z 505.15 (M+H)+

Examples 51/52: (R&S)-N-(isoxazol-3-yl)- l-(2-(l-methyl-lH-pyrazol-5-yl)-4- (trifluoromethyl)phenyl)-2,3-dihydro-lH-indene-5-sulfonamide;

Figure imgf000093_0001

The title compounds were prepared from perfluorophenyl l-(2-(l -methyl- lH-pyrazol-5- yl)-4-(trifluoromethyl)phenyl)-2,3-dihydro-lH-indene-5-sulfonate (prepared as in Step-1 of Example 49/50) and isoxazol-3-amine by following similar procedure as described in the synthesis of Intermediate-3.

Further the enantiomers were separated using chiral preparative HPLC [Column: ChiralPak OX Mobile phase: HEX_0.1% TFA] to afford isomer- 1 and isomer-2. These isomers were obtained at retention time 7.30 min (Example-51) and 8.30 min (Example -

52).

¾ NMR (400 MHz, DMSO-ifc) δ 1 1.58 (s, 1H), 8.69 (d, J = 1.8 Hz, 1H), 7.82 - 7.76 (m, 2H), 7.73 (d, J = 2.0 Hz, 1H), 7.67 - 7.60 (m, 1H), 7.53 (d, J = 1.9 Hz, 1H), 7.30 (d, J = 8.3 Hz, 1H), 7.05 (d, J = 8.0 Hz, 1H), 6.46 - 6.40 (m, 2H), 4.24 (t, J = 8.7 Hz, 1H), 3.67 (s, 3H), 3.13 - 3.03 (m, 1H), 2.97 - 2.88 (m, 1H), 2.48 - 2.50 (m, 1H), 2.09 - 1.97 (m, 1H). LCMS (ESI): m/z 489.16 (M+H)+

Example 53/54: (R&S)-l-(2-(l -methyl- lH-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N- (pyridazin-3-yl)-2,3-dihydro-lH-indene-5-sulfonamide;

Figure imgf000093_0002

The title compounds were prepared from perfluorophenyl l-(2-(l -methyl- lH-pyrazol-5- yl)-4-(trifluoromethyl)phenyl)-2,3-dihydro-lH-indene-5-sulfonate (prepared as in Step-1 of Example 49/50) and pyridazin-3-amine by following similar procedure as described in the synthesis of Intermediate-3. Further the enantiomers were separated using chiral preparative HPLC [Column: ChiralPak OX Mobile phase: B = HEX O.1%TFA] to afford isomer- 1 and isomer-2. These isomers were obtained at retention time 9.36 min (Example-53).and 10.51 min (Example- 54)

¾ NMR (400 MHz, DMSO-i¾) δ 14.23 (s, 1H), 8.33 (s, 1H), 7.77 - 7.82 (m, 4H), 7.62 (d, J = 8.4 Hz, 2H), 7.54 (s, 1H), 7.29 (d, J = 8.3 Hz, 1H), 6.97 (d, J = 7.9 Hz, 1H), 6.44 (s, 1H), 4.22 (t, J = 8.7 Hz, 1H), 3.68 (s, 3H), 3.05 (d, J = 10.2 Hz, 1H), 3.01 - 2.84 (m, 1H), 2.50 (m, lH), 2.01 (s, 1H). LCMS (ESI): m/z 500.19 (M+H)+.

The S-enantiomer was also selectively synthesized using intermediate-8, pyridazin-3- amine and LiHMDS by following the similar procedure as described for synthesis of intermediate-3.

Examples 55/56: (R&S)- 1 -(4-isopropyl-2-( 1 -methyl- 1 H-pyrazol-5-yl)phenyl)-N- (pyrimidin-2-yl)-2,3-dihydro-lH-indene-5-sulfonamide;

Figure imgf000094_0001

The title compounds were prepared by following similar procedure as described in Intermediate-3 using Intermediate- 17 and pyrimidin-2-amine in presence of LiHMDS. Further the enantiomers were separated using chiral preparative HPLC [Column: CHIPvALPAK IC ; Mobile phase: (MeOH_0.1%TFA)] to afford Isomer-1 and Isomer-2. These isomers were obtained at retention time 7.19 min (Example-55) and 8.68 min (Example-56)

¾ NMR (400 MHz, DMSO-ifc) δ 1 1.70 (s, 1H), 8.51 (d, J = 4.9 Hz, 2H), 7.86 (s, 1H), 7.76 (d, J = 8.1 Hz, 1H), 7.47 (d, J = 1.9 Hz, 1H), 7.29 (dd, J = 8.2, 2.0 Hz, 1H), 7.19 (d, J = 2.0 Hz, 1H), 7.06 (s, 1H), 6.98 (dd, J = 8.2, 5.1 Hz, 2H), 6.33 (d, J = 1.8 Hz, 1H), 4.15 (t, J = 8.9 Hz, 1H), 3.65 (s, 3H), 3.09 - 3.00 (m, 1H), 2.95 - 2.87 (m, 2H), 2.45 - 2.40 (m, 1H), 2.03 - 1.91 (m, 1H), 1.26 - 1.20 (m, 6H). LCMS (ESI) : m/z 474.30 (M+H)+. Examples 57/58: (R&S)-N-(6-fluoropyridin-2-yl)- 1 -(4-isopropyl-2-( 1 -methyl- 1 H- pyrazol-5-yl)phenyl)-2,3-dihydro-lH-indene-5-sulfonamide;

Figure imgf000095_0001

Step 1 : N-(2,4-dimethoxybenzyl)-N-(6-fluoropyridin-2-yl)- 1 -(4-isopropyl-2-( 1 -methyl- lH-pyrazol-5-yl)phenyl)-2,3-dihydro-lH-indene-5-sulfonamide

The title compound was prepared by following similar procedure as described in Intermediate-3 using Intermediate- 17 and N-(2,4-dimethoxybenzyl)-6-fluoropyridin-2- amine in presence of LiHMDS. LCMS (ESI) : m/z 640.97 (M+H)+.

Step 2: (R&S)-N-(6-fluoropyridin-2-yl)- 1 -(4-isopropyl-2-( 1 -methyl- 1 H-pyrazol-5- yl)phenyl)-2,3-dihydro-lH-indene-5-sulfonamide

The title compounds were prepared by following similar procedure as described in Example- 1/2 (Step-2) using Step-1 intermediate.

Further the enantiomers were separated using chiral preparative HPLC (Column: CHIRALPAK IC; Mobile phase: A = (Hexane + 0.1% TFA), B = (IPA : DCM =1 : 1), A:B = 50:50] to afford Isomer-1 and Isomer-2. These isomers were obtained at retention time 4.60 min (Example-57) and 5.48 min (Example-58).

¾ NMR (400 MHz, DMSO-ifc) δ 1 1.35 (s, 1H), 7.90 - 7.80 (m, 2H), 7.71 (dd, J = 8.0, 1.8 Hz, 1H), 7.47 (d, J = 1.8 Hz, 1H), 7.29 (dd, J = 8.2, 2.0 Hz, 1H), 7.18 (d, J = 2.0 Hz, 1H), 7.01 (d, J = 8.0 Hz, 1H), 6.98 - 6.93 (m, 2H), 6.73 (dd, J = 8.0, 2.5 Hz, 1H), 6.32 (d, J = 1.8 Hz, 1H), 4.15 (t, J = 8.7 Hz, 1H), 3.64 (s, 3H), 3.12 - 2.98 (m, 1H), 2.96 - 2.81 (m, 2H), 2.44 - 2.36 (m, 1H), 2.02 - 1.89 (m, 1H), 1.22 (d, J = 6.9 Hz, 6H). LCMS (ESI) : m/z 491.02 (M+H)+. Example 59/60: (R&S)- 1 -(4-(tert-butyl)-2-( 1 -methyl- 1 H-pyrazol-5-yl)phenyl)-N- (pyrimidin-2-yl)-2,3-dihydro-lH-indene-5-sulfonamide;

Figure imgf000096_0001

The title compounds were prepared by following similar procedure as described in Intermediate-3 using Intermediate- 18 and pyrimidin-2-amine in presence of LiHMDS.

Further the enantiomers were separated using chiral preparative HPLC [Column: CHIRALPAK IC ; Mobile phase: A = (Hexane + 0.1% TFA), B = (IPA : DCM =1 : 1), A:B = 60:40 ] to afford Isomer- 1 and Isomer-2. These isomers were obtained at retention time 5.01 min (Example-59) and 6.37 min (Example-60).

1H NMR (400 MHz, DMSO-ifc) δ 1 1.70 (s, 1H), 8.51 (d, J = 4.8 Hz, 2H), 7.86 (s, 1H), 7.79 - 7.73 (m, 1H), 7.48 (d, J = 1.8 Hz, 1H), 7.44 (dd, J = 8.3, 2.2 Hz, 1H), 7.30 (d, J = 2.2 Hz, 1H), 7.06 (t, J = 4.8 Hz, 1H), 6.98 (dd, J = 8.2, 3.9 Hz, 2H), 6.33 (d, J = 1.8 Hz, 1H), 4.16 (t, J = 8.6 Hz, 1H), 3.65 (s, 3H), 3.05 (s, 1H), 2.98 - 2.83 (m, 1H), 2.44 - 2.40 (m, 1H), 1.97 (dd, J = 12.5, 9.0 Hz, 1H), 1.30 (s, 9H). LCMS (ESI) : m/z 488.36 (M+H)+.

Example 61/62: (R&S)- 1 -(4-(tert-butyl)-2-( 1 -methyl- 1 H-pyrazol-5-yl)phenyl)-N-(6- fluoropyridin-2-yl)-2,3-dihydro- lH-indene-5-sulfonamide;

Figure imgf000096_0002
The title compounds were prepared by following similar procedure as described in Intermediate-3 using Intermediate- 18 and 6-fluoropyridin-2-amine.

Further the enantiomers were separated using chiral preparative HPLC [Column: CHIRALPAK IC ; Mobile phase: A = (Hexane + 0.1% TFA), B = (IPA : DCM =1 : 1), A:B = 70:30] to afford Isomer-1 and Isomer-2. These isomers were obtained at retention time 5.59 min (Example-61) and 7.03 min (Example-62).

¾ NMR (400 MHz, DMSO-ifc) δ 11.35 (s, 1H), 7.85 (dd, J = 14.4, 6.2 Hz, 2H), 7.71 (dd, J = 7.9, 1.8 Hz, 1H), 7.47 (d, J = 1.8 Hz, 1H), 7.44 (dd, J = 8.3, 2.2 Hz, 1H), 7.30 (d, J = 2.2 Hz, 1H), 7.08 - 6.89 (m, 3H), 6.73 (dd, J = 8.0, 2.4 Hz, 1H), 6.32 (d, J = 1.9 Hz, 1H), 4.17 (t, J = 8.7 Hz, 1H), 3.65 (s, 3H), 3.09 - 3.00 (m, 1H), 2.94 - 2.82 (m, 1H), 2.42 (dd, J = 8.8, 4.8 Hz, 1H), 2.02 - 1.89 (m, 1H), 1.27 (d, J = 21.3 Hz, 9H). LCMS (ESI) : m/z 505.31 (M+H)+.

Example 63/64: (R&S)- 1 -(2-(oxazol-2-yl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-2- yl)-2,3-dihydro-lH-indene-5-sulfonamide;

Figure imgf000097_0001

The title compounds were prepared by following similar procedure as described in the synthesis of Intermediate-3 using Intermediate- 19 and pyrimidin-2-amine.

Further the enantiomers were separated using chiral preparative HPLC [Column: CHIRALPAK IC ; Mobile phase: A = (Hexane + 0.1% TFA), B = (IPA : MeOH = 1 : 1), A:B = 65:35] to afford Isomer-1 and Isomer-2. These isomers were obtained at retention time 10.15 min (Example-63) and 1 1.70 min (Example-64). ¾ NMR (400 MHz, DMSO-ifc) δ 1 1.74 (s, 1H), 8.53 (d, J = 4.8 Hz, 2H), 8.34 (s, 1H), 8.22 (s, 1H), 7.94 (s, 1H), 7.79 (t, J = 8.6 Hz, 2H), 7.49 (s, 1H), 7.31 (d, J = 8.3 Hz, 1H), 7.1 1 - 7.04 (m, 2H), 5.66 (t, J = 8.4 Hz, 1H), 3.21 - 3.10 (m, 1H), 3.10 - 2.97 (m, 1H), 2.79 - 2.64 (m, 1H), 2.15 - 2.01 (m, 1H). LCMS (ESI) : m/z 487.14 (M+H)+. Example 65/66: (R&S)-N-(6-fluoropyridin-2-yl)-l-(2-(oxazol-2-yl)-4-

(trifluoromethyl)phenyl)-2,3-dihydro-lH-indene-5-sulfonamide;

Figure imgf000098_0001

The title compounds were prepared by following similar procedure as described in Intermediate-3 using Intermediate- 19 and 6-fluoropyridin-2-amine.

Further the enantiomers were separated using chiral preparative HPLC [Column: CHIRALPAK IC ; Mobile phase: A = (Hexane + 0.1% TFA), B = (IPA) A:B = 80 : 20 ] to afford Isomer- 1 and Isomer-2. These isomers were obtained at retention time 1 1.98 min (Example-65) and 12.98 min (Example-66).

¾ NMR (400 MHz, DMSO-i¾) δ 1 1.47 - 11.32 (m, 1H), 8.34 (s, 1H), 8.28 - 8.14 (m, 1H), 7.85 (d, J = 42.3 Hz, 4H), 7.48 (s, 1H), 7.30 (d, J = 8.2 Hz, 1H), 7.09 (d, J = 7.9 Hz, 1H), 6.99 (s, 1H), 6.75 (d, J = 7.5 Hz, 1H), 5.66 (m, 1H), 3.19 - 2.95 (m, 2H), 2.78 - 2.65 (m, 1H), 2.08 (s, 1H). LCMS (ESI) : m/z 504.14 (M+H)+.

Example-67: (S)-N-(6-fluoropyridin-2-yl)- 1 -(4'-isopropyl-5-(trifluoromethyl)-[ 1 , 1 '- biphenyl]-2-yl)-2,3-dihydro-lH-indene-5-sulfonamide;

Figure imgf000099_0001

Step 1 : (S)-N-(2,4-dimethoxybenzyl)-N-(6-fluoropyridin-2-yl)- l -(4'-isopropyl-5- (trifluoromethyl)-[l,r-biphenyl]-2-yl)-2,3-dihydro- lH-indene-5-sulfonamide.

To a stirred suspension of (S)- l -(2-chloro-4-(trifluoromethyl)phenyl)-N-(2,4- dimethoxybenzyl)-N-(6-fluoropyridin-2-yl)-2,3-dihydro- lH-indene-5-sulfonamide (0.12 g, 0.19 mmol) (Intermediate 3a), (4-isopropylphenyl)boronic acid (0.08 g, 0.48 mmol) and sodium carbonate (0.05 g, 0.48 mmol) in a solvent mixture of degassed 5 mL Dioxane and 0.2 mL water was added Bis(di-tert-butyl(4- dimethylaminophenyl)phosphine)dichloropalladium(II) (0.02 g, 0.03 mmol) and the reaction mixture heated at 100 °C for 18 h. The reaction mixture was filtered through a celite pad and the filtrate concentrated under reduced pressure to get the crude which was purified by column chromatography to get the required compound as an off white solid. (Yield = 90 mg, 66%).

¾ NMR (400 MHz, Chloroform-if) δ 7.74 (dd, J = 15.6, 7.9 Hz, 1H), 7.64 - 7.53 (m, 3H), 7.52 - 7.45 (m, 1H), 7.38 - 7.29 (m, 5H), 7.25 (d, J = 8.0 Hz, 1H), 7.16 (d, J = 8.2 Hz, 1 H), 6.96 - 6.91 (m, 1H), 6.73-6.67 (m, 1H), 6.42 - 6.33 (m, 2H), 4.98 (d, J = 4.3 Hz, 2H), 4.57 (t, J = 8.8 Hz, 1H), 3.77 (s, 3H), 3.72 (s, 3H), 3.10 -2.86 (m, 3H), 2.62 - 2.52 (m, 1H), 2.18 - 2.09 (m, 1H), 1.32 (d, J = 6.9 Hz, 6H).

Step 2: (S)-N-(6-fluoropyridin-2-yl)- 1 -(4'-isopropyl-5-(trifluoromethyl)-[ 1 , 1 '-biphenyl]- 2-yl)-2,3-dihydro- lH-indene-5-sulfonamide

The title compound was prepared by following the procedure as described in Example- l/2(Step-2) using Step-1 intermediate and TFA. Yield: 83%

¾ NM (400 MHz, DMSO-ifc) δ 1 1.37 (s, 1H), 7.89 - 7.81 (m, 2H), 7.72 (dd, J = 8.0, 1.8 Hz, 1H), 7.65 (dd, J = 8.3, 2.0 Hz, 1H), 7.55 (d, J = 2.0 Hz, 1H), 7.35 (s, 4H), 7.23 (d, J = 8.2 Hz, 1H), 7.01 (d, J = 8.0 Hz, 1H), 6.96 (dd, J = 7.9, 2.1 Hz, 1H), 6.73 (dd, J = 8.0, 2.4 Hz, 1H), 4.46 (t, J = 8.8 Hz, 1H), 3.12 - 3.04 (m, 1H), 2.99 - 2.85 (m, 2H), 2.53 (d, J = 1.8 Hz, 1H), 2.15 - 2.03 (m, 1H), 1.23 (d, J = 6.9 Hz, 6H). LCMS (ESI) : m/z 555.11 (M+H)+ & 577.07 (M+Na)+.

Example-68: (S)- l-(3'-chloro-4'-fluoro-5-(trifluoromethyl)-[ 1 , 1 '-biphenyl] -2-yl)-N-(6- fluoropyridin-2-yl)-2,3-

Figure imgf000100_0001

Step 1 : (S)- 1 -(3'-chloro-4'-fluoro-5-(trifluoromethyl)-[l , 1 '-biphenyl] -2-yl)-N-(2,4- dimethoxybenzyl)-N-(6-fluoropyridin-2-yl)-2,3-dihydro-lH-indene-5-sulfonamide.

The title compound was prepared by following the procedure as described in Example-67 (Step- 1) using intermediate 3a and (3-chloro-4-fluorophenyl)boronic acid. Yield: 72% LCMS (ESI) : m/z 737.19 (M+Na)+.

Step 2: (S)- 1 -(3'-chloro-4'-fluoro-5-(trifluoromethyl)-[ 1 , 1 '-biphenyl] -2-yl)-N-(6- fluoropyridin-2-yl)-2,3-dihydro- lH-indene-5-sulfonamide.

The title compound was prepared by following the procedure as described in Example- 1/2 (Step-2) using Step-1 intermediate and TFA. Yield: 10%

¾ NMR (400 MHz, DMSO-ifc) δ 1 1.36 (s, 1H), 7.89 - 7.80 (m, 2H), 7.76 -7.67 (m, 3H), 7.62 (d, J = 2.1 Hz, 1H), 7.51 (t, J = 8.9 Hz, 1H), 7.48 - 7.42 (m, 1H), 7.22 (d, J = 8.2 Hz, 1H), 7.09 (d, J = 8.0 Hz, 1H), 6.96 (dd, J = 8.0, 2.1 Hz, 1H), 6.74 (dd, J = 8.0, 2.5 Hz, 1H), 4.38 (t, J = 8.7 Hz, 1H), 3.06 (dd, J = 15.7, 9.3 Hz, 1H), 2.96 - 2.86 (m, 1H), 2.48 - 2.42 (m, 1H), 2.10 - 1.99 (m, 1H). LCMS (ESI) : m/z 565.10 (M+H)+ & 587.03 (M+Na)+. Example-69: (S)-N-(6-fluoropyridin-2-yl)- 1 -(4'-methoxy-5-(trifluoromethyl)- [1,1'- biphenyl]-2-yl)-2,3-dihydro-lH-indene-5-sulfonamide;

Figure imgf000101_0001

CF3

Step 1 : (S)-N-(2,4-dimethoxybenzyl)-N-(6-fluoropyridin-2-yl)- 1 -(4'-methoxy-5-

(trifluoromethyl)-[l,r-biphenyl]-2-yl)-2,3-dihydro-lH-indene-5-sulfonamide.

The title compound was prepared by following the procedure as described in Example-67 (Step- 1) using intermediate 3a and (4-methoxyphenyl)boronic acid Yield: 90%.

¾ NMR (400 MHz, Chloroform-if) δ 7.72 (q, J = 8.0 Hz, 1H), 7.63 (s, 1H), 7.58 - 7.49 (m, 3H), 7.36 (dd, J = 7.9, 1.9 Hz, 1H), 7.33 - 7.29 (m, 2H), 7.25 (d, J = 8.0 Hz, 1H), 7.15 (d, J = 8.1 Hz, 1H), 7.04 - 6.99 (m, 2H), 6.93 (d, J = 8.2 Hz, 1H), 6.69 (dd, J = 8.0, 3.0 Hz, 1H), 6.42 - 6.36 (m, 2H), 4.99 (s, 2H), 4.56 (t, J = 8.9 Hz, 1H), 3.88 (s, 3H), 3.78 (d, J = 2.5 Hz, 3H), 3.72 (s, 3H), 3.1 1 - 3.02 (m, 1H), 2.95 - 2.87 (m, 1H), 2.59 - 2.50 (m, 1H), 2.15 - 2.09 (m, 1H). LCMS (ESI) : m/z 715.24 (M+Na)+.

Step 2: (S)-N-(6-fluoropyridin-2-yl)-l -(4'-methoxy-5-(trifluoromethyl)-[ 1 , 1 '-biphenyl] -2- yl)-2,3-dihydro-lH-indene-5-sulfonamide.

The title compound was prepared by following the procedure as described in Example- l/2(Step-2) using Step-1 intermediate and TFA. Yield: 63%

¾ NM (400 MHz, DMSO-ifc) δ 1 1.36 (s, 1H), 7.90 - 7.80 (m, 2H), 7.71 (dd, J = 7.9, 1.8 Hz, 1H), 7.64 (dd, J = 8.4, 2.0 Hz, 1H), 7.53 (d, J = 2.0 Hz, 1H), 7.40 - 7.33 (m, 2H), 7.21 (d, J = 8.2 Hz, 1H), 7.03 (dd, J = 8.8, 2.2 Hz, 3H), 6.96 (dd, J = 7.9, 2.1 Hz, 1H), 6.74 (dd, J = 8.0, 2.5 Hz, 1H), 4.48 (t, J = 8.8 Hz, 1H), 3.79 (s, 3H), 3.12 - 3.03 (m, 1H), 2.96 - 2.85 (m, 1H), 2.48 - 2.41 (m, 1H), 2.13 - 2.00 (m, 1H). LCMS (ESI) : m/z 543.01 (M+H)+ & 564.97 (M+Na)+.

Example-70: (S)- 1 -(2',4'-difluoro-5-(trifluoromethyl)-[ 1 , 1 '-biphenyl] -2-yl)-N-(6- fluoropyridin-2-yl)-2,3-dihydro- lH-indene-5-sulfonamide;

Figure imgf000102_0001

Step 1: (S)- l-(2',4'-difluoro-5-(trifluoromethyl)-[l, l'-biphenyl]-2-yl)-N-(2,4- dimethoxybenzyl)-N-(6-fluoropyridin-2-yl)-2,3-dihydro-lH-indene-5-sulfonamide.

The title compound was prepared by following the procedure as described in Example-67 (Step- 1) using intermediate 3a and (2,4-difluorophenyl)boronic acid Yield: 89%.

¾ NMR (400 MHz, Chloroform-if) δ 7.76 - 7.69 (m, 1H), 7.62 (d, J = 9.2 Hz, 2H), 7.53 (s, 2H), 7.39 - 7.31 (m, 2H), 7.18 (t, J = 9.8 Hz, 1H), 7.01 (dd, J = 32.4, 9.1 Hz, 3H), 6.83 (d, J = 8.0 Hz, 1H), 6.70 (d, J = 7.2 Hz, 1H), 6.39 (d, J = 9.3 Hz, 2H), 4.98 (d, J = 10.0 Hz, 2H), 4.31 (t, J = 8.8 Hz, 1H), 3.77 (s, 3H), 3.72 (s, 3H), 3.06 (s, 1H), 2.91 (s, 1H), 2.43 (s, 1H), 2.14 (s, 1H). LCMS (ESI) : m/z 721.17 (M+Na)+.

Step 2: (S)- 1 -(2',4'-difluoro-5-(trifluoromethyl)-[ 1 , 1 '-biphenyl]-2-yl)-N-(6-fluoropyridin- 2-yl)-2,3-dihydro-lH-indene-5-sulfonamide.

The title compound was prepared by following the procedure as described in Example- l/2(Step-2) using Step-1 intermediate and TFA. Yield: 70%

¾ NMR (400 MHz, DMSO-i¾) δ 1 1.37 (s, 1H), 7.85 (s, 2H), 7.79 - 7.67 (m, 2H), 7.63 (d, J = 2.0 Hz, 1H), 7.61 - 7.46 (m, 1H), 7.40 (s, 1H), 7.32 - 7.16 (m, 2H), 7.05 - 6.90 (m, 2H), 6.74 (d, J = 8.0 Hz, 1H), 4.23 (s, 1H), 3.06 (s, 1H), 2.91 (s, 1H), 2.48 - 2.41 (m, 1H), 2.12 - 1.95 (m, 1H). LCMS (ESI) : m/z 548.99 (M+l)+ & 570.95 (M+Na)+.

Example-71 : (S)-N-(2,4-dimethoxybenzyl)-N-(6-fluoropyridin-2-yl)- 1 -(2-(pyridin-3-yl)- 4-(trifluoromethyl)phenyl)-2,3-dihydro- 1 H-indene-5-sulfonamide;

Figure imgf000103_0001

Step 1 : (S)-N-(2,4-dimethoxybenzyl)-N-(6-fluoropyridin-2-yl)- 1 -(2-(pyridin-4-yl)-4- (trifluoromethyl)phenyl)-2,3-dihydro-lH-indene-5-sulfonamide

The title compound was prepared by following the procedure as described in Example-67 (Step- 1 ) using intermediate 3a and pyridin-3 -ylboronic acid Yield: 71 %

¾ NMR (400 MHz, Chloroform-if) δ 8.79 (d, J = 5.1 Hz, 2H), 7.76 - 7.70 (m, 1H), 7.67 (d, J = 8.8 Hz, 2H), 7.58 - 7.53 (m, 2H), 7.50 (d, J = 5.0 Hz, 2H), 7.34 (dd, J = 7.9, 1.9 Hz, 1H), 7.25 (d, J = 8.2 Hz, 2H), 6.93 (d, J = 8.0 Hz, 1H), 6.70 (dd, J = 8.0, 2.9 Hz, 1H), 6.44 - 6.35 (m, 2H), 4.97 (s, 2H), 4.41 (t, J = 8.7 Hz, 1H), 3.77 (s, 3H), 3.71 (s, 3H), 3.09 (dd, J = 16.2, 8.6 Hz, 1H), 3.00 - 2.90 (m, 1H), 2.60 - 2.50 (m, 1H), 2.14 (d, J = 9.1 Hz, 1H). LCMS (ESI) : m/z bb\22 (M+H)+.

Step 2: (S)-N-(2,4-dimethoxybenzyl)-N-(6-fluoropyridin-2-yl)- 1 -(2-(pyridin-3-yl)-4- (trifluoromethyl)phenyl)-2,3-dihydro-lH-indene-5-sulfonamide

The title compound was prepared by following the procedure as described in Example- l/2(Step-2) using Step-1 intermediate and TFA. Yield: 74%

¾ NMR (400 MHz, DMSO-ifc) 8 1 1.37 (s, 1H), 8.73 - 8.64 (m, 2H), 7.90 - 7.80 (m, 2H), 7.77 - 7.70 (m, 2H), 7.63 (d, J = 2.0 Hz, 1H), 7.55 - 7.48 (m, 2H), 7.27 (d, J = 8.2 Hz, 1H), 7.07 (d, J = 8.0 Hz, 1H), 6.96 (dd, J = 7.9, 2.1 Hz, 1H), 6.74 (dd, J = 8.0, 2.5 Hz, 1H), 4.38 (t, J = 8.7 Hz, 1H), 3.13 - 3.03 (m, 1H), 2.98 - 2.86 (m, 1H), 2.46 (s, 1H), 2.13 - 2.00 (m, 1H). LCMS (ESI) : m/z 513.94 (M+H)+.

Example-72: (S)-N-(6-fluoropyridin-2-yl)-l-(2-(pyridin-4-yl)-4- (trifluoromethyl)phenyl)-2,3-dihydro-lH-indene-5-sulfonamide;

Figure imgf000104_0001

Step 1 : (S)-N-(2,4-dimethoxybenzyl)-N-(6-fluoropyridin-2-yl)- 1 -(2-(pyridin-4-yl)-4- (trifluoromethyl)phenyl)-2,3-dihydro-lH-indene-5-sulfonamide

The title compound was prepared by following the procedure as described in Example-67 (Step- 1) using intermediate 3a and pyridin-4-ylboronic acid Yield: 80%.

¾ NMR (400 MHz, Chloroform-if) δ 8.73 (d, J = 6.7 Hz, 2H), 7.82 (d, J = 7.8 Hz, 1H), 7.72 (q, J = 8.1 Hz, 1H), 7.65 (d, J = 6.7 Hz, 2H), 7.57 (d, J = 2.0 Hz, 1H), 7.55 - 7.50 (m, 2H), 7.34 (dd, J = 7.7, 1.9 Hz, 1H), 7.27 - 7.21 (m, 2H), 6.93 (d, J = 8.0 Hz, 1H), 6.70 (dd, J = 7.9, 2.9 Hz, 1H), 6.42 - 6.34 (m, 2H), 4.98 (s, 2H), 4.41 (t, J = 8.8 Hz, 1H), 3.77 (s, 3H), 3.71 (s, 3H), 3.08 (dd, J = 15.6, 9.4 Hz, 1H), 2.96 - 2.86 (m, 1H), 2.61 - 2.51 (m, 1H), 2.18 - 2.10 (m, 1H). LCMS (ESI) : m/z bb\22 (M+H)+.

Example-73: (S)-N-(6-fluoropyridin-2-yl)-l-(2-(l -methyl-lH-indol-5-yl)-4- (trifluoromethyl)phenyl)-2,3 e;

Figure imgf000104_0002

Step 1 : (S)-N-(2,4-dimethoxybenzyl)-N-(6-fluoropyridin-2-yl)- 1 -(2-( 1 -methyl- 1 H-indol- 5-yl)-4-(trifluoromethyl)phenyl)-2,3-dihydro-lH-indene-5-sulfonamide.

The title compound was prepared by following the procedure as described in Example-67 (Step- 1) using Intermediate 3a and l -methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)- lH-indole. Yield: 80%. ¾ NMR (400 MHz, Chloroform-if) δ 7.71 (q, J = 8.1 Hz, 1H), 7.66 - 7.59 (m, 3H), 7.57 - 7.49 (m, 2H), 7.41 (d, J = 8.4 Hz, 1H), 7.36 (dd, J = 7.7, 1.9 Hz, 1H), 7.24 (td, J = 8.2, 1.2 Hz, 2H), 7.19 - 7.13 (m, 2H), 6.98 (d, J = 8.0 Hz, 1H), 6.68 (dd, J = 8.0, 2.9 Hz, 1H), 6.56 (dd, J = 3.1, 0.8 Hz, 1H), 6.37 (s, 2H), 4.99 (s, 2H), 4.63 (t, J = 8.9 Hz, 1H), 3.87 (s, 3H), 3.77 (s, 3H), 3.71 (s, 3H), 3.03 (dd, J = 16.1, 8.6 Hz, 1H), 2.84 (dt, J = 16.6, 8.9 Hz, 1H), 2.59 - 2.49 (m, 1H), 2.17 - 2.04 (m, 1H). LCMS (ESI) : m/z 716.22 (M+H)+ & 738.17 (M+Na)+.

Step 2: (S)-N-(6-fluoropyridin-2-yl)- 1 -(2-( 1 -methyl- 1 H-indol-5-yl)-4-

(trifluoromethyl)phenyl)-2,3-dihydro-lH-indene-5-sulfonamide

The title compound was prepared by following the procedure as described in Example- l/2(Step-2) using Step-1 intermediate and TFA. Yield: 15%

¾ NM (400 MHz, DMSO-ifc) δ 1 1.36 (s, 1H), 7.87 - 7.80 (m, 2H), 7.72 (dd, J = 8.0, 1.8 Hz, 1H), 7.64 (dd, J = 8.4, 2.1 Hz, 1H), 7.58 (dd, J = 5.7, 1.8 Hz, 2H), 7.52 (d, J = 8.4 Hz, 1H), 7.40 (d, J = 3.1 Hz, 1H), 7.26 - 7.15 (m, 2H), 7.06 (d, J = 8.0 Hz, 1H), 6.96 (dd, J = 8.0, 2.1 Hz, 1H), 6.72 (dd, J = 8.0, 2.5 Hz, 1H), 6.46 (d, J = 3.1 Hz, 1H), 4.54 (t, J = 8.8 Hz, 1H), 3.82 (s, 3H), 3.06 (dd, J = 16.5, 8.4 Hz, 1H), 2.91 - 2.78 (m, 1H), 2.47 - 2.38 (m, 1H), 2.14 - 2.02 (m, 1H). LCMS (ESI) : m/z 566.10 (M+H)+ & 588.07 (M+Na)+.

Example-74: (S)- 1 -(2-(pyridin-3-yl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-2-yl)-2,3- dihydro- 1 H-indene-5-sulfonami

Figure imgf000105_0001

Step 1 : (S)-N-(2,4-dimethoxybenzyl)- 1 -(2-(pyridin-3-yl)-4-(trifluoromethyl)phenyl)-N- (pyrimidin-2-yl)-2,3-dihydro-lH-indene-5-sulfonamide.

The title compound was prepared by following the procedure as described in Example-67 (Step- 1) using intermediate 4b and pyridin-3-ylboronic acid Yield: 65%. LCMS (ESI) : m/z 647.12 (M+H)+.

Step 2: (S)- 1 -(2-(pyridin-3-yl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-2-yl)-2,3- dihydro- 1 H-indene-5-sulfonamide

The title compound was prepared by following the procedure as described in Example- l/2(Step-2) using Step-1 intermediate and TFA. Yield: 85%

¾ NMR (400 MHz, DMSO-ifc) δ 1 1.79 (s, 1H), 8.73 - 8.61 (m, 2H), 8.50 (d, J = 4.9 Hz, 2H), 7.98 - 7.83 (m, 2H), 7.80 - 7.71 (m, 2H), 7.66 (d, J = 2.0 Hz, 1H), 7.51 (dd, J = 7.9, 4.9 Hz, 1H), 7.28 (d, J = 8.2 Hz, 1H), 7.08 - 7.02 (m, 2H), 4.35 (t, J = 8.7 Hz, 1H), 3.08 (dd, J = 17.5, 8.6 Hz, 1H), 2.97 - 2.84 (m, 1H), 2.18 - 2.03 (m, 1H), 1.20 - 1.09 (m, 1H). LCMS (ESI) : m/z 497.17 (M+H)+.

Example 75: (S)- 1 -(2-(6-ethoxypyridin-3-yl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-2- yl)-2,3-dihydro-lH-indene-5-sulfonamide;

Figure imgf000106_0001

To a stirred solution of (S)-l-(2-(6-fluoropyridin-3-yl)-4-(trifluoromethyl)phenyl)-N- (pyrimidin-2-yl)-2,3-dihydro-lH-indene-5-sulfonamide (0.1 g, 0.19 mmol) in 5 mL EtOH, K2CO3 (0.08 g, 0.58 mmol) was added and the reaction heated at 70°C for 9 h. The progress of the reaction was monitored by TLC. After completion the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over Na2S04 and concentrated under reduced pressure to get the crude, which was purified by prep HPLC to get the pure title compound (Yield = 41 mg, 39% yield)

¾ NMR (400 MHz, DMSO-ifc) δ 1 1.73 (s, 1H), 8.51 (d, J = 4.9 Hz, 2H), 8.23 (d, J = 2.5 Hz, 1H), 7.88 (d, J = 1.7 Hz, 1H), 7.85 - 7.73 (m, 2H), 7.73 - 7.65 (m, 1H), 7.62 (d, J = 2.0 Hz, 1H), 7.24 (d, J = 8.2 Hz, 1H), 7.1 1 - 6.98 (m, 2H), 6.89 (d, J = 8.5 Hz, 1H), 4.41 (t, J = 8.7 Hz, 1H), 4.34 (q, J = 7.0 Hz, 2H), 3.19 - 3.00 (m, 1H), 3.00 - 2.86 (m, 1H), 2.18 - 1.97 (m, 1H), 1.33 (t, J = 7.0 Hz, 3H). LCMS (ESI): m/z 541.32 (M+H)+. Examples-76: (S)- 1 -(2-(pyridin-4-yl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-2-yl)-2,3- dihydro- 1 H-indene-5-sulfonamide;

Figure imgf000107_0001

Step 1 : (S)-N-(2,4-dimethoxybenzyl)- 1 -(2-(pyridin-4-yl)-4-(trifluoromethyl)phenyl)-N- (pyrimidin-2-yl)-2,3-dihydro-lH-indene-5-sulfonamide.

The title compound was prepared by following the procedure as described in Example-67 (Step- 1) using intermediate 4b and pyridin-4-ylboronic acid. Yield: 57%.

LCMS (ESI) : m/z 647.22 (M+H)+.

Step 2: (S)- 1 -(2-(pyridin-4-yl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-2-yl)-2,3- dihydro- 1 H-indene-5-sulfonamide.

The title compound was prepared by following the procedure as described in Example- l/2(Step-2) using Step-1 intermediate and TFA. Yield: 45%

¾ NMR (400 MHz, DMSO-ifc) δ 1 1.7 (s,lH)8.78 (d, J = 5.4 Hz, 2H), 8.51 (d, J = 4.8 Hz, 2H), 7.89 (s, 1H), 7.84 - 7.76 (m, 2H), 7.69 (dd, J = 1 1.0, 3.7 Hz, 3H), 7.30 (d, J = 8.2 Hz, 1H), 7.06 (dd, J = 6.2, 3.8 Hz, 2H), 4.37 (t, J = 8.7 Hz, 1H), 3.09 (dd, J = 16.2, 8.7 Hz, 1H), 3.00 - 2.83 (m, 1H), 2.40 (m,lH), 2.08 (dd, J = 12.5, 9.0 Hz, 1H). LCMS (ESI) : m/z 496.93 (M+H)+.

Examples-77: (S)- 1 -(2-( 1 -methyl- 1 H-indol-5-yl)-4-(trifluoromethyl)phenyl)-N-

(pyrimidin-2-yl)-2,3-dihydro-lH-indene-5-sulfonamide;

Figure imgf000108_0001

CF3

Step 1 : (S)-N-(2,4-dimethoxybenzyl)- 1 -(2-( 1 -methyl- lH-indol-5-yl)-4-

(trifluoromethyl)phenyl)-N-(pyrimidin-2-yl)-2,3-dihydro-lH-indene-5-sulfonamide.

The title compound was prepared by following the procedure as described in Example-67 (Step- 1) using intermediate 4b and l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)- lH-indole. Yield: 86%.

¾ NMR (400 MHz, DMSO-ifc) δ 8.57 (d, J = 4.8 Hz, 2H), 7.80 (d, J = 7.9 Hz, 2H), 7.66 (d, J = 13.6 Hz, 2H), 7.59 (d, J = 6.6 Hz, 2H), 7.53 (d, J = 8.4 Hz, 1H), 7.41 (d, J = 3.1 Hz, 1H), 7.23 - 7.17 (m, 2H), 7.12 (t, J = 4.8 Hz, 1H), 7.01 - 6.94 (m, 2H), 6.50 - 6.41 (m, 3H), 5.28 (s, 2H), 4.54 (d, J = 8.7 Hz, 1H), 3.83 (s, 3H), 3.71 (s, 3H), 3.57 (s, 3H), 2.96 (s, 1H), 2.81 (d, J = 8.4 Hz, 1H), 2.07 (d, J = 12.0 Hz, 1H). LCMS (ESI) : m/z 699.19 (M+H)+.

Step 2: (S)- l-(2-(l-methyl-lH-indol-5-yl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-2-yl)- 2,3-dihydro-lH-indene-5-sulfonamide.

The title compound was prepared by following the procedure as described in Example- l/2(Step-2) using Step-1 intermediate and TFA. Yield: 14%

¾ NMR (400 MHz, DMSO-ifc) δ 1 1.75 (s, 1H), 8.49 (d, J = 4.9 Hz, 2H), 7.86 (s, 1H), 7.77 (dd, J = 8.0, 1.8 Hz, 1H), 7.65 (dd, J = 8.3, 2.1 Hz, 1H), 7.59 (dd, J = 6.2, 1.9 Hz, 2H), 7.53 (d, J = 8.4 Hz, 1H), 7.40 (d, J = 3.1 Hz, 1H), 7.26 - 7.17 (m, 2H), 7.04 (d, J = 8.1 Hz, 2H), 6.47 (d, J = 3.1 Hz, 1H), 4.54 (q, J = 8.8, 8.1 Hz, 1H), 3.80 (s, 3H), 3.14 - 3.00 (m, 1H), 2.93 - 2.80 (m, 1H), 2.48 - 2.40 (m, 1H), 2.13 - 2.04 (m, 1H).LCMS (ESI) : m/z 548.95 (M+H)+.

Examples-78: (S)-l-(2-(l -methyl-lH-indazol-5-yl)-4-(trifluoromethyl)phenyl)-N- (pyrimidin-2-yl)-2,3-dihydro-lH-indene-5-sulfonamide;

Figure imgf000109_0001

CF3

Step 1 : (S)-N-(2,4-dimethoxybenzyl)- 1 -(2-(l -methyl- 1 H-indazol-5-yl)-4-

(trifluoromethyl)phenyl)-N-(pyrimidin-2-yl)-2,3-dihydro-lH-indene-5-sulfonamide.

The title compound was prepared by following the procedure as described in Example-67 (Step- 1) using intermediate 4b and l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)- lH-indazole. Yield: 67%.

¾ NMR (400 MHz, DMSO-i¾) δ 8.57 (d, J = 4.8 Hz, 2H), 8.12 - 8.08 (m, 1H), 7.86 - 7.79 (m, 2H), 7.78 - 7.69 (m, 3H), 7.66 - 7.60 (m, 2H), 7.47 (dd, J = 8.6, 1.6 Hz, 1H), 7.21 (d, J = 8.3 Hz, 1H), 7.13 (t, J = 4.8 Hz, 1H), 6.98 (dd, J = 10.9, 8.2 Hz, 2H), 6.48 (d, J = 2.4 Hz, 1H), 6.44 (dd, J = 8.3, 2.4 Hz, 1H), 5.28 (s, 2H), 4.46 (t, J = 8.6 Hz, 1H), 4.09 (d, J = 1.2 Hz, 3H), 3.71 (s, 3H), 3.57 (s, 3H), 3.03 - 2.96 (m, 1H), 2.85 - 2.76 (m, 1H), 2.05 (dd, J = 12.6, 9.1 Hz, 1H). LCMS (ESI) : m/z 700.16 (M+H)+.

Step 2: (S)- 1 -(2-( 1 -methyl- 1 H-indazol-5-yl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-2- yl)-2,3-dihydro-lH-indene-5-sulfonamide. The title compound was prepared by following the procedure as described in Example- l/2(Step-2) using Step-1 intermediate and TFA. Yield: 50%

¾ NMR (400 MHz, DMSO-ifc) δ 1 1.73 (s, 1H), 8.50 (d, J = 4.9 Hz, 2H), 8.09 (d, J = 0.9 Hz, 1H), 7.89 - 7.80 (m, 2H), 7.80 - 7.67 (m, 3H), 7.61 (d, J = 2.0 Hz, 1H), 7.46 (dd, J = 8.6, 1.6 Hz, 1H), 7.25 (d, J = 8.2 Hz, 1H), 7.10 - 6.96 (m, 2H), 4.46 (t, J = 8.7 Hz, 1H), 4.08 (s, 3H), 3.15 - 3.00 (m, 1H), 2.92 - 2.83 (m, 1H), 2.47 - 2.36 (m, 1H), 2.14 - 2.01 (m, 1H). LCMS (ESI) : m/z 549.95 (M+H)+. Example-79: (S)- l-(3'-chloro-4'-fluoro-5-(trifluoromethyl)-[l, l'-biphenyl]-2-yl)-N- (pyrimidin-2-yl)-2,3-dihydro-lH-indene-5-sulfonamide;

Figure imgf000110_0001

Step 1 : (S)- 1 -(3'-chloro-4'-fluoro-5-(trifluoromethyl)-[l , 1 '-biphenyl]-2-yl)-N-(2,4- dimethoxybenzyl)-N-(pyrimidin-2-yl)-2,3-dihydro-lH-indene-5-sulfonamide.

The title compound was prepared by following the procedure as described in Example-67 (Step- 1) using intermediate 4b and (3-chloro-4-fluorophenyl)boronic acid. Yield: 89%.

LCMS (ESI) : m/z 698.18 (M+l)+ & 720.13 (M+Na)+.

Step 2: (S)-l -(3'-chloro-4'-fluoro-5-(trifluoromethyl)-[l,l'-biphenyl]-2-yl)-N-(pyrimidin- 2-yl)-2,3-dihydro-lH-indene-5-sulfonamide.

The title compound was prepared by following the procedure as described in Example- l/2(Step-2) using Step-1 intermediate and TFA. Yield: 71%

1H NMR (400 MHz, DMSO-ifc) δ 1 1.76 (s, 1H), 8.51 (d, J = 4.9 Hz, 2H), 7.88 (s, 1H), 7.77 (dd, J = 8.1, 1.8 Hz, 1H), 7.74 - 7.67 (m, 2H), 7.63 (d, J = 2.0 Hz, 1H), 7.55 - 7.48 (m, 1H), 7.46 - 7.42 (m, 1H), 7.23 (d, J = 8.2 Hz, 1H), 7.06 (d, J = 7.0 Hz, 2H), 4.38 (t, J = 8.7 Hz, 1H), 3.07 (dd, J = 16.9, 8.3 Hz, 1H), 2.90 (dd, J = 16.5, 8.6 Hz, 1H), 2.45 (dd, J = 8.1, 4.9 Hz, 1H), 2.08 - 1.99 (m, 1H). LCMS (ESI) : m/z 547.95 (M+H)+.

Examples-80: (S)- 1 -(4'-chloro-5-(trifluoromethyl)-[l , 1 '-biphenyl]-2-yl)-N-(pyrimidin-2- yl)-2,3-dihydro-lH-indene-5-sulfonamide;

Figure imgf000111_0001

CF3

Step 1 : (S)- 1 -(4'-chloro-5-(trifluoromethyl)-[ 1 , 1 '-biphenyl] -2-yl)-N-(2,4- dimethoxybenzyl)-N-(pyrimidin-2-yl)-2,3-dihydro-lH-indene-5-sulfonamide.

The title compound was prepared by following the procedure as described in Example-67 (Step- 1) using intermediate 4b and (4-chlorophenyl)boronic acid. Yield: 62%.

¾ NMR (400 MHz, DMSO-ifc) δ 8.58 (t, J = 4.2 Hz, 2H), 7.89 - 7.78 (m, 4H), 7.71 (t, J = 1 1.8 Hz, 2H), 7.60 - 7.53 (m, 2H), 7.49 (d, J = 8.1 Hz, 1H), 7.23 (d, J = 11.6 Hz, 1H), 7.13 (d, J = 6.9 Hz, 1H), 7.03 - 6.94 (m, 2H), 6.49 (d, J = 2.0 Hz, 1H), 6.45 (d, J = 8.8 Hz, 1H), 5.29 (s, 2H), 4.52 (d, J = 16.0 Hz, 1H), 3.72 (d, J = 4.3 Hz, 3H), 3.58 (s, 3H), 3.00 (s, 1H), 2.87 (s, 1H), 2.09 (s, 1H). LCMS (ESI) : m/z 680.14 (M+H)+ & 702.14 (M+Na)+.

Step 2: (S)- 1 -(4'-chloro-5-(trifluoromethyl)-[l , 1 '-biphenyl]-2-yl)-N-(pyrimidin-2-yl)-2,3- dihydro- 1 H-indene-5-sulfonamide.

The title compound was prepared by following the procedure as described in Example- l/2(Step-2) using Step-1 intermediate and TFA. Yield: 14%

¾ NMR (400 MHz, DMSO-ifc) δ 1 1.76 (s, 1H), 8.50 (d, J = 4.9 Hz, 2H), 7.88 (d, J = 1.7 Hz, 1H), 7.76 (dd, J = 8.0, 1.8 Hz, 1H), 7.69 (dd, J = 8.4, 2.1 Hz, 1H), 7.58 (d, J = 2.0 Hz, 1H), 7.57 - 7.52 (m, 2H), 7.51 - 7.46 (m, 2H), 7.24 (d, J = 8.3 Hz, 1H), 7.09 - 7.00 (m, 2H), 4.39 (t, J = 8.7 Hz, 1H), 3.15 - 3.03 (m, 1H), 2.97 - 2.84 (m, 1H), 2.49 - 2.30 (m, 1H), 2.12 - 1.92 (m, 1H). LCMS (ESI) : m/z 530.07 (M+H)+. Examples-81 : (S)- 1 -(4'-methoxy-5-(trifluoromethyl)-[ 1 , 1 '-biphenyl] -2-yl)-N-(pyrimidin- 2-yl)-2,3-dihydro-lH-indene-5-sulfonamide;

Figure imgf000112_0001

Step 1 : (S)-N-(2,4-dimethoxybenzyl)- 1 -(4'-methoxy-5-(trifluoromethyl)-[ 1 , 1 '-biphenyl] - 2-yl)-N-(pyrimidin-2-yl)-2,3-dihydro-lH-indene-5-sulfonamide.

The title compound was prepared by following the procedure as described in Example-67 (Step- 1) using intermediate 4b and (4-methoxyphenyl)boronic acid. Yield: 67%.

LCMS (ESI) : m/z 676.14 (M+H)+.

Step 2: (S)- l-(4'-methoxy-5-(trifluoromethyl)-[l, l'-biphenyl]-2-yl)-N-(pyrimidin-2-yl)- 2,3-dihydro-lH-indene-5-sulfonamide.

The title compound was prepared by following the procedure as described in Example- l/2(Step-2) using Step-1 intermediate and TFA. Yield: 75%

¾ NMR (400 MHz, DMSO-ifc) δ 1 1.74 (s, 1H), 8.51 (d, J = 4.8 Hz, 2H), 7.91 - 7.83 (m, 1H), 7.76 (dd, J = 8.0, 1.8 Hz, 1H), 7.64 (dd, J = 8.3, 2.1 Hz, 1H), 7.54 (d, J = 2.1 Hz, 1H), 7.37 (d, J = 8.6 Hz, 2H), 7.22 (d, J = 8.2 Hz, 1H), 7.12 - 6.97 (m, 4H), 4.47 (t, J = 8.8 Hz, 1H), 3.79 (s, 3H), 3.14 - 3.03 (m, 1H), 2.95 - 2.84 (m, 1H), 2.45 (dd, J = 7.9, 2.6 Hz, 1H), 2.14 - 2.02 (m, 1H). LCMS (ESI) : m/z 526.07 (M+H)+.

Example 82: (S)- 1 -(4'-(dimethylamino)-5-(trifluoromethyl)- [1,1 '-biphenyl] -2-yl)-N- (pyrimidin-2-yl)-2,3-dihydro-lH-indene-5-sulfonamide;

Figure imgf000113_0001

CF3

Step 1 : (S)-N-(2,4-dimethoxybenzyl)- 1 -(4'-(dimethylamino)-5-(trifluoromethyl)-[ 1 , 1 '- biphenyl]-2-yl)-N-(pyrimidin-2-yl)-2,3-dihydro-lH-indene-5-sulfonamide.

The title compound was prepared by following the procedure as described in Example-67 (Step- 1) using intermediate 4b and N,N-dimethyl-4-(4,4,5,5-tetramethyl- 1,3,2- dioxaborolan-2-yl)aniline. Yield: 81%.

LCMS (ESI) : m/z 689.11 (M+H)+.

Step 2: (S)- 1 -(4'-(dimethylamino)-5-(trifluoromethyl)-[ 1 , l'-biphenyl] -2-yl)-N-(pyrimidin- 2-yl)-2,3-dihydro-lH-indene-5-sulfonamide.

The title compound was prepared by following the procedure as described in Example- l/2(Step-2) using Step-1 intermediate and TFA. Yield: 17%

¾ NMR (400 MHz, DMSO-ifc) δ 1 1.77 (s, 1H), 8.50 (d, J = 4.9 Hz, 2H), 7.88 (d, J = 1.7 Hz, 1H), 7.76 (dd, J = 8.0, 1.8 Hz, 1H), 7.60 (dd, J = 8.4, 2.1 Hz, 1H), 7.51 (d, J = 2.1 Hz, 1H), 7.29 - 7.23 (m, 2H), 7.20 (d, J = 8.2 Hz, 1H), 7.05 (t, J = 4.9 Hz, 1H), 6.98 (d, J = 8.0 Hz, 1H), 6.86 - 6.76 (m, 2H), 4.56 (t, J = 8.8 Hz, 1H), 3.09 (dd, J = 16.0, 8.7 Hz, 1H), 2.93 (s, 6H), 2.88 (d, J = 9.3 Hz, 1H), 2.40 (m, lH), 2.14 - 2.07 (m, 1H). LCMS (ESI) : m/z 539.03 (M+H)+.

Example 83: (S)- 1 -(4'-fluoro-2'-methoxy-5-(trifluoromethyl)-[ 1 , 1 '-biphenyl] -2-yl)-N- (pyrimidin-2-yl)-2,3-dihydro-lH-indene-5-sulfonamide;

Figure imgf000114_0001

CF3

Step 1 : (S)-N-(2,4-dimethoxybenzyl)- 1 -(4'-fluoro-2'-methoxy-5-(trifluoromethyl)- [1,1'- biphenyl]-2-yl)-N-(pyrimidin-2-yl)-2,3-dihydro-lH-indene-5-sulfonamide.

The title compound was prepared by following the procedure as described in Example-67 (Step- 1) using intermediate 4b and 2-(4-fluoro-2-methoxyphenyl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane. Yield: 85%.

LCMS (ESI) : m/z 694.08 (M+H)+.

Step 2: (S)-l-(4'-fluoro-2'-methoxy-5-(trifluoromethyl)-[l, l'-biphenyl]-2-yl)-N- (pyrimidin-2-yl)-2,3-dihydro-lH-indene-5-sulfonamide.

The title compound was prepared by following the procedure as described in Example- l/2(Step-2) using Step-1 intermediate and TFA. Yield: 72%.

¾ NMR (400 MHz, DMSO-ifc) δ 11.71 (s, 1H), 8.51 (dd, J = 12.2, 4.9 Hz, 2H), 7.84 (dd, J = 14.7, 8.4 Hz, 2H), 7.65 (dt, J = 8.4, 2.2 Hz, 1H), 7.45 (dd, J = 7.0, 2.0 Hz, 1H), 7.36 (dd, J = 8.4, 6.8 Hz, 1H), 7.31 - 7.20 (m, 1H), 7.15 (d, J = 8.2 Hz, 1H), 7.10 - 6.97 (m, 2H), 6.93 - 6.83 (m, 1H), 4.15 (t, J = 8.6 Hz, 1H), 3.74 (d, J = 28.9 Hz, 3H), 3.15 - 3.04 (m, 1H), 2.96 - 2.84 (m, 1H), 2.36 - 2.25 (m, 1H), 1.94 - 1.83 (m, 1H). LCMS (ESI) : m/z 544.07 (M+H)+.

Example 84: (S)- 1 -(4'-isopropoxy-5-(trifluoromethyl)-[ 1 , 1 '-biphenyl] -2-yl)-N- (pyrimidin-2-yl)-2,3-dihydro-lH-indene-5-sulfonamide;

Figure imgf000115_0001

Step 1 : (S)-N-(2,4-dimethoxybenzyl)- 1 -(4'-isopropoxy-5-(trifluoromethyl)-[ 1,1'- biphenyl]-2-yl)-N-(pyrimidin-2-yl)-2,3-dihydro-lH-indene-5-sulfonamide

The title compound was prepared by following the procedure as described in Example-67 (Step- 1) using intermediate 4b and (4-isopropoxyphenyl)boronic acid Yield: 77%.

¾ NMR (400 MHz, DMSO-ifc) δ 8.58 (d, J = 4.9 Hz, 2H), 7.80 (dd, J = 8.0, 1.9 Hz, 1H), 7.72 - 7.64 (m, 2H), 7.57 (d, J = 2.0 Hz, 1H), 7.37 (t, J = 7.9 Hz, 1H), 7.20 (d, J = 8.2 Hz, 1H), 7.13 (t, J = 4.8 Hz, 1H), 7.02 - 6.90 (m, 5H), 6.48 (d, J = 2.4 Hz, 1H), 6.47 - 6.42 (m, 1H), 5.29 (s, 2H), 4.78 - 4.62 (m, 1H), 4.45 (s, 1H), 3.71 (s, 3H), 3.57 (s, 3H), 3.08 - 2.93 (m, 1H), 2.93 - 2.78 (m, 1H), 2.47 - 2.41 (m, 1H), 2.13 - 2.02 (m, 1H), 1.28 - 1.23 (m, 6H). LCMS (ESI): m/z 704.17 (M+H)+

Step 2: (S)- l-(4'-isopropoxy-5-(trifluoromethyl)-[l,r-biphenyl]-2-yl)-N-(pyrimidin-2-yl)- 2,3-dihydro-lH-indene-5-sulfonamide.

The title compound was prepared by following the procedure as described in Example- l/2(Step-2) using Step-1 intermediate and TFA. Yield: 64%.

¾ NMR (400 MHz, DMSO-ifc) δ 1 1.72 (s, 1H), 8.50 (d, J = 4.9 Hz, 2H), 7.88 (d, J = 1.7 Hz, 1H), 7.79 - 7.73 (m, 1H), 7.70 - 7.63 (m, 1H), 7.57 (d, J = 2.0 Hz, 1H), 7.36 (t, J = 7.9 Hz, 1H), 7.24 (d, J = 8.2 Hz, 1H), 7.10 - 7.00 (m, 2H), 7.01 - 6.91 (m, 3H), 4.76 - 4.62 (m, 1H), 4.45 (t, J = 8.7 Hz, 1H), 3.18 - 3.01 (m, 1H), 3.01 - 2.80 (m, 1H), 2.46 - 2.37 (m, 1H), 2.14 - 2.01 (m, 1H), 1.26 (d, J = 6.0 Hz, 3H), 1.21 (d, J = 6.0 Hz, 3H). LCMS (ESI): m/z 554.32 (M+H)+.

Example 85: (S)- 1 -(4'-isopropyl-5-(trifluorom ethyl)- [1,1 '-biphenyl] -2-yl)-N-(pyrimidin- 2-yl)-2,3-dihydro-lH-indene-5-sulfonamide;

Figure imgf000116_0001

Step 1: (S)-N-(2,4-dimethoxybenzyl)-l-(4'-isopropyl-5-(rrifluoromethyl)-[l,r-biphenyl]- 2-yl)-N-(pyrimidin-2-yl)-2,3-dihydro-lH-indene-5-sulfonamide

The title compound was prepared by following the procedure as described in Example-67 (Step- 1) using intermediate 4b and 2-(4-isopropylphenyl)-4,4,5,5-tetramethyl- 1,3,2- dioxaborolane. Yield 73%.

¾ NMR (400 MHz, DMSO-ifc) δ 8.58 (d, J = 4.8 Hz, 2H), 7.88 - 7.76 (m, 1H), 7.68 (d, J = 6.4 Hz, 2H), 7.56 (d, J = 2.0 Hz, 1H), 7.37 (s, 4H), 7.20 (d, J = 8.2 Hz, 1H), 7.13 (t, J = 4.8 Hz, 1H), 7.02 - 6.78 (m, 2H), 6.55 - 6.38 (m, 2H), 5.28 (s, 2H), 4.45 (s, 1H), 3.71 (s, 3H), 3.58 (s, 3H), 3.06 - 2.84 (m, 3H), 2.53 (d, J = 1.8 Hz, 1H), 2.19 - 2.02 (m, 1H), 1.26 - 1.24 (m, 3H), 1.23 (d, J = 0.9 Hz, 3H). LCMS (ESI): m/z 688.50 (M+H)+.

Step 2: (S)-l -(4'-isopropyl-5-(trifluoromethyl)-[l,r-biphenyl]-2-yl)-N-(pyrimidin-2-yl)- 2,3-dihydro-lH-indene-5-sulfonamide.

The title compound was prepared by following the procedure as described in Example- l/2(Step-2) using Step-1 intermediate and TFA. Yield: 66%.

¾ NMR (400 MHz, DMSO-ifc) δ 1 1.72 (s, 1H), 8.51 (d, J = 4.9 Hz, 2H), 7.88 (s, 1H), 7.76 (dd, J = 8.0, 1.8 Hz, 1H), 7.70 - 7.63 (m, 1H), 7.56 (d, J = 2.0 Hz, 1H), 7.36 (s, 4H), 7.24 (d, J = 8.2 Hz, 1H), 7.06 (t, J = 4.9 Hz, 1H), 6.99 (d, J = 8.1 Hz, 1H), 4.46 (t, J = 8.8 Hz, 1H), 3.15 - 3.05 (m, 1H), 3.03 - 2.86 (m, 2H), 2.15 - 1.95 (m, 1H), 1.23 (d, J = 6.8 Hz, 7H). LCMS (ESI): m/z 538.30 (M+H)+.

Example 86: (S)-l-(2^4'-difluoro-5-(trifluoromethyl)-[l, l'-biphenyl]-2-yl)-N-(pyrimidin- 2-yl)-2,3-dihydro-lH-indene-5-sulfonamide;

Figure imgf000117_0001

Step 1 : (S)- 1 -(2',4'-difluoro-5-(trifluoromethyl)-[l , 1 '-biphenyl]-2-yl)-N-(2,4- dimethoxybenzyl)-N-(pyrimidin-2-yl)-2,3-dihydro-lH-indene-5-sulfonamide

The title compound was prepared by following the procedure as described in Example-67 (Step- 1) using intermediate 4b and (2,4-difluorophenyl)boronic acid. Yield 63%.

¾ NMR (400 MHz, DMSO-ifc) δ 7.78 (t, J = 15.7 Hz, 2H), 7.70 - 7.61 (m, 2H), 7.54 (s, 1H), 7.42 (t, J = 9.7 Hz, 1H), 7.31 - 7.20 (m, 2H), 7.14 (t, J = 4.9 Hz, 1H), 6.95 (dd, J = 18.3, 8.1 Hz, 2H), 6.55 - 6.39 (m, 2H), 5.28 (s, 2H), 4.22 (t, 1H), 3.72 (s, 3H), 3.58 (d, J = 3.0 Hz, 3H), 3.08 - 2.93 (m, 1H), 2.93 - 2.78 (m, 1H). LCMS (ESI): m/z 682.17 (M+H)+.

Step 2: (S)- 1 -(2',4'-difluoro-5-(trifluoromethyl)-[ 1 , 1 '-biphenyl]-2-yl)-N-(pyrimidin-2-yl)- 2,3-dihydro-lH-indene-5-sulfonamide

The title compound was prepared by following the procedure as described in Example- l/2(Step-2) using Step-1 intermediate and TFA. Yield: 95%. ¾ NMR (400 MHz, DMSO-i¾) δ 1 1.75 (s, 1H), 8.51 (s, 2H), 7.88 (s, 1H), 7.83 - 7.70 (m, 2H), 7.62 - 7.48 (m, 1H), 7.46 - 7.35 (m, 1H), 7.35 - 7.25 (m, 2H), 7.06 (s, 1H), 6.98 (s, 1H), 4.23 (t, J = 8.8 Hz, 1H), 3.15 - 2.99 (m, 1H), 2.99 - 2.82 (m, 1H), 2.43 - 2.32 (m, 1H), 2.14 - 2.01 (m, 1H). LCMS (ESI): m/z 531.96 (M+H)+.

Example 87: (S)-N-(3,5-difluoropyridin-2-yl)-l-(2-(l-methyl-lH-pyrazol-5-yl)-4- (trifluoromethyl)phenyl)-2,3-dihydro-lH-indene-5-sulfonamide;

Figure imgf000118_0001

The title compound was prepared by following similar procedure as described in Intermediate-3 using Intermediate-8 and 3,5-difluoropyridin-2-amine. Yield= 71% ¾ NMR (400 MHz, DMSO-ifc) δ 1 1.03 (s, 1H), 8.15 (d, J = 2.5 Hz, 1H), 8.08 - 7.92 (m, 1H), 7.86 - 7.78 (m, 2H), 7.74 (d, J = 2.0 Hz, 1H), 7.73 - 7.66 (m, 1H), 7.54 (d, J = 1.9 Hz, 1H), 7.30 (d, J = 8.3 Hz, 1H), 7.04 (d, J = 8.0 Hz, 1H), 6.45 (d, J = 1.9 Hz, 1H), 4.25 (t, J = 8.6 Hz, 1H), 3.68 (s, 3H), 3.15 - 3.04 (m, 1H), 2.95 (d, J = 8.4 Hz, 1H), 2.46 (d, J = 3.1 Hz, 1H), 2.04 (d, J = 3.6 Hz, 1H). LCMS (ESI): m/z 535.3 (M+H)+.

Example 88: (S)- 1 -(2-( 1 -methyl- 1 H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N-(oxazol- 2-yl)-2,3-dihydro-lH-indene-5-sulfonamide;

Figure imgf000118_0002

The title compound was prepared by following similar procedure as described in Intermediate-3 using Intermediate-8 and oxazol-2-amine. Yield= 51%

¾ NMR (400 MHz, DMSO-ifc) δ 12.07 (s, 1H), 7.83 - 7.75 (m, 2H), 7.73 (d, J = 2.0 Hz, 1H), 7.66 -7.58 (m, 2H), 7.54 (d, J = 1.9 Hz, 1H), 7.33 - 7.23 (m, 2H), 6.99 (d, J = 8.0 Hz, 1H), 6.45 (d, J = 1.9 Ηζ, ΙΗ), 4.23 (t, J = 8.6 Hz, 1H), 3.68 (s, 3H), 3.15 - 3.01 (m, 1H), 2.98 - 2.83 (m, 1H), 2.49 - 2.41 (m, 1H),2.13 - 1.94 (m, 1H). LCMS (ESI): m/z 489.2 (M+H)+.

Example 89: (S)- 1 -(2-( 1 -methyl- 1 H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N-(pyridin- 2-yl)-2,3-dihydro-lH-indene-5-sulfonamide;

Figure imgf000119_0001

The title compound was prepared by following similar procedure as described in Intermediate-3 using Intermediate-8 and pyridin-2-amine. Yield= 35%

¾ NMR (400 MHz, DMSO-ifc) δ 8.01 (s, 1H), 7.85 - 7.69 (m, 4H), 7.66 (dd, J= 7.9, 1.8 Hz, 1H), 7.53 (d, J = 1.8 Hz, 1H), 7.28 (d, J = 8.2 Hz, 1H), 7.17 (d, J= 8.7 Hz, 1H), 6.99 (d, J = 8.0 Hz, 1H), 6.88 (d, J = 6.8 Hz, 1H), 6.43 (d, J = 1.9 Hz, 1H), 4.22 (t, J = 8.6 Hz, 1H), 3.67 (s, 1H), 3.10 - 3.05 (m, 1H), 2.94 - 2.90 (m, 1H), 2.47 - 2.42 (m, 1H), 2.04 - 1.99 (m, 1H). LCMS (ESI): m/z 499.36 (M+H)+. Example 90: (S)-N-(4-fluoropyridin-2-yl)-l-(2-(l -methyl- lH-pyrazol-5-yl)-4- (trifluoromethyl)phenyl) -2,3-dihydro- lH-indene-5-sulfonamide;

Figure imgf000119_0002

The title compound was prepared by following similar procedure as described in Intermediate-3 using Intermediate-8 and 4-fluoropyridin-2-amine. Yield= 33%

¾ NMR (400 MHz, DMSO-ifc) δ 8.12 (t, J= 7.4 Hz, 1H), 7.84 - 7.76 (m, 2H), 7.73 (d, J = 2.0 Hz, 1H), 7.68 (d, J= 8.0 Hz, 1H), 7.53 (d, J= 1.9 Hz, 1H), 7.29 (d, J= 8.2 Hz, 1H), 7.01 (d, J= 8.0 Hz, 1H), 6.96 - 6.83 (m, 2H), 6.43 (d, J= 1.9 Hz, 1H), 4.23 (t, J= 8.6 Hz, 1H), 3.67 (s, 3H), 3.13 - 3.02 (m, 1H), 2.96 - 2.90 (m, 1H), 2.48 - 2.41 (m, 1H), 2.06 - 1.98 (m, 1H). LCMS (ESI): m/z 516.98 (M+H)+.

Example 91: (S)-N-(5-fluoropyridin-2-yl)-l-(2-(l -methyl- 1 H-pyrazol-5-yl)-4- (trifluoromethyl)phenyl)-2,3-dihydro-lH-indene-5-sulfonamide;

Figure imgf000120_0001

The title compound was prepared by following similar procedure as described in Intermediate-3 using Intermediate-8 and 5-fluoropyridin-2-amine. Yield= 80%

¾ NMR (400 MHz, DMSO-ifc) δ 1 1.10 (s, 1H), 8.19 (d, J = 3.1 Hz, 1H), 7.84 - 7.76 (m, 2H), 7.73 (d, J = 2.0 Hz, 1H), 7.71 - 7.63 (m, 2H), 7.53 (d, J = 1.8 Hz, 1H), 7.28 (d, J = 8.2 Hz, 1H), 7.18 - 7.08 (m, 1H), 7.03 (d, J = 8.0 Hz, 1H), 6.43 (d, J = 1.8 Hz, 1H), 4.23 (t, J = 8.6 Hz, 1H), 3.67 (s, 3H), 3.14 - 2.96 (m, 1H), 2.96 - 2.81 (m, 1H), 2.43 - 2.47 (m, 1H), 2.09 - 1.95 (m, 1H). LCMS (ESI): m/z 517.10 (M+H)+.

Example 92: (S)- 1 -(4'-fluoro-5-(trifluoromethyl)- [1, 1 '-biphenyl]-2-yl)-N-(pyrimidin-2- yl)-2,3-dihydro -lH-indene-5-sulfonamide;

Figure imgf000120_0002

The title compound was prepared by following similar procedure as described in Intermediate-3 using Intermediate-9 and pyrimidin-2-amine. Yield= 25%

¾ NMR (400 MHz, DMSO-ifc) δ 8.51 (d, J = 4.9 Hz, 2H), 7.88 (d, J = 1.7 Hz, 1H), 7.76 (dd, J = 8.0, 1.8 Hz, 1H), 7.68 (dd, J = 8.4, 2.1 Hz, 1H), 7.57 (d, J = 2.1 Hz, 1H), 7.54 - 7.44 (m, 2H), 7.38 - 7.28 (m, 2H), 7.24 (d, J= 8.2 Hz, 1H), 7.1 1 - 6.95 (m, 2H), 4.40 (t, J = 8.7 Hz, 1H), 3.1 1 - 3.08 (m, 1H), 2.92 - 2.88 (m, 1H), 2.46 (d, J = 2.8 Hz, 1H), 2.16 - 1.98 (m, 1H). LCMS (ESI): m/z 513.99 (M+l)+. Example 93 : (S)- 1 -(4'-fluoro-5-(trifluoromethyl)-[ 1 , 1 '-biphenyl]-2-yl)-N-(6- fluoropyridin-2-yl)-2,3-dihydro- lH-indene-5-sulfonamide;

Figure imgf000121_0001

The title compound was prepared by following similar procedure as described Intermediate-3 using Intermediate-9 and 6-fluoropyridin-2-amine. Yield= 44%

¾ NMR (400 MHz, DMSO-ifc) δ 1 1.36 (s, 1H), 7.91 - 7.79 (m, 2H), 7.78 - 7.70 (m, J = 15.8, 8.1, 1.9 Hz, 2H), 7.57 (d, J= 2.0 Hz, 1H), 7.53 - 7.43 (m, 2H), 7.37 - 7.27 (m, 2H), 7.23 (d, J= 8.2 Hz, 1H), 7.05 (d, J= 8.0 Hz, 1H), 6.97 (dd, J= 7.9, 2.1 Hz, 1H), 6.74 (dd, J = 8.0, 2.4 Hz, 1H), 4.40 (t, J = 8.7 Hz, 1H), 3.10 - 3.05 (m, 1H), 2.92 - 2.88 (m, 1H), 2.49 - 2.40 (m, 1H), 2.09 - 2.03 (m, 1H). LCMS (ESI): m/z 531.32 (M+H)+.

Example 94: (S)-l-(4'-fluoro-5-(trifluoromethyl)-[l, l'-biphenyl]-2-yl)-N-(thiazol-2-yl)- 2,3-dihydro-lH-indene-5-sulfonamide;

Figure imgf000121_0002

The title compound was prepared by following similar procedure as described in Intermediate-3 using Intermediate-9 and thiazol-2-amine. Yield= 43%

¾ NMR (400 MHz, DMSO-ifc) δ 12.69 (s, 1H), 7.76 - 7.65 (m, 2H), 7.62 - 7.53 (m, 2H), 7.53 - 7.44 (m, 2H), 7.38 - 7.29 (m, 2H), 7.28 - 7.18 (m, 2H), 6.98 (d, J = 7.9 Hz, 1H), 6.82 (d, J= 4.6 Hz, 1H), 4.39 (t, J= 8.7 Hz, 1H), 3.14 - 2.99 (m, 1H), 2.92 - 2.85 (m, 1H), 2.46 - 2.38 (m, 1H), 2.10 - 2.04 (m, 1H). LCMS (ESI): m/z 519.07 (M+H)+. Example 95: (S)- 1 -(4'-fluoro-5-(trifluoromethyl)-[ 1 , 1 '-biphenyl]-2-yl)-N-(oxazol-2-yl)- 2,3-dihydro-lH-indene-5-sulfonamide;

Figure imgf000122_0001

The title compound was prepared by following similar procedure as described in Intermediate-3 using Intermediate-9 and oxazol-2-amine. Yield= 34%

¾ NMR (400 MHz, DMSO-i¾) δ 12.07 (s, 1H), 7.76 (d, J = 1.7 Hz, 1H), 7.69 (dd, J = 8.3, 2.1 Hz, 1H), 7.65 - 7.55 (m, 3H), 7.55 - 7.47 (m, 2H), 7.38 - 7.21 (m, 4H), 6.98 (d, J = 8.0 Hz, 1H), 4.40 (t, J = 8.7 Hz, 1H), 3.15 - 3.08 (m, 1H), 2.99 - 2.88 (m, 1H), 2.50 - 2.40 (m, 1H), 2.10 - 2.03 (m, 1H). LCMS (ESI): m/z 503.19 (M+H)+.

Example 96: (S)-l-(2-chloro-4-(trifluoromethyl)phenyl)-N-(4-fluoropyridin-2-yl)-2,3- dihydro- 1 H-indene-5-sulfonamide;

Figure imgf000122_0002

The title compound was prepared by following similar procedure as described Intermediate-3 using Intermediated and 4-fluoropyridin-2-amine. Yield= 38%

¾ NMR (400 MHz, DMSO-ifc) δ 12.13 (s, 1H), 8.13 (t, J = 7.4 Hz, 1H), 7.93 (d, J = 1.9 Hz, 1H), 7.86 (d, J= 1.7 Hz, 1H), 7.72 (dd, J= 7.9, 1.8 Hz, 1H), 7.65 (dd, J= 8.3, 1.9 Hz, 1H), 7.21 (d, J= 8.1 Hz, 1H), 7.12 (d, J= 8.0 Hz, 1H), 6.70 - 6.88 (m, 2H), 4.90 (t, J= 8.2 Hz, 1H), 3.14 - 2.97 (m, 2H), 2.66 - 2.60 (m, 1H), 2.08 - 2.01 (m, 1H). LCMS (ESI): m/z 471.20 (M+H)+. Example 97: (S)- 1 -(2-chloro-4-(trifluoromethyl)phenyl)-N-(pyrimidin-2-yl)-2,3-dihydro- 1 H-indene-5-sulfonamide;

Figure imgf000123_0001

The title compound was prepared by following similar procedure as described in Intermediate-3 using Intermediated and pyrimidin-2-amine. Yield= 53%

¾ NMR (400 MHz, DMSO-ifc) δ 1 1.76 (s, 1H), 8.52 (d, J = 4.9 Hz, 2H), 7.94 (t, J = 2.4 Hz, 2H), 7.86 - 7.77 (m, 1H), 7.70 - 7.61 (m, 1H), 7.21 (d, J = 8.2 Hz, 1H), 7.14 (d, J = 8.0 Hz, 1H), 7.07 (t, J = 4.9 Hz, 1H), 4.91 (t, J = 8.2 Hz, 1H), 3.18 - 2.98 (m, 2H), 2.73 - 2.59 (m, 1H), 2.10 - 1.97 (m, 1H). LCMS (ESI): m/z 453.90 (M+H)+.

Example 98: (S)- 1 -(2-chloro-4-(trifluoromethyl)phenyl)-N-(6-fluoropyridin-2-yl)-2,3- dihydro- 1 H-indene-5-sulfonamide;

Figure imgf000123_0002

The title compound was prepared by following similar procedure as described in Intermediate-3 using Intermediate-2a and 6-fluoropyridin-2-amine. Yield= 40%

¾ NMR (400 MHz, DMSO-ifc) δ 1 1.39 (s, 1H), 7.95 - 7.90 (m, 2H), 7.86 (q, J = 8.2 Hz, 1H), 7.80 - 7.73 (m, 1H), 7.68 - 7.60 (m, 1H), 7.21 (d, J = 8.2 Hz, 1H), 7.16 (d, J = 8.0 Hz, 1H), 7.03 - 6.94 (m, 1H), 6.79 - 6.72 (m, 1H), 4.91 (t, J = 8.2 Hz, 1H), 3. 17 - 2.95 (m, 2H), 2.73 - 2.58 (m, 1H), 2.09 - 1.90 (m, 1H). LCMS (ESI): m/z 470.91 (M+H)+. Example 99: (R)- 1 -(2-(2-fluoroethyl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-2-yl)-2,3- dihydro- 1 H-indene-5-sulfonamide;

Figure imgf000124_0001

The title compound was prepared by following similar procedure as described in Intermediate-3 using Intermediate-20 and pyrimidin-2-amine. Yield= 34%

¾ NMR (400 MHz, Chloroform-if) δ 8.66 (d, J = 5.0 Hz, 2H), 8.08 (s, 1H), 7.97 (dd, J = 8.1, 1.8 Hz, 1H), 7.54 (t, J = 1.4 Hz, 1H), 7.43 (d, J = 8.6 Hz, 1H), 7.06 - 6.97 (m, 3H), 4.80 - 4.74 (m, 1H), 4.70 (t, J = 8.6 Hz, 1H), 4.67 - 4.61 (m, 1H), 3.40 - 2.97 (m, 4H), 2.74 - 2.66 (m, 1H), 2.1 1 - 1.98 (m, 2H). LCMS (ESI) : m/z 466.17 (M+H)+.

Example 100: (R)- 1 -(2-(2-fluoroethyl)-4-(trifluoromethyl)phenyl)-N-(6-fluoropyridin-2- yl)-2,3-dihydro-lH-indene-5-sulfonamide;

Figure imgf000124_0002

The title compound was prepared by following similar procedure as described in Intermediate-3 using Intermediate-20 and 6-fluoropyridin-2-amine. Yield= 28%

¾ NMR (400 MHz, Chloroform-if) δ 7.88 (d, J = 1.8 Hz, 1H), 7.79 - 7.71 (m, 2H), 7.62 (s, 1H), 7.54 (d, J = 1.9 Hz, 1H), 7.43 (dd, J = 8.2, 2.0 Hz, 1H), 7.28 - 7.25 (m, 1H), 6.98 (t, J = 7.8 Hz, 2H), 6.64 (dd, J = 8.0, 2.4 Hz, 1H), 4.76 (tt, J = 6.5, 3.4 Hz, 1H), 4.70 (d, J = 8.8 Hz, 1H), 4.67 - 4.60 (m, 1H), 3.33 - 3.00 (m, 4H), 2.73 - 2.62 (m, 1H), 2.10 - 1.99 (m, 1H). LCMS (ESI) : m/z 483.17 (M+H)+.

Pharmacological activity Certain illustrative compounds within the scope of the invention are screened for

Nav activity according to the procedure given below. The screening of the compounds may be carried by other methods and procedures known to skilled in the art.

Analysis of inhibition of sodium channels by test compounds:

HEK-293 cells overexpressing the channel of interest were seeded in a 96-well plate at a density of 30000 cells/well and incubated at 37°C / 5% C02 for 48 hr. The assay was carried out using the Red Membrane Potential Dye (Molecular Devices) following the manufacturer's instructions. Briefly, the cells were incubated with IX red membrane potential dye for 1.5 hour. The cells were then treated with various concentrations of the test compounds for 15-20 min followed by depolarization with 10-30 μΜ Veratridine. The fluorescence was read following excitation at 510-545 nm and emission at 565-625 nm in FLIPR. The "max-min" fluorescence values were used to calculate the % inhibition. IC50 values were calculated by plotting % inhibition against concentration and curve fitting into a sigmoidal dose response.

Certain compounds of the present invention are shown to have functional activity as inhibitors of Nav 1.7 and Nav 1.5 in vitro.

Nav 1.7 (IC5o (nM)) Example Number

0.1 to 100 nM 1, 2, 5, 7, 9, 1 1, 12, 13, 15, 16, 31, 33, , 41, 45, 49, 51, 53, 55, 58, 60,

62, 66, 70, 71, 72, 74, 75, 76, 83, 84, 88, 89, 90, 92, 93, 94, 95 lOlnM to 1000 nM 6, 8, 14, 17, 19, 23, 25, 32, 34, 35, 36, 37, 39, 42, 44, 46, 47, 48, 50,

61, 64, 65, 68, 69, 79, 80, 81, 82, 85, 86, 91, 96, 97, 98

1001 nM to 10 μΜ 3, 4, 10, 18, 20, 21, 24, 26, 27, 28, 29, 30, 38, 40, 43, 52, 54, 57, 59, 63,

67, 73, 77, 78, 87, 99, 100 Navl .5 ICso (nM) Example Number

lOO nM to ΙΟΟΟηΜ 1, 3, 1 1, 13, 16, 42, 49, 70, 75, 79, 80, 81, 83, 86, 92, 95,

1001 nM to 10 μΜ 2, 4, 5, 9, 12, 14, 15, 17, 18, 31, 35, 36, 41, 44, 45, 46, 50, 51, 53, 57,

58, 60, 61, 62, 63, 64, 65, 66, 68, 69, 71, 72, 73, 74, 78, 82, 84, 85, 88, 89, 90, 91, 93, 94, 97, 98

>10 μΜ 6, 7, 8, 10, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 32, 33, 34, 37,

38, 39, 40, 43, 47, 48, 52, 54, 55, 56, 59, 76, 77, 87, 96, 99, 100

Claims

1. A compound having the Formula (I):
Figure imgf000127_0001
wherein,
ring A is five or six membered monocyclic heteroaryl;
Ri is selected from the group consisting of hydrogen, halogen, cyano, substituted or unsubstituted alkyl and substituted or unsubstituted alkoxy;
R2, which may be same or different at each occurrence, is independently selected from the group consisting of halogen, cyano, substituted or unsubstituted alkyl, haloalkyl, -(CH2)o-4-S(0)2-alkyl, -ORe, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted monocyclic heterocyclyl, -COOH, -COO-alkyl and -CONR4R5;
R3, which may be same or different at each occurrence, is independently selected from the group consisting of halogen, cyano, substituted or unsubstituted alkyl and substituted or unsubstituted alkoxy;
R4 and R5 are independently hydrogen or substituted or unsubstituted alkyl; or R4 and R5 together with the nitrogen atom to which they are attached, form a substituted or unsubstituted 5- to 6- membered heterocyclic ring;
R6 is selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted monocyclic heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
'm' is an integer ranging from 1 to 3, both inclusive;
'n' is an integer ranging from 0 to 3, both inclusive; wherein the substituents on alkyl, alkoxy, cycloalkyl, aryl, heteroaryl, heterocyclyl, heterocyclic ring, alkoxyalkyl are one or more, same or different and independently selected from the group consisting of halogen, cyano, nitro, oxo (=0), alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclic ring, heterocyclylalkyl, heteroarylalkyl, -C(0)ORx, -C(0)Ry, -C(S)Ry, -C(0)NRxRz, -NRxC(0)NRxRz, - NRx-S(0)2Ry, -NRxRz, -NRxC(0)Ry, -NRxC(S)Ry, -NRXC(S)NRXRZ, -S(0)2NRxRz, -ORx, -OC(0)Ry, -(CRaRb)i-3C(0)ORx, -(CRaRb)i-3C(0)NRxRz, -0-(CRaRb)i-3- ORx, -0-(CRaRb)i-3-NRxRz, -0-(CRaRb)i-3-S(0)o-2Ry, -(CRaRb)i-3-NRxRz, - (CRaRb)i-3-S(0)o-2Ry, -0(CRaRb)i-3-C(0)NRxRz, -0(CRaRb)i-3-C(0)ORx and - S(0)o-2Ry; each Rx independently is selected from the group consisting of hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic ring, heterocyclylalkyl and heteroarylalkyl; each Ry independently is selected from the group consisting of alkyl, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic ring, heterocyclylalkyl and heteroarylalkyl; each Rz independently is selected from the group consisting of hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic ring, heterocyclylalkyl and heteroarylalkyl; or Rx and Rz together with the nitrogen atom to which they are attached form a substituted or unsubstituted, saturated or unsaturated 4- to 8- membered cyclic ring, wherein the unsaturated cyclic ring may have one or two double bonds; and each of Ra and Rb are independently selected individually from the group consisting of hydrogen, halogen and alkyl; or N-oxides thereof or a pharmaceutically acceptable salt thereof or stereoisomer thereof.
The compound of claim 1 having the structure of Formula (II)
Figure imgf000129_0001
or N-oxides thereof or a pharmaceutically acceptable salt thereof or stereoisomer thereof;
wherein,
R2a is halogen, cyano, substituted or unsubstituted alkyl, haloalkyl and substituted or unsubstituted cycloalkyl;
R2b is selected from the group consisting of halogen, cyano, substituted or unsubstituted alkyl, haloalkyl, -(CH2)o-4-S(0)2-alkyl, -OR6, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted monocyclic heterocyclyl, -COOH, -COO-alkyl and -CONR4R5; ring A, R3, R4, R5, R6 and 'n' are as defined herein above.
The compound of claim 1 to 3, wherein ring A is selected from thiazole, pyridine, pyrimidine, pyridazine, oxazole, isoxazole and thiadiazole.
The compound of claim 1, wherein R2 is selected from halogen, substituted or unsubstituted alkyl, haloalkyl, -COOH, -COO-alkyl, substituted or unsubstituted aryl, substituted or unsubstituted monocyclic heterocyclyl, substituted or unsubstituted heteroaryl and -OR6; wherein R6 is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted monocyclic heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl.
The compound of claim 1, wherein R2 is selected from group consisting of halogen, haloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted monocyclic heterocyclyl, substituted or unsubstituted heteroaryl, -(CH2)o^-S(0)2- alkyl and -OR6'; wherein R6' is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted monocyclic heterocyclyl.
6. The compound of claim 1, wherein R2 is selected from chlorine, CF3, 0Η(Ο¾)2, C(CH3)3, fluoropropane, -(CH2)2-S(0)2-methyl,
Figure imgf000130_0001
7. The compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 6, wherein the compound is selected from: l-(2-(6-Fluoropyridin-3-yl)-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)-2,3- dihydro- lH-indene-5-sulfonamide;
l-(2-(6-Methylpyridin-3-yl)-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)-2,3- dihydro- lH-indene-5-sulfonamide;
l-(2-(6-Fluoropyridin-3-yl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-2-yl)-2,3- dihydro- lH-indene-5-sulfonamide;
l-(2-(6-Methylpyridin-3-yl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-2-yl)-2,3- dihydro- lH-indene-5-sulfonamide;
1 -(2-( 1 -Methyl- 1 H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-2-yl)- 2,3-dihydro-lH-indene-5-sulfonamide;
N-(6-Fluoropyridin-2-yl)- 1 -(2-(6-fluoropyridin-3-yl)-4-(trifluoro
methyl)phenyl)-2,3-dihydro-lH-indene-5-sulfonamide;
N-(6-Fluoropyridin-2-yl)- 1 -(2-(6-methylpyridin-3-yl)-4-(trifluoro
methyl)phenyl)-2,3-dihydro-lH-indene-5-sulfonamide; N-(6-Fluoropyridin-2-yl)- 1 -(2-( 1 -methyl- 1 H-pyrazol-5-yl)-4-(trifluoro methyl)phenyl)-2,3-dihydro-lH-indene-5-sulfonamide;
2'-(5-(N-(6-Fluoropyridin-2-yl)sulfamoyl)-2,3-dihydro- lH-inden- 1 -yl)-5'- (trifluoromethyl)- [1, 1 '-biphenyl] -4-carboxylic acid;
2'-(5-(N-(pyrimidin-2-yl)sulfamoyl)-2,3-dihydro-lH-inden- l-yl)-5'- (trifluoromethyl)- [1, 1 '-biphenyl] -4-carboxylic acid;
l-(2-(2-oxopyrrolidin-l-yl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-2-yl)-2,3- dihydro- lH-indene-5-sulfonamide;
N-(6-fluoropyridin-2-yl)- 1 -(2-(2-oxopyrrolidin- 1 -yl)-4-(trifluoromethyl)phenyl)- 2,3-dihydro-lH-indene-5-sulfonamide;
l-(2-(2-oxooxazolidin-3-yl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-2-yl)-2,3- dihydro- lH-indene-5-sulfonamide;
N-(6-fluoropyridin-2-yl)- l-(2-(2-oxooxazolidin-3-yl)-4- (trifluoromethyl)phenyl)-2,3-dihydro-lH-indene-5-sulfonamide;
N-(6-fluoropyridin-2-yl)- 1 -(2-(2-(methylsulfonyl)ethyl)-4- (trifluoromethyl)phenyl)-2,3-dihydro-lH-indene-5-sulfonamide;
l-(2-(3-fluoro-l-methylazetidin-3-yl)-4-(trifluoromethyl)phenyl)-N-(6- fluoropyridin-2-yl)-2,3-dihydro- lH-indene-5-sulfonamide hydrochloride;
1- (2-(3-fluoro-l-methylazetidin-3-yl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-
2- yl)-2,3-dihydro-lH-indene-5-sulfonamide hydrochloride;
N-(6-fluoropyridin-2-yl)- 1 -(2-((tetrahydrofuran-3-yl)oxy)-4- (trifluoromethyl)phenyl)-2,3-dihydro-lH-indene-5-sulfonamide;
N-(pyrimidin-2-yl)-l-(2-((tetrahydrofuran-3-yl)oxy)-4-(trifluoromethyl)phenyl)- 2,3-dihydro-lH-indene-5-sulfonamide;
1 -(2-(4-methylpiperazin- 1 -yl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-2-yl)- 2,3-dihydro-lH-indene-5-sulfonamide;
N-(6-fluoropyridin-2-yl)- 1 -(2-(4-methylpiperazin- 1 -yl)-4- (trifluoromethyl)phenyl)-2,3-dihydro-lH-indene-5-sulfonamide;
l-(2-Morpholino-4-(trifluoromethyl)phenyl)-N-(pyrimidin-2-yl)-2,3-dihydro- lH-indene-5-sulfonamide;
N-(6-Fluoropyridin-2-yl)- 1 -(2-morpholino-4-(trifluoromethyl) phenyl)-2,3- dihydro- lH-indene-5-sulfonamide; l-(2-(Oxetan-3-yloxy)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-2-yl)-2,3- dihydro- lH-indene-5-sulfonamide;
1 -(2-( 1 -methyl- 1 H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)- 2,3-dihydro-lH-indene-5-sulfonamide;
N-(isoxazol-3-yl)- 1 -(2-( 1 -methyl- 1 H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)- 2,3-dihydro-lH-indene-5-sulfonamide;
1 -(2-( 1 -methyl- 1 H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N-(pyridazin-3-yl) 2,3-dihydro-lH-indene-5-sulfonamide;
1 -(4-isopropyl-2-( 1 -methyl- 1 H-pyrazol-5-yl)phenyl)-N-(pyrimidin-2-yl)-2,3- dihydro- lH-indene-5-sulfonamide;
N-(6-fluoropyridin-2-yl)- 1 -(4-isopropyl-2-( 1 -methyl- 1 H-pyrazol-5-yl)phenyl)- 2,3-dihydro-lH-indene-5-sulfonamide;
l-(4-(tert-butyl)-2-(l -methyl- lH-pyrazol-5-yl)phenyl)-N-(pyrimidin-2-yl)-2,3- dihydro- lH-indene-5-sulfonamide;
l-(4-(tert-butyl)-2-(l -methyl- lH-pyrazol-5-yl)phenyl)-N-(6-fluoropyridin-2-yl) 2,3-dihydro-lH-indene-5-sulfonamide;
l-(2-(oxazol-2-yl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-2-yl)-2,3-dihydro- lH-indene-5-sulfonamide;
N-(6-fluoropyridin-2-yl)- l-(2-(oxazol-2-yl)-4-(trifluoromethyl)phenyl)-2,3- dihydro- lH-indene-5-sulfonamide;
N-(6-fluoropyridin-2-yl)- l-(4'-isopropyl-5-(trifluoromethyl)-[l, r-biphenyl]-2- yl)-2,3-dihydro- lH-indene-5-sulfonamide;
l-(3'-chloro-4'-fluoro-5-(trifluoromethyl)-[l, l'-biphenyl]-2-yl)-N-(6- fluoropyridin-2-yl)-2,3-dihydro- lH-indene-5-sulfonamide;
N-(6-fluoropyridin-2-yl)- 1 -(4'-methoxy-5-(trifluoromethyl)-[ 1 , 1 '-biphenyl] -2- yl)-2,3-dihydro- lH-indene-5-sulfonamide;
l-(2',4'-difluoro-5-(trifluoromethyl)-[ 1 , 1 '-biphenyl]-2-yl)-N-(6-fluoropyridin-2- yl)-2,3-dihydro- lH-indene-5-sulfonamide;
N-(2,4-dimethoxybenzyl)-N-(6-fluoropyridin-2-yl)-l-(2-(pyridin-3-yl)-4- (trifluoromethyl)phenyl)-2,3-dihydro-lH-indene-5-sulfonamide;
N-(6-fluoropyridin-2-yl)- l-(2-(pyridin-4-yl)-4-(trifluoromethyl)phenyl)-2,3- dihydro- lH-indene-5-sulfonamide; N-(6-fluoropyridin-2-yl)- 1 -(2-( 1 -methyl- lH-indol-5-yl)-4- (trifluoromethyl)phenyl)-2,3-dihydro-lH-indene-5-sulfonamide;
l-(2-(pyridin-3-yl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-2-yl)-2,3-dihydro- lH-indene-5-sulfonamide;
l-(2-(6-ethoxypyridin-3-yl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-2-yl)-2,3- dihydro- lH-indene-5-sulfonamide;
l-(2-(pyridin-4-yl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-2-yl)-2,3-dihydro- lH-indene-5-sulfonamide;
1 -(2-( 1 -methyl- 1 H-indol-5-yl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-2-yl)- 2,3-dihydro-lH-indene-5-sulfonamide;
1 -(2-( 1 -methyl- 1 H-indazol-5-yl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-2-yl)- 2,3-dihydro-lH-indene-5-sulfonamide;
l-(3'-chloro-4'-fluoro-5-(trifluoromethyl)-[l, r-biphenyl]-2-yl)-N-(pyrimidin-2- yl)-2,3-dihydro- lH-indene-5-sulfonamide;
1 -(4'-chloro-5-(trifluoromethyl)-[ 1 , 1 '-biphenyl] -2-yl)-N-(pyrimidin-2-yl)-2,3- dihydro- lH-indene-5-sulfonamide;
1- (4'-methoxy-5-(trifluoromethyl)-[l, r-biphenyl]-2-yl)-N-(pyrimidin-2-yl)-2,3- dihydro- lH-indene-5-sulfonamide;
1 -(4'-(dimethylamino)-5-(trifluoromethyl)-[ 1 , 1 '-biphenyl] -2-yl)-N-(pyrimidin-2- yl)-2,3-dihydro- lH-indene-5-sulfonamide;
1 -(4'-fluoro-2'-methoxy-5-(trifluoromethyl)- [1,1 '-biphenyl]-2-yl)-N-(pyrimidin-
2- yl)-2,3-dihydro-lH-indene-5-sulfonamide;
l-(4'-isopropoxy-5-(trifluoromethyl)-[ 1 , 1 '-biphenyl]-2-yl)-N-(pyrimidin-2-yl)- 2,3-dihydro-lH-indene-5-sulfonamide;
l-(4'-isopropyl-5-(trifluoromethyl)-[ 1 , 1 '-biphenyl]-2-yl)-N-(pyrimidin-2-yl)-2,3- dihydro- lH-indene-5-sulfonamide;
l-(2',4'-difluoro-5-(trifluoromethyl)-[ 1 , 1 '-biphenyl]-2-yl)-N-(pyrimidin-2-yl)- 2,3-dihydro-lH-indene-5-sulfonamide;
l-(2',4'-difluoro-5-(trifluoromethyl)-[ 1 , 1 '-biphenyl]-2-yl)-N-(pyrimidin-2-yl)- 2,3-dihydro-lH-indene-5-sulfonamide;
N-(3,5-difluoropyridin-2-yl)- 1 -(2-( 1 -methyl- 1 H-pyrazol-5-yl)-4- (trifluoromethyl) phenyl)-2,3-dihydro-lH-indene-5-sulfonamide; 1 -(2-( 1 -methyl- 1 H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N-(oxazol-2-yl)- 2,3-dihydro-lH-indene-5-sulfonamide;
1 -(2-( 1 -methyl- 1 H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N-(pyridin-2-yl)- 2,3-dihydro-lH-indene-5-sulfonamide;
N-(4-fluoropyridin-2-yl)- 1 -(2-( 1 -methyl- lH-pyrazol-5-yl)-4- (trifluoromethyl)phenyl) -2,3-dihydro-lH-indene-5-sulfonamide;
N-(5-fluoropyridin-2-yl)- 1 -(2-( 1 -methyl- lH-pyrazol-5-yl)-4- (trifluoromethyl)phenyl)-2,3-dihydro-lH-indene-5-sulfonamide;
l-(4'-fluoro-5-(trifluoromethyl)-[l,r-biphenyl]-2-yl)-N-(pyrimidin-2-yl)-2,3- dihydro - 1 H-indene-5-sulfonamide;
l-(4'-fluoro-5-(trifluoromethyl)-[l,r-biphenyl]-2-yl)-N-(6-fluoropyridin-2-yl)- 2,3-dihydro-lH-indene-5-sulfonamide;
l-(4'-fluoro-5-(trifluoromethyl)-[l, l'-biphenyl]-2-yl)-N-(thiazol-2-yl)-2,3- dihydro- lH-indene-5-sulfonamide;
l-(4'-fluoro-5-(trifluoromethyl)-[l, l'-biphenyl]-2-yl)-N-(oxazol-2-yl)-2,3- dihydro- lH-indene-5-sulfonamide;
l-(2-chloro-4-(trifluoromethyl)phenyl)-N-(4-fluoropyridin-2-yl)-2,3-dihydro- lH-indene-5-sulfonamide;
l-(2-chloro-4-(trifluoromethyl)phenyl)-N-(pyrimidin-2-yl)-2,3-dihydro-lH- indene-5-sulfonamide;
l-(2-chloro-4-(trifluoromethyl)phenyl)-N-(6-fluoropyridin-2-yl)-2,3-dihydro- lH-indene-5-sulfonamide;
l-(2-(2-fluoroethyl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-2-yl)-2,3-dihydro- lH-indene-5-sulfonamide; and
l-(2-(2-fluoroethyl)-4-(trifluoromethyl)phenyl)-N-(6-fluoropyridin-2-yl)-2,3- dihydro- lH-indene-5-sulfonamide.
A pharmaceutical composition comprising at least one compound of claim 1 to 7 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.
A method of treating, managing and/or lessening the severity of the diseases, disorders, syndromes or conditions associated with the modulation or blocking of Navl .7 functions in a subject in need thereof, comprising administering to the subject, an effective amount of compound as claimed in claim 1 to 7, or their pharmaceutically acceptable salt thereof.
10. Use of compound for the manufacture of medicament for treating, managing and/or lessening the severity of diseases, disorders, syndromes or conditions associated with the modulation or blocking of Navl .7 functions in a subject in need thereof, comprising administering to the subject, an effective amount of compound as claimed in claim 1 to 7, or their pharmaceutically acceptable salt thereof.
1 1. The use of claim 10, wherein the diseases, disorders, syndromes or conditions associated with the modulation or blocking of Navl .7 functions are selected from the group consisting of pain and erythromelalgia.
12. The use of claim 1 1, wherein the pain is neuropathic pain.
13. The use of claim 11 , wherein the pain is inflammatory pain.
14. The use of claim 1 1, wherein the diseases, disorders, syndromes or conditions associated with the modulation or blocking of Navl .7 functions are selected from the group consisting of postoperative pain, arthritis pain, osteoarthritis pain, pain associated with cancer including chemotherapy pain, neuropathic pain secondary to metastatic inflammation, neuralgic, orofacial pain, burn pain, somatic pain, dental pain, sciatica pain, intestinal obstruction pain, visceral pain, colicky pain, myofacial pain, trauma pain, labour pain, trigeminal neuralgia, glossopharangyl neuralgia, adiposis dolorosa, acute herpetic and postherpetic neuralgia, diabetic neuropathy, causalgia, brachial plexus avulsion, occipital neuralgia, reflux sympathetic dystrophy, fibromyalgia, gout, phantom limb pain, pain following stroke, thalamic lesions, radiculopathy, chronic headache, migraine pain, familial hemiplegic migraine, conditions associated with cephalic pain, sinus headache, tension headache, cardiac pain arising from an ischemic myocardium, pain following stroke, neuropathy secondary to metastatic inflammation, pain due to connective tissue damage, and other forms of neuralgic, neuropathic, and idiopathic pain syndromes in a subject in need thereof comprising administering to the subject with a therapeutically effective amount.
15. The use of claim 10, wherein the diseases, disorders, syndromes or conditions associated with the modulation or blocking of Navl .7 functions are selected from the group consisting of, pruritis, cough, diabetes, cancer, or benign prostatic hyperplasia (BPH).
16. The use of claim 10, wherein one or more compounds as claimed in claim 1 is used in combination with one or more other therapeutic agent used to treat pain such as nonsteroidal anti-inflammatory compounds (NSAIDs), steroidal compounds, cyclooxygenase inhibitors and opioid analgesics.
17. The composition of claim 8 wherein the composition is suitable for topical, oral, patches, subcutaneous, intramuscular or intravenous administration.
PCT/IB2018/051464 2017-03-08 2018-03-07 Indanyl compounds as voltage gated sodium channel modulators WO2018163077A1 (en)

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