OA20271A

OA20271A - Novel substituted sulfonylurea derivatives.

Info

Publication number: OA20271A
Application number: OA1202100336
Authority: OA
Inventors: Rajiv Sharma; SARKHEJ Vaishnodevi Circle; Sameer Agarwal; SARKHEJ Nr. Vaishnodevi Circle
Original assignee: Cadila Healthcare Limited
Priority date: 2019-01-14
Filing date: 2020-01-13
Publication date: 2022-04-14

Abstract

The present invention relates to novel heterocyclic compounds of the general formula (I) their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers and polymorphs. The invention also relates to processes for the preparation of the compounds of invention, pharmaceutical compositions containing the compounds and their use as the compounds of the invention belong to the family of NOD-like receptor family (NLR) protein NLRP3 modulators. The present invention thus relates to novel NLRP3 modulators as well as to the use of the novel inhibitor compounds in the treatment of diseases or conditions in which interleukin lB activity is implicated.

Description

NOVEL SUBSTITUTED SULFONYLUREA DERIVATIVES

FIELD OF THE INVENTION

The présent invention relates to novel heterocyclic compounds of the general formula (I) their pharmaceutically acceptable salts, pharmaceutically acceptable solvatés, enantiomers, diastereomers and polymorphs. The invention also relates to processes for the préparation of the compounds of invention, pharmaceutical compositions containing the compounds and their use as the compounds of the invention belong to the family of NOD-like receptor family (NLR) protein NLRP3 modulators. The présent invention thus relates to novel NLRP3 modulators as well as to the use of the novel inhibitor compounds in the treatment of diseases or conditions in which interleukin 1 β activity is implicated.

BACKGROUND OF THE INVENTION

The NOD-like receptor family (NLR) protein NLRP3 is an intracellular signaling molécule that senses many pathogens, environmental and host-derived factors. (Wen., et. al., Immunity. 2013; 39:432-441). Activation of NLRP3 leads to binding with apoptosis associated speck-like protein containing a CARD (ASC). ASC in turn interacts with the cysteine protease caspase-1, forming a complex termed the inflammasome. This results in the activation of caspase-1, which cleaves the pro-inflammatory cytokines IL-Ιβ and IL-18 to their active forms and médiates a type of inflammatory cell death known as pyroptosis. Other intracellular pattern récognition receptors (PRRs) are also capable of forming inflammasomes. These include other NLR family members such as NLRP1 and NLRC4 and non-NLR PRRs such as the double-stranded DNA (dsDNA) sensors absent in melanoma 2 (AIM2) and interferon, gamma inducible protein 16 (IFI16) (Latz, et. al., Nat Rev Immunol. 2013; 13:397U11). NLRP3-dépendent IL-Ιβ processing can also be activated by an indirect, non-canonical pathway downstream of caspase-1 (Lamkanfi, et. al., Cell. 2014; 157:1013-1022).

g Inflammasome components such as NLRP3, ASC and caspase-1 are expressed in immune cells in the liver including Kupffer cells, infiltrating macrophages, hépatocytes, and hepatic stellate cells.

| 30 Inflammasome activation is dépendent on two successive signais. Signal 1 is driven by TLR and IL-1R signaling, includes expression of component proteins including NLRP3, ASC, pro-caspase] 1, pro-IL-1 β, and pro-IL-18. Signal 2 is provided by danger signais (DAMPS) that during NASH development are mainly released by stressed or dying hépatocytes or via a ”leaky” gut (PAMPs).

| This process leads to oligomérization of the inflammasome components and cleavage of pro35 caspase-1, leading to the release of active pro-inflammatory cytokines.

I

The NLRP3 inflammasome acts as a key mediator of inflammatory responses through the activation of caspase-1 leading to processing and release of the pro-inflammatory cytokines interleukin-ΐβ (IL-1 β) and interleukin-18 (IL-18). The NLRP3 inflammasome is a component of 5 the inflammatory process and its aberrant activation is pathogenic in inherited disorders such as the rare periodic fever syndrome, cryopyrin associated periodic syndromes (CAPS), Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) and complex diseases such as multiple sclerosis, Inflammatory bowel disease (IBD), type 2 diabètes, atherosclerosis, asthma, gouty arthritis, and inflammatory central nervous system (CNS) diseases including Parkinson's, 10 Alzheimer’s and other brain diseases. (Masters, et. al., Annu Rev Immunol. 2009; 27:621—668;

Strowig, et. aL, Nature 2012, 481, 278—286; Guo, et. al., Nat. Med. 2015, 21, 677; Ising, et.al., Nature 2019, 575, 669-673.)

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I

I 1

I I

Inflammation is an essential host response to infection and injury. The régulation of the proinflammatory cytokine interleukin-ΐβ (IL-Ιβ), which is central to host responses to infection, also causes tissue injury when activated inappropriately. (Dinarello, et. al., Nat. Rev. Drug Discovery 2012, 11, 633-652.) NLRP3 inflammasome activation plays a key rôle in each ofthe components including induction of pro-inflammatory signaling, hepatocellular injury and cell death, and activation ofthe hepatic stellate cells (HSC) that are responsible for collagen déposition and liver fibrosis. In particular, the transition from NAFLD to NASH associâtes with NLRP3inflammasome activation and an increased expression of inflammasome-related components, including apoptosis-associated speck-like protein containing a carboxy-terminal CARD (ASC), caspase-1 (CASP-1) and pannexin. (Mridha, et. al., Journal of Hepatology, 2017, 66 (5), 10371046)

Current treatments for NLRP3 related diseases include biologie agents that target IL-1. These are the recombinant IL-1 receptor antagonist Anakinra, the neutralizing IL-1 β antibody Canakinumab and the soluble decoy IL-1 receptor Rilonacept.

| 30 Wipo patent application WO98/32733, WO2001/019390, WO2014/190015, WO2016/123229 WO2016/131098 disclosed sulfonylureas dérivatives and related compounds as NLRP3 j|| inflammasome inhibitors. WO2017/017469 disclosed certain cyclic diarylboron dérivatives as NLRP3 inflammasome inhibitors for the treatment of diseases or conditions in which interleukin 1β activity is implicated. Some of the recent patent applications such as WO2017/031161, 35 WO2017/079352, WO2017/129897, WO2017/184623, WO2018/225018, WO2019/043610,

I

WO2019/023147, WO2019/008029, WO2019/068772 also disclosed certain class of compounds as NLRP3 inhibitors.

We herein disclose novel heterocyclic compounds of general formula (I) which are NLRP3 5 modulators for the prévention and treatment of disease States mediated by NLRP3 or conditions in which interleukin 1β activity is implicated, including inflammation, Cryopyrin-associated periodic syndrome (CAPS), gouty arthritis, multiple sclerosis, Inflammatory bowel disease (IBD), type 2 diabètes, atherosclerosis, liver fibrosis inflammatory central nervous system (CNS) diseases like Parkinson’s, Alzheimer’s and other brain diseases, mediated via NLRP3 pathway. More 10 particularly, embodiments of the présent invention are useful as therapeutics in the treatment of a variety ofpathological conditions including (but not limited to) lymphoma, auto-immune diseases, heteroimmune diseases, inflammatory diseases, cancer, and neurodegenerative diseases or conditions.

I

1²⁰

I

1³⁰

I

SUMMARY OF THE INVENTION

The présent invention discloses heterocyclic compounds as defined by the general formula (I) that are NLRP3 modulators for the prévention and treatment of disease States mediated by NLRP3 as well as treatment of diseases or conditions in which interleukin 1β activity is implicated. The compounds of the présent invention are useful in the treatment of human or animal body, by inhibition of NLRP3. The compounds of this invention are therefore suitable for the prévention and treatment of disease States mediated by NLRP3.

EMBODIMENT(S) OF THE INVENTION

An embodiment of the présent invention provides novel heterocyclic compounds represented by the general formula (I), their tautomeric forms, their enantiomers, their diastereoisomers, their stereoisomers, their pharmaceutically acceptable salts and pharmaceutical compositions containing them or their mixtures thereof.

In an another embodiment of the présent invention is provided pharmaceutical compositions containing compounds ofthe general formula (I), their tautomeric forms, their enantiomers, their diastereoisomers, their stereoisomers, their pharmaceutically acceptable salts, or their mixtures in combination with suitable carriers, solvents, diluents and other media normally employed in preparing such compositions.

In a further embodiment is provided the use of heterocyclic compounds of the présent invention as NLRP3 modulators, by administering a therapeutically effective and non-toxic amount of compounds of general formula (I) or their pharmaceutically acceptable compositions to the mammals.

In a still further embodiment compound of formula (I) of the présent invention may be used in combination with one or more suitable pharmaceutically active agents.

In another further embodiment is provided a process for preparing the novel compounds of the présent invention.

A further objective of the présent invention is to provide novel intermediates involved in the process.

A further objective of the présent invention to provide process for the préparation of intermediates involved in the process.

DESCRIPTION OF THE INVENTION

Accordingly, the présent invention relates to the compounds of the general formula (I)

r

Formula (I) their tautomeric forms, their stereoisomers, their enantiomers, their pharmaceutically acceptable salts, and pharmaceutical compositions containing them wherein,

R¹ at each occurrence independently represents hydrogen, halogen, haloalkyl, cyano, optionally substituted groups selected from (Ci-Côjalkyl, (Ci-Côjhaloalkyl, (C₂-C6)alkenyl, (Ci-Cô)alkoxy, (C₃-C₇)cycloalkyl, NH₂, NH(Ci-C₆)alkyl, N(C₃-C₇)cycloalkyl; N(Ci-C₆ alkyl)₂, aryl, heteroaryl, heterocyclyl, benzyl, thiol, mercapto alkyh SO₂(Ci-C6)alkyl,, (Ci-Cejthio-alkoxy, amide; m and n is independently selected from integer 0-3;

I q and r is independently selected from integer 1-4;

X is N-R⁵; O, S, S0₂;

R⁵ at each occurrence independently represents hydrogen, halogen, haloalkyl, cyano, optionally substituted groups selected from (Ci-Cô)alkyl, (Ci-Cejhaloalkyl, (C2-C6)alkenyl, (C2-Cô)alkynyl, 5 (Ci-C6)alkoxy, (C3-C7)cycloalkyl, (Ci-C6)alkylSO2(Ci-C6)alkyl, (Ci-C6)alkylN(Ci-C6)alkyl, (CiC6)alkylN(C₃-C₇)cycloalkyl, aryl, heteroaryl, heterocyclyl, benzyl, tert-butyloxycarbonyl, thiol, mercaptoalkyl, SO2(Ci-C6)alkyl, SO2(C₃-C7)cycloalkyl, SCh-aryl, SO2-heterocyclyl, (CiCô)thioalkyl, (Ci-Côjthioalkoxy, (Ci-Cô)alkylSO2NH2, -C0NH2, -CO(Ci-C6)alkyl, -CO(CiC₆)haloalkyl, -CO-aryl, -CO-heteroaryl, -CO-heterocyclyl, 4- to 7-membered heterocyclic ring, 710 to 14-membered bicyclic heterocyclic ring system, bridged or spiro ring system having optionally one or more than one heteroatoms;

R² at each occurrence independently represents hydrogen, halogen, haloalkyl, cyano, optionally substituted groups selected from (Ci-Cô)alkyl, (Ci-Cô)alkoxy, (C2-C6)alkenyl, (C₃-C7)cycloalkyl, 15 benzyl, aryl, heteroaryl, heterocyclyl, thiol, thioalkyl, thio-alkoxy, SO2(Ci-Ce)alkyl, SO(CiCô)alkyl, bridged or spiro ring system having optionally one or more than one heteroatoms;

Each of R³ and R⁴ at each occurrence represents hydrogen, halogen, haloalkyl, cyano, nitro, amide, sulphonamide, acyl, hydroxyl, optionally substituted groups selected from (Ci-Cô)alkyl, (Ci20 C₆)haloalkyl, (C₃-C₆)cycloalkyl, (Ci-C₆)alkoxy, SO₂(Ci-C₆)alkyl, thiol, mercapto alkyl benzyl, aryl, heteroaryl, heterocyclyl; Altematively R₃, and R₄ forms a bond;

‘B’ is selected from the following ring system

Where in W, Y, Z at each occurrence independently represents C, N, S, SO2, and O, which may be optionally substituted;

Each of R⁶, R⁷, R⁸, R⁹, R¹⁰ and R¹¹ at each occurrence are independently selected from hydrogen, halogen, cyano, amide, sulphonamide, acyl, hydroxyl, optionally substituted groups selected from 30 (Ci-C₆)alkyl, (Ci-C₆)haloalkyl, (C₃-C₆)cycloalkyl, (Ci-C₆)alkoxy, benzyl, aryl, heteroaryl,

I

I heterocyclyl; Altematively each of R⁷ and R⁸, R⁸ and R⁹, R⁹ and R¹⁰ and R¹⁰ and R¹¹ wherever possible, together may form a 4 to 7 membered saturated or partially saturated ring containing from 0-2 additional heteroatoms selected from the group consisting of N, O, and S(O)_P; p = 1-2.

When any of above defined group is substituted the substitutions on them may be selected from those described above or may be selected from hydrogen, hydroxy, cyano, halo, haloalkyl, haloalkyloxy, alkylthio (Ci-Ce)alkyl, (C2-Cô)alkenyl, (C2-Cô)alkynyl, (Cs-Cyjcycloalkyl, Ci-Cô alkoxy, aryl, heterocyclyl, heteroaryl, -COR12, -CSR12, C(O)ORi2, C(O)-Ri2, -C(O)-NRi2Ri3, C(S)-NRi₂Ri3, -SO2R12 group, wherein each of R12 and R13 is independently selected from hydrogen, optionally substituted group selected from (Ci-Côjalkyl, (C2-Cô)alkenyl, (C2Cô)alkynyl, (C3-C7)cycloalkyl, aryl, heteroaryl, heterocyclyl groups;

In a preferred embodiment R¹ at each occurrence independently represents hydrogen, halogen, haloalkyl optionally substituted groups selected from (Ci-Cô)alkyl;

In a preferred embodiment R² at each occurrence independently represents hydrogen, halogen, haloalkyl, optionally substituted groups selected from (Ci-Cô)alkyl;

In a preferred embodiment Each of R³ and R⁴ at each occurrence independently represents hydrogen, halogen, haloalkyl, optionally substituted groups selected from (Ci-Côjalkyl.

In a preferred embodiment each of R⁶, R⁷, R⁸, R⁹, R¹⁰ and R¹¹ at each occurrence independently selected from hydrogen, halogen optionally substituted groups selected from (Ci-Côjalkyl, (CiCôjhaloalkyl;

In a preferred embodiment, the groups, radicals described above may be selected from:

Alkyl, as well as other groups having the prefix alk, such as alkoxy and alkanoyl, means a carbon chain which may further be substituted with an oxygen atom as is well understood by a skilled artisan, which may further be either linear or branched, and combinations thereof, unless 30 the carbon chain is defined otherwise. Examples of alkyl group include but not are limited to methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert. -butyl, pentyl, hexyl etc. Where the specifïed number of carbon atoms permits e.g. from C3-10, the term alkyl also includes cycloalkyl groups, and combinations of linear or branched alkyl chains combined with cycloalkyl structures. When no number of carbon atoms is specified, Ci-6 is intended. Substituted alkyl includes alkyl

I

Ï substituted with one or more moieties selected from the group consisting of halo {e.g., CI, F, Br,

Iand I); halogenated alkyl {e.g., CF3, 2-Br-ethyl, CH2F, CH2CI, CH2CF3, or CF2CF3); hydroxyl;

amino; carboxylate; carboxamide; alkylamino; arylamino; alkoxy; aryloxy; nitro; azido; cyano;

Ïthio; sulfonic acid; sulfate; phosphonic acid; phosphate; and phosphonate as well as those 5 described under the définition of Optionally substituted’.

Ï Alkenyl means carbon chains which contain at least one carbon-carbon double bond, and which may be linear or branched or combinations thereof, unless the carbon chain is defined otherwise.

I Examples of alkenyl include but not limited to vinyl, allyl, isopropenyl, hexenyl, pentenyl, heptenyl, 1 -propenyl,: 2-butenyl, 2-methyl -2-butenyl etc. Where the specified number of carbon * 10 atoms permits, e.g., from C5-10, the term alkenyl also includes cycloalkenyl groups and ® combinations of linear, branched and cyclic structures. When no number of carbon atoms is | specified, C2-6) is intended.

* Alkynyl means carbon chaims which contain at least one carbon-carbon triple bond, and which * 15 may be linear or branched or combinations thereof. Examples of alkynyl include ethynyl,

W propargyl, 3-methyl-1 -pentynyl etc. When no number of carbon atoms is specified, is intended.

I

1²⁰t

I

I £ 30

I

I the “thioalkyl” group used either alone or in combination with other radicals, dénotés an alkyl group, as defined above, attached to a group of formula —SR’, (sulfur and its oxidized forms) where R’ represents hydrogen, alkyl or aryl group, e.g. thiomethyl, methylthiomethyl, phenylthiomethyl and the like, which may be optionally substituted.

As used herein, carbocycle or carbocyclic residue is intended to mean any stable monocyclic or bicyclic or tricyclic ring, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin). In a broader perspective, the term carbocycle is intended to include, wherever applicable, the groups representing cycloalkyl, phenyl and other saturated, partially saturated or aromatic residues;

The terms cycloalkyl and cycloalkenyl refers to optionally substituted, saturated and unsaturated monocyclic, bicyclic or tricyclic carbon groups. Where appropriate, the cycloalkyl or cycloalkenyl group may hâve a specified number of carbon atoms, for example, C3-C6 cycloalkyl or cycloalkenyl includes within its scope a carbocyclic group having 3, 4, 5 or 6 carbon atoms. Examples of such substituents may be selected from the group consisting of cyclopropyl,

I I

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1³⁰I cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl and the like. Substituted cycloalkyl or cycloalkenyl includes substitutions with one or more moieties selected from the group consisting of halo (e.g., CI, F, Br, and I); halogenated alkyl (e.g., CF3, 2-Br-ethyl, CH₂F, CH2CI, CH2CF3, or CF2CF3); hydroxyl; amino; carboxylate; carboxamido; alkylamino; arylamino; alkoxy; aryloxy; nitro; azido; cyano; thio; sulfonic acid; sulfate; phosphonic acid; phosphate; and phosphonate as well as those described under the définition of Optionally substituted’.

The alkoxy refers to the straight or branched chain alkoxides of the number of carbon atoms specified.

Aryl means a mono- or polycyclic aromatic ring system containing carbon ring atoms. The preferred aryls are monocyclic or bicyclic 6-10 membered aromatic ring Systems. Phenyl and naphthyl are preferred aryls.

“Heterocyclyl” means a saturated, partially saturated or unsaturated aromatic or non-aromatic mono, bi or tricyclic radicals, containing one or more heteroatoms selected from nitrogen, sulfur and oxygen, further optionally including the oxidized forms of sulfur, namely SO & SO2. Heterocyclyl Systems may be attached to another moiety via any number of carbon atoms or heteroatoms of the radical and may be both saturated and unsaturated. Examples of heterocycles include tetrahydrofuran (THF), dihydrofuran, 1 ,4-dioxane, morpholine, 1,4-dithiane, piperazine, piperidine, 1 ,3-dioxolane, imidazoline, imidazolidine, pyrrolidine, pyrroline, tetrahydropyran, tetrahydro-2H-thiopyran, dihydropyran, oxathiolane, dithiolane, 1 ,3-dioxane, 1 ,3-dithiane, oxathiane, thiomorpholine, etc. The term heterocycloalkyl refers to a heterocyclic group as defined above connected to an alkyl group as defined above;

Heteroaryl means an aromatic or partially aromatic heterocycle that contains at least one ring heteroatom selected from O, S and N. Heteroaryls thus include heteroaryls fused to other kinds of rings, such as aryls, cycloalkyls, and heterocycles that are not aromatic. Examples of heteroaryl groups include; pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, triazinyl, thienyl, pyrimidyl, benzisoxazolyl, benzoxazolyl, benzthiazolyl, benzothiadiazolyl, dihydrobenzofuranyl, indolinyl, pyridazinyl, indazolyl, isoindolyl, dihydrobenzothienyl, indolinyl, pyridazinyl, indazolyl, isoindolyl, dihydrobenzothienyl, indolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, napthyridinyl, carbazolyl, benzodioxolyl, quinoxalinyl, purinyl, furazanyl, isobenzylfùranyl, benzimidazolyl, benzofuranyt, benzothienyl, quinolyl, indolyl, isoquinolyl, dibenzofuranyl etc. For heterocyclyl

I

I I I

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I I I I I I I and heteroaryl groups, rings and ring Systems containing from 3-15 carbon atoms are included, forming 1-3 rings.

The term haloalkyl means an alkyl structure in which at least one hydrogen is repiaced with a halogen atom. In certain embodiments in which two or more hydrogen atoms are repiaced with halogen atoms, the halogen atoms are ail the same as one another.

the “haloalkoxy” group is selected from suitable haloalkyl, as defined above, directly attached to an oxygen atom, more preferably groups selected from fluoromethoxy, chloromethoxy, fluoroethoxy, chloroethoxy and the like;

In certain other embodiment in which two or more hydrogen atoms are repiaced with halogen atoms, the halogen atoms are not ail the same as one another.

Aryloxy alkyl means an alkyl radical substituted with aryloxy group as defined herein.

Aryloxyaryl means an aryl radical substituted with aryloxy group as defmed herein.

Aryloxyheteroaryl means a heteroaryl radical substituted with aryloxy group as defined herein.

Halo/ Halogen refers to fluorine, chlorine, bromine, iodine. Chlorine and fluorine are generally preferred.

Suitable groups and substituents on the groups may be selected from those described anywhere in the spécification.

The term substituted, as used herein, means that any one or more hydrogen on the designated atom is repiaced with a sélection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. The term substituted, as used herein, means that any one or more hydrogens on the designated atom is repiaced with a sélection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound.

Pharmaceutically acceptable salts refer to dérivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, minerai or organic acid salts of the basic residues. Such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from sodium, potassium, 1,2-ethanedisulfonic, 2-acetoxybenzoic, 2hydroxyethanesulfonic, acetic, ascorbic, benzenesulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic, ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromie, hydrochloric, hydroiodide, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, -lauryl sulfonic, maleic, malic, mandelic, methanesulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic, salicyclic, stearic, subacetic, succinic, sulfamic, sulfanilic, sulfuric, tannic, tartaric, and toluenesulfonic.

The term 'optional' or ‘optionally’ means that the subséquent described event or circumstance may or may not occur, and the description includes instances where the event or circumstance occur and instances in which it does not. For example, optionally substituted alkyl' means either 'alkyl' or 'substituted alkyl'. Further an optionally substituted group includes an unsubstituted group.

Unless otherwise stated in the spécification, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically ennched atoms.

Particularly useful compounds may be selected from but not limited to the following:

(R,E)-2-(l-ethylpyrrolidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethanesulfonamide;

(S,E)-2-(l-ethylpyrrolidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethanesulfonamide ;

(R,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(pyrrolidin-2-yl)ethene-lsulfonamide;

(R,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l-propylpyrrolidin-2-yl)ethene1-sulfonamide;

(R,E)-2-(l-(cyclopropylmethyl)pyrrolidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)ethene-1 -sulfonamide;

(R,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l-methylpyrrolidin-2-yl)ethene1-sulfonamide;

(R,E)-N-((l,2,3,5,6,7-hexahydro-s-mdacen-4-yl)carbamoyl)-2-(l-(methylsulfonyl)-pyrrolidin-2yl)ethene-1 -sulfonamide;

(R,E)-2-(l-acetylpyrrolidin-2-yl)-N-(( 1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoy l)-ethene1-sulfonamide;

(E)-2-(l-benzylpiperidin-4-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethanesulfonamide;

tert-butyl (R,E)-2-(2-(N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)pyrrolidine-1 -carboxylate;

(R,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l-(2-methoxyethyl)pynOlidin-2yl)ethenesulfonamide;

(R,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l-(isopropylsulfonyl)pyrrolidin2-yl)ethenesulfonamide;

(R,E)-2-(l-((3-fluorophenyl)sulfonyl)pyrrolidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)ethenesulfonamide;

(R,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l-(pyrazine-2carbonyl)pyrrolidin-2-yl)ethenesulfonamide;

(R,E)-2-(2-(N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)pyrrolidine-lcarboxamide;

(R,E)-2-(l-(cyclopropanecarbonyl)pyrrolidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)ethene-1 -sulfonamide;

(R,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l-(2,2,2trifluoroacetyl)pyrrolidin-2-yl)ethene-1 -sulfonamide;

(R,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2 -(1-(2(methylthio)ethyl)pyrrolidin-2-yl)ethene-1 -sulfonamide;

(R,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l-(2,2,2trifluoroethyl)pyrrolidin-2-yl)ethene-1 -sulfonamide;

(R,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l-isobutylpyrrolidin-2-yl)ethene1-sulfonamide;

(R,E)-2-(l-(ethylsulfonyl)pyrrolidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)ethene-1 -sulfonamide;

(R,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l-isopropylpyrrolidin-2yl)ethene-1 -sulfonamide;

(R,E)-N-(( 1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-( 1 -(3 (methylsulfonyl)propyl)pyrrolidin-2-yl)ethenesulfonamide;

(R,E)-2-(l-benzoylpyrrolidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)ethenesulfonamide;

(R,E)-N-((2-(l-benzoylpyrrolidin-2-yl)vinyl)sulfonyl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)benz amide;

(R,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(pyrrolidin-2yl)ethenesulfonamide;

(R,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l-(thiophene-3carbonyl)pyrrolidin-2-yl)ethenesulfonamide;

(R,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(pyrrolidin-2-yl)ethene-lsulfonamide methane sulfonate;

(R,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(pyrrolidin-2-yl)ethene-lsulfonamide maleate;

(R,Z)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(pyrrolidin-2-yl)ethene-lsulfonamide;

(S,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-(pyrrolidin-2-yl)prop-l-ene-lsulfonamide;

(R,E)-2-(l-(cyclohexylsulfonyl)pyrrolidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)ethene-1 -sulfonamide;

(R,Z)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l-methylpyrrolidin-2-yl)ethene1-sulfonamide;

(R,E)-2-(l-(cyclohexylmethyl)pyrrolidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)ethene-1 -sulfonamide;

(R,E)-2-(l-cyclohexylpyrrolidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)ethene-1 -sulfonamide;

(R,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l-(l-methylpiperidin-4yl)pyrrolidin-2-yl)ethene-1 -sulfonamide;

(R,Z)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l-isopropylpyrrolidin-2yl)ethene-1 -sulfonamide;

(R,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l-(tetrahydro-2H-pyran-4yl)pyrrolidin-2-yl)ethene-1 -sulfonamide;

I (R,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l-(oxetan-3-yl)pyrrolidin-2yl)ethene-1 -sulfonamide;

(R,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l-(tetrahydro-2H-thiopyran-4yl)pyrrolidin-2-yl)ethene-1 -sulfonamide;

(R,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l-(thiazol-2-ylmethyl)pyrrolidin2-yl)ethene-1 -sulfonamide;

(E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(piperidin-4-yl)ethenesulfonamide;

(E)-N-((l, 2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l-methylpiperidin-4yl)ethenesulfonamide;

(E)-N-((l,2,3,5,6,7-hexahydro-s-mdacen-4-yl)carbamoyl)-2-(l-(methylsulfonyl)piperidin-4yl)ethenesulfonamide;

(E)-2-(l-acetylpiperidin-4-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethenesulfonamide;

tert-butyl (E)-4-(2-(N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)15 piperidine-l-carboxylate;

(E)-2-( 1 -ethylpiperidin-4-yl)-N-(( 1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1 sulfonamide;

(R,E)-2-(l-ethylpyrrolidin-3-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethenesulfonamide;

(R,E)-1,1 -diethyl-3-(2-(N-((l ,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)pyrrolidin-1 -iumbromide;

(E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(pyrrolidin-3-yl)ethenesulfonamide;

(R,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-methylpyrrolidin-2-yl)ethene25 1-sulfonamide;

tert-butyl (R,E)-2-(2-(N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)-2methylpyrrolidine-1 -carboxylate;

I

I (R,E)-2-(l-acetyl-2-methylpyrrolidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)ethene-1 -sulfonamide;

(R,E)-1,1 -diethyl-2-(2-(N-((l ,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-vinyl)2-methylpyrrolidin-l-ium bromide;

(R,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-methyl-l-(methylsulfonyl)pyrrolidin-2-yl)ethene-1 -sulfonamide; :

(R,E)-2-(l,2-dimethylpyrrolidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)ethene-1 -sulfonamide;

(R,E)-2-(l-ethyl-2-methylpyrrolidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)ethene-1 -sulfonamide;

(R,E)-2-(l-(cyclopropylmethyl)-2-methylpyrrolidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen4-yl)carbamoyl)ethene-1 -sulfonamide;

(S,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(pyrrolidin-2-yl)ethenesulfonamide;

(S,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l-methylpyrrolidin-2yl)ethenesulfonamide;

(S,E)-tert-butyl2-(2-(N-((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)sulfamoyl)vinyl)pyrrolidine-1 -carboxylate;

(S,E)-2-(l-(cyclopropylmethyl)pyrrolidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-420 yl)carbamoyl)ethenesulfonamide;

(S,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l-(pyridin-3-ylsulfonyl)pyrrolidin-2-yl)ethenesulfonamide;

(S,E)-N-((2,6-diisopropylphenyl)carbamoyl)-2-(pyrrolidin-2-yl)ethenesulfonamide;

(S,E)-N-((2,6-diisopropylphenyl)carbamoyl)-2-(l-ethylpyrrolidin-2-yl)ethenesulfonamide;

(S,E)-N-((2,6-diisopropylphenyl)carbamoyl)-2-(l-(methylsulfonyl)pyrrolidin-2-yl)ethenesulfonamide;

(S,E)-N-((2,6-diisopropylphenyl)carbamoyl)-2-(l-methylpyrrolidin-2-yl)ethenesulfonamide;

(S,E)-2-(l-acetylpyrrolidin-2-yl)-N-((2,6-diisopropylphenyl)carbamoyl)ethenesulfonamide;

I

I (S,E)-2-(l-acetylpyrrolidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethenesulfonamide ;

(S,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l-(tetrahydro-2H-pyran-4carbonyl)pyrrolidin-2-yl)ethenesulfonamide;

(E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(tetrahydro-2H-pyran-4yl)ethenesulfonamide;

(S,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l-nicotinoylpyrrolidin-2yl)ethenesulfonamide;

(E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(tetrahydrofuran-2-yl)ethene-l- sulfonamide;

(S,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l-(thiophen-2-ylmethyl)pyrrolidin-2-yl)ethene-1 -sulfonamide;

tert-butyl (S,E)-2-(2-(N-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)sulfamoyl)vinyl)pyrrolidine-1 -carboxylate;

(S,E)-N-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)-2-(pyrrolidin-2-yl)ethene-l-sulfonamide;

(S,E)-N-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)-2-(l-methylpyrrolidin-2-yl)ethene-lsulfonamide;

(R,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l-isobutyl-2-methyl-pyrrolidin2-yl)ethene-1 -sulfonamide;

(R,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-methyl-l-propylpyrrolidin-2yl)ethene-l -sulfonamide;

(S,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l-(thiazol-2-yl)pyrrolidin-2yl)ethene-1 -sulfonamide;

(E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(piperidin-3-yl)ethene-sulfonamide;

(E)-2-(l-ethylpiperidin-3-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethenesulfonamide;

(E)-tert-butyl 3-(2-(N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)piperidine-1 -carboxylate;

I

I (E)-N-((l, 2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l-(methylsulfonyl)piperidin-3yl)ethenesulfonamide;

(E)-2-(l-acetylpiperidin-3-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethenesulfonamide;

tert-butyl (E)-2-(2-(N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)azetidine-1 -carboxylate;

(E)-N-(( 1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l -methylazetidin-2-yl)ethene-1 sulfonamide;

(E)-2-(azetidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-lsulfonamide;

(S,E)-2-(l-((5-chlorothiophen-2-yl)sulfonyl)pyrrolidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-sindacen-4-yl)carbamoyl)ethenesulfonamide;

(S,E)-2-(l-(benzylsulfonyl)pyrrolidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)ethenesulfonamide;

(S,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l-((4-methoxyphenyl)sulfonyl) pyrrolidin-2-yl)ethenesulfonamide;

(S,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l-((4-fluorophenyl)sulfonyl) pyrrolidin-2-yl)ethenesulfonamide;

(S,E)-2-(l-((2-cyanophenyl)sulfonyl)pyrrolidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carb amoyl)ethenesulfonamide ;

(S,E)-2-(l-(cyclohexylsulfonyl)pyrrolidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)ethenesulfonamide;

(S,E)-2-(l-(4-fluorobenzyl)pyrrolidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)ethenesulfonamide;

(S,E)-2-(l-((4-cyanophenyl)sulfonyl)pyrrolidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)ethene-1 -sulfonamide;

I (S,E)-2-(l-(4-cyanobenzyl)pyrrolidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)ethene-1 -sulfonamide;

(S,E)-N-((l,2,3,6,7,8-hexahydro-as-indacen-4-yl)carbamoyl)-2-(pyrrolidin-2-yl)ethene-lsulfonamide;

(E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(piperidin-2-yl)ethene-lsulfonamide;

(E)-N-((l ,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-( 1 -methylpiperidin-2-yl)ethene-1 sulfonamide;

(E)-N-(( 1,2,3,6,7,8-hexahydro-as-indacen-4-yl)carbamoyl)-2-(l-methylpyrrolidin-2-yl)ethene-l10 sulfonamide;

(E)-N-(( 1,2,3,6,7,8-hexahydro-as-indacen-4-yl)carbamoyl)-2-(l-(methylsulfonyl)pynOlidin-2yl)ethene-1 -sulfonamide;

((E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-(piperidin-2-yl)prop-l-ene-lsulfonamide;

(S,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-methylpyrrolidin-2-yl)ethene1-sulfonamide;

(S,E)-2-(l,2-dimethylpyrrolidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)ethene-1 -sulfonamide;

(E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(indolin-2-yl)ethene-l-sulfonamide;

tert-butyl(E)-2-(2-(N-(( 1,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)sulfamoyl)vinyl)indoline-1 -carboxylate;

((S,E)-2-(l-(cyclopropylmethyl)-2-methylpyrrolidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen4-yl)carbamoyl)ethene-1 -sulfonamide;

(S,E)-2-(l-(cyclopropylsulfonyl)pyrrolidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-425 yl)carbamoyl)ethene-l-sulfonamide;

tert-butyl (S,E)-2-(2-(N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)-2methylpyrrolidine-1 -carboxylate;

I

I I

I • 10

I

1¹⁵

I

1²⁰

I tert-butyl (R,E)-2-(2-(N-((2,6-diisopropylphenyl)carbamoyl)sulfamoyl)vinyl)-2methylpyrrolidine-1 -carboxylate;

(R,E)-N-((2,6-diisopropylphenyl)carbamoyl)-2-(2-methylpyrrolidin-2-yl)ethene-l-sulfonamide 2,2,2-trifluoroacetate ;

(R,E)-N-((2,6-diisopropylphenyl)carbamoyl)-2-(l,2-dimethylpyrrolidin-2-yl)ethene-lsulfonamide;

(S,E)-2-(l-ethyl-2-methylpyrrolidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)ethene-1 -sulfonamide;

Bis sodium (R,E)-((2-(l,2-dimethylpyrrolidin-2-yl)vinyl)sulfonyl)((l,2,3,5,6,7-hexahydro-sindacen-4-y l)carbamoyl) amide ;

Sodium (R,E)-((2-(l,2-dimethylpyrrolidin-2-yl)vinyl)sulfonyl)((l,2,3,5,6,7-hexahydro-sindacen-4-yl)carbamoyl)amide;

tert-butyl (S,E)-2-(2-(N-((2,6-diisopropylphenyl)carbamoyl)sulfamoyl)vinyl)-2methylpyrrolidine-1 -carboxylate;

(S,E)-N-((2,6-diisopropylphenyl)carbamoyl)-2-(2-methylpyrrolidin-2-yl)ethene-l-sulfonamide 2,2,2-trifluoroacetate;

(S,E)-N-((2,6-diisopropylphenyl)carbamoyl)-2-(l,2-dimethylpyrrolidin-2-yl)ethene-lsulfonamide;

(R,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-methyl-l-(oxetan-3yl)pynOlidin-2-yl)ethene-1 -sulfonamide;

tert-butyl (S,E)-2-(2-(N-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)sulfamoyl)vinyl)-2methylpyrrolidine-1 -carboxylate;

(S,E)-N-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)-2-(2-methylpyrrolidin-2-yl)ethene-lsulfonamide 2,2,2-trifluoroacetate;

(S,E)-2-(l,2-dimethylpyrrolidin-2-yl)-N-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)ethene-lsulfonamide;

(E)-2-(l-acetylazetidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-lsulfonamide;

tert-butyl (R,E)-(2-(2-(2-(N-((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)sulfamoyl)vinyl)pyrrolidin-l-yl)ethyl)(methyl)carbamate;

I

I (S,E)-2-(l-allylpyrrolidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-lJ sulfonamide;

(S,E)-2-(l-(lH-benzo[d]imidazole-6-carbonyl)pyrrolidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s| indacen-4-yl)carbamoyl)ethene-1 -sulfonamide;

(S,E)-2-(l-(cyclopropylsulfonyl)-2-methylpyrrolidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-

4-yl)carbamoyl)ethene-1 -sulfonamide;

| (S,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l-(4-methoxybenzyl)pyrrolidin2-yl)ethene-1 -sulfonamide;

tert-butyl 5-((R)-2-((E)-2-(N-((l,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)sulfamoyl)vinyl)pyrrolidin-1 -yl)hexahydrocyclopenta[c]pyrrole-2( 1H)- ^e carboxylate;

(E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-((2R)-l-(octahydrocyclo- penta[c]pyrrol-5-yl)pyrrolidin-2-yl)ethene-l -sulfonamide 2,2,2-trifluoroacetate;

| (E)-2-(l-(cyclopropylsulfonyl)azetidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)ethene-1 -sulfonamide;

| (S,E)-N-((2,6-diisopropylphenyl)carbamoyl)-2-( 1 -(thiazol-2-yl)pyrrolidin-2-yl)ethene-1 sulfonamide;

tert-butyl (S,E)-(2-(2-(2-(N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)| 2-methylpyrrolidin-1 -yl)ethyl)(methyl)carbamate;

potassium (R,E)-((2-(l,2-dimethylpyrrolidin-2-yl)vinyl)sulfonyl)((l,2,3,5,6,7-hexahydro-s| indacen-4-yl)carbamoyl)amide;

| tert-butyl (E)-(2-(2-(2-(N-((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)sulfamoyl)vinyl)azetidin-l-yl)ethyl)(methyl)carbamate;

I (S,E)-2-(l-(cyclohexylmethyl)-2-methylpyrrolidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4- — 25 yl)carbamoyl)ethene-l-sulfonamide;

I Sodium (R,E)-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)((2-(l-(tetrahydro-2H_ thiopyran-4-yl)pyrrolidin-2-yl)vinyl)sulfonyl)amide;

sodium(R,E)-((2-(l-cyclohexylpyrrolidm-2-yl)vinyl)sulfonyl)((l,2,3,5,6,7-hexahydro-s-indacen- । 4-yl)carbamoyl)amide;

| 19

I sodium (S,E)-((2,6-diisopropylphenyl)carbamoyl)((2-(l,2-dimethylpyrrolidin-2। yl)vinyl)sulfonyl)amide;

sodium (R,E)-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)((2-(l-methylpynOlidin-2| yl)vinyl)sulfonyl)amide;

potassium (R,E)-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)((2-(l-methylpyrrolidin-2yl)vinyl)sulfonyl)amide;

| sodium (S,E)-((2-(l,2-dimethylpynOlidin-2-yl)vinyl)sulfonyl)((l,2,3,5,6,7-hexahydro-s-indacen4-yl)carbamoyl)amide;

sodium (S,E)-((2-(l-ethylpyrrolidin-2-yl)vinyl)sulfonyl)((l,2,3,5,6,7-hexahydro-s-indacen-4- | 10 yl)carbamoyl)amide;

(S,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l-(2-hydroxyethyl)pyrrolidin-2| yl)ethene-l-sulfonamide;

tert-butyl (E)-2-(2-(N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)-2- methylazetidine-1-carboxylate;

(E)-2-(l,2-dimethylazetidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-

1-sulfonamide;

| tert-butyl (S,E)-2-ethyl-2-(2-(N-((l,2,3,5,6,7-hexahydro-s-indacen-4_yl)c«bamoyl)sulf^oyl)vmyl)pyrrolidme-l-carboxylate;

tert-butyl (S,E)-2-(2-(N-((l,2,3,6,7,8-hexahydro-as-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)-2| 20 methylpyrrolidine-1-carboxylate;

(S,E)-2-(2-ethylpyrrolidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-l| sulfonamide 2,2,2-trifluoroacetate;

| (S,E)-N-((l,2,3,6,7,8-hexahydro-as-indacen-4-yl)carbamoyl)-2-(2-methylpyrrolidin-2-yl)ethene-

-sulfonamide 2,2,2-trifluoroacetate;

I 25 (S,E)-2-(l,2-dimethylpyrrolidin-2-yl)-N-((l,2,3,6,7,8-hexahydro-as-indacen-4- । yl)carbamoyl)ethene-1 -sulfonamide;

tert-butyl (R,E)-2-(2-(N-((l,2,3,6,7,8-hexahydro-as-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)-2- | methylpyrrolidine-1 -carboxylate;

I

I (R,E)-N-((l,2,3,6,7,8-hexahydro-as-indacen-4-yl)carbamoyl)-2-(2-methylpyrrolidin-2-yl)ethene1 -sulfonamide 2,2,2-trifluoroacetate;

(R,E)-2-(l,2-dimethylpynOlidin-2-yl)-N-((l,2,3,6,7,8-hexahydro-as-indacen-4yl)carbamoyl)ethene-1 -sulfonamide;

tert-butyl (R,E)-2-(3-(N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)allyl)-2methylpyrrolidine-1 -carboxylate;

tert-butyl (R,E)-(2-(2-(3-(N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)allyl)2-methylpyrrolidin-1 -yl)ethyl)(methyl)carbamate;

(R,E)-3-(l,2-dimethylpynOlidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)prop-1 -ene-1 -sulfonamide;

tert-butyl (S,E)-(3-(2-(2-(N-((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)sulfamoyl)vinyl)pynOlidin-l-yl)propyl)(methyl)carbamate;

tert-butyl (E)-(3-(2-(2-(N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)-2methylazetidin-1 -yl)propyl)(methyl)carbamate;

tert-butyl (E)-(2-(2-(2-(N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)-2methylazetidin-1 -yl)ethyl)(methyl)carbamate;

(E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-methyl-l-(2(methylthio)ethyl)azetidin-2-yl)ethene-1 -sulfonamide;

(E)-N-(( 1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-methyl-l-(oxetan-3-yl)azetidin20 2-yl)ethene-l-sulfonamide;

tert-butyl (S)-2-(((S)-2-((E)-2-(N-((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)sulfamoyl)vinyl)-2-methylazetidin-1 -yl)methyl)-2-methylpyrrolidine-1 carboxylate;

tert-butyl (S)-2-(((R)-2-((E)-2-(N-((l,2,3,5,6,7-hexahydro-s-indacen-425 yl)carbamoyl)sulfamoyl)vinyl)-2-methylazetidin-1 -yl)methyl)-2-methylpyrrolidine-1 carboxylate;

(R,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l-(2-sulfamoylethyl)pynOlidin2-yl)ethene-1 -sulfonamide;

I (S,E)-2-(2-ethyl-l-methylpyrrolidin-2-yl)-N-((l, 2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)ethene-1 -sulfonamide;

(R,E)-2-(l-(but-2-yn-l-yl)pyrrolidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)ethene-1 -sulfonamide;

or pharmaceutically acceptable salts of any of the compounds above.

Following is a list of abbreviations used in the description of the préparation of the compounds of the présent invention:

pg: microgram ' H NMR : Proton nuclear magnetic résonance bs: broad singlet

CDCh: Deuterated chloroform

CHCI3: Chloroform d: doublet

DAMP: damage-associated molecular pattern;

DCM: Dichloromethane dd: doublet of doublet

DMAC: N,N-(Dimethylacetamide)

DM AP: 4-(Dimethylamino) pyridine

DMF: Ν,Ν-Dimethyl formamide

DMSO: Dimethyl sulfoxide dt: doublet of triplet

EDTA: Ethylenediaminetertraacetic acid

EtOAc: Ethyl acetate

EtOH: Ethanol

HCl(g): Hydrogen chloride (gas)

ΙΣΙβ: Interleukin 1 beta

K2CO3: Potassium carbonate

LPS: Lipopolysaccharide m: multiplet

MeOH: Methanol mmol: millimoles

MS: Mass spectrum

N₂: Nitrogen

Na₂CO₃: Sodium carbonate ng: nanogram

NIS: N-iodosuccinimide

NLRP3: NOD-like receptor family, pyrin domain-containing protein 3

P AMP: pathogen-associated molecular pattern;

PMA: Phorbol 12-myristate 13-acetate

POCI₃: Phosphorylchloride

RM: reaction mixture

R.T; r.t: room température s: singlet t: Triplet td: triplet of doublet

THF: Tetrahydrofuran

TLC: Thin layer chromatography

TLR: Toll-like receptor.

TNF a: Tumor necrosis factor alpha

The novel compounds of the présent invention can be prepared using the reactions and techniques described below, together with conventional techniques known to those skilled in the art of organic synthesis, or variations thereon as appreciated by those skilled in the art.

General Process for Préparation

The reactions can be performed in solvents appropriate to the reagents and materiais employed and suitable for the transformations being affected. Preferred methods include, but not limited to those described below, where ail symbols are as defined earlier unless and otherwise defined below.

The compounds ofthe general formula (I) can be prepared as described in schemes below along 10 with suitable modifications/variations which are well within the scope of a person skilled in the art.

Scheme 2

I

I I

I I I I

I I I

I I 1 I I I

I ¹⁵

Wherein each of A, B, R¹, R², R³, and R⁴, are as defined earlier. Compound (2) can be prepared by variety of methods familiar to those skilled in art using a reagent like Boc anhydride from commercially available methane sulfonamide (1). Compound (2) on treatment with diphenylphosphinic chloride under suitable conditions and appropriate solvents provided compound 3 (ref. Synthesis 2003,15,2321-24). Compound 3 on treatment with aldéhyde or ketone dérivative (4) under suitable conditions in presence of base like sodium hydride and appropriate solvent provided compound (5), which can be deprotected under suitable conditions to afford compound (6). Compound (3) on treatment with isocyanato dérivative (7) under suitable conditions in presence of base like sodium hydride and appropriate solvent to afford compound of formula (I) (Scheme 1). Alternatively, compound of formula (I) can also be prepared as depicted in Scheme 2 and Scheme 3.

Spécifie reaction conditions, solvents and other parameters necessary for carrying out the process steps as described above are well within the capabilities of a person skilled in the art.

I

The invention is further illustrated by the following non-limiting examples which describe the preferred way of carrying out the présent invention. These are provided without limiting the scope of the présent invention in any way.

’H NMR spectral data given in the examples (vide infra) are recorded using a 400 MHz spectrometer (Bruker AVANCE-400) and reported in δ scale. Until and otherwise mentioned the solvent used for NMR is CDCh using TMS as the internai standard.

According to a feature of the présent invention, there is provided general structure of an intermediate of formula (5),

where ail symbols are as defined above.

In another embodiment, there is provided general structure of an Intermediate of formula (6) (R¹)q

^r3 , /0 ^snh₂ formula (6) where ail symbols are as defined above.

In another embodiment, there is provided general structure of an intermediate of formula (15) _Ph ° o. <9 ^PhTP-OsC

Ph NH₂

R⁴

Formula (15)

Where ail symbols are as defined above.

In another embodiment, there is provided general structure of an intermediate of formula (16)

O O, „O 9 _r

Ph^₄ H H

Formula (16)

Where ail symbols are as defined above.

In yet another embodiment, there is provided a process for the préparation of intermediate of formula (5), (6), 15) and (16) as per Scheme 1 and 3 disclosed in the spécification.

Intermediate-la: Préparation of tert-butyl (R,E)-2-(2-(N-(tert-butoxycarbonyl)-sulfamoyl)5 vinyl)pyrrolidine-l-carboxylate

A 500 mL, three neck, round-bottomed flask was equipped with magnetic stirrer, N2 balloon, thermos-pocket, dry ice bath. tert-butyl ((diphenylphosphoryl)methyl)sulfonylcarbamate (3) (10 g, 25.3 mmol) was dissolved in DMF (100 mL) under Nitrogen atmosphère. It was cooled to -20 10 °C and added NaH (2.023 g, 50.6 mmol). It was gradually warmed to 25 °C and stirred for 30 min.

Again cooled to -20 °C and a solution of (R)-tert-butyl 2-formylpyrrolidine-l-carboxylate (Org. Lett. 2008, 10, 4, 3045-3048) (6.05 g, 30.3 mmol) in DMF (50 mL) was added dropwise over a period of Ih at - 20 °C temp. After the addition reaction mixture was warmed to r.t. and further stirred for 17 h. Reaction mixture was cooled to 0 °C and acidified with saturated citric acid 15 solution (30 mL), and water (200 mL), solid was precipitate out, which was filtered, washed and dried to yield, (R,E)-tert-butyl 2-(2-(N-(tert-butoxycarbonyl)sulfamoyl)vinyl)pyrrolidine-lcarboxylate (4.6 g, 12.22 mmol, 48 % yield).

Ή NMR (400 MHz, DMSO-dé): δ = 11.33 (s, 1H), 6.78 - 6.67 (m, 1H), 6.52 (d, J= 14.2 Hz, 1H), 4.50-4.42 (m, 1H), 3.33-3.27 (m, 2H),2.1 (brs, 1H), 1.79-1.71 (m, 3H), 1.44-1.35(m, 18H); 20 MS (ESI): m/z (%) = 375.30 (100%) (M-H)’.

Intermediate-lb: Préparation of tert-butyl (S,E)-2-(2-(N-(tert-butoxycarbonyl)-sulfamoyl)vinyl)pyrrolidine-l-carboxylate

N

Boc

Intermediate-lb was also prepared as per the procedure described for synthesis of Intermediate25 la using (S)-tert-butyl 2-formylpyrrolidine-l-carboxylate.

Intermediate-2a: Préparation of (R,E)-tert-butyl 2-(2-sulfamoylvinyl)pyrrolidine-lcarboxylate

I

I o ' Y nh₂

Boc O ^z

The compound [Intermediate la] (18 g) was dissolved in DMSO (180 mL) and heated to 85°C (disappearance of the starting material was monitored by TLC).The reaction was cooled, poured into water (900 mL) & extracted with EtOAc (3 x 300 mL).The solvent was concentrated in vacuo & purified by column chromatography on silica gel (50% EtOAcm-Hexane) to give product (R,E)tert-butyl 2-(2-sulfamoylvinyl)pyrrolidine-l-carboxylate (14.3 g, 53.7 mmol, 67% yield).

’H NMR (400 MHz, DMSO-r/₆): δ = 6.99 (s, 2H), 6.40 - 6.38 (m, 1H), 6.34 - 6.30 (m, 1H), 4.40 -4.32 (m, 2H), 3.28-3.25 (m, 1H), 2.21 - 1.99 (m, 1H), 1.81 - 1.67 (m, 3H), 1.38 (m, 9H); MS (ESI): m/z (%) = 299.09 (50%) (M+Na)⁺, 275.09 (100%) (M-l).

Intermediate-2b: Préparation of (S,E)-tert-butyl 2-(2-sulfamoylvinyl)pyrrolidine-lcarboxylate

N „ i Boc

Y

Y NH₂

Intermediate-2b was also prepared as per the procedure described for synthesis of Intermediate2a using Intermediate 1b.

Intermediate-2c: Préparation of tert-butyl (R,Z)-2-(2-sulfamoyivinyl)pyrrolidine-lcarboxylate

H₂N

J_s^o

O

Boc

Intermediate-2c was also obtained as per the procedure described for synthesis of Intermediate2a.

’H NMR (400 MHz, DMSO-d₆): δ = 7.06 (s, 2H), 6.22 (d, J = 12 Hz, 1H), (dd, J = 12 Hz, J = 11.2 Hz, 1H), 5.24-4.92 (m, 1H), 3.41-3.23 (m, 1H), 2.31 - 2.03 (m, 2H), 1.99-1.71 (m, 1H), 1.68 - 1.62 (m, 1H), 1.39 (m, 9H); MS (ESI): m/z (%) = 299.09 (40%) (M+Na)T

Intermediate-2d: Préparation of tert-butyl (S,Z)-2-(2-sulfamoylvinyl)pyrrolidine-l-

carboxylate

I I

I

I £ 20

I

I 25

I

Intermediate-2d was also obtained as per the procedure described for synthesis of Intermediate

2b.

Intermediate-3a (Example 10): Préparation of tert-butyl (R,E)-2-(2-(N-((l,2,3,5,6,7 hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-vinyl)pyrrolidine-l-carboxylate

To a solution of the sulfonamide [Intermediate 2a] (22.0 gm, 80 mmol) in DMF (220 mL) at 0°C was added NaH (60 % dispersion in minerai oil) (3.82 gm, 96 mmol). The reaction was allowed to warm to r.t. and stirred for 30 min. 4-isocyanato-l,2,3,5,6,7-hexahydro-s-indacene (19.03 gm, 96 mmol) was added portionwise at 0°C the reaction was warm to r.t. and stirred overnight. The reaction was acidified using 50% aq.citric acid up to pH=2.0, diluted with water (1500 mL), precipitate was filtered and dried to give product (38 g, 80 mmol, 100% yield).

IH NMR (400 MHz, DMSO-d6): δ = 10.42 (s, IH), 8.09 (s, IH), 6.96 (s, IH), 6.71 - 6.68 (m, IH), 6.59 (d, J = 14.8 Hz, IH), 4.45 - 4.38 (m, IH), 3.29 - 3.27 (m, 2H), 2.79 (t, J = 7.2 Hz, 4H), 2.65 (t, J = 7.2 Hz, 4H), 2.30 - 1.93 (m, 5H), 1.78-1.71 (m, 3H), 1.39 - 1.33 (m, 9H); MS (ESI): m/z (%) = 498.18 (40%) (M+Na)+, 474.18 (100%) (M-l).

Intermediate-3b (Example 61): Préparation of tert-butyl (S,E)-2-(2-(N-((l,2,3,5,6,7hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-vinyl)pyrrolidine-l-carboxylate

Intermediate-3b was also prepared as per the procedure described for synthesis of Intermediate2b.

Ή NMR (400 MHz, DMSO): δ = 10.42 (bs, 1H), 8.09 (s, 1H), 6.96 (s, 1H), 6.71-6.67 (m, 1H), 6.61-6.57 (m, 1H), 4.45-4.38 (m, 1H), 3.29-3.25 (m, 2H), 2.81 (t, J=7.2Hz, 4H), 2.67 (t, J=7.2Hz, 5 4H), 2.09-1.93 (m, 5H), 1.78-1.71 (m, 3H), 1.33 (s, 9H); MS (ESI): m/z (%) = 498.18 (80%) (M+Na)⁺.

Intermediate-4a: Préparation of tert-butyl (R)-2-formyl-2-methylpyrrolidine-l-carboxylate

Boc

I I I

I

I I I

To a solution of 1-(tert-butyl) 2-methyl (R)-2-methylpyrrolidine-l,2-dicarboxylate (Singh et. al., RSC Adv., 2013, 3, 19533-19544) (98 g, 403 mmol) in dry DCM (2000 mL) to give a solution.

DIBAL-H (806 mL of 1.5M in Toluene, 537 mmol) was added dropwise at -78°C. The reaction mixture was stirred at -78 C for 2h then was quenched with methanol (100 mL) at -78°C température. The reaction mixture was acidified with 50 % citric acid solution up to pH=4.0. Water (1000 mL) and DCM (1000 mL) were added. The aqueous layer was extracted with DCM (2X1500 mL).The combined organic layers was washed with water (1500 mL), brine (1000 mL), and dried over NazSCL. The solvent was removed to give a product (83 g, 389 mmol, 97 % yield).

^XH NMR (400 MHz, DMSO-J₆): δ = 9.28 (m, 1H), 3.64 - 3.41 (m, 2H), 1.97 - 1.85 (m, 2H), 1.70 -1.50 (m, 2H), 1.38 - 1.28 (m, 12H), rotamers; MS (ESI): m/z (%) = 214.3 (100%) (M+H)\

Intermediate-4b: Préparation of tert-butyl (S)-2-formyl-2-methylpyrrolidine-l-carboxylate ί X-CHO N i Boc

Intermediate-4b was also prepared as per the procedure described for synthesis of Intermediate4a using 1-(tert-butyl) 2-methyl (S)-2-methylpyrrolidine-l,2-dicarboxylate.

Intermediate-5a: Préparation of tert-butyl butoxycarbonyl)sulfamoyl)vinyl)-2-methylpyrrolidine-l-carboxylate (R,E)-2-(2-(N-(tert-

To a solution of tert-butyl (((diphenylphosphoryl)methyl)sulfonyl)carbamate (153.0 gm, 387 mmol) in DMF (1530 mL) at 0°C was added NaH (60 % dispersion in minerai oil) (34 gm, 851 mmol).The reaction was allowed to warm to r.t. and stirred for 30 min. The aldéhyde (tert-butyl (R)-2-formyl-2-methylpyrrolidine-l-carboxylate) (83 gm, 387 mmol) in DMF (830mL) was added at dropwise at -20°C the reaction was warm to r.t. & stirred ovemight. The reaction was acidified using 50% aqueous citric acid (—500 mL) up to pH=2.0 the diluted with water (3000 mL) & extracted with EtOAc (2000 mL x 2).The combined organic layer was washed with water (2000 mL x 3), brine (1000 mL), dried over Na2SÛ4, concentrated & dried to give crude product. The residue was purified by column chromatography on silica gel using 25% EtOAC: n-Hexane, to | 10 obtain title compound (121g, 310 mmol, 80% yield).

Ή NMR (400 MHz, DMSO-J₆): δ = 11.35 (s, IH), 6.78 (d, J = 15.2 Hz, IH), 6.44 (d, J = 15.6 I Hz, IH), 3.42-3.36 (m,2H), 1.99- 1.92 (m, IH), 1.88 - 1.59 (m, 3H), 1.49 - 1.36 (m, 21H); MS (ESI): m/z (%) = 413.15 (90%) (M+Na), 389.15 (100%) (M-l).

’ Intermediate-5b: Préparation of tert-butyl (S,E)-2-(2-(N-(tert-butoxycarbonyl)sulfamoyl)vinyl)-

2-methylpyrrolidine-l-carboxylate

Ο Ο Ο i

S À

H

Boc

Intermediate-5b was also prepared as per the procedure described for synthesis of Intermediate5a using tert-butyl (S)-2-formyl-2-methylpyrrolidine-l-carboxylate.

Intermediate-6a: Préparation of tert-butyl (R,E)-2-methyl-2-(2-sulfamoylvmyl)pyrrolidine-lcarboxylate

O,,O I 'Boc

Intermediate 5a (121 g) was dissolved in DMSO (1200 mL) & heated to 85°C (disappearance of the starting material was monitored by TLC).The reaction was cooled, poured into water (3000mL) 25 & extracted with EtOAc (2000 mL x 4) & dried over Na2SO4.The solvent was concentrated in vacuo & purified by column chromatography on silica gel (50% EtOAc:n-Hexane) to give product (61.4 g, 211 mmol, 68.2 % yield).

’H NMR (400 MHz, DMSO-î/₆): δ = 6.98 (s, 2H), 6.61 - 6.49 (m, 1H), 6.25 (d, J = 15.2 Hz, 1H),

3.43 - 3.35 (m, 2H), 1.99 - 1.66 (m, 4H), 1.47 - 1.43 (m, 3H), 1.40 - 1.37 (m, 9H); MS (ESI):

m/z (%) = 289.13 (100%) (M-l).

| Intermediate-6b: Préparation of tert-butyl (S,E)-2-methyl-2-(2-sulfamoylvinyl)pyrrolidine5 1-carboxylate

0

V nh₂IVn_sBoc

Intermediate-6b was also prepared as per the procedure described for synthesis of Intermediate 6a using Intermediate-5b.

Intermediate-7a (Example 52): Préparation of tert-butyl (R,E)-2-(2-(N-((l,2,3,5,6,7-hexahydros-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)-2-methylpyrrolidine-l-carboxylate

x

H H Boc

To a solution ofthe tert-butyl (R, E)-2-methyl-2-(2-sulfamoylvinyl)pyrrolidine- 1-carboxylate (Intermediate 6a) (61.0 gm, 210 mmol) in DMF (610 mL) at 0°C was added NaH (60% dispersion in minerai oil) (10.08 gm, 252 mmol).The reaction was allowed to warm to r.t. and stirred for 30 minutes. 4-isocyanato-l,2,3,5,6,7-hexahydro-s-indacene (50.2 gm, 252 mmol) was added portion wise at 0°C the reaction was warm to r.t. & stirred overnight. The reaction was acidified at 0°C using 50% aq.citric acid up to pH=2.0 and diluted with cold water (3000 mL), precipitate was filtered through Buchner funnel & dried to give product (100 g, 204 mmol, 97 % yield).

Ή NMR (400 MHz, DMSO-*): δ = 10.41 (s, 1H), 8.06 (s, 1H), 6.96 (s, 1H), 6.87 - 6.77 (m, 1H), 6.55 (d, J= 15.2 Hz), 3.43 - 3.37 (m, 2H), 2.81 (t, J = 6.8 Hz, 4H), 2.67 (t, J= 6.8 Hz, 4H), 2.00 - 1.93 (m, 5H), 1.86 - 1.65 (m, 3H), 1.41 - 1.43 (m, 3H), 1.40 - 1.38 (s, 9H); MS (ESI): m/z (%) = 488.16 (100%) (M-l).

Intermediate-7b (Example 111): Préparation of tert-butyl (S,E)-2-(2-(N-((l,2,3,5,6,725 hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)-2-methylpyrrolidine-1 -carboxylate

I

I I I

I I

I I 1 I

I I I I I I I f

I I

ο ο 2

V< H H Boc

Intermediate-7b (Example 111) was also prepared as per the procedure described for synthesis of

Intermediate-7a using Intermediate-6b.

Intermediate-8: Préparation of (diphenylphosphoryl)methanesulfonamide CXp°°v° ^NH2 tert-butyl(((diphenylphosphoryl)methyl)sulfonyl)carbamate (Synthesis 2003, 15, 2321-24) (10.0 g, 25.3 mmol) was dissolved in DCM (100 mL) under N2 atm. It was cooled to 0 °C temp. and added TFA (19.48 mL, 253 mmol) dropwise, after the addition ice bath was removed and RM was stirred further for 4 h. TLC was checked no starting materiai observed. The R.M was concentrated under reduced pressure and added water (50 mL) solid was ppt out, it was filtered and washed with water (25 mLX2) and dried over P2O5 to yield, (diphenylphosphoryl)methanesulfonamide (7.3 g, 24.72 mmol, 98 % yield). Ή NMR (400 MHz, DMSO-di): δ = 7.86 - 7.81 (m, 4H), 7.61 - 7.51 (m, 6H), 6.84 (s, 2H), 4.63 (d, J= 9.2 Hz, 2H); MS (ESI): m/z (%) = 296.05 (100%) (M+H)⁺.

Intermediate-9: Préparation of l-(diphenylphosphoryl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)methanesulfonamide

(diphenylphosphoryl)methanesulfonamide [Intermediate 8] (6.0 g, 20.32 mmol) was taken in DMF (60 mL) under N2 atm. it was cooled to 0 °C temp. and NaH (1.170 g, 24.38 mmol) was added and RM was stirred for 30 min. at RT. then a solution of 4-isocyanato-1,2,3,5,6,7hexahydro-s-indacene (4.86 g, 24.38 mmol) in DMF ( 15 mL) was added and the RM was stirred further for 17 h at RT. TLC was checked no starting materiai observed. The reaction mixture was poured into ice cold water (180 mL ) and acidified with sat. Citric acid, stirred and filtered to give crude product. It was purified by triturating in ethyl acetate gives, l-(diphenylphosphoryl)-N((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)methanesulfonamide (9.1 g, 18.40 mmol, 91% yield).

’H NMR (400 MHz, DMSO-JJ: J = 10.4 (bs, IH), 8.14 (s, IH), 7.88 - 7.83 (m, 4H), 7.63 - 7.53 (m, 6H), 6.96 (s, IH), 4.99 (d, J= 8.8 Hz, 2H), 2.81 (t, J= 7.2 Hz, 4H), 2.71 (t, J = 7.2 Hz, 4H),

2.00 - 1.91 (m, 4H); MS (ESI): m/z (%) = 495.14 (100%) (M+H)⁺.

Intermediate-7b (Example 111): Préparation of tert-butyl (S,E)-2-(2-(N-((l,2,3,5,6,7hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)-2-methylpyrrolidine-l-carboxylate

O. .0 θ

N N H H

Boc

-(diphenylphosphoryl)-N-(( 1,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)methanesulfonamide [Intermediate 9] (0.5 g, 1.011 mmol) was dissolved in DMF (5 mL) under N2 atm. It was cooled to 0 °C and added NaH (0.089 g, 2.224 mmol) under N2 atm at 0 °C. After that ice bath was removed and RM was stirred at RT for 30 min. Then a solution of tert-butyl (S)-2-formyl-2-methylpyrrolidine-l-carboxylate (0.259 g, 1.213 mmol) in DMF (2.5 mï.) was added dropwise to above suspension at -20 °C. Then RM was warmed to RT & stirred further for 18 h. TLC was checked small amount of starting material observed. RM was diluted with water (15 ml,), aqueous layer it was acidified with citric acid solution solid ppt, it was filtered off and washed with water (15 mL), dried under on P2O5. Crude product was purified by column chromatography using 40 % EtOAc : Hexane to give tert-butyl (S,E)-2-(2-(N-((l,2,3,5,6,7hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)-2-methylpyrrolidine-l-carboxylate (0.125 g, 0.255 mmol, 25.3 % yield).

Intermediate-7a (Example 52) was also be prepared as per the procedure described for synthesis of Intermediate-7b (Example 111) using tert-butyl (R)-2-formyl-2-methylpyrrolidine-lcarboxylate.

Intermediate-3a (Example 10) was also be prepared as per the procedure described for synthesis of Intermediate-7b using tert-butyl (R)-2-formylpyrrolidine-l-carboxylate.

Intermediate-3b (Example 61) was also be prepared as per the procedure described for synthesis of Intermediate-7b using tert-butyl (S)-2-formylpyrrolidine-1 -carboxylate.

Intermediate-lOa: Préparation of tert-butyl 2-formylazetidine-l-carboxylate

I I

I I I

I 1 I

I I

To a solution of 1-(tert-butyl) 2-methyl azetidine-l,2-dicarboxylate (European Journal of Médicinal Chemistry, 2000, 35(11), 979-988; Journal of the American Chemical Society (2010), 132(40), 14027-14029) (4.26 gm, 19.79 mmol) in dry DCM (86 mL) to give a solution. DIBAL-H (26.4 mL of 1.5M in Toluene, 39.6 mmol) was added dropwise at -78°C. The reaction mixture was stirred at -78°C for 2 h then was quenched with methanol (5 mL) at -78°C température. The reaction mixture was acidified with 50 % citric acid solution up to pH=4.0. Water (100 mL) and DCM (50 mL) were added. The aqueous layer was extracted with DCM (2 X 80 mL).The combined organic layers was washed with water (150 mL), brine (10 mL), dried over Na₂SÛ4 and solvent was evaporated to give a product tert-butyl 2-formylazetidine-l-carboxylate (3.4 gm, 18.36 mmol, 93% yield).

Intermediate-lOb: Préparation of tert-butyl 2-formyl-2-methylazetidine-l-carboxylate

Intermediate-lOb was also prepared as per the procedure described for synthesis of Intermediate-lOa using 1-(tert-butyl) 2-methyl 2-methylazetidine-l,2-dicarboxylate.

Intermediate-1 la: Préparation of tert-butyl (E)-2-(2-(N-(tertbutoxycarbonyl)sulfamoyl)vinyl)azetidine-1 -carboxylate

To a solution of tert-butyl (((diphenylphosphoryl)methyl)sulfonyl)carbamate (6.0 gm, 15.17 mmol) in DMF (60 ml,) at 0°C was added NaH (60 % dispersion in minerai oil) (1.34 gm, 33.4 mmol).The reaction was allowed to warm to r.t. and stirred for 30 min. The tert-butyl 2formylazetidine-1-carboxylate (3.37 g, 18.21 mmol) in DMF (35 mL) was added at dropwise at 20°C the reaction was warm to r.t. & stirred overnight. The reaction was acidified using 50% aqueous citric acid (~10 mL) up to pH=2.0 the diluted with water (200 mL) & extracted with 35

EtOAc (100 mL x 3).The combined organic layer was washed with water (150 mL x 3), brine (80 mL), dried over Na₂SO4, concentrated & dried to give crude product. The residue was purified by column chromatography on silica gel using 30% EtOAC: n-Hexane to obtain tert-butyl (E)-2-(2(N-(tert-butoxycarbonyl)sulfamoyl)vinyl)azetidine-l-carboxylate (1.8 g, 4.97 mmol, 33% yield). ’H NMR (400 MHz, DMSO-î/₆): δ = 11.36 (s, 1H), 6.86 (d, J = 15.2 Hz, J = 5.6 Hz, 1H), 6.65 (d, J = 14.8 Hz, 1H), 4.88 - 4.83 (m, 1H), 3.84 - 3.72 (m, 2H), 2.46 - 2.40 (m, 1H), 2.02 - 1.96 (m, 1H), 1.44 (s, 9H), 1.41 (s, 9H); MS (TOF): m/z (%) = 385.2035 (100%) (M+Na), 361.1853 (100%) (M-l).

Intermediate-11: Préparation of tert-butyl (E)-2-(2-sulfamoylvinyl)azetidine-l-carboxylate tert-butyl

, _ZO %h₂

N.

Boc (E)-2-(2-(N-(tert-butoxycarbonyl)sulfamoyl)vinyl)azetidine-l-carboxylate (Intermediate lia) (1.8 g, 4.97 mmol) was dissolved in DMSO (18 mL) & heated to 85°C (disappearance of the starting material was monitored by TLC).The reaction was cooled, poured into water (90mL) & extracted with EtOAc (40 mL x 4) & dried over Na₂SO4.The solvent was concentrated in vacuo & purified by column chromatography on silica gel (60% EtOAc:n-Hexane) to give tert-butyl (E)-2(2-sulfamoylvinyl)azetidine-l-carboxylate (2.02 g, 3.74 mmol, 83% yield).

’H NMR (400 MHz, DMSO-Jô): δ = 7.06 (s, 2H), 6.62 - 6.57 (m, 1H), 6.49 (dd, J = 14.8 Hz, J = 1.2 Hz, 1H), 4.81-4.76 (m, 1H), 3.81 - 3.71 (m, 2H), 2.41 - 2.37 (m, 1H), 2.00 - 1.93 (m, 1H), 1.38 (s, 9H),; MS (TOF): m/z (%) = 285.1431 (100%) (M+Na), 261.1290 (100%) (M-l).

Intermediate-12a: Préparation of tert-butyl (E)-2-(2-(N-(tert-butoxycarbonyl)sulfamoyl)vinyl)2-methylazetidine-1 -carboxylate

O ⁰ I

N. ^H

Boc

To a solution of tert-butyl (((diphenylphosphoryl)methyl)sulfonyl)carbamate (4.5 gm, 11.38 mmol) in DMF (45 ml,) at 0°C was added NaH (60 % dispersion in minerai oil) (1.00 gm, 25.04 mmol). The reaction was allowed to warm to r.t. and stirred for 30 min. tert-butyl 2-formyl-236

methylazetidine-1 -carboxylate (Journal of Médicinal Chemistry, 2014, 57(23), 10044-10057) (2.72 gm, 13.66 mmol) in DMF (30 mL) was added at dropwise at -20°C the reaction was warm to r.t. & stirred overnight. The reaction was acidified using 50% aqueous citric acid up to pH=2.0 the diluted with water (100 mL) & extracted with EtOAc (80 mL x 3).The combined organic layer was washed with water (100 mL x 3), brine (50 mL), dried over Na2SÛ4, concentrated & dried to give crude product. The residue was purified by column chromatography on silica gel using 30% EtOAC: n-Hexane to tert-butyl (E)-2-(2-(N-(tert-butoxycarbonyl)sulfamoyl)vinyl)-2methylazetidine-1-carboxylate (3.73 g, 9.91 mmol, 87% yield). ’H NMR (400 MHz, DMSO-î/ô): δ = 11.39 (s, 1H), 6.94 - 6.88 (m, 1H), 6.63 - 6.56 (m, 1H), 3.75 - 3.71 (m, 1H), 3.66 - 3.63 (m, 1H), 2.21 - 2.11 (m, 2H), 1.44 - 1.41 (m, 9H), 1.38 - 136 (m, 9H); MS (ESI): m/z (%) = 399.20 (100%) (M+Na), 375.20 (100%) (M-l).

Intermediate-12: Préparation of tert-butyl (E)-2-methyl-2-(2-sulfamoylvinyl)azetidine-lcarboxylate

Ο_χΧ ,p

Boc tert-butyl(E)-2-(2-(N-(tert-butoxycarbonyl)sulfamoyl)vinyl)-2-methylazetidine-l-carboxylate (Intermediate-12a) (3.73 g, 9.91 mmol) was dissolved in DMSO (20 mL) & heated to 85°C (disappearance of the starting material was monitored by TLC).The reaction was cooled, poured into water (70 ml,) & extracted with EtOAc (30 mL x 4) & dried over Na2SO4.The solvent was concentrated in vacuo & purified by column chromatography on silica gel (60% EtOAc :n-Hexane) to give tert-butyl (E)-2-methyl-2-(2-sulfamoylvinyl)azetidine-l-carboxylate (2.52 g, 9.12 mmol, 92% yield).

’H NMR (400 MHz, DMSO-Jd: δ = 7.06 (s, 2H), 6.68 - 6.61 (m, 1H), 6.46 - 6.40 (m, 1H), 3.82 - 3.60 (m, 2H), 2.19 - 1.99 (m, 2H), 1.50 (m, 3H), 1.39 - 1.37 (m, 9H); MS (ESI): m/z (%) = 299.10 (100%) (M+Na), 275.05 (100%) (M-l).

Example-1 (R,E)-2-(l-ethylpyrrolidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethanesulfonamide

To solution of Intermediate 3 a (1 eq.) in DCM (2.5 mL) added TFA (1 eq.) at 0°C.The reaction Iwas warmed to r.t. & stirred further for 3h. The reaction mixture was concentrated in vacuo & purified by prep. HPLC to give product. To a solution of this product (1 eq.) in MeOH (7.0 mL) Iwas added NaHCO₃ (1.2 eq.) at r.t. & stirred for 5 min. Acetaldehyde (5 eq.) was added at r.t. and 5 stirred for 2h. Thereafter reaction mixture was treated with NaBH₄ (1.5 eq.) portion wise at 0°C then reaction mixture was allowed to warm to r.t. stirred ovemight. The reaction mixture was purified by prep. HPLC to give pure product (Example 1).

| Altematively: To a solution of Intermediate 3 (1 eq.) in DCM (2.5 mL) added TFA (1 eq.) at 0°C.

The reaction was warmed to r.t. & stirred further for 3h. The reaction mixture was concentrated in | 10 vacuo & purified by prep. HPLC to give product. To a solution of this product (1 eq.) in dry THF (5.0 mL) was added NaH (1.2 eq.) at 0 °C & stirred for 5 min. Ethyl bromide (1.6 eq.) was added | and stirred for 14 h at r.t. The reaction mixture was purified by prep. HPLC to give pure product (Example 1).

I

Altematively: To a solution of (R,E)-tert-butyl 2-(2-(N-(tert-butoxycarbonyl)sulfamoyl) 15 vinyl)pyrrolidine-l-carboxylate (3.4 g, 9.04 mmol) in DCM was added trifluoro acetic acid (15.3 mL) and stirred for 1 h at room température. DCM was distilled and excess of trimethylamine (5.23 g, 7.2 mL, 53.1 mmol) was added to the reaction mixture at 0 °C, followed by addition of ethyl bromide (1.35 g, 0.926 mL, 12.74 mmol). Crude mixture afforded (R,E)-2-(l-ethylpyrrolidin-2| yl)ethene-l-sulfonamide. To a solution of (R,E)-2-(l-ethylpyrrolidin-2-yl)ethene-l -sulfonamide (2.11 g, 10.33 mmol) in DMF (50 mL) under Nitrogen atmosphère conditions was added sodium | hydride (60% in minerai oil) (0.5 g, 12.39 mmol) in one portion. The resulted suspension was stirred further for 1 h atroom température. Further 4-isocyanato-l,2,3,5,6,7-hexahydro-s-indacene | (2 g, 10.05 mmol) was added and reaction mixture (RM) was stirred rt for 16 h. The reaction mixture was concentrated under reduced pressure, and acidified with citric acid. Crude product | 25 was purified by préparative HPLC to give pure product (Example 1).

_ Ή NMR (400 MHz, DMSO-Jé): d = 8.03 (s, 1H), 6.92 (s, 1H), 6.87 (d, J=14.8Hz, 1H), 6.60 6.54 (m, 1H), 3.27-3.16 (m, 3H), 2.80 (t, J=7.2Hz, 4H), 2.67 (t, >7.2Hz, 4H), 2.35-2.33 (m, 2H),

- 2.09-1.94 (m, 6H), 1.81-1.73 (m, 2H), 1.03 (t, J=7.2Hz, 3H); MS (ESI): m/z (%) = 404.20 (100%) (M+H)⁺.

| 30

Using appropriate starting materials and suitable modifications of the process described in | example 1, including suitable addition and/or délétion of steps as may be necessary which are well

I 38 within the scope of a person skilled in the art, the following compounds were prepared in an analogues manner.

Example-2 (S,E)-2-(l-ethylpyrrolidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethanesulfonamide

I

I I

I

I I ’H NMR (400 MHz, DMSO4): δ = 8.03 (s, 1H), 6.92 (s, 1H), 6.87 (d, J=14.8Hz, 1H), 6.606.54 (m, 1H), 3.27-3.16 (m, 3H), 2.80 (t, J=7.2Hz, 4H), 2.67 (t, J=7.2Hz, 4H), 2.35-2.33 (m, 2H), 2.09-1.94(m, 6H), 1.81-1.73 (m, 2H), 1.03 (t, J=7.2Hz, 3H); MS (ESI): m/z (%) = 404.20 (100%) (M+H)⁺.

Example-3 (R,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(pyrrolidin-2-yl)ethene-l sulfonamide

’H NMR (400 MHz, DMSO-î/₆): δ = 9.71 (brs, 1H), 7.49 (s, 1H), 6.95 (d, J= 15.2 Hz, 1H), 6.80 (s, 1H), 6.36 (dd, J=7.2Hz, J= 15.2 Hz, 1H), 4.08-4.02 (m, 1H), 3.18 - 3.03 (m, 2H), 2.77 (t, J= 7.2 Hz, 4H), 2.70 (t, J= Ί2 Hz, 4H), 2.14-2.07 (m, 4H), 2.03 - 1.80 (m, 6H), 1.70 - 1.60 (m, 1H); MS (ESI): m/z (%) = 376.10 (100%) (M+H)⁺, 374.05 (100%) (M-l).

Example-4 (R,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l-propyIpyrrolidin-2yl)ethene-l-sulfonamide

I I

I

I I

I

1¹⁰

I

I ⁵

I

Ή NMR (400 MHz, DMSO-î/₆): δ = 8.00 (s, IH), 6.93 (s, IH), 6.84 (d, J = 14.8 Hz, IH), 6.58 (dd, J = 7.6 Hz, J = 15.2 Hz, IH), 3.15 (s, IH), 2.80 (t, J = 7.2 Hz, 4H), 2.67 (t, J = 7.2 Hz, 4H), 2.33 - 2.22 (m, 2H), 2.09 - 1.91 (m, 6H), 1.78 - 1.73 (m, 2H), 1.62 - 1.50 (m, IH), 1.46 - 1.33 (m, 2H), 0.82 (t, J= 7.2 Hz, 3H); MS (ESI): m/z (%) = 418.22 (100%) (M+H)⁺.

Example-5 (R,E)-2-(l-(cyclopropylmethyl)pyrrolidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)ethene-l-sulfonamide

Ή NMR (400 MHz, DMSO4): δ = 10.42 (brs, IH), 8.03 (s, IH), 6.93 (s, IH), 6.87 (d, J= 15.2 Hz, IH), 6.62 (dd, J= 7.2 Hz, J= 15.2 Hz, IH), 3.38 - 3.22 (m, 3H), 2.80 (t, J= 7.2 Hz, 4H), 2.67 (t, J=7.2 Hz, 4H), 2.60-2.57 (m, IH), 2.30-2.05 (m, IH), 2.04 - 1.91 (m, 5H), 1.87-1.71 (m, 2H), 1.70 - 1.50 (m, IH), 0.91 - 0.67 (m, IH), 0.53 - 0.35 (m, 2H), 0.18 - 0.09 (m, 2H); MS (ESI): m/z (%) = 430.20 (100%) (M+H)⁺, 428.11 (100%) (M-l).

Example-6 (R,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l-methylpyrrolidin-2yl)ethene-l-sulfonamide

To solution of Intermediate 3a (1 eq.) in DCM (2.5 mL) added TFA (1 eq.) at 0°C.The reaction was warmed to r.t. & stirred further for 3h. The reaction mixture was concentrated in vacuo & 20 purified by prep. HPLC to give product. To a solution of this product (1 eq.) in MeOH (7.0 mL) at r.t. was added Solid NaHCOs (1.2 eq.) & stirred for 5 min. Formaldéhyde (37% solution) (5 eq.) was added at r.t. and stirred for 2 h. Thereafter reaction mixture was treated with NaBH4 (1.5 eq.) portion wise at 0°C then reaction mixture was allowed to warm to r.t. stirred overnight. The reaction mixture was purified by prep. HPLC to give pure product.

Altemateviely, Example 6 was also be prepared as per the procedure described for synthesis of Intermediate-7b (Example 111) using Intermediate 9 and (R)-l-methylpyrrolidine-2-

I

I ® 10

I I

I

I ¹⁵

I

J 20

I

I carbaldehyde, together with conventional techniques known to those skilled in the art of organic synthesis.

’H NMR (400 MHz, DMSO-Jô): δ = 10.53 (brs, IH), 7.97 (s, IH), 6.92 (s, IH), 6.84 (d, J= 15.2 Hz, IH), 6.53 (dd, J = Ί.6 Hz, J = 15.2 Hz, IH), 3.13 - 3.04 (m, IH), 3.05 - 2.92 (m, IH), 2.80 (t, J= 7.2 Hz, 4H), 2.67 (t, J= 7.2 Hz, 4H), 2.33 - 2.28 (m, IH), 2.26 (s, 3H), 2.05 - 1.91 (m, 5H), 1.79 - 1.72 (m, 2H), 1.59 - 1.54 (m, IH); MS (ESI): m/z (%) = 390.17 (100%) (M+H)⁺, 388.07 (30%) (M-l).

Example-7 (R,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l-(methylsuIfonyl)pyrrolidin-2-yl)ethene-l-sulfonamide

’H NMR (400 MHz, DMSO-d₆): δ = 10.55 (bs, IH), 8.06 (s, IH), 6.94 (s, IH), 6.79 - 6.69 (m, 2H), 4.50 - 4.47 (m, IH), 3.34 - 3.33 (m, IH), 2.94 (s, 3H), 2.80 (t, J= 7.2 Hz, 4H), 2.68 (t, J = 7.6 Hz, 4H), 2.11-2.07 (m, 2H), 1.95 (quin, J= 7.6 Hz, 4H), 1.88- 1.85 (m, IH), 1.80- 1.79 (m, 2H); MS (ESI): m/z (%) = 454.17 (100%) (M+H)⁺.

Example-8 (R,E)-2-(l-acetyIpyrrolidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yI)carbamoyl)ethene-l-sulfonamide

*H NMR (400 MHz, DMSO-*): <5 = 10.25 (bs, IH), 8.07 (s, IH), 6.95 (s, IH), 6.73 - 6.67 (m, IH), 6.63 (d, J= 15.2 Hz, IH), 4.69 - 4.62 (m, IH), 3.55 - 3.42 (m, IH), 2.83 (t, J= 7.2 Hz, 4H), 2.69 (q, J= 7.2 Hz, 4H), 2.21 - 2.09 (m, IH), 2.01 - 1.95 (m, 6H), 1.85 (s, 3H), 1.82 - 1.72 (m, 2H); MS (ESI): m/z (%) = 418.20 (100%) (M+H)⁺.

Example-9 (E)-2-(l-benzylpiperidin-4-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethanesulfonamide

Ή NMR (400 MHz, DMSO-//₆): δ = 10.23 (br s, 1H), 8.02 (s, 1H), 7.35 - 7.25 (s, 5H), 6.94 (s, 5 1H), 6.76 - 6.63 (m, 2H), 3.55 (s, 2H), 2.89 - 2.69 (m, 6H), 2.65 (t, J = 7.2 Hz, 4H), 2.30 - 2.27 (m, 1H), 2.12 - 2.07 (m, 2H), 2.00 - 1.91 (m, 4H), 1.71 - 1.69 (m, 2H), 1.43 - 1.38 (m, 2H); MS (ESI): m/z (%) = 480.23 (100%) (M+H)⁺.

Example-10 tert-butyl (R,E)-2-(2-(N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)10 vinyl)pyrrolidine-l -carboxylate

N „ i Boc

1H NMR (400 MHz, DMSO-d6): δ = 10.42 (s, 1H), 8.09 (s, 1H), 6.96 (s, 1H), 6.71 - 6.68 (m, 1H), 6.59 (d, J = 14.8 Hz, 1H), 4.45 - 4.38 (m, 1H), 3.29 - 3.27 (m, 2H), 2.79 (t, J = 7.2 Hz, 4H), 15 2.65 (t, J = 7.2 Hz, 4H), 2.30- 1.93 (m, 5H), 1.78-1.71 (m, 3H), 1.39- 1.33 (m, 9H); MS (ESI):

m/z (%) = 498.18 (40%) (M+Na)+, 474.18 (100%) (M-l).

Example-11 (R,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l-(220 methoxyethyl)pyrrolidin-2-yl)ethenesulfonamide

1H NMR (400 MHz, DMSO-d6): δ = 7.38 (s, 1H), 6.77 (s, 1H), 6.67 (d, J = 15.2 Hz, 1H), 6.04 (dd, Jl = 8.0 Hz, J2 = 15.2 Hz, 1H), 3.37 (t, J = 6.0 Hz, 2H), 3.37 (s, 3H), 3.13 - 3.10 (m, 1H),

I

2.82-2.74 (m, 6H), 2.69 (t, J = 7.2 Hz, 4H), 2.22 - 2.13 (m, 2H), 1.95 - 1.93 (m, 5H), 1.76 - 1.67 (m, 2H), 1.48 - 1.41 (m, IH); MS (ESI): m/z (%) = 434.19 (100%) (M+H)+.

Example-12

(R,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l(isopropylsulfonyl)pyrrolidin-2-yl)ethenesulfonamide ’H NMR (400 MHz, DMSO-Jé): δ = 7.34 (s, IH), 6.77 (s, IH), 6.67 (d, J = 15.2 Hz, IH), 6.20 6.19 (m, IH), 4.39 (bs, IH), 3.46 (q, J= 9.6 Hz, IH), 3.29 - 3.24 (m, 2H), 2.76 (t, J= 7.2 Hz, 4H), 2.70 (t, J = 7.2 Hz, 4H), 2.09 - 2.04 (m, IH), 1.93 (t, J= 7.2 Hz, 4H), 1.87 (t, J= 8.4 Hz, 4H), 1.73 - 1.69 (m, IH), 1.19 (d, J= 6.4 Hz, 6H); MS (ESI): m/z (%) = 482.13 (65%) (M+H)⁺, 504.10 (100%) (M+Na)⁺;

Example-13 (R,E)-2-(l-((3-fluorophenyl)sulfonyl)pyrrolidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen4-yl)carbamoyl)ethenesulfonamide

’H NMR (400 MHz, DMSO-ri₆): δ = 10.46 (s, IH), 8.07 (s, IH), 7.71 - 7.70 (m, 3H), 7.62 - 7.58 (m, IH), 6.95 (s, IH), 6.90 (d, J= 14.8 Hz, IH), 6.74 (dd, Ji = 5.6 Hz, J₂ = 15.2 Hz IH), 4.49 (t, J = 5.6 Hz, IH), 3.42 - 3.38 (m, IH), 3.18 - 3.14 (m, IH), 2.80 (t, J= 7.6 Hz, 4H), 2.69 (t, J= 7.2 Hz, 4H), 1.96 (qum, ./=7.2 Hz, 4H), 1.76-1.60 (m, 3H), 1.55- 1.52 (m, IH); MS (ESI):m/z(%) = 534.18 (100%) (M+H)⁺;

Example-14 (R,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l-(pyrazine-2carbonyl)pyrrolidin-2-yl)ethenesulfonamide

Ή NMR (400 MHz, DMSO-îZ₆): δ = 10.46 (s, 1H), 8.95 - 8.88 (m, 1H), 8.78 - 8.65 (m, 1H), 8.70

- 8.57 (m, 1H), 8.04 (s, 1H), 6.93 (s, 1H), 6.76 (d, J= 15.6 Hz, 1H), 6.95 (d, J = 15.2 Hz, 1H),

4.93-4.90 (m, 1H), 3.84 - 3.81 (m, 1H), 3.66 - 3.59 (m, 1H), 2.82 (t,J=8.0 Hz, 4H), 2.66 fi J = 7.6 Hz, 4H), 2.16 - 1.97 (m, 1H), 1.95 - 1.78 (m, 7H); MS (ESI): m/z (%) = 482.16 (100%) (M+H)⁺.

I I

I I I I

I I I

I I

I I 1

Example-15 (R,E)-2-(2-(N-((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)sulfamoyl)vinyl)pyrrolidine-l-carboxamide

’H NMR (400 MHz, DMSO-^): δ = 7.95 (s, 1H), 6.91 (s, 1H, 6.58 - 6.52 (m, 2H), 5.77 (s, 2H), 4.51 -4.48 (m, 1H), 3.25-3.21 (m, 1H), 2.80 (t, J =1.2 Hz, 4H), 2.68 fi J=6.8 Hz, 4H), 2.001.91 (m, 6H), 1.81-1.69 (m, 3H); MS (ESI): m/z (%) = 419.16 (100%) (M+H)⁺.

Example-16 (R,E)-2-(l-(cyclopropanecarbonyl)pyrrolidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)ethene-l-sulfonamide

’H NMR (400 MHz, DMSO-<&): δ = 10.45 (s, 1H), 8.11 (d, J= 14.4 Hz, 1H), 6.96 (s, 1H), 6.87 6.52 (m, 2H), 4.97-4.65 (m, 1H), 3.76 - 3.61 (m, 1H), 3.41 - 3.32 (m, 1H), 2.81 (t, J = 12 Hz, 4H), 2.67 (q, J= 6.0 Hz, 4H), 2.17 -2.16 (m, 1H), 2.02 - 1.95 (m, 5H), 1.88 - 1.74 (m, 3H), 1.76 - 0.69 (m, 2H), 0.66 - 0.59 (m, 2H); MS (ESI): m/z (%) = 444.15 (100%) (M+H)⁺.

Example-17 (R,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l-(2,2,2trifluoroacetyl)pyrrolidin-2-yl)ethene-l-sulfonamide

<o O

A

J g NN °^Acf_s ^{0 HH} ’H NMR (400 MHz, DMS0U₆): δ = 10.45 (s, 1H), 8.03 (s, 1H), 6.94 (s, 1H), 6.76 - 6.67 (m, 2H), 4.80 (bs, 1H), 3.75 (bs, 1H), 3.67 - 3.54 (m, 1H), 2.80 (t, J= 7.6 Hz, 4H), 2.67 (t, J= 6.4 Hz, 4H), 2.15-2.5 (m, 1H), 2.00 - 1.91 (m, 6H), 1.81 - 1.76 (m, 1H); MS (ESI): m/z (%) = 472.14 (100%) (Μ-Η)λ

Example-18 (R,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l-(2(methylthio)ethyl)pyrrolidin-2-yl)ethene-l-sulfonamide

Ή NMR (400 MHz, DMSO-^): δ = 10.38 (s, 1H), 8.06 (s, 1H), 6.95 (s, 1H), 6.91 (d, J= 14.8 Hz, 1H), 6.68 (d, J= 15.2 Hz, 1H), 3.21 - 3.12 (m, 2H), 2.81 (t, J= 7.2 Hz, 5H), 2.68 (t, J = 7.2 Hz, 5H), 2.46-2.40 (m, 1H), 2.33 -2.24 (m, 1H), 2.09 - 1.91 (m, 9H), 1.74 - 1. 70 (m, 2H), 1.54 1.49 (m, 1H); MS (ESI): m/z (%) = 450.14 (100%) (M+H)⁺.

Example-19 (R,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l-(2,2,2trifluoroethyl)pyrrolidin-2-yl)ethene-l-sulfonamide '' N N cf₃ ° ^{H H} ,Ο θ

’H NMR (400 MHz, DMSOUe): δ = 7.91 (s, 1H), 6.88 (s, 1H), 6.76 (d, J = 15.2 Hz, 1H), 6.41 (dd, Ji = 7.2 Hz, J₂, 14.8, 1H), 3.34 - 3.21 (m, 1H), 3.16 - 3.09 (m, 2H), 2.78 (t, J= 7.2 Hz, 4H), 2.67 (t,J=7.2 Hz, 4H), 2.59-2.54 (m, 1H), 2.02 - 1.91 (m, 6H), 1.80-1.75 (m, 2H), 1.57-1.48 (m, 1H); MS (ESI): m/z (%) = 458.15 (100%) (M+H)⁺.

I

Example-20 (R,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l-isobutylpyrrolidin-2yl)ethene-l-sulfonamide

Ή NMR (400 MHz, DMSO-J₆): δ = 10.4 (brs, IH), 8.00 (s, IH), 6.92 (s, IH), 6.80 (d, J= 15.2 Hz, IH), 6.56 (dd, J= 15.2 Hz , J = 6.8 Hz, IH), 3.12 - 3.00 (m, 3H), 2.80 (t, J= 7.2 Hz, 4H), 2.68 (t, J= 7.2 Hz, 4H), 2.25 - 2.14 (m, 2H), 2.10- 2.04 (m, 2H), 1.99 - 1.91 (m, 4H), 1.76 - 1.65 (m, 2H), 1.55 - 1.48 (m, IH), 0.85 (t, J= 6.8 Hz, 3H), 0.79 (d, J= 6.4 Hz, 3H); MS (ESI): m/z (%) = 432.21 (100%) (M+H)⁺.

Example-21 (R,E)-2-(l-(ethylsulfonyl)pyrrolidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)ethene-l-sulfonamide

Ή NMR (400 MHz, DMSO-î/₆): δ = 10.39 (brs, IH), 8.01 (s, IH), 7.38 (s, IH), 6.77 (d, J= 15.2 15 Hz, IH), 6.68 (dd, J= 15.2 Hz, J= 5.2 Hz, IH), 4.63 - 4.39 (m, IH), 3.38 - 3.33 (m, 2H), 3.09 2.97 (m, 2H), 2.80 (t, J= 7.2 Hz, 4H), 2.68 (t, J= 7.2 Hz, 4H), 2.15 - 2.04 (m, IH), 2.00 - 1.91 (m, 4H), 1.88 - 1.77 (m, 3H), 1.19 (t, J = 7.2 Hz, 3H); MS (ESI): m/z (%) = 468.12 (100%) (M+H)⁺.

Example-22 (R,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l-isopropyIpyrrolidin-2yl)ethene-l-sulfonamide

I

I ’H NMR (400 MHz, DMSO-î/₆): δ = 10.23 (brs, 1H), 7.96 (s, 1H), 6.92 (s, 1H), 6.89 (d, J= 15.2

Hz, 1H), 6.61 (d, J= 15.2 Hz, J= Ί2 Hz, 1H), 2.98 - 2.85 (m, 2H), 2.80 (t, J= 7.2 Hz, 4H), 2.67 (t, J=72 Hz, 4H), 2.51 -2.50(m, 1H), 2.02-1.91 (m, 6H), 1.75- 1.73 (m, 2H), 1.61 - 1.56 (m,

1H), 1.04 (d, J = 6.4 Hz, 3H), 0.99 (d, J = 6.4 Hz, 3H); MS (ESI): m/z (%) = 418.21 (100%) (M+H)⁺, 416.18 (100%) (M-l).

Example-23 (R,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l-(3(methylsulfonyl)propyl)pyrrolidin-2-yl)ethenesulfonamide

’H NMR (400 MHz, DMSO-rfi): δ = 10.37 (brs, 1H), 8.08 (s, 1H), 6.95 (s, 1H), 6.82 (d, J= 14.8 Hz, 1H), 6.61 (d, J= 14.8 Hz, J= 7.2 Hz, 1H), 3.13 - 3.06 (m, 3H), 2.98 - 2.91 (m, 1H), 2.86 (s, 3H), 2.67 (t, J= 7.2 Hz, 4H), 2.81 (t, J= 7.2 Hz, 4H), 2.33 - 2.28 (m, 1H), 2.27 - 2.20 (m, 1H), 2.03-1.91 (m, 6H), 1.83-1.72 (m, 4H), 1.57-1.50 (m, 1H); MS (ESI): m/z (%) = 496.16(100%) (M+H)⁺, 494.15 (100%) (M-l).

Example-24 (R,E)-2-(l-benzoylpyrrolidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)ethenesulfonamide

’H NMR (400 MHz, DMSO-ώί): δ = 10.41 (brs, 1H), 8.03 (s, 1H), 7.54 - 7.30 (m, 5H), 6.93 (s, 1H), 6.80 - 6.50 (m, 2H), 4.85 - 4.49 (m, 1H), 3.62 - 3.36 (m, 2H), 2.78 (t, J= 6.8 Hz, 4H), 2.66 (t, J= 6.8 Hz, 4H), 2.19-2.08 (m, 1H), 1.94 - 1.90 (m, 4H), 1.82 - 1.76 (m, 3H); MS (ESI): m/z (%) = 480.17 (100%) (M+H)⁺, 478.15 (100%) (M-l).

Example-25 (R,E)-N-((2-(l-benzoylpyrrolidin-2-yl)vinyl)sulfonyl)-N-((l,2,3,5,6,7-hexahydro-s-indacen4-yl)carbamoyl)benzamide ’H NMR (400 MHz, DMSO-î/₆): δ = 7.61 - 7.52 (m, 2H), 7.47 - 7.32 (m, 8H), 7.22- 7.09 (m,

1H), 6.97 (s, 1H), 6.56 (d, J = 14.4 Hz, 1H), 6.31 (d,J= 14.4 Hz, 1H), 4.76-4.37 (m, 1H), 3.783.42 (m, 1H), 2.84-2.67 (m, 8H), 2.10-2.05 (m, 1H), 1.95-1.91 (m, 4H), 1.84- 1.76 (m, 3H),

1.68 - 1.64 (m, 1H); MS (ESI): m/z (%) = 584.19 (100%) (M+H)⁺, 606.17(50%) (M+Na), 582.17 (10%) (M-l).

Example-26 (R,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(pyrrolidin-2yl)ethenesulfonamide

.0 ο

A N N ° H H

’H NMR (400 MHz, DMSO4): δ = 7.54 (s, 1H), 6.81 (s, 1H), 6.70 (d, J= 15.2 Hz, 1H), 6.33 6.26 (m, 1H), 3.53 - 3.46 (m, 2H), 3.15 - 3.00 (m, 3H), 2.77 (t, J = 7.2 Hz, 4H), 2.70 (t, J = Ί2 Hz, 4H), 2.03 - 1.81 (m, 7H), 1.62 - 1.43 (m, 1H); MS (ESI): m/z (%) = 390.16 (100%) (M+H)⁺, 388.14(100%) (M-l).

Example-27 (R,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l-(thiophene-3carbonyl)pyrrolidin-2-yl)ethenesulfonamide

’H NMR (400 MHz, DMSO-rf_é): δ = 10.36 (brs, 1H), 8.01 (s, 1H), 7.58 - 7.48 (m, 1H), 7.36 7.22 (m, 1H), 6.93 (s, 1H), 6.81 - 6.56 (m, 2H), 4.83 - 4.74 (m, 1H), 3.78 - 3.67 (m, 1H), 3.66 48

3.52 (m, IH), 2.79 (t, J= 7.2 Hz, 4H), 2.66 (t, J = 6.8 Hz, 4H), 2.15 - 1.76 (m, 8H); MS (ESI):

m/z (%) = 486.13 (100%) (M+H)⁺, 484.11 (100%) (M-l).

Example-28 (R,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(pyrrolidin-2-yl)ethene-l5 sulfonamide methane sulfonate

Procedure: To solution of (R,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2(pyrrolidin-2-yl)ethene-l -sulfonamide (0.105 g, 0.28 mmol) in EtOH (2.0 mL) was added Methanesulfonic acid (27 mg, 0.280 mmol) at r.t. The reaction was refluxed for Ih then cooled 10 to r.t. precipitate was formed, then filtered through Buchner funnel, dried in vacuo to give product.

’H NMR (400 MHz, DMSO-</₆): δ = 10.59 (brs, IH), 9.05 (brs, 2H), 8.27 (s, IH), 7.13 (d, J = 15.2 Hz, IH), 6.97 (s, IH), 6.90 - 6.85 (m, IH), 4.32 - 4.30 (m, IH), 3.32 - 3.12 (m, 2H), 3.993.78 (m, 4H), 3.75 -3.66 (m, 4H), 2.37 (s, IH), 2.28-2.12 (m, IH), 2.10-1.88 (m, 6H), 1.27 1.22(m, IH); MS (ESI): m/z (%) = 376.10 (100%) (M+H)⁺.

Example-29 (R,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(pyrrolidin-2-yI)ethene-lsulfonamide maleate

Procedure: - To solution of (R,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-220 (pyrrolidin-2-yl)ethene-l-sulfonamide (0.2 g, 0.533 mmol) in EtOH (4.0 mL) was added Maleic acid (0.124 g, 1.07 mmol) at r.t. The reaction was refluxed for 30 min. then cooled to r.t. precipitate was formed, then filtered through Buchner funnel, dried in vacuo to give product.

I I

I

I I I I ’H NMR (400 MHz, DMSO-</₆): δ = 9.06 (brs, IH), 8.15 (s, IH), 7.12 (d, J= 15.6 Hz, IH), 6.96 (s, IH), 6.87 - 6.82 (m, IH), 6.03 (s, 2H), 4.29- 4.03 (m, 4H), 3.57 - 3.23 (m, 2H), 2.98 - 2.83 (m, 4H), 2.85 - 2.69 (m, 4H), 2.26 - 2.10 (m, IH), 2.09- 1.83 (m, 6H), 1.82- 1.63 (m, IH); MS (ESI): m/z (%) = 376.15 (100%) (M+H)⁺.

Exampie-30 (R,Z)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(pyrrolidin-2-yl)ethene-lsulfonamide

’H NMR (400 MHz, DMSO-î/₆): δ = 9.70 (brs, IH), 7.94 (s, IH), 6.83 (s, IH), 6.36 (dd, J= 11.6 10 Hz, J= 1.6 Hz, IH), 5.82 (dd, J= 11.2 Hz, J= 6.0 Hz, IH), 4.95 - 4.94 (m, IH), 3.17 - 3.03 (m, IH), 2.99-2.89 (m, IH), 2.79-2.63 (m, 9H), 2.03 - 1.76 (m, 8H); MS (ESI): m/z (%) = 376.16 (60%) (M+H)⁺.

• 15 Example-31

I(S,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-(pyrrolidin-2-yl)prop-l-ene1-sulfonamide >ex ο or' ii « iiL II

B V-NH Ο h H V—/ | Procedure: - To solution of corresponding N-Boc dérivatives (0.20 g, 0.408 mmol) in DCM (2.5 mL) added TFA (0.315 mL, 4.08 mmol) at 0°C. The reaction was warmed to r.t. & stirred further | for 3h. The reaction mixture was concentrated in vacuo & purified by prep. HPLC to give product.

a ’H NMR (400 MHz, DMSO-rf₆): δ = 7.54 (s, IH), 6.80 (s, IH), 6.69 (d, J= 15.2 Hz, IH), 6.29 -

6.25 (m, IH), 3.52 - 3.44 (m, 2H), 3.17 - 3.02 (m, 3H), 2.77 (t, J = 7.2 Hz, 4H), 2.70 (t, J = 7.2 g Hz, 4H), 2.01 - 1.76 (m, 8H), 1.53 - 1.50 (m, IH); MS (ESI): m/z (%) = 390.16 (100%) (M+H)T

Example-32 | 50 (R,E)-2-(l-(cycIohexylsulfonyl)pyrrolidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)ethene-l-sulfonamide

Ή NMR (400 MHz, DMSO-^): δ = 10.4 (brs, 1H), 8.04 (s, 1H), 6.94 (s, 1H), 6.78 (d, J = 15.2 Hz, 1H), 6.69 (dd, J= 15.2 Hz, J = 6.0 Hz, 1H), 4.57 - 4.53 (m, 1H), 3.45 - 3.39 (m, 1H), 3.31 3.27 (m, 1H), 3.14 - 3.08 (m, 1H), 2.80 (t, J= 7.2 Hz, 4H), 2.68 (t, J= 7.2 Hz, 4H), 2.17 - 2.09 (m, 1H), 2.00 - 1.91 (m, 5H), 1.88 - 1.60 (m, 5H), 1.55 - 1.52 (m, 1H), 1.40- 1.00 (m, 6H); MS (ESI): m/z (%) = 522.20 (100%) (M+H)⁺, 544.25 (100%) (M+Na), 520.15 (100%) (M-l).

Example-33 (R,Z)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l-methylpyrrolidiii-2yl)ethene-l-sulfonamide

N h₃c

Ή NMR (400 MHz, DMSO4): δ = 7.85 (s, 1H), 6.84 (s, 1H), 6.52 (dd,J= 11.2 Hz, J= 1.2 Hz, 1H), 5.84 (dd, J= 11.2 Hz, J= 8.0 Hz, 1H), 4.54-4.53 (m, 1H), 3.24-3.18 (m, 2H), 2.77 (t, J = 7.2 Hz, 4H), 2.70 (t, J= 7.2 Hz, 4H), 2.56 (s, 3H), 2.33-2.18 (m, 1H), 1.99-1.91 (m, 8H), 1.85 - 1.70 (m, 1H); MS (ESI): m/z (%) = 390.20 (100%) (M+H)⁺,388 (100%) (M-l).

Example-34 (R,E)-2-(l-(cyclohexylmethyl)pyrrolidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)ethene-l-sulfonamide

I I

I I I

I I

I I 1

I I

I | 20

I

Ή NMR (400 MHz, DMS(W δ = 10.38 (brs, 1H), 8.06 (s, 1H), 6.94 (s, 1H), 6.82 (d, J = 14.8 Hz, 1H), 6.62 (dd, J= 15.2 Hz, J= 6.8 Hz, 1H), 3.00 - 3.17 (m, 2H), 2.80 (t, J= 7.2 Hz, 4H), 2.68 (t, J= 7.2 Hz, 4H), 2.40 - 2.28 (m, 1H), 2.26 - 2.13 (m, 1H), 2.12- 1.90 (m, 6H), 1.89 - 1.82 (m, 1H), 1.81-1.67 (m, 2H), 1.66 - 1.47 (m, 5H), 1.45- 1.30 (m, 1H), 1.28 - 0.92 (m, 3H), 0.78 0.69 (m, 2H); MS (ESI): m/z (%) - 472.29 (100%) (M+H)⁺.

Example-35 (R,E)-2-(l-cyclohexylpyrrolidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)ethene-l-sulfonamide

Ή NMR (400 MHz, DMSO-J₆): δ = 10.38 (brs, 1H), 8.01 (s, 1H), 6.92 (s, 1H), 6.85 (d, J= 15.2 Hz, 1H), 6.65 (dd, J = 14.4 Hz, J= 6.4 Hz, 1H), 3.90 - 3.62 (m, 1H), 3.09 - 2.96 (m, 1H), 2.80 (t, J = Ί 2 Hz, 4H), 2.70 - 2.67 (m, 5H), 1.99 - 1.91 (m, 6H), 1.83 - 1.63 (m, 7H), 1.58 - 1.50 (m, 1H), 1.27- 1.02 (m, 5H); MS (ESI): m/z (%) = 458.29 (100%) (M+H)⁺.

Example-36 (R,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l-(l-methylpiperidin-4yl)pyrrolidin-2-yl)ethene-l-sulfonamide

Ή NMR (400 MHz, DMSO-îZQ: δ = 7.46 (s, 1H), 7.29 (s, 1H), 6.77 (s, 1H), 6.64 (d, J= 15.2 Hz, 1H), 6.11 (âà,J= 15.2 Hz, J= 8.0 Hz, 1H), 3.35 - 3.30 (m, 1H), 2.84-2.80 (m, 1H), 2.76 (t, J= 72 Hz, 4H), 2.72 - 2.68 (m, 5H), 2.34 - 2.29 (m, 1H), 2.09 (s, 3H), 1.95 - 1.88 (m, 4H), 1.85 52

I I

I

1.77 (m, 4H), 1.76 - 1.60 (m, 4H), 1.50- 1.35 (m, 3H); MS (ESI): m/z (%) = 473.32 (100%) (M+H)⁺.

Example-37 (R,Z)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l-isopropylpyrrolidiii-2yl)ethene-l-sulfonamide

Ή NMR (400 MHz, DMSO-*): δ = 10.14 (brs, 1H), 7.73 (s, 1H), 6.85 (s, 1H), 6.59 (d, J= 11.2

Hz, 1H), 6.04-5.99 (m, 1H), 4.91-4.89 (m, 1H), 3.48-3.45 (m, 1H), 3.26-3.20 (m, 1H), 3.173.01 (m, 1H), 2.78 (t, J= 7.2 Hz, 4H), 2.69 (t, J = 7.2 Hz, 4H), 2.25 - 2.18 (m, 1H), 1.97 - 1.85 (m, 6H), 1.75 - 1.66 (m, 1H), 1.22 (d, J = 6.8 Hz, 3H), 1.17 (t, J = 6.4 Hz, 3H); MS (ESI): m/z (%) = 418.23 (100%) (M+H)⁺, 416.21 (100%) (M-l).

Example-38 (R,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yI)carbamoyl)-2-(l-(tetrahydro-2H-pyran-4yl)pyrroIidin-2-yl)ethene-l-sulfbnamide

Ή NMR (400 MHz, DMSO-J₆): δ = 10.30 (brs, 1H), 8.05 (s, 1H), 6.95 (s, 1H), 6.85 (d, J= 15.2

Hz, 1H), 6.70 (dd, J= 14.8 Hz, J= 6.4 Hz, 1H), 3.83 - 3.73 (m, 2H), 3.69 - 3.59 (m, 1H), 3.23 3.15 (m, 2H), 3.03 - 2.91 (m, 1H), 2.80 (t, J= 7.2 Hz, 4H), 2.67 (t, J= 7.2 Hz, 4H), 2.58 - 2.53 (m, 2H), 2.00 - 1.91 (m, 5H), 1.71 - 1.62 (m, 3H), 1.58 - 1.52 (m, 2H), 1.42 - 1.33 (m, 2H); MS 20 (ESI): m/z (%) = 460.30 (100%) (M+H)⁺.

Example-39 (R,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l-(oxetan-3-yl)pyrrolidin-2yl)ethene-l-sulfonamide

Ή NMR (400 MHz, DMSO-î/î): <5 = 10.41 (brs, IH), 8.10 (s, IH), 6.96 (s, IH), 6.83 (d, J= 14.8 Hz, IH), 6.61 (dd, J= 15.2 Hz, J= 8.0 Hz, IH), 4.51 - 4.44 (m, 2H), 4.43 - 4.38 (m, 2H), 3.81 3.74 (m, IH), 3.23 - 3.17 (m, IH), 3.00 - 2.95 (m, IH), 2.81 (t, J = 7.2 Hz, 4H), 2.68 (t, J = 7.2 Hz, 4H), 2.41-2.33 (m, IH), 2.01 - 1.91 (m, 5H), 1.78-1.71 (m, 2H), 1.62- 1.55 (m, IH); MS (ESI): m/z (%) = 432.22 (100%) (M+H)⁺.

Example-40 (R,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l-(tetrahydro-2Hthiopyran-4-yl)pyrrolidin-2-yl)ethene-l-sulfonamide

Ή NMR (400 MHz, DMSO-d₆): δ = 10.32 (brs, IH), 8.06(s, IH), 6.95 (s, IH), 6.84 (d, J= 14.8 Hz, IH), 6.64 (dd, J= 14.8 Hz, J= 6.4 Hz, IH), 3.71-3.58 (m, IH), 2.98-2.87 (m, IH), 2.81 (t, J= 7.2 Hz, 4H), 2.68 (t, J= 7.2 Hz, 4H), 2.63 - 2.58 (m, 2H), 2.54 - 2.51 (m, 2H), 2.48 - 2.38 (m, 2H), 2.13-2.01 (m, IH), 1.99 - 1.89 (m, 6H), 1.76 - 1.62 (m, 2H), 1.58 - 1.45 (m, 3H); MS (ESI): m/z (%) = 476.24 (100%) (M+H)⁺.

Example-41 (R,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yI)carbamoyl)-2-(l-(thiazol-2ylmethyl)pyrrolidin-2-yl)ethene-l-sulfonamide

Ή NMR (400 MHz, DMSO4): δ = 10.33 (brs, IH), 8.08 (s, IH), 7.71 (d, J= 3.2 Hz, IH), 6.41 (d, J= 3.2 Hz, IH), 6.92 - 6.86 (m, 2H), 6.70 (dd, J= 15.2 Hz, J= 6.8 Hz, IH), 4.04 (d, J= 14.8

I

Hz, IH), 3.78 (d, J= 14.8 Hz, IH), 3.44 - 3.39 (m, IH), 3.07 - 3.02 (m, IH), 2.77 (t, J = 6.8 Hz,

4H), 2.61 (t, .7= 6.8 Hz, 4H), 2.43-2.33 (m, 1 H), 2.08 - 1.97 (m, IH), 1.96 - 1.87 (m, 4H), 1.80

- 1.74 (m, 2H), 1.63- 1.57 (m, IH); MS (ESI): m/z (%) = 473.19 (100%) (M+H)⁺

Example-42 (E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(piperidin-4yl)ethenesulfonamide

’H NMR (400 MHz, DMSO-ri₆): δ = 10.55 (s, IH), 8.78 (s, IH), 8.26 (s, 2H), 6.95 (s, IH), 6.79 6.70 (m, 2H), 3.29 (d, J= 11.2 Hz, 2H), 2.80 (t, J = 6.8 Hz, 4H), 2.66 (t, J = 6.4 Hz, 4H), 1.95 (t, J= 6.8 Hz, 4H), 1.90 (d, J= 13.2 Hz, 2H); MS (ESI): m/z (%) = 390.20 (100%) (M+H)⁺.

Example-43 (E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l-methylpiperidin-4yl)ethenesulfonamide

’H NMR (400 MHz, DMSO-î/₆): <5 = 7.80 (s, IH), 6.86 (s, IH), 6.64 (s, IH), 6.60 (d, J= 16.4 Hz, IH), 6.48 (dd, Ji = 6.0 Hz, J₂ = 15.2 Hz IH), 3.03 - 2.99 (m, 3H), 2.78 (t, J= 7.6 Hz, 4H), 2.68 (t, J= 7.6 Hz, 4H), 2.38 (s, 3H), 2.36 - 2.24 (m, 2H), 1.94 (t, J = 7.2 Hz, 4H), 1.77 - 1.74 (m, 2H), 1.47 - 1.37 (m, 2H); MS (ESI): m/z (%) = 404.20 (100%) (M+H)⁺.

Example-44 (E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l-(methylsuIfonyl)piperidin-4yl)ethenesulfonamide

I

I 5

I I

I i ίο

I

I 20

I ’H NMR (400 MHz, DMSO-ùk): δ = 10.37 (bs, IH), 8.11 (s, IH), 6.96 (s, IH), 6.78 - 6.7 (m, 2H), 3.57 (d, J= 12.0 Hz, 2H), 2.85 (s, 3H), 2.81 (t, J= 7.2 Hz, 4H), 2.75 - 2.67 (m, 6H), 1.97 (t, J = 7.2 Hz, 4H), 1.82 (d, J= 11.6 Hz, 2H), 1.45 - 1.37 (m, 2H); MS (ESI): m/z (%) = 468.12 (100%) (M+H)⁺.

Example-45 (E)-2-(l-acetylpiperidin-4-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethenesulfonamide

’H NMR (400 MHz, DMSO-ri₆): δ = 10.38 (bs, IH), 8.04 (s, IH), 6.94 (s, IH), 6.64 (dd, Ji = 5.6 Hz, J₂ = 15.6 Hz, IH), 6.68 (d, J= 15.6 Hz, IH), 4.33 (d, J= 13.3 Hz, IH), 3.81 (d, J= 14.4 Hz, IH), 3.06 (t, J = 12.0 Hz, IH), 2.80 (t, J= 7.2 Hz, 4H), 2.67 (t, J= 7.2 Hz, 4H), 2.63 - 2.56 (m, 2H), 2.00 - 1.91 (m, 7H), 1.72 (t, J= 15.6 Hz, 2H), 1.35 - 1.24 (m, IH), 1.21 - 1.11 (m, IH); MS (ESI): m/z (%) = 432.17 (100%) (M+H)⁺.

Example-46 tert-butyl(E)-4-(2-(N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)piperidine-l-carboxylate

’H NMR (400 MHz, DMSO-^): δ = 10.37 (bs, IH), 8.05 (s, IH), 6.96 (s, IH), 6.8 (dd, Ji = 6.0 Hz, J₂ = 15.2 Hz, IH), 6.69 (d, J = 15.6 Hz, IH), 3.93 (d, J = 11.6 Hz, 2H), 2.81 (t, J = 7.2 Hz, 6H), 2.66 (t, J= 6.8 Hz, 4H), 1.97 (t, J =7.2 Hz, 4H), 1.71 (d, J= 11.6 Hz, 2H), 1.39 (s, 9H), 1.23 -1.17 (m, 3H); MS (ESI): m/z (%) = 488.18 (100%) (M-H)⁺.

Example-47 (E)-2-(l-ethylpiperidin-4-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-lsulfonamide

P J /'rt ° H ’H NMR (400 MHz, DMSO-^): δ = 7.87 (s, 1H), 6.94 (s, 1H), 6.65 (d, J = 15.6 Hz, 1H), 6.52 (dd, Ji = 6.0 Hz, J₂ = 15.2 Hz, 1H), 3.16 (d, J= 11.6 Hz, 3H), 2.79 (t, J= 7.2 Hz, 4H), 2.73 - 2.67 (m, 6H), 1.98 - 1.91 (m, 5H), 1.82 - 1.75 (m, 3H), 1.52 - 1.44 (m, 2H), 1.10 (t, J= Ί2 Hz, 3H),

MS (ESI): m/z (%) = 418.18 (100%) (M+Hf, 416.17 (100%) (M-l)'.

Example-48 (R,E)-2-(l-ethylpyrrolidin-3-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethenesulfonamide ,0 ο

A N N ° H H

’H NMR (400 MHz, DMSO-fr₆): δ = 7.95 (s, 1H), 6.43 (s, 1H), 6.60 (d, J= 14.4 Hz, 1H), 6.55 6.45 (m, 1H), 3.18 (d, J= 4.8Hz, 2H), 3.05 - 2.95 (m, 4H), .2.79 (t, J= 7.2 Hz, 4H), 2.73 - 2.67 (m, 5H), 1.95 (t, J= 7.2 Hz, 4H), 1.55 (t, J= 7.2 Hz, 3H), 1.09 (t, J= 7.2 Hz, 2H); MS (ESI): m/z (%) = 404.18 (100%) (M+H)⁺.

ExampIe-49 (R,E)-l,l-diethyI-3-(2-(N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)siilfamoyl)vinyl)pyrrolidin-l-ium bromide

Br ,O P

A N N ⁰ H H

Ή NMR (400 MHz, DMSO-î/₆): δ = 7.27 (s, 1H), 6.77 (s, 1H), 6.73 (s, 1H), 6.27 (dd, Ji = 6.8 Hz, J₂ = 15.6 Hz, 1H), 5.59 (bs, 1H), 4.12 (s, 1H), 3.78 - 3.72 (m, 2H), 3.62 (t, J= 7.6Hz, 1H), 3.54 (t, J= 8.0 Hz, 1H), 3.41 - 3.36 (m, 2H), 3.30 - 3.24 (m, 2H), 2.76 - 2.69 (m, 8H), 2.33 - 2.25 (m, 1H), 1.93 - 2.90 (m, 4H), 1.20 (t, J= 6.8 Hz, 6H); MS (ESI): m/z (%) = 432.20 (100%) (M)⁺.

Example-50 (E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(pyrrolidin-3-yl)ethenesulfonamide

I I

I

I I

I/O

I

I β 20

I

Ή NMR (400 MHz, DMSO-t/₆): δ = 7.41 (s, 1H), 6.78 (s, 1H), 6.64 (d, J = 15.6 Hz, 1H), 6.23 (dd, Ji = 7.6 Hz, J₂ = 15.2 Hz, 1H), 3.18 - 3.14 (m, 1H), 2.99 - 2.95 (m, 1H), 2.76 (t, J= 7.6 Hz, 4H), 2.70 (t, J= 7.2 Hz, 4H), 2.00 - 1.97 (m, 2H), 1.95 (t, J = 7.6 Hz, 4H), 1.90 - 1.88 (m, 2H), 1.76 - 1.54 (m, 1H); MS (ESI): m/z (%) = 376.15 (100%) (M+H)⁺.

Example-51 (R,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-methylpyrrolidin-2yl)ethene-l-sulfonamide

Ή NMR (400 MHz, DMSO-^é): δ = 7.56 (s, 1H), 6.91 (d, J= 15.6 Hz, 1H), 6.82 (s, 1H), 6.52 (d, J = 15.2 Hz, 1H), 3.23 - 3.19 (m, 2H), 3.14 - 3.07 (m, 1H), 2.77 (t, J = 7.6 Hz, 4H), 2.69 (t, J= 7.2 Hz, 4H), 1.96 - 1.87 (m, 8H), 1.79 - 1.74 (m, 1H), 1.34 (s, 3H); MS (ESI): m/z (%) = 390.14 (100%) (M+H)⁺.

Example-52 tert-butyl(R,E)-2-(2-(N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)2-methylpyrrolidine-l-carboxyIate

Ή NMR (400 MHz, DMSO-d₆): δ = 10.41 (s, 1H), 8.05 (s, 1H), 6.95 (s, 1H), 6.87 (d, J= 16.0 Hz, 1H), 6.56 (d, J = 15.6 Hz, 1H), 3.38 - 3.32 (m, 2H), 2.82 (t, J = 7.6 Hz, 4H), 2.75 (t, J= 7.2 Hz, 4H), 1.95 (t, J= 7.2 Hz, 5H), 1.86 - 1.69 (m, 3H), 1.48-1.41 (m, 3H), 1.34 (s, 9H); MS (ESI): m/z (%) = 488.16 (100%) (M-H)⁺.

Example-53 (R,E)-2-(l-acetyI-2-methylpyrrolidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)ethene-l-sulfonamide

I I

I

I I

I

’H NMR (400 MHz, DMSO-^): δ = 10.40 (s, IH), 8.06 (s, IH), 6.96 (s, IH), 6.91 (d, J= 15.6 Hz, IH), 6.58 (d, J= 15.2 Hz, IH), 3.57 - 3. 50 (m, 2H), 2.81 (t, J= 7.2 Hz, 4H), 2.68 (t, J= 7.2 Hz, 4H), 2.01 - 1.88 (m, 8H), 1.82 - 1. 74 (m, 3H), 1.52 (s, 3H); MS (ESI): m/z (%) = 432.09 (100%) (M+H)⁺.

Example-54 (R,E)-l,l-diethyl-2-(2-(N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)-2-methylpyrrolidin-l-ium bromide;

’H NMR (400 MHz, DMSO-t/J: δ = 6.88 (s, IH), 6.65 (d, J= 15.6 Hz, IH), 6.21 - 6.15 (m, IH), 2.84 - 2.75 (m, 6H), 2.68 - 2.58 (m, 3H), 2.35 - 2.29 (m, 2H), 1.96 - 1.91 (m, 7H), 1.76 - 1.59 (m, 4H), 0.97 (t, J= 7.2 Hz, 6H), 0.88 (s, 3H); MS (ESI): m/z (%) = 446.19 (100%) (M+H)⁺.

Example-55 (R,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-methyI-l(methylsulfonyl)-pyrrolidin-2-yl)ethene-l-sulfonamide;:

’H NMR (400 MHz, DMSO-JJ: δ = 10.43 (bs, IH), 8.09 (s, IH), 6.96 (s, IH), 6.90 (d, J= 15.2

Hz, IH), 6.72 (d, J= 15.2 Hz, IH), 3.44 (t, J= 6.0 Hz, 2H), 2.95 (s, 3H), 2.81 (t, J= 7.2 Hz, 4H),

2.68 (t,J= 7.2 Hz, 4H), 2.07- 1.83 (m,7H), 1.79- 1.74 (m, IH), 1.24 (s, 3H), MS (ESI): m/z (%) * 20 = 468.11 (100%) (M+H)⁺.

f Example-56 (R,E)-2-(l,2-dimethyIpyrrolidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4| yl)carbamoyl)ethene-l-sulfonamide;

I

I 15

I

J 20

I

Ή NMR (400 MHz, DMSO-t/Q: δ = 8.04 (s, 1H), 6.93 (s, 1H), 6.74 (d, J= 15.6 Hz, 1H), 6.65 (d, J= 15.2 Hz, 1H), 2.93 - 2.86 (m, 1H), 2.80 (t, J= 72 Hz, 4H), 2.67 (t, J = 72 Hz, 4H), 2.19 (s, 3H), 1.99 - 1.91 (m, 5H), 1.80 - 1.69 (m, 4H), 1.13 (s, 3H), MS (ESI): m/z (%) = 404.16 (100%) (M+H)⁺.

Altematively, Example 56 was also be prepared as per the procedure described for synthesis of Intermediate-7b (Example 111) using Intermediate 9 and (R)-l,2-dimethylpyrrolidine-2carbaldehyde, together with conventional techniques known to those skilled in the art of organic synthesis.

Example-57 (R,E)-2-(l-ethyl-2-methylpyrrolidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)ethene-l-sulfonamide

‘H NMR (400 MHz, DMSO-^): δ = 8.82 (bs, 1H), 6.96 (s, 1H), 6.92 (d, J= 9.6 Hz, 1H), 6.41 (m, 1H), 3.60 - 3.51 (m, 2H), 3.22 - 3.17 (m, 2H), 2.80 - 2.73 (m, 5H), 2.61 (t, J= 7.2 Hz, 4H), 1.97

- 1.93 (m, 6H), 1.84 - 1.80 (m, 1H), 1.53 (s, 3H), 0.90 (t, J= 6.4 Hz, 3H); MS (ESI): m/z (%) = 418.18 (100%) (M+H)⁺;

ExampIe-58 (R,E)-2-(l-(cyclopropylmethyl)-2-methylpyrrolidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-sindacen-4-yl)carbamoyl)ethene-l-sulfonamide

*H NMR (400 MHz, DMSO-JQ: δ = 10.39 (s, 1H), 8.06 (s, 1H), 6.94 (s, 1H), 6.75 (d, J= 15.6 Hz, 1H), 6.69 (d, J= 15.6 Hz, 1H), 3.18 - 3.13 (m, 1H), 2.80 (t, J= 7.2 Hz, 5H), 2.67 (t, J= 7.2 Hz, 60

4H), 2.33-2.11 (m, 2H), 1.94 (t, <7=7.2 Hz, 4H), 1.80-1.71 (m, 4H), 1.12 (s, 3H), 0.86-0.79 (m, IH), 0.42 (quin, J = 8.8 Hz, 2H), 0.05 - 0. 04 (m, 2H); MS (ESI): m/z (%) = 444.17 (100%) (M+H)⁺.

Example-59 (S,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(pyrrolidm-2-yl)ethenesulfonamide

O 9 //N N O H H

’H NMR (400 MHz, DMSO): δ = 8.75 (bs, IH), 7.50 (s, IH), 6.95 (d, J=15.6Hz, IH), 6.80 (s, IH), 6.39-6.33 (m, IH), 4.08-4.02 (m, IH), 3.16-4.11 (m, 2H), 2.77 (t, J=7.2Hz, 4H), 2.71 (t, J=7.2Hz, 4H), 2.12-2.08 (m, IH), 1.96-1.85(m, 6H), 1.68-1.62(m, IH); MS (ESI): Wz(%) = 376.16 (100%) (M+H)⁺.

Example-60 (S,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l-methyIpyrrolidin-2yl)ethenesulfonamide o 9 '/N N

O H H

’H NMR (400 MHz, DMSO): δ = 8.00 (s, IH), 6.93 (s, IH), 6.85 (d, J=15.2Hz, IH), 6.58-6.52 (m, IH), 3.12-3.04 (m, 2H), 2.80 (t, J=7.2Hz, 4H), 2.67 (t, J=7.2Hz, 4H), 2.36-2.31 (m, IH), 2.27 (s, 3H), 2.08-1.91 (m, 5H), 1.80-1.72 (m, 2H), 1.70-1.50 (m, IH); MS (ESI): m/z (%) = 390.17 (100%) (M+H)⁺.

Example-61 (S,E)-tert-butyl2-(2-(N-((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)sulfamoyl)vinyl)pyrrolidine-l-carboxylate

Ή NMR (400 MHz, DMSO): δ = 10.42 (bs, IH), 8.09 (s, IH), 6.96 (s, IH), 6.71-6.67 (m, IH),

6.61-6.57 (m, IH), 4.45-4.38 (m, IH), 3.29-3.25 (m, 2H), 2.81 (t, ,/=7.2 Hz, 4H), 2.67 (t, J=7.2Hz,

4H), 2.09-1.93 (m, 5H), 1.78-1.71 (m, 3H), 1.33 (s, 9H); MS (ESI): m/z (%) = 498.18 (80%) (M+Na)⁺.

Example-62 (S,E)-2-(l-(cyclopropylmethyl)pyrrolidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)ethenesulfonamide

Ή NMR (400 MHz, DMSO-d₆):<5= 10.32 (bs, IH), 8.02 (bs, 1H),6.93 (s, IH), 6.86 (d, J=14.8Hz, 10 IH), 6.64 - 6.50 (m, IH), 3.50 - 3.20 (m, 3H), 2.80 (t, J=7.2Hz, 4H), 2.67 (t, J=7.2Hz, 4H), 2.61 2.56 (m, IH), 2.15 - 1.91 (m, 6H), 1.85 - 1.78 (m, 2H), 1.62 - 1.53 (m, IH), 0.86 - 0.80 (m, IH), 0.50 - 0.30 (m, 2H), 0.15 - 0.14 (m, 2H); MS (ESI): m/z (%) = 430.19 (100%) (M+H)⁺.

Example-63 (S,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l-(pyridin-3-ylsulfonyl)15 pyrrolidin-2-yl)ethenesuIfonamide ’H NMR (400 MHz, DMSO-d_ë): δ = 10.40 (bs, IH), 9.02 (d, .7=2.0Hz, IH), 8.90 - 8.88 (m, IH), 8.29 - 8.26 (m, IH), 8.04 (s, IH), 7.68 - 7.65 (m, IH), 6.94 - 6.87 (m, 2H), 6.72 - 6.67 (m, IH), 4.52 - 4.49 (m, IH), 3.44 - 3.42 (m, IH), 3.21 - 3.15 (m, IH), 2.80 (t, J=7.2Hz, 4H), 2.69 (t, 20 J=7.2Hz, 4H), 1.99 - 1.91 (m, 4H), 1.76 - 1.65 (m, 4H); MS (ESI): m/z (%) = 517.11 (100%) (M+H)⁺.

Example-64 (S,E)-N-((2,6-diisopropylphenyl)carbamoyl)-2-(pyrrolidin-2-yl)ethenesulfonamide

I

I I I

I

’H NMR (400 MHz, DMSO): δ = 9.50 (bs, 1H), 7.48 (bs, 1H), 7.17 - 7.05 (m, 3H), 6.99 - 6.88 (m, 1H), 6.43 (bs, 1H), 4.15 - 3.90 (m, 1H), 3.20 - 3.00 (m, 4H), 2.15 - 2.00 (m, 1H), 1.99 - 1.80 (m, 3H), 1.79 - 1.60 (m, 1H), 1.20 - 1.00 (m, 12H); MS (ESI): m/z (%) = 380.16 (100%) (M+H)⁺.

Example-65 (S,E)-N-((2,6-diisopropylphenyl)carbamoyl)-2-(l-ethylpyrrolidin-2-yl)ethenesulfonamide

Ή NMR (400 MHz, DMSO-d₆): δ = 10.60 (bs, 1H), 7.86 (s, 1H), 7.27 - 7.23 (m, 1H), 7.15 - 7.13 (m, 2H), 6.84 (d, J=15.2Hz, 1H), 6.66 - 6.61 (m, 1H), 3.32 - 3.02 (m, 4H), 2.75 - 2.60 (m, 1H),

2.41 -2.25 (m, 2H), 2.05 - 1.96 (m, 1H), 1.90- 1.70 (m, 2H), 1.65 - 1.45 (m, 1H), 1.12 - 1.11 (m, 12H), 1.01 (t, J=7.2Hz, 3H); MS (ESI): m/z (%) = 408.19 (100%) (M+H)⁺.

J Example-66 (S,E)-N-((2,6-diisopropylphenyI)carbamoyI)-2-(l-(methylsulfonyl)pyrrolidin-2-yl)ethene| 15 sulfonamide i2 n

IO ' W NN |

S^O ° HH 0^

Ή NMR (400 MHz, DMSO-d₆): δ = 7.81 (s, 1H), 7.25 - 7.21 (m, 1H), 7.13-7.11 (m, 2H), 6.75{ 6.64 (m, 2H), 4.46 (s, 1H), 3.29 - 3.24 (m, 1H), 3.10 - 3.03 (m, 2H), 2.93 (s, 3H), 2.09 - 2.04 (m,

1H), 1.89 - 1.83 (m, 1H), 1.77 - 1.73 (m, 3H), 1.12-1.11 (m, 12H); MS (ESI): m/z (%) = 458.15 । 20 (100%) (M+H)⁺.

£ Example-67 (S,E)-N-((2,6-diisopropylphenyl)carbamoyl)-2-(l-methylpyrrolidin-2-yl)ethenesulfonamide ’H NMR (400 MHz, DMSO-d₆): <5 = 7.69 (s, IH), 7.22 - 7.18 (m, IH), 7.11 - 7.09 (m, 2H), 6.75 (d, J=15.2Hz, IH), 6.55 - 6.30 (m, IH), 3.12 - 2.99 (m, 3H), 2.79 - 2.76 (m, IH), 2.23 - 2.18 (m,

4H), 2.00 - 1.95 (m, IH), 1.76 - 1.68 (m, 2H), 1.54 - 1.49 (m, 1 H), 1.11 - 1.09 (m, 12H); MS (ESI):

m/z (%) = 394.19 (100%) (M+H)⁺.

I I

I 0 I I 1¹⁵! !

I

I ₂0 I

I I

Example-68 (S,E)-2-(l-acetylpyrrolidin-2-yl)-N-((2,6-diisopropylphenyl)carbamoyl)ethenesuIfonamide

’HNMR(400 MHz, DMSO-d₆): δ = 10.55 (bs, IH), 7.89 - 7.86 (m, IH), 7.28 - 7.23 (m, IH), 7.15 - 7.13 (m, 2H), 6.76 - 6.69 (m, IH), 6.63 - 6.53 (m, IH), 4.68 - 4.61 (m, IH), 3.52 - 3.39 (m, IH), 3.08 - 3.02 (m, 2H), 1.97 (s, 3H), 1.93 - 1.70 (m, 5H), 1.13 - 1.11 (m, 12H); MS (ESI): m/z (%) = 422.18 (100%) (M+H)⁺.

Example-69 (S,E)-2-(l-acetylpyrrolidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethenesulfonamide

’HNMR (400 MHz, DMSO-t/e): 10.30 (bs, IH), 8.11 -8.05 (m, IH), 6.95 (s, IH), 6.78-6.56 (m, 2H), 4.72 - 4.62 (m, IH), 3.57 - 3.35 (m, 2H), 2.81 (t, J = 7.2 Hz, 4H), 2.67 (q, J = 7.2 Hz, 4H), 1.99 - 1.95 (m, 6H), 1.85 (s, 3H), 1.84 - 1.71 (m, 2H); MS (ESI): m/z (%) = 418.16 (100%) (M+H)⁺.

Example-70 (S,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l-(tetrahydro-2H-pyran-4carbonyl)pyrrolidin-2-y!)ethenesulfonamide *H NMR (400 MHz, DMSO-d₆): δ = 10.40 (bs, 1H), 8.03 (s, 1H), 6.94 - 6.93 (m, 1H), 6.74 - 6.49 (m, 2H), 6.64 - 6.50 (m, 1H), 4.84 - 4.65 (m, 1H), 3.87 - 3.78 (m, 2H), 3.64 - 3.52 (m, 1H), 3.50 3.25 (m, 2H), 2.81 (t, J=7.6Hz, 4H), 2.73 - 2.67 (m, 5H), 2.01 - 1.89 (m, 5H), 1.82 - 1.72 (m, 3H),

1.61 - 1.49 (m, 4H); MS (ESI): m/z (%) = 488.21 (100%) (M+H)⁺.

I I I I

Example-71 (E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyI)-2-(tetrahydro-2H-pyran-4yl)ethenesulfonamide

‘H NMR (400 MHz, DMSO-d₆): δ = 10.33 (bs, 1H), 8.07 (s, 1H), 6.96 (s, 1H), 6.80 - 6.74 (m, 1H), 6.69 - 6.65 (m, 1H), 3.87 - 3.83 (m, 2H), 3.37 - 3.34 (m, 3H), 2.81 (t, J=7.6Hz, 4H), 2.67 (t, J=7.6Hz, 4H), 2.08 -1.94 (m, 4H), 1.65 - 1.62 (m, 2H), 1.55 - 1.30 (m, 2H); MS (ESI): m/z (%) = 391.15 (100%) (M+H)⁺.

Example-72 (S,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l-nicotinoylpyrrolidin-2yl)ethenesulfonamide

I I I I I

’H NMR (400 MHz, DMSO-d₆): <5 = 10.35 (bs, 1H), 8.76 - 8.59 (m, 2H), 8.05 (s, 1H), 6.72 (d, J=8Hz, 0.72H), 7.77 (d, J=8Hz, 0.23H), 7.48 - 7.40 (m, 1H), 6.94 (s, 1H), 6.84 (s, 1H), 6.57 - 6.55 (m, 1H), 4.86 - 4.50 (m, 1H), 3.65 - 3.59 (m, 1H), 3.41 - 3.37 (m, 1H), 2.78 (t, J=1.6Hz, 4H), 2.65 (t, J=7.6Hz, 4H), 2.20 - 2.13 (m, 1H), 1.96 - 1.84 (m, 7H); MS (ESI): m/z (%) = 481.18 (100%) (M+H)⁺.

I

Example-73 (E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(tetrahydrofuran-2-yl)ethene1-sulfonamide

I I !

I I

Γ

I I

I L

I 1 1

I Γ°

I

Ή NMR (400 MHz, DMSO-d₆): δ = 10.40 (bs, 1H), 8.11 (s, 1H), 6.96 (s, 1H), 6.81 (dd, J=4.0Hz, J=14.8Hz, 1H), 6.74 (dd, J=1.2Hz, J=15.2Hz, 1H), 4.57 - 4.53 (m, 1H), 3.86 - 3.81 (m, 1H), 3.76 - 3.70 (m, 1H), 2.81 (t, J=7.2Hz, 4H), 2.67 (t, J=7.2Hz, 4H), 2.16 - 2.07 (m, 1H), 2.01 - 1.94 (m, 4H), 1.90 - 1.79 (m, 2H), 1.67 - 1.62 (m, 1H); MS (ESI): m/z (%) = 377.15 (100%) (M+H)⁺.

Example-74 (S,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyI)-2-(l-(thiophen-2-ylmethyl)pyrrolidin-2-yl)ethene-l-sulfonamide

’H NMR (400 MHz, DMSO-d₆): δ = 10.40 (bs, 1H), 8.10 (s, 1H), 7.43 - 7.39 (m, 1H), 7.01 - 6.86 (m, 4H), 6.71 - 6.63 (m, 1H), 3.93 (d, J=14Hz, 1H), 3.58 (d, J=14Hz, 1H), 3.28 - 3.24 (m, 1H), 2.97 - 2.92 (m, 1H), 2.77 (t, J=7.2Hz, 4H), 2.63 (t, J=7.2Hz, 4H), 2.33 - 2.04 (m, 1H), 2.04 - 1.88 (m, 5H), 1.75 - 1.68 (m, 2H), 1.59 - 1.54 (m, 1H); MS (ESI): m/z (%) = 472.12 (100%) (M+H)⁺.

Example-75 tert-butyl(S,E)-2-(2-(N-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)sulfamoyl)vinyI)pyrrolidine-l-carboxylate

’H NMR (400 MHz, DMSO): δ = 10.06 (bs, 1H), 7.93 (s, 1H), 6.97 - 6.95 (m, 2H), 6.72 - 6.55 (m, 2H), 4.46 - 4.02 (m, 1H), 3.30 - 3.26 (m, 2H), 3.02 - 2.99 (m, 2H), 2.22 - 1.99 (m, 1H), 1.78 - 1.68 (m, 3H), 1.45 (s, 9H), 1.11 (d, J=6.8Hz, 12H); MS (ESI): m/z (%) - 398.29 (100%) (M-lOOf;

520.36 (15%) (M+Na)⁺; 496.32 (100%) (M-llf

Example-76 (S,E)-N-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)-2-(pyrrolidin-2-yl)ethene-lsulfonamide

I I I

I

I I

I ï 13

I

’H NMR (400 MHz, DMSO): <5 = 9.40 (bs, IH), 7.39 (bs, IH), 7.02 - 6.76 (m, 3H), 6.39 - 6.22 (m, IH), 4.05 - 4.04 (m, IH), 3.17 - 3.13 (m, 4H), 2.06 - 1.56 (m, 5H), 1.10 - 1.09 (m, 12H); MS (ESI): m/z (%) = 398.26 (100%) (M-H)⁺.

Example-77 (S,E)-N-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)-2-(l-methylpyrrolidin-2-yl)ethene-lsulfonamide.

Ή NMR (400 MHz, DMSO-d₆): δ = 10.90 (bs, IH), 7.84 (bs, IH), 6.94 (d, J=9.6Hz, 2H), 6.90 (d, J=15.2Hz, IH), 6.58 - 6.53 (m, IH), 3.08 - 2.95 (m, 4H), 2.33 - 2.27 (m, IH), 2.23 (s, 3H), 2.07 - 1.97 (m, IH), 1.78 - 1.73 (m, 2H), 1.59 - 1.50 (m, IH), 6.75 (d, J=6.8Hz, 12H); MS (ESI): m/z (%) = 412.26 (100%) (M+H)⁺.

Example-78 (R,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l-isobutyl-2-methylpyrrolidin-2-yI)ethene-l-sulfonamide

I

I I

I

I ίο

I I

I

1¹⁵

I I

Ή NMR (400 MHz, DMSO-ds): i = 8.03 (bs, 1H), 6.89 (s, 1H), 6.88 (d, ./=15,61% 1H), 6.54 (d, J=15.6Hz, 1H), 2.81 - 2.77 (m, 6H), 2.70 - 2.57 (m, 5H), 2.13 - 2.00 (m, 2H), 1.98-1.91 (m,4H), 1.75 - 1.53 (m, 5H), 1.06 (s, 3H), 0.90 - 0.79 (m, 6H); MS (ESI): m/z (%) = 446.26 (100%) (M+H)’.

Example-79 (R,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-methyl-lpropylpyrrolidin-2-yl)ethene-l-sulfonamide

Ή NMR (400 MHz, DMSO-d₆): δ = 7.99 (bs, 1H), 6.90 (s, 1H), 6.67 (d, J=15.6Hz, 1H), 6.57 (d, J=16.0Hz, 1H), 2.93 - 2.87 (m, 1H), 2.79 (t, J=7.2Hz, 4H), 2.70 - 2.66 (m, 5H), 2.33 - 2.29 (m, 2H), 1.99-1.91 (m, 4H), 1.85 - 1.66 (m, 4H), 1.45 - 1.33 (m, 2H), 1.09 (s, 3H), 0.80 (t, J=7.6Hz, 3H); MS (ESI): m/z (%) = 432.25 (100%) (M+H)⁺.

Example-80 (S,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l-(thiazol-2-yl)pyrrolidin-2yl)ethene-l-sulfonamide

Ή NMR (400 MHz, DMSO-d₆): δ = 10.4 (bs, 1H), 8.09 (s, 1H), 7.14 (d, J=3.6Hz, 1H), 6.96 (s, 1H), 6.84 - 6.79 (m, 1H), 6.75 (d, J=3.6Hz, 1H), 6.72 - 6.66 (m, 1H), 4.59 - 4.58 (m, 1H), 3.58 3.53 (m, 1H), 3.41 - 3.34 (m, 1H), 2.81 (t, J=7.2Hz, 4H), 2.64 (t, J=7.2Hz, 4H), 2.30 - 2.18 (m, 1H), 2.04 - 1.87 (m, 7H); MS (ESI): m/z (%) = 459.17 (100%) (M+H)⁺.

Example-81 (E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(piperidin-3-yl)ethenesulfonamide

’H NMR (400 MHz, DMSO-îZ₆): δ = 10.04 (brs, 1H), 7.57 (s, 1H), 6.81 (s, 1H), 6.67 (d, J= 15.2

Hz, 1H), 6.24 (dd, J= 15.2 Hz, J= 6.0 Hz, 1H), 3.23 - 3.12 (m, 2H), 2.77 (t, J= 7.2 Hz, 4H), 2.70 (t, J= 7.2 Hz, 4H), 2.51 - 2.49 (m, 2H), 1.97- 1.89 (m, 5H), 1.79 - 1.76 (m, 2H), 1.63 - 1.59 (m,

1H), 1.37 - 1.29 (m, 1H); MS (ESI): m/z (%) = 390.15 (100%) (M+H)⁺.

Example-82 (E)-2-(l-ethylpiperidin-3-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethenesulfonamide ’H NMR (400 MHz, DMSO-rfd): δ = 7.82 (s, 1H), 6.94 (s, 1H), 6.70 (d, J = 15.2 Hz, 1H), 6.53 (dd, J= 15.2 Hz, J= 6.0 Hz, 1H), 2.98 - 2.89 (m, 2H), 2.79(t, J= 7.2 Hz, 4H), 2.68 (t, J= 7.2 Hz, 4H), 2.57 - 2.54 (m, 2H), 2.21- 2.09 (m, 2H), 1.99- 1.91 (m, 4H), 1.72 - 1.69 (m, 2H), 1.58 1.50 (m, 1H), 1.24 - 1.32 (m, 2H), 1.05(t, J= 7.2 Hz, 3H); MS (ESI): m/z (%) = 418.18 (100%) (M+H)⁺.

Example-83 (E)-tert-butyl3-(2-(N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)suIfamoyi)vinyl)piperidine-l-carboxylate ’H NMR (400 MHz, DMSO-î/₆): δ = 10.4 (brs, 1H), 7.93 (s, 1H), 6.93 (s, 1H), 6.74 (d, J= 15.2 Hz, 1H), 6.61 (dd, J= 15.2 Hz, J= 6.8 Hz, 1H), 3.75 - 3.64(m, 2H), 2.93 - 2.88 (m, 2H), 2.80 (t, 20 J= 7.2 Hz, 4H), 2.68 (t, J= 7.2 Hz, 4H), 2.38 - 2.33 (m, 1H), 2.00- 1.93 (m, 4H), 1.80- 1.70 (m, 1H), 1.59 - 1.55 (m, 1H), 1.39 (s, 9H), 1.36 - 1.34 (m, 1H), 0.91 - 0.81 (m, 1H); MS (ESI): m/z (%) = 390.16 (100%) [(M-100)+H]⁺,488.17 (100%) (M-l).

Example-84 (E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l-(methylsulfonyI)piperidin-3yl)ethenesulfonamide

I

’H NMR (400 MHz, DMSO-î/₆): δ = 10.4 (brs, 1H), 7.98 (s, 1H), 6.93 (s, 1H), 6.79 (d, J= 15.2

Hz, 1H), 6.66 (dd, J= 15.2 Hz, J= 6.4 Hz, 1H), 3.47 - 3.39 (m, 2H), 2.87 (s, 3H), 2.80 (t, J= 7.6

Hz, 4H), 2.68 (t, J = 7.6 Hz, 4H), 2.60 - 2.46 (m, 3H), 2.00- 1.91 (m, 4H), 1.80- 1.72 (m, 2H),

1.57 - 1.49 (m, 1H), 1.35 - 1.24 (m, 1H); MS (ESI): m/z (%) = 468.14 (100%) (M+H)⁺, 490.40 (50%) (M+Na), 466.11 (100%) (M-l).

Example-85 (E)-2-(l-acetylpiperidin-3-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethenesulfonamide

’H NMR (400 MHz, DMSO-î/₆): δ = 8.00 (s, 1H), 6.94 (s, 1H), 6.80-6.65 (m, 2H), 4.16-4.10 (m, 1H), 3.77 - 3.63 (m, 1H), 3.09 - 2.93 (m, 1H), 2.80 (t, J= 7.2 Hz, 4H), 2.75 - 2.64 (m, 5H), 2.39-2.26 (m, 1H), 2.00- 1.91 (m, 7H), 1.90- 1.77 (m, 1H), 1.74 - 1.57 (m, 1H), 1.54 - 1.28 (m, 2H); MS (ESI): m/z (%) = 468.14 (100%) (M+H)⁺, 490.40 (50%) (M+Na), 466.11 (100%) (ΜΙ)·

Example-86

I I

I

I tert-butyl(E)-2-(2-(N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)azetidine-l-carboxylate

Example 86 was prepared as per the procedure described for synthesis of Intermediate-3a using Intermediate-11.

’H NMR (400 MHz, DMSO-J₆): δ = 10.57 (brs, 1H), 7.83 (s, 1H), 6.89 (s, 1H), 6.73 (d, J= 15.2 Hz, 1H), 6.66 (dd, J= 15.2 Hz, J AA Hz, 1H), 4.73-4.84 (m, 1H), 3.80 - 3.70 (m, 2H), 2.79 (t,

I I

I

I Γ°

I

I ⁵

I

I ι²⁰

I !

I I

J= 7.2 Hz, 4H), 2.69 (t, J= 7.2 Hz, 4H), 2.46-2.33 (m, IH), 2.04 - 1.97 (m, 5H), 1.35 (s, 9H);

MS (ESI): m/z (%) = 484.84 (90%) (M+H)⁺ , 460.23 (100%) (M-l).

Example-87 (E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l-methylazetidin-2-yl)ethenel-sulfonamide

’H NMR (400 MHz, DMSO-J₆): δ = 10.45 (brs,lH), 7.98 (s, IH), 6.92 (s, IH), 6.84 (d, J= 14.8 Hz, IH), 6.72 (dd, J = 15.2 Hz, J= 5.2 Hz IH), 3.95 - 3.82 (m, IH), 3.44 - 3.36 (m, 2H), 3.09 2.95 (m, IH), 2.80 (t, J= 7.2 Hz, 4H), 2.68 (t, J= 6.8 Hz, 4H), 2.30 (s, 3H), 2.26 - 2.20 (m, IH), 2.03 - 1.89 (m, 4H); MS (ESI): m/z (%) = 376.19 (100%) (M+H)⁺, 374.16 (100%) (M-l).

Example-88 (E)-2-(azetidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-lsulfonamide

’H NMR (400 MHz, DMSO-d₆): δ = 7.51 (s, IH), 6.94 (d, J = 15.2 Hz, IH), 6.80 (s, IH), 6.55 (dd, J = 15.2 Hz, J= 7.2 Hz, IH), 5.01 - 4.95 (m, IH), 3.89 - 3.82 (m, IH), 3.72 - 3.62 (m, IH), 2.77 (t, J = 7.2 Hz, 4H), 2.70 (t, J= 6.8 Hz, 4H), 2.50 - 2.33 (m, IH), 1.96 - 1.88 (m, 5H); MS (ESI): m/z (%) = 362.24 (100%) (M+H)⁺.

Example-89 (R,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l-(tetrahydro-2H-pyran-4yl)pyrrolidin-2-yl)ethene-l-sulfonamide

’H NMR (400 MHz, DMSO-rf₆): δ = 10.36 (brs, IH), 7.99 (s, IH), 6.94 - 6.90 (m, 2H), 6.77 (dd, J= 14.8 Hz, J= 5.2 Hz, IH), 3.99 - 3.86 (m, IH), 3.46 - 3.39 (m, 2H), 3.13 - 2.96 (m, IH), 2.80 (t, J= 7.2 Hz, 4H), 2.66 (t, J= 7.2 Hz, 4H), 2.51 - 2.33 (m, 1H), 2.30-2.16 (m, 1H), 1.99 - 1.92 (m, 5H), 0.82 - 0.61 (m, 1H), 0.50 - 0.30 (m, 2H), 0.22 - 0.08 (m, 2H); MS (ESI): m/z (%) =

416.29 (100%) (M+H)⁺.

Example-90 (S,E)-2-(l-((5-chlorothiophen-2-yl)sulfonyl)pyrrolidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-sindacen-4-yl)carbamoyl)ethenesulfonamide

Ή NMR (400 MHz, DMSO-d₆): δ =8.01 (s, 1H), 7.68 (t, J= 1.2 Hz, 1H),7.36 (d, J=4.0 Hz, 1H),

6.90 (s, 1H), 6.85 (s, 1H), 6.82 (s, 1H), 4.40 (d, J= 5.2 Hz, 1H), 3.43 (t, J = 6.8 Hz, 1H), 3.32 (s,lH), 3.20 (d, J = 7.6 Hz, 1H) , 2.80 (t, J = 7.2 Hz, 4H), 2.69 (t, J= 8.8 Hz, 4H), 1.95 (m,4H),

1.74 (m, 3H), 1.64 (s, 1H); MS (ESI): m/z (%) = 556 (100%) (M+l).

Example-91 (S,E)-2-(l-(benzylsulfonyl)pyrroIidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)ethenesulfonamide

I I I I ! I

Ή NMR (400 MHz, DMSO-îZ₆): δ =7.86 (s, 1H), 7.42 (m, 2H), 7.34 (t, J= 4.0 Hz, 3H), 6.87 (s, 1H), 6.71 (s, 1H), 6.45 (m, 1H), 4.46 (s,2H), 4.37(d, J= 8.0 Hz, 1H), 3.22 (s, 1H), 2.78 (t, J= Ί.6 Hz, 4H) , 2.66 (t, J= 7.2 Hz, 4H), 1.99 (m,lH), 1.95 (m, 4H), 1.74 (m, 3H); MS (ESI): m/z (%) = 530 (100%) (M+l).

Example-92

I (S,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l-((4methoxyphenyl)sulfonyl) pyrrolidin-2-yl)ethenesulfonamide

I I I

I I

I

I 10

I I

I

I ¹⁵

I I ι²⁰

I I

’H NMR (400 MHz, DMSO-d₆): δ =7.93 (s, IH), 7.79 (d, J = 2.8 Hz, 2H), 7.12 (d, J = 2.0 Hz, 2H), 6.90 (s, IH), 6.85 (s, IH), 6.66 (s, IH), 6.60 (d, J= 5.6 Hz, IH), 6.57 (d, J= 4.4 Hz, IH), 4.4 (m,lH), 3.84 (s, 3H), 3.22 (m, IH), 2.78(t, J = 7.2 Hz, 4H) , 2.70 (t, J = 7.2 Hz, 4H), 1.99 (m, 4H), 1.68 (m, 3H), 1.60 (m, IH); MS (ESI): m/z (%) = 546 (100%) (M+l).

Example-93 (S,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l-((4-fluorophenyl)sulfonyl) pyrrolidin-2-yl)ethenesulfonamide

’H NMR (400 MHz, DMSO-^): δ =8.02 (s, IH), 7.94 (d, J = 2.0 Hz, 2H), 7.47 (d, J = 3.6 Hz, 2H), 6.90 (s, IH), 6.87 (s, IH), 6.68 (d, J= 9.6 Hz, IH), 4.41 (m,lH), 3.36 (m, IH), 2.78(t, J= 7.2 Hz, 4H) , 2.69 (t, J= 7.2 Hz, 4H), 1.99 (m, 4H), 1.68 (m, 3H), 1.60 (m, IH); MS (ESI): m/z (%) = 534 (100%) (M+l).

Example-94 (S,E)-2-(l-((2-cyanophenyl)sulfonyl)pyrrolidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen4-yl)carbamoyl)ethenesulfonamide

I I

I

‘H NMR (400 MHz, DMSO-dJ: δ =8.11 (d, J= 1.2 Hz, 2H), 7.90 (d, J= 1.2 Hz, 2H), 7.83 (s, IH), 6.82 (s, IH), 6.70 (d, J= 14.8 Hz, IH), 6.30 (s, IH), 4.51 (s,lH), 3.32 (s, 2H), 2.77(t, J= 7.2 Hz, 4H), 2.70 (t, J= 7.2 Hz, 4H), 1.92 (m, 4H), 1.80 (m, 2H), 1.74 (m, 2H); MS (ESI): m/z (%) = 541.14 (100%) (M+l).

Example-95 (S,E)-2-(l-(cyclohexylsulfonyl)pyrrolidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)ethenesulfonamide

’H NMR (400 MHz, DMSO-JJ: ô =7.78 (s, IH), 6.85 (s, IH), 6.70 (d, J= 14.8 Hz, IH), 6.41 (s, IH), 4.46 (s,lH), 3.42 (m, IH), 3.08 (s, IH), 2.78(t, J= 7.6 Hz, 4H), 2.70 (t, J= 7.2 Hz, 4H), 2.09 (d, J = 4.8 Hz, IH )1.94 (m, 7H), 1.83 (m, 3H), 1.72 (m, IH), 1.52 (s, IH), 1.32 (m, 3H), 1.24 (s, 2H), 1.08 (s, IH); MS (ESI): m/z (%) = 522.19 (100%) (M+l).

| 15 Example-96 (S,E)-2-(l-(4-fluorobenzyl)pyrrolidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4| yl)carbamoyl)ethenesulfonamide

I I

I

Ή NMR (400 MHz, DMSO-rt₆): δ =8.03 (s, IH), 7.28 (t, J= 6.0 Hz, 2H), 7.06 (t, J= 8.8 Hz, 2H), 6.89 (s, IH), 6.86 (s, IH), 6.62 (m, IH), 3.81 (d, J= 13.2 Hz, 2H), 3.16 (m,2H), 2.68 (t, J = 5.6 Hz, 4H) , 2.62 (t, J = 7.2 Hz, 4H), 2.16 (m, IH), 1.90 (m,lH), 1.85 (m, 4H), 1.70 (m, 2H), 1.55 (m,. IH); MS (ESI): m/z (%) = 484.19 (100%) (M+l).

Example-97 (S,E)-2-(l-((4-cyanophenyl)sulfonyl)pyrrolidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen4-yl)carbamoyI)ethene-l-sulfonamide

’H NMR (400 MHz, DMSO-J_Ô): δ =8.06 (d, J= 8.4 Hz, 2H), 8.01 (t, J= 8.6 Hz, 2H), 7.86 (s, IH), 6.87 (s, IH), 6.80 (d, J = 14.8 Hz, IH), 6.42 (d, J = 9.6 Hz, IH), 4.44 (t, J = 5.6 Hz, IH ), 3.36 (m,2H), 3.18 (m, IH), 2.78 (t, J= 7.2 Hz, 4H), 2.70 (t, J= 7.2 Hz, 4H), 1.92 (m, 4H), 1.67 (m,3H), 1.56 (m, IH); MS (ESI): m/z (%) = 541.15 (100%) (M+l).

Example-98 (S,E)-2-(l-(4-cyanobenzyl)pyrrolidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)ethene-l-sulfonamide

Ή NMR (400 MHz, DMSO-d₆): 3 =8.01 (s, 1H), 7.89 (d, J = 8.4 Hz, 2H), 7.51 (d, J = 8.4 Hz, 2H), 6.97 (d, J = 6.0 Hz, 1H), 6.91 (s, 1H), 6.65 (m, 1H), 3.86 (d, J= 13.6 Hz, 2H), 3.25 (m, 1H) , 2.79 (m, 5H), 2.61 (m, 4H), 2.22 (m, 1H), 2.12 (m, 1H), 1.98 (m, 4H), 1.72 (m, 2H), 1. 76 (m, 1H); MS (ESI): m/z (%) = 491.15 (100%) (M+l).

I

I I

I 1

I I

Example-99 (S,E)-N-((l,2,3,6,7,8-hexahydro-as-indacen-4-yI)carbamoyl)-2-(pyrrolidin-2-yl)ethene-lsulfonamide

’H NMR (400 MHz, DMSO-ti₆): δ =8.90 (s, 1H), 7.59 (s, 1H), 7.26 (s, 1H), 6.98 (d, J1 = 0.8 Hz, 1H), 6.98 (t, J2= 1.2 Hz, 1H), 6.38 (m, 1H), 4.08 (m, 1H ), 3.22 (m,2H), 2.70 (m, 8H), 2.15 (m, 1H), 1.98 (m, 6H), 1.71 (m,lH), 1.56 (m, 1H); MS (ESI): m/z (%) = 372.87 (100%) (M-l).

Example-100 (E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yI)carbamoyl)-2-(piperidin-2-yl)ethene-lsulfonamide

Ή NMR (400 MHz, DMSO-î/₆): δ =7.41 (s, 1H), 6.86 (d, J = 15.6 Hz, 1H), 6.79 (s, 1H), 6.28 (d, J=6.Q Hz, 1H), 3.61 (s,2H), 3.14 (d, J = 12.8 Hz, 1H), 2.81 (t, J = 7.2 Hz, 4H) , 2.70 (t, J= 7.2 Hz, 4H), 1.98 (m, 5H), 1.81 (m,2H), 1.69 (m, 1H), 1.48 (m, 3H); MS (ESI): m/z (%) = 390.13 (100%) (M+l).

Example-101

(E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l-methylpiperidin-2-yl)ethene1-sulfonamide

I I I I I I I I I I I I I I I I

’H NMR (400 MHz, DMSO-ri_é): δ =7.92 (s, IH), 6.89 (s, IH), 6.80 (d, J= 14.8 Hz, IH), 6.42 (d, J= 8.4 Hz, IH), 2.92 (t, J = 5.2 Hz, 2H), 2.82 (t, J = 7.2 Hz, 4H) , 2.72 (t, J = 7.2 Hz, 4H), 2.27 (m, 4H), 1.92 (m, 5H), 1.62 (m, 3H), 1.44 (s, 2H); MS (ESI): m/z (%) = 404.15 (100%) (M+l).

Example-102 (E)-N-((l,2,3?6,7,8-hexahydro-as-mdacen-4-yI)carbamoyl)-2-(l-methylpyrrolidin-2yl)ethene-l-sulfonamide

IH NMR (400 MHz, DMSO-d6): δ =7.83 (s, IH), 7.44 (s, IH), 6.88 (d, J= 14.8 Hz, IH), 6.53 (d, J= 8.0 Hz, IH), 3.13 (s, 3H), 2.82 (t, J= 7.2 Hz, 4H), 2.72 (t, J= 7.2 Hz, 4H) , 2.39 (s, 2H), 2.33 (d, J= 2.0 Hz, 3H), 2.11 (m, 5H), 1.81 (m, 2H), 1.78 (m, IH); MS (ESI): m/z (%) = 390.14 (100%) (M+l).

Example-103 (E)-N-((l,2,3,6,7,8-hexahydro-as-indacen-4-yl)carbamoyl)-2-(l-(methylsulfonyl)pyrrolidin2-yl)ethene-l-sulfonamide

’H NMR (400 MHz, DMSO-d₆): δ =7.87 (s, IH), 7.45 (s, IH), 6.77 (d, J= 14.8 Hz, IH), 6.68 (d, 20 J= 4.8 Hz, IH), 4.48 (t, J= 4.0 Hz, IH), 2.99 (s, 3H), 2.82 (t, J = 12 Hz, 4H) , 2.72 (t, J = 12 Hz, 4H) , 2.11 (m, 5H), 1.81 (m, 3H); MS (ESI): m/z (%) = 454.09 (100%) (M+l).

Example-104 ((E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-(piperidin-2-yl)prop-l-ene-lsulfonamide

’H NMR (400 MHz, DMSO-ûfc): δ =7.44 (s, 1H), 6.79 (s, 1H), 6.47 (d, J= 15.2 Hz, 1H), 6.20 (m,lH), 2.85 (t, J= 72 Hz, 5H), 2.70 (t, J= 7.2 Hz, 4H) , 2.33 (t, J= 1.6 Hz, 2H) , 1.98 (m, 6H), 1.73 (m, 3H), 1.61 (s, 1H), 1.38 (m,2H). 1.24 (s, 1H); MS (ESI): m/z (%) = 404.20 (100%) (M+l).

Example-105 (S,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-methylpyrrolidin-2yl)ethene-l-sulfonamide

’H NMR (400 MHz, DMSO-t/Q: δ =7.52 (s, 1H), 6.88 (d, J= 15.6 Hz, 1H), 6.81 (s, 1H), 6.46 (d, J= 15.6 Hz, 1H), 3.21 (m, 2H ), 3.12 (m,lH), 2.75 (t, J= 7.2 Hz, 4H ), 2.69 (t, J = 7.2 Hz, 4H ), 1.98 (m, 7H), 1.78 (s,2H), 1.38 (s, 3H); MS (ESI): m/z (%) = 390.24 (100%) (M+l).

Example-106 (S,E)-2-(l,2-dimethylpyrrolidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)ethene-l-sulfonamide

I

1H NMR (400 MHz, DMSO-d6): δ =8.04 (s, 1H), 6.93 (s, 1H), 6.73 (d, J= 15.2 Hz, 1H), 6.65 (d, J= 15.2 Hz, 1H), 2.80 (t, J= 7.2 Hz, 4H) , 2.68 (t, J= 7.2 Hz, 4H) , 2.20 (s, 3H), 1.96 (m, 4H), 1.72 (m, 4H), 1.13 (s, 3H); MS (ESI): m/z (%) = 404.25 (100%) (M+l).

Altemateviely, Example 106 was also be prepared as per the procedure described for synthesis of

Intermediate-7b (Example 111) using Intermediate 9 and (S)-l,2-dimethylpyrrolidine-278

Example-107 (E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(indolin-2-yl)ethene-l- sulfonamide

Ή NMR (400 MHz, DMSO-riQ: δ =7.89 (s, 1H), 7.04 (d, J=3.2 Hz, 1H), 6.99 (d, J=6.8 Hz, 1H), 6.93 (d, ,7=8.0 Hz, 1H), 6.82 (d, .7=8.0 Hz, 1H), 6.62 (d, J = 13.8 Hz, 1H), 6.51 (d, J= 7.6 Hz, 2H), 5.95 (s, 1H), 4.4 (t, J=7.2 Hz, 4H), 2.67 (t, J=7.2 Hz, 4H), 1.95 (m, 1H ); MS (ESI): m/z (%) = 10 424.20 (100%) (M+l).

Example-108 tert-butyl(E)-2-(2-(N-((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)sulfamoyl)vinyl)indoline-l-carboxylate

Ή NMR (400 MHz, DMSO-î/Q: δ =8.11 (s, 1H), 7.71 (s, 1H), 7.20 (d, J= 8.8 Hz, 1H), 7.17 (s, 1H), 6.99 (d, Jl= 0.8 Hz, 1H), 6.97 (d, J2= 0.8 Hz, 1H), 6.95 (s, 1H), 6.78 (d, J= 6.0 Hz, 1H), 6.66 (d, J= 15.6 Hz, 1H), 5.10 (m, 1H), 5.12 (m, 1H), 3.50 (m, 1H), 2.80 (t, <7 = 7.2 Hz, 5H), 2.62 (t, J= 7.2 Hz, 4H), 1.96 (m, 5H), 1.45 (s, 10H); MS (ESI): m/z (%) = 522.20 (100%) (M-l).

Example-109 ((S,E)-2-(l-(cyclopropylmethyl)-2-methylpyrrolidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-sindacen-4-yl)carbamoyl)ethene-l-sulfonamide

I ’H NMR (400 MHz, DMSO-d6): δ =7.42 (s, IH), 6.78 (s, IH), 6.57 (d, J= 15.6 Hz, IH), 6.21 (d,

J= 15.2 Hz, IH), 2.93 (t, J= 6.4 Hz, IH) , 2.76 (t, J= 7.2 Hz, 4H), 2.69 (t, J= 7.2 Hz, 4H), 2.33 (t, J = 1.62 Hz, IH), 2.27 (t, J = 6.8 Hz, IH), 2.01 (m, IH), 1.93 (m, 4H), 1.76 (d, J = 5.62 Hz,

IH), 1.68 (d, J= 8.0 Hz, IH), 1.60 (d, J = 4.4 Hz, IH), 1.0 (s, 2H), 0.38 (t, J= 7.6 Hz, 2H); MS (ESI): m/z (%) = 444.26 (100%) (M+l).

Example-110 (S,E)-2-(l-(cyclopropylsulfbnyl)pyrrolidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)ethene-l-sulfonamide

I

I i²⁰

I

’H NMR (400 MHz, DMSO-d6): δ =8.05 (s, IH), 6.94 (s, IH), 6.81 (d, J= 0.8 Hz, IH), 6.77 (d, J= 1.2 Hz, IH), 6.68 (d, J= 15.2 Hz, IH), 4.57 (m, IH), 3.43 (m, IH), 2.80 (t, J = 7.2 Hz, IH) , 2.68 (t, J= 7.2 Hz, 4H), 1.99 (m, 5H), 1.81 (m, 2H), 0.95 (d, J= 6.4 Hz, 4H); MS (ESI): m/z (%) = 480.20 (100%) (M+l).

Example-111 tert-butyl(S,E)-2-(2-(N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)2-methylpyrrolidine-l-carboxyIate

’H NMR (400 MHz, DMSO-J₆): Ô =7.97 (s, IH), 6.91 (s, IH), 6.72 (d, J= 15.2 Hz, IH), 6.54 (d, J= 7.68 Hz, IH), 2.80 (t, J = 7.2 Hz, 4H) , 2.68 (t, J = 7.2 Hz, 5H) , 1.97 (m, 4H), 1.89 (s, 3H), 1.80 (m, 4H), 1.48 (s, 2H0, 1.44 (s, 2H), 1.38 (s, 10H); MS (ESI): m/z (%) = 488.24 (100%) (ΜΙ)·

Example-112 tert-butyl(R,E)-2-(2-(N-((2,6-diisopropylphenyl)carbamoyl)sulfamoyl)vinyl)-2methylpyrrolidine-l-carboxylate

Ή NMR (400 MHz, DMSO-^): δ = 10.55 (s, 1H), 7.89 (d, J= 16.0 Hz, 1H), 7.27 (t, J= 7.6 Hz, 5 1H), 7.16 (d, J= 7.6 Hz, 2H), 6.89 - 6.79 (m, 1H), 6.56 - 6.49 (m, 1H), 3.39 - 3.35 (m, 2H), 3.05

- 3.00 (m, 2H), 1.93 - 1.90 (m, 1H), 1.83 - 1.77 (m, 2H), 1.69 - 1.64 (m, 1H), 1.44 (s, 3H), 1.37 (s, 9H), 1.13 (d, J = 6.8 Hz, 12H); MS (ESI): m/z (%) = 492.24 (100%) (M-l)'.

Example-113 (R,E)-N-((2,6-diisopropylphenyl)carbamoyl)-2-(2-methylpyrrolidin-2-yl)ethene-lsulfonamide 2,2,2-trifluoroacetate

’H NMR (400 MHz, DMSO-î/₆): δ = 11.10 (bs, 1H), 9.08 (bs, 2H), 8.24 (s, 1H), 7.27 (t, J = 7.6 Hz, 1H), 7.16 (d, J= 7.6 Hz, 2H), 7.11 (d, J= 15.6 Hz, 1H), 7.05 (d, J= 15.2 Hz, 1H), 3.33 - 3.29 (m, 2H), 3.07 - 3.00 (m, 2H), 2.13 - 1.83 (m, 4H), 1.46 (s, 3H), 1.12 (d, J = 6.8 Hz, 12H); MS (ESI): m/z (%) = 392.22 (100%) (M-TFA)⁺;

Example-114 (R,E)-N-((2,6-diisopropylphenyl)carbamoyl)-2-(l,2-dimethylpyrrolidin-2-yI)ethene-lsulfonamide

’H NMR (400 MHz, DMSO-t/₆): δ = 10.45 (bs, 1H), 7.83 (s, 1H), 7.25 (t, J= 7.6 Hz, 1H), 7.15 (d,

J= 8.0 Hz, 2H), 6.73 (d, J= 15.2 Hz, 1H), 6.68 (d, J= 15.6 Hz, 1H), 3.33 - 3.22 (m, 2H), 2.83 20

2.80 (m, 1H), 2.73 - 2.67 (m, 1H), 2.15 (s, 3H), 1.80 - 1.69 (m, 4H), 1.18 - 1.10 (m, 15H); MS (ESI): m/z (%) = 408.23 (100%) (M+H)⁺.

Example-115 (S,E)-2-(l-ethyl-2-methylpyrrolidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)ethene-l-sulfonamide

I I

I

I g

I I

I

I I

I

I ¹⁵

I

I ²⁰

I

I I

’H NMR (400 MHz, DMSO-d₆): δ = 10.45 (bs, 1H), 8.05 (bs, 1H), 6.93 (s, 1H), 6.74 (d, J= 15.2 Hz, 1H), 6.68 (d, J = 15.6 Hz, 1H), 2.96 - 2.89 (m, 2H), 2.80 (t, J = 7.2 Hz, 4H), 2.67 (t, J= 7.6 Hz, 6H), 1.96 (quin, J= 7.2 Hz, 4H), 1.79 - 1.72 (m, 4H), 1.14 (s, 3H), 1.02 (t, J = 6.4 Hz, 3H); MS (ESI): m/z (%) = 418.16 (100%) (M+H)⁺.

ExampIe-116

Bissodium (R,E)-((2-(l,2-dimethylpyrrolidm-2-yl)vmyl)sulfonyl)((l,2,3,5,6,7-hexahydro-sindacen-4-yI)carbamoyl)amide

’H NMR (400 MHz, DMSO-îZ₆): δ = 6.76 (s, 1H), 6.56 (d, J = 15.6 Hz, 1H), 6.20 (d, J= 15.6 Hz, 1H), 2.75 (t, J= 7.6 Hz, 5H), 2.69 (t, J= 7.2 Hz, 4H), 2.64 - 2.59 (m, 1H), 2.08 (s, 3H), 1.90 (quin, J = 7.2 Hz, 4H), 1.74 - 1.68 (m, 3H), 1.62 - 1.61 (m, 1H), 1.01 (s, 3H); MS (ESI): m/z (%) = 404.17 (100%) (M-2Na)⁺.

Example-117

Sodium(R,E)-((2-(l,2-dimethylpyrrolidin-2-yl)vinyl)sulfonyl)((l,2,3,5,6,7-hexahydro-sindacen-4-yl)carbamoyl)amide

Ή NMR (400 MHz, DMSO-î7₆): δ = 7.36 (s, 1H), 6.77 (s, 1H), 6.57 (d,J= 15.6 Hz, 1H), 6.19 (d,

J= 15.6 Hz, 1H), 2.76 (t, J = 7.2 Hz, 5H), 2.69 (t, J= 72 Hz, 4H), 2.64 - 2.59 (m, 1H), 2.08 (s,

3H), 1.91 (quin, J= 7.6 Hz, 4H), 1.74-1.68 (m, 3H), 1.62-1.60 (m, IH), 1.01 (s, 3H); MS (ESI):

m/z (%) = 404.17 (100%) (M-Na)⁺.

Example-118 tert-butyl(S,E)-2-(2-(N-((2,6-diisopropylphenyl)carbamoyl)sulfamoyl)vinyl)-2methylpyrrolidine-l-carboxylate

’H NMR (400 MHz, DMSO-J₆): δ = 10.55 (s, IH), 7.89 (s, IH), 7.27 (t, J = 7.6 Hz, IH), 7.16 (d, J= 7.6 Hz, 2H), 6.84 (d, J= 15.6 Hz, IH), 6.56 (d, J= 15.6 Hz, IH), 3.37 (t, J= 6.4 Hz, 2H), 3.03 (t, J = 6.4 Hz, 2H), 1.91 - 1.90 (m, IH), 1.83 - 1.77 (m, 2H), 1.69 - 1.64 (m, IH), 1.44 (s, 3H), 1.37 (s, 9H), 1.13 (d, J= 6.8 Hz, 12H); MS (ESI): m/z (%) = 494.31 (10%) (M+l)⁺.

Example-119 (S,E)-N-((2,6-diisopropylphenyl)carbamoyl)-2-(2-methylpyrrolidin-2-yI)ethene-lsulfonamide 2,2,2-trifluoroacetate

’H NMR (400 MHz, DMSO-d₆): δ = 11.10 (bs, IH), 9.10 (bs, 2H), 8.28 (s, IH), 7.27 (t, J = 7.6 Hz, IH), 7.16 (d, J= 7.6 Hz, 2H), 7.12 (d, J= 15.6 Hz, IH), 7.00 (d, J= 15.2 Hz, IH), 3.35 - 3.30 (m, IH), 3.24-3.20 (m, IH), 3.07 - 3.00 (m, 2H), 2.10-1.98 (m, 2H), 1.93 - 1.85 (m, 2H), 1.46 (s, 3H), 1.12 (d, J= 6.8 Hz, 12H); MS (ESI): m/z (%) = 394.27 (100%) (M-TFA)⁺.

Example-120 (S,E)-N-((2,6-diisopropylphenyl)carbamoyl)-2-(l,2-dimethylpyrrolidin-2-yl)ethene-lsulfonamide

I I

I

B

I 1¹⁰

I

I ¹⁵

I

’H NMR (400 MHz, DMSO-d₆): δ = 10.10 (bs, IH), 7.92 (s, IH), 7.25 (t, J= 7.6 Hz, IH), 7.13 (d, J= 7.6 Hz, 2H), 6.68 (d, J= 14.8 Hz, IH), 6.61 (d, J= 15.6 Hz, IH), 3.07 - 3.02 (m, 2H), 2.85 2.83 (m, IH), 2.69 - 2.67 (m, IH), 2.14 (s, 3H), 1.82 - 1.66 (m, 4H), 1.12 - 1.07 (m, 15H); MS (ESI): m/z (%) = 408.23 (100%) (M+H)⁺.

Example-121 (R,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-methyl-l-(oxetan-3yl)pyrroIidin-2-yl)ethene-l-sulfonamide

’H NMR (400 MHz, DMSO-d₆): δ = 10.39 (bs, IH), 8.14 (s, IH), 6.95 (s, IH), 6.71 - 6.59 (m, 2H), 4.65 (t, J=6.4Hz, IH), 4.55 (t, J=6.8Hz, IH), 4.45 - 4.39 (m, 2H), 4.05 - 3.98 (m, IH), 3.13 - 3.07 (m, IH), 3.02 - 2.99 (m, IH), 2.81 (t, ,/=7.2Hz, 4H), 2.69 (t, J=7.2Hz, 4H), 2.01 - 1.63 (m, 8H), 1.03 (s, 3H); MS (ESI): m/z (%) = 446.24 (100%) (M+H)⁺.

Example-122 tert-butyl (S,E)-2-(2-(N-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)sulfamoyl)vinyl)-2methylpyrrolidine-l-carboxylate

’H NMR (400 MHz, DMSO-d₆): δ = 10.61 (bs, IH), 7.89 - 7.85 (m, IH), 6.97 (d, J=10Hz, 2H), 6.90 - 6.79 (m, IH), 6.55 - 6.49 (m, IH), 3.38 - 3.35 (m, 2H), 3.03 - 3.01 (m, 2H), 1.92 - 1.64 (m, 3H), 1.47 - 1.43 (m, 3H), 1.36 (s, 9H), 1.11 (d, J=7.2Hz, 12H); MS (ESI): m/z (%) = 512.30 (8%) (M+H)⁺, 534.29 (8%) (M+Na)⁺.

Example-123 (S,E)-N-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)-2-(2-methylpyrrolidin-2-yl)ethene-lsulfonamide 2,2,2-trifluoroacetate

I I I 1 I I I I 1 I I I

Ή NMR (400 MHz, DMSO-d₆): <5=11.11 (bs, 1H), 9.08 (bs, 2H), 8.25 (s, 1H), 7.09 (d, J=15.6Hz, 1H); 7.00-6.95 (m, 3H), 3.42 - 3.40 (m, 1H), 3.21 - 3.17 (m, 1H), 3.06-2.99 (m, 2H), 2.10 - 1.83 (m, 4H), 1.45 (s, 3H), 1.11 (d, J=5.6Hz, 12H); MS (ESI): m/z (%) = 412.23 (100%) (M+H)⁺;

Example-124 (S,E)-2-(l,2-dimethylpyrrolidin-2-yl)-N-((4-fluoro-2,6diisopropylphenyl)carbamoyl)ethene-l-sulfonamide

’H NMR (400 MHz, DMSO-d₆): δ = 7.87 (s, 1H), 6.93 (d, J=10Hz, 2H); 6.66 - 6.92 (m, 2H), 3.10 - 3.04 (m, 2H), 2.83 - 2.67 (m, 2H), 2.15 (s, 3H), 1.76 - 1.69 (m, 4H), 1.11 - 1.09 (m, 15H); MS (ESI): m/z (%) = 426.29 (100%) (M+H)⁺;

! ⁵

Example-125

J (E)-2-(l-acetylazetidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-lsulfonamide

’H NMR (400 MHz, DMSO-î/₆): δ = 10.40 (br s, IH), 8.15 - 8.09 (m, IH), 6.96 - 6.71 (m, 3H),

5.14-4.87 (m, 1H),2.81 (t,J=12 Hz, 4H), 2.77-2.64 (m, 4H), 2.60-2.56 (m, 1H),2.O1 - 1.94 (m, 5H), 1.78 (s, 2H), 1.66 (s, IH); MS (ESI): m/z (%) = 404.11 (100%) (M+H)⁺.

Example-126 tert-butyl(R,E)-(2-(2-(2-(N-((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)sulfamoyl)vinyl)pyrrolidin-l-yl)ethyl)(methyl)carbamate

’H NMR (400 MHz, DMSO-rf₆): δ = 10.38 (brs, IH), 8.05 (s, IH), 6.95 (s, IH), 6.80 (d, J= 14.4 Hz, IH), 6.63 (dd, J= 14.8 Hz J= 6.8 Hz, IH), 3.23 - 3.07 (m, 4H), 2.81 (t,J = 7.2 Hz, 4H), 2.72 - 2.58 (m, 8H), 2.33 - 2.18 (m, 2H), 2.03 - 1.91 (m, 5H), 1.83 - 1.62 (m, 2H), 1.55 - 1.46 (m, IH), 1.37 (s, 9H); MS (ESI): m/z (%) = 533.21 (100%) (M+H)⁺.

Example-127 (S,E)-2-(l-aIlylpyrrolidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)ethene-l-sulfonamide

’H NMR (400 MHz, DMSO-îZ₆): δ = 8.07 (s, IH), 6.95 (s, IH), 6.84 (d, J = 15.2 Hz, IH), 6.64 (dd, J= 15.2 Hz, J = 7.2 Hz, IH), 5.85 - 5.80 (m, IH), 5.19 - 5.14 (m, IH), 5.09 - 5.07 (m, IH), 3.28 - 3.27 (m, IH), 3.21 - 3.15 (m, IH), 3.05 - 3.01 (m, IH), 2.86 - 2.78 (m, 4H), 2.73 - 2.64 (m, 4H), 2.60-2.56 (m, IH), 2.30-2.23 (m, IH), 2.07 - 1.97 (m, 5H), 1.80- 1.70 (m, 2H), 1.59 - 1.50 (m, IH); MS (ESI): m/z (%) = 416.14 (100%) (M+H)⁺.

Example-128 (S,E)-2-(l-(lH-benzo[d]imidazole-6-carbonyl)pyrrolidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-sindacen-4-yl)carbamoyl)ethene-l-sulfonamide

Ή NMR (400 MHz, DMSO-</₆): δ = 12.65 (brs, 1H), 8.40 (s, 1H), 8.04 (s, 1H), 7.85 - 7.69 (m, 5 1H), 7.67 - 7.50 (m, 1H), 7.49 - 7.23 (m, 1H), 6.92 (s, 1H), 6.91 - 6.53 (m, 2H), 4.98 - 4.68 (m,

1H), 3.72 - 3.53 (m, 1H), 3.50 - 3.42 (m, 1H), 2.86 - 2.72 (m, 4H), 2.66 (t, J= 6.8 Hz, 4H), 2.29 - 2.12 (m, 1H), 1.98 - 1.77 (m, 7H); MS (ESI): m/z (%) = 520.24 (90%) (M+H)⁺.

Example-129 (S,E)-2-(l-(cyclopropylsulfonyl)-2-methylpyrrolidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s10 indacen-4-yl)carbamoyl)ethene-l-sulfonamide

Ή NMR (400 MHz, DMSO-</₆): δ = 8.01 (s, 1H), 6.94 (s, 1H), 6.86 (d, J = 15.2 Hz, 1H), 6.71 (dd, J= 14.8 Hz, J= 6.4 Hz, 1H), 3.46 (t, J= 6.8 Hz, 2H), 2.80 (t, J= 7.2 Hz, 4H), 2.68 (t, J= 7.2 Hz, 4H), 2.63 -2.56 (m, 2H), 2.07 - 1.91 (m, 6H), 1.90- 1.74 (m, 1H), 1.57 (s, 3H), 0.97 - 0.89 (m, 4H); MS (ESI): m/z (%) = 494.22 (100%) (M+H)⁺.

Example-130 (S,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l-(4methoxybenzyl)pyrrolidin-2-yl)ethene-l-sulfonamide

I I I 1

I I I

I I 1

I I

I I ’H NMR (400 MHz, DMSO-^): δ =8.01 (s, IH), 7.20 (d, J = 8.4 Hz, 2H), 7.16 (d, J = 8.4 Hz, 2H), 6.97 (d, J= 6.0 Hz, IH), 6.91 (s, IH), 6.65 (m, IH), 3.86 (d, J= 13.6 Hz, 2H), 3.25 (m, IH) , 2.80 (t, J= 7.2 Hz, IH) , 2.68 (t, J = 7.2 Hz, 4H), 2.12 (m, IH), 1.98 (m, 4H), 1.72 (m, 2H), 1. 76 (m, IH); MS (ESI): m/z (%) = 496.33 (100%) (M+l).

Example-131 tert-butyl 5-((R)-2-((E)-2-(N-((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)sulfamoyl)vinyl)pyrrolidin-l-yl)hexahydrocyclopenta[c]pyrrole-2(lH)carboxylate

’H NMR (400 MHz, DMSO-î/₆): δ = 10.34 (brs, IH), 8.03 (s, IH), 6.94 (s, IH), 6.84 (d, J = 14.8 Hz, IH), 6.66 (dd, J= 14.8 Hz, J= 7.6 Hz, IH), 3.48 - 3.35 (m, IH), 3.14 - 3.07 (m, 2H), 3.99 2.88 (m, 2H), 2.81 (t, J= 6.8 Hz, 4H), 2.69 - 2.66 (m, 5H), 2.47 - 2.39 (m, 3H), 2.01 - 1.91 (m, 7H), 1.81- 1.69 (m, 2H), 1.66 - 1.50 (m, 2H), 1.38 (s, 9H), 1.31-1.08 (m, 2H); MS (ESI): m/z (%) = 585.29 (100%) (M+H)⁺.

Example-132 (E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-((2R)-l-(octahydrocyclopenta[c]pyrrol-5-yl)pyrrolidin-2-yl)ethene-l-sulfonamide 2,2,2-trifluoroacetate

Ν Η ,ο Ο

N N

H H

Ή NMR (400 MHz, DMSO-î/ô): δ = 10.54 (brs, 1Η), 9.08 (s, 1H), 8.57 (s, 2H), 7.24 - 7.22 (m, 1H), 6.97 (s, 1H), 6.91 - 6.81(m, 1H), 4.50 - 4.28 (m, 1H), 3.63 - 3.45 (m, 2H), 3.39 - 3.16 (m, 2H), 3.17 - 2.93 (m, 2H), 2.82 (t, J= 7.2 Hz, 4H), 2.77 - 2.64 (m, 5H), 2.38 - 2.09 (m, 3H), 2.01 - 1.91 (m, 6H), 1.90- 1.78 (m, 1H), 1.62-1.39 (m, 2H), 1.05 - 1.03 (m, 2H); MS (ESI): m/z(%) = 485.25 (100%) (M+H)⁺.

Example-133 (E)-2-(l-(cyclopropylsulfonyl)azetidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)ethene-l-sulfonamide ^N'°O

Ο θ ' A 'N^N

H H

’H NMR (400 MHz, DMSO-d₆): δ = 10.54 (brs, 1H), 8.12 (s, 1H), 6.97 - 6.93 (m, 2H),6.86 (dd, J= 15.2 Hz, J= 4.8 Hz, 1H), 5.08 - 5.02 (m, 1H), 4.05 - 3.99 (m, 1H), 3.66 - 3.61 (m, 1H), 2.81 (t, J= 7.2 Hz, 4H), 2.78 - 2.73 (m, 1H), 2.68 (t, J= 7.2 Hz, 4H), 2.46 - 2.43 (m, 1H), 2.15-2.10 (m, 1H), 2.01- 1.94 (m, 4H), 1.05 - 0.98 (m, 2H), 0.94 - 0.90 (m, 2H); MS (ESI): m/z (%) = 466.08 (100%) (M+H)⁺.

Example-134 (S,E)-N-((2,6-diisopropylphenyl)carbamoyl)-2-(l-(thiazol-2-yl)pyrrolidin-2-yl)ethene-lsulfonamide

1 I

I I I

I I

I I I ’H NMR (400 MHz, DMSO-d₆): δ = 10.59 (bs, 1H), 7.92 (s, 1H), 7.28 - 7.25 (m, 1H), 7.16-7.13 (m, 3H), 6.85 - 6.76 (m, 2H), 6.66 (d, J=15.2Hz, 1H), 4.57 - 4.55 (m, 1H), 3.51 - 3.50 (m, 1H), 3.39 - 3.37 (m, 1H), 3.05 - 2.98 (m, 2H), 2.23 - 2.19 (m, 1H), 1.99 - 1.83 (m, 3H), 1.11 (d, J=6.8Hz, 12H); MS (ESI): m/z (%) = 463.16 (100%) (M+H)⁺.

Example-135 tert-butyl(S,E)-(2-(2-(2-(N-((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)sulfamoyl)vinyl)-2-methylpyrrolidin-l-yl)ethyl)(methyl)carbamate

’H NMR (400 MHz, DMSOU₆): δ = 10.37 (bs, 1H), 8.06 (s, 1H), 6.95 (s, 1H), 6.72 (d, J = 15.6 Hz, 1H), 6.66 (d, J = 15.6 Hz, 1H), 3.2 - 3.17 (m, 1H), 2.81 (t, J= 6.8 Hz, 4H), 2.68 - 2.65 (m, 8H), 2.43-2.42 (m, 1H), 1.96 (quin, J= 7.2 Hz, 4H), 1.75 - 1.65 (m, 4H), 1.41 - 1.37 (m, 12H), 1.1 (s, 3H); MS (ESI): m/z (%) = 547.32 (100%) (M+H)⁺.

Example-136 potassium (R,E)-((2-(l,2-dimethylpyrrolidin-2-yl)vinyl)sulfonyl)((l,2,3,5,6,7-hexahydro-sindacen-4-yl)carbamoyl)amide

’H NMR (400 MHz, DMSOUQ: δ = 7.33 (s, 1H), 6.77 (s, 1H), 6.58 (d,J = 15.6 Hz, 1H), 6.18 (d, J= 15.6 Hz, 1H), 2.77 - 2.72 (m, 5H), 2.69 (t, J= 7.2 Hz, 4H), 2.64 - 2.58 (m, 1H), 2.08 (s, 3H),

1.90 (quin, J= 7.6 Hz, 4H), 1.75 - 1.70 (m, 3H), 1.62 - 1.60 (m, 1H), 1.01 (s, 3H); MS (ESI): m/z (%) = 404.21 (100%) (M-K)⁺.

Example-137 tert-butyl(E)-(2-(2-(2-(N-((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)sulfamoyl)vinyl)azetidin-l-yl)ethyl)(methyl)carbamate

Οχ zO 9 /SC X

N N

H H

N-^Boc ’H NMR (400 MHz, DMSO-î/₆): δ = 8.03 (s, 1H), 6.94 (m, 1H), 6.85 - 6.64 (m, 2H), 3.88 - 3.72 (m, 1H), 2.96 - 2.88 (m, 1H), 2.80 (t, J = 7.2 Hz, 4H), 2.75 - 2.71 (m, 4H), 2.67 (t, J = 7.2 Hz, 4H), 2.61 -2.54 (m, 1H), 2.46-2.40 (m, 1H), 2.25-2.19 (m, 1H), 1.99 - 1.92 (m, 2H), 1.41 1.38 (m, 12H); MS (ESI): m/z (%) = 519.26 (90%) (M+H)⁺, 517.20 (90%) (M-l).

Example-138 (S,E)-2-(l-(cycIohexylmethyl)-2-methylpyrrolidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-sindacen-4-yl)carbamoyl)ethene-l-sulfonamide

_ZO i sC X

N N

H H

’H NMR (400 MHz, DMSO-î/₆): δ = 10.36 (brs, 1H), 8.04 (s, 1H), 6.95 (m, 1H), 6.78 - 6.62 (m, 2H), 2.81(t, J= 7.2 Hz, 4H), 2.68 (t, J= 7.2 Hz, 4H), ), 2.65 - 2.55 (m, 1H), 2.26 - 2.02 (m, 2H), 2.00-1.91 (m, 5H), 1.86-1.71 (m, 4H), 1.70-1.50 (m, 5H), 1.43-1.24 (m, 1H), 1.23-1.13 (m, 2H), 1.12-1.00 (m, 4H), 0.86 - 0.67 (m, 2H); MS (TOF): m/z (%) = 486.2891 (100%) (M+H)⁺, 484.2571 (100%) (M-l).

Example-139

Sodium(R,E)-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)((2-(l-(tetrahydro-2Hthiopyran-4-yl)pyrroIidin-2-yl)vinyl)sulfonyl)amide ‘H NMR (400 MHz, DMSO-î/ô): δ = 7.31 (s, 1H), 6.76 (s, 1H), 6.63 (d, J = 15.2 Hz, 1H), 6.06 (dd, J = 15.2 Hz, J = 7.6 Hz, 1H), 3.43 - 3.36 (m, 1H), 2.87 - 2.64 (m, 10H), 2.65 - 2.42 (m, 5H),

2.03 - 1.84 (m, 7H), 1.68 - 1.43 (m, 5H); MS (ESI): m/z (%) = 476.25 (100%) (M+H)⁺, 474.20 (100%) (M-l).

Example-140 sodium(R,E)-((2-(l-cyclohexylpyrrolidiii-2-yl)vmyl)sulfonyl)((l,2,3,5,6,7-hexahydro-sindacen-4-yl)carbamoyl)amide

Ή NMR (400 MHz, DMSO-*): δ = 7.33 (s, 1H), 6.77 (s, 1H), 6.63 (d, J = 15.2 Hz, 1H), 6.09 (dd, J = 15.2 Hz, J = 7.6 Hz, 1H), 3.34 - 3.42 (m, 1H), 2.84 - 2.79 (m, 1H), 2.76 (t, J= 7.2 Hz, 4H), 2.70 (t, J=1.2Hz,AH), 2.41-2.31 (m, 1H), 1.94- 1.80 (m, 5H), 1.75-1.61 (m, 7H), 1.54 - 1.41 (m, 2H), 1.24 - 1.07 (m, 5H); MS (TOF): m/z (%) = 458.2811 (100%) (M+H)⁺.

Example-141 sodium(S,E)-((2,6-diisopropylphenyl)carbamoyl)((2-(l,2-dimethylpyrrolidin-2yl)vinyl)sulfonyl)amide

’H NMR (400 MHz, DMSO-^): δ = 7.24 (s, 1H), 7.11 (t, J = 8.4 Hz, 1H), 7.04 (d, J = 7.6 Hz, 2H), 6.54 (d, J = 15.6 Hz, 1H), 6.21 (d, J = 16.0 Hz, 1H), 3.23 - 3.16 (m, 2H), 2.74 - 2.67 (m,

IH), 2.65 -2.59 (m, IH), 2.08 (s, 3H), 1.75-1.71 (m, 3H), 1.61 - 1.59 (m, IH), 1.1 (d, J = 6A Hz, 12H), 1.0 (s, 3H); MS (ESI): m/z (%) = 408.25 (100%) (M-Naf.

Example-142 sodium(R,E)-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)((2-(l-methylpyrrolidin-25 yl)vinyl)sulfonyl)amide ’H NMR (400 MHz, DMSO-J₆): δ = 7.37 (s, IH), 6.77 (s, IH), 6.64 (d, J= 15.2 Hz, IH), 6.07 (d, J= 15.2 Hz, IH), 3.0 - 2.95 (m, IH), 2.76 (t, J= 7.2 Hz, 4H), 2.69 (t, J= 7.2 Hz, 4H), 2.59 - 2.53 (m, IH), 2.14 (s, 3H), 2.13-2.06 (m, 2H), 1.91 (quin, J= 7.2 Hz, 4H), 1.73 - 1.60 (m, 3H), 1.54 10 - 1.49 (m, IH); MS (ESI): m/z (%) = 390.20 (100%) (M-Na)⁺.

Example-143 potassium(R,E)-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)((2-(l-methylpyrroIidin2-yl)vinyl)sulfonyl)amide ’H NMR (400 MHz, DMSO-t/₆): δ = 7.31 (s, IH), 6.76 (s, IH), 6.67 (d, J= 15.2 Hz, IH), 6.03 6.01 (m, IH), 2.97 (bs, IH), 2.76 (bs, 4H), 2.69 (bs, 4H), 2.14 - 2.08 (m, 4H), 1.91 (bs, 5H), 1.68 (bs, 3H), 1.49 (bs, IH); MS (ESI): m/z (%) = 390.20 (100%) (M-K)⁺.

Example-144 sodium(S,E)-((2-(l,2-dimethylpyrrolidin-2-yl)vinyl)sulfonyl)((l,2,3,5,6,7-hexahydro-sindacen-4-yl)carbamoyl)amide

IH NMR (400 MHz, DMSO-d6): δ =7.33 (s, IH), 6.77 (s, IH), 6.56 (d, J= 15.2 Hz, IH), 6.16 (d,

J= 16 Hz, IH), 2.76 (t, J= 7.2 Hz, 4H), 2.69 (t, J= 7.2 Hz, 4H) , 2.62 (m, IH), 2.08 (s, 3H), 1.90 (m, 4H), 1.72 (m, 4H), 1.60 (m, 3H), 1.01 (s, 3H); MS (ESI): m/z (%) = 404.20 (100%) (M+l).

Example-145 sodium(S,E)-((2-(l-ethylpyrrolidin-2-yl)vinyl)sulfonyl)((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)amide

’H NMR (400 MHz, DMSO-d₆): δ = 7.36 (s, IH), 6.77 (s, IH), 6.61 (d, J=15.2Hz, IH); 6.05 (dd, J=8.0Hz, J=15.2Hz, IH); 3.10 - 3.05 (m, IH), 2.78 - 2.65 (m, 10H), 2.12 - 1.85 (m, 7H), 1.71 1.66 (m, 2H), 1.49 - 1.44 (m, IH), 0.98 (t, J=7.2Hz, 3H); MS (ESI): m/z (%) = 426.20 (50%) (M+H)⁺.

g Example-146 (S,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l-(2| hydroxyethyl)pyrrolidin-2-yl)ethene-l-sulfonamide

I fl 15 OH

IH NMR (400 MHz, DMSO-d6): δ =7.90 (s, IH), 6.90 (s, IH), 6.84 (d, J= 15.8 Hz, IH), 6.51 (d, | J= 14.8 Hz, IH), 4.57 (s, IH), 3.57 (d, J = 8.8 Hz, 2H), 3.17 (s, 2H), 2.80 (t, J = 7.2 Hz, IH) , * 2.72 (t, J= 7.2 Hz, 4H), 2.33 (d, J= 1.6 Hz, 2H), 1.96 (m, 4H), 1.91 (s, 2H), 1.72 (m, 2H), 1.56 g (m, IH); MS (ESI): m/z (%) = 420.23 (100%) (M+l).

f Example-147 tert-butyl(E)-2-(2-(N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yI)carbamoyI)sulfamoyl)vinyl)-2B methylazetidine-l-carboxylate

Example 147 was prepared as per the procedure described for synthesis of Intermediate-3a using

Intermediate-12, together with conventional techniques known to those skilled in the art of organic synthesis.

Ή NMR (400 MHz, DMSO-îZ₆): δ = 10.47 (br s, IH), 8.12 (s, IH), 6.96 (s, IH), 6.92 (d, J= 15.2 Hz, IH), 6.70 (d, J = 15.2 Hz, IH), 3.82 - 3.61 (m, 2H), 2.81 (t, J = 7.2 Hz, 4H), 2.68 (t, J= 6.8 Hz, 4H), 2.20 - 2.08 (m, 2H), 2.00 - 1.93 (m, 4H), 1.52 (s, 3H), 1.38- 1.33 (m, 9H); MS (TOF): m/z (%) = 498.2359 (90%) (M+Na)⁺, 474.2308 (100%) (M-l).

Example-148 (E)-2-(l,2-dimethylazetidin-2-yl)-N-((l,2,3,50,6,7-hexahydro-s-indacen-4yl)carbamoyl)ethene-l-sulfonamide

’H NMR (400 MHz, DMSO4): δ = 7.91 (s, IH), 6.91 (s, IH), 6.79(d, J= 14.8 Hz, IH), 6.72 (d, J = 15.2 Hz, IH), 3.33 - 3.16 (m, 2H), 2.79 (t, J= 7.2 Hz, 4H), 2.68 (t, J = 7.2 Hz, 4H), 2.22 (s, 3H), 2.18 - 2.11 (m, IH), 2.00 - 1.91 (m, 5H), 1.34 (s, 3H); MS (TOF): m/z (%) = 390.2279 (70%) (M+H)⁺, 388.2130 (100%) (M-l).

Example-149 tert-butyl(S,E)-2-ethyl-2-(2-(N-((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)sulfamoyl)vinyl)pyrrolidine-l-carboxylate

’H NMR (400 MHz, DMSO-t/₆): δ =10.38 (s, IH), 8.0 (d, J = 4.4 Hz, IH), 6.99 (s, IH), 6.89 (d, J= 15.2 Hz, IH), 6.50 (d, J= 15.2 Hz, IH), 3.50 (m, IH), 3.25 (m, IH), 2.81 (t, J= 7.2 Hz, 4H), 95

2.65 (t, J = 7.2 Hz, 5H) , 1.95 (m, 4H), 1.77 (s, 3H), 1.80 (m, 4H), 1.58 (m, IH), 1.36 (d, J = 10

Hz, 9H), 0.81 (m, 3H); MS (ESI): m/z (%) = 502.23 (100%) (M-l).

Example-150 tert-butyl(S,E)-2-(2-(N-((l,2,3,6,7,8-hexahydro-as-indacen-4yl)carbamoyl)sulfamoyl)vinyl)-2-methylpyrrolidine-l-carboxylate

N N

N, ^{H H}

Boc ’H NMR (400 MHz, DMSO-îZ₆): δ =7.95 (s, IH), 7.42 (d, J = 15.2 Hz, IH), 6.79 (d, J= 7.68 Hz, IH), 6.55 (d, J= 15.2 Hz, IH), 3.39 (m, 2H), 2.80 (q, J= 7.6 Hz, 4H), 2.70 (t, J= 7.2 Hz, 5H) , 2.01 (m, 6H), 1.82 (m, 2H), 1.68 (m, IH), 1.46 (d, J= 10 Hz, 3H), 1.38 (s, 3H), 1.32 (s, 7H); MS (ESI): m/z (%) = 488.24 (100%) (M-l).

Example-151 (S,E)-2-(2-ethylpyrrolidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)ethene-l-sulfonamide 2,2,2-trifluoroacetate

’H NMR (400 MHz, DMSO-d₆): δ =9.19 (s, IH), 90.6 (s, IH), 8.39 (s, IH), 7.56 (s, IH), 7.11 (s, IH), 6.97 (s, IH), 6.84 (d, J= 15.6 Hz, IH), 3.32 (s, IH), 3.17 (s, IH), 2.81 (t, J= 6.8 Hz, 4H ), 2.65 (t, J = 7.2 Hz, 4H ), 2.24 (m, 1H),1.96 (m, 6H), 1.83 (m, 4H), 0.85 (q, J = 6.8 Hz, 3H); MS (ESI): m/z (%) = 404.3 (100%) (M+l).

Example-152 (S,E)-N-((l,2,3,6,7,8-hexahydro-as-indacen-4-yl)carbamoyl)-2-(2-methylpyrrolidin-2yl)ethene-l-sulfonamide 2,2,2-trifluoroacetate

I I

I

I I

I

I 10

I

I I

I

Ή NMR (400 MHz, DMSO-Λ): ί =7.39 (s, 1H), 7.11 (d, J = 15.6 Hz, 1H), 7.02 (d, 7 = 15.6 Hz, 1H), 2.79 (q, J-7.6 Hz, 5H ),2.71 (1,7-7.2 Hz, 4H ), 2.01 (m, 9H), 1.47 (q, 7=7.2 Hz, 3H ), 1.04 (d, J= 6.0 Hz, 2H); MS (ESI): m/z (%) = 390.24 (100%) (M+l).

Example-153 (S,E)-2-(l,2-dimethylpyrrolidin-2-yl)-N-((l,2,3,6,7,8-hexahydro-as-mdacen-4yl)carbamoyl)ethene-l-sulfonamide

1H NMR (400 MHz, DMSO-d6): δ =7.88 (s, 1H), 7.43 (s, 1H), 6.72 (d, J= 15.2 Hz, 1H), 6.62 (d, J= 15.2 Hz, 1H), 3.09 (q, J = 7.2 Hz, 4H) , 2.75 (m, 4H), 2.60 (t, J= 6.8 Hz, 4H) , 2.21 (s, 3H), 1.95 (m, 4H), 1.78 (t, J =10 Hz, 4H) , 1.17 (m, 8H); MS (ESI): m/z (%) = 404.30 (100%) (M+l).

Example-154 tert-butyl(R,E)-2-(2-(N-((l,2,3,6,7,8-hexahydro-as-indacen-4yl)carbamoyl)sulfamoyl)viny!)-2-methylpyrrolidine-l-carboxylate

Boc

’H NMR (400 MHz, DMSO-îZ₆): δ = 10.85 (s, 1H), 7.98 (s, 1H), 7.43 (d, J = 9.2 Hz, 1H), 6.89 (q, J= 15.6 Hz, 1H), 6.58 (d, J= 15.2 Hz, 1H), 3.42 - 3.36 (m, 2H), 2.81 - 2.74 (m, 4H), 2.70 (t, J= 7.2 Hz, 4H), 2.21 - 1.94 (m, 5H), 1.88 - 1.75 (m, 2H), 1.72 - 1.66 (m, 1H), 1.48 (d, J = 9.6 Hz, 3H), 1.32 (s, 9H); MS (ESI): m/z (%) = 512.21 (40%) (M+Naf; 502.28 (100%) (M-H)’.

I ²⁰

ExampIe-155

I (R,E)-N-((l,2,3,6,7,8-hexahydro-as-indacen-4-yl)carbamoyl)-2-(2-methylpyrrolidin-2yl)ethene-l-sulfonamide 2,2,2-trifluoroacetate

Ή NMR (400 MHz, DMSO-tid): δ = 9.09 (bs, 2H), 8.21 (s, 1H), 7.39 (s, 1H), 7.13 (d, J= 15.6 Hz, 5 1H), 7.03 (d,J= 15.2 Hz, 1H), 2.81 - 2.64 (m, 10H), 2.10 - 1.89 (m, 9H), 1.48 (s, 3H); MS (ESI):

m/z (%) = 390.18 (100%) (M-TFA)⁺.

Example-156 (R,E)-2-(l,2-dimethylpyrrolidin-2-yl)-N-((l,2,3,6,7,8-hexahydro-as-indacen-4yl)carbamoyl)ethene-l-sulfonamide

Ή NMR (400 MHz, DMSO-ti₆): δ = 7.86 (s, 1H), 7.44 (s, 1H), 6.75 (d, J= 15.6 Hz, 1H), 6.63 (d, J = 15.2 Hz, 1H), 2.90 - 2.88 (m, 4H), 2.80 (q, J = 7.2 Hz, 5H), 2.20 (s, 3H), 2.04 (quin, J= 7.2 Hz, 4H), 1.84 - 1.72 (m, 4H), 1.13 (s, 3H); MS (ESI): m/z (%) = 404.30 (100%) (M+H)⁺; 402.50 (100%) (M-l)’.

Example-157 tert-butyl(R,E)-2-(3-(N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyI)allyl)2-methylpyrrolidine-l-carboxylate

Ή NMR (400 MHz, DMSO-d₆): δ = 10.38 (s, 1H), 8.07 (d,J=7.2 Hz, 1H), 6.95 (s, 1H), 6.81 (q, 20 J= 15.2 Hz, 1H), 6.64 (dd, J, = 8.0 Hz, J₂ = 15.2 Hz, 1H), 3.19 - 3.17 (m, 1H), 2.91 - 2.86 (m, 1H), 2.81 (t, J= 7.2 Hz, 4H), 2.67 (t, J= 7.2 Hz, 5H), 2.63 - 2.58 (m, 1H), 1.97 (quin, J= 7.2 Hz, 4H), 1.88 - 1.83 (m, 1H), 1.70 - 1.62 (m, 3H), 1.41 (d, J= 6.8 Hz, 9H), 1.30 (s, 3H); MS (ESI): m/z (%) = 526.28 (50%) (M+Na)⁺; 502.28 (100%) (M-H)'.

Example-158 tert-butyl(R,E)-(2-(2-(3-(N-((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)sulfamoyl)allyl)-2-methylpyrrolidin-l-yl)ethyl)(methyl)carbamate

I I I I I I I

I I I I I I I ’H NMR (400 MHz, DMSO-riQ: δ = 10.37 (bs, IH), 8.03 (s, IH), 6.95 (s, IH), 6.74 (d, J= 8.0 Hz, 2H), 3.12 (q, J= 7.2 Hz, 2H), 2.90 (bs, IH), 2.80 (t, J= 7.2 Hz, 6H), 2.67 (t, J= 6.8 Hz, 5H), 2.29 -2.26 (m, 2H), 1.96 (quin, J= 7.2 Hz, 4H), 1.68 - 1.67 (m, 4H), 1.38 (s, 12H), 1.28 (s, 3H); MS (ESI): m/z (%) = 560.31 (100%) (M+H)⁺; 559.29 (100%) (M-l)'.

Example-159 (R,E)-3-(l,2-dimethylpyrrolidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)prop-l-ene-l-sulfonamide

’H NMR (400 MHz, DMSO-riQ: δ = 8.04 (s, IH), 6.90 (s, IH), 6.75 - 6.72 (m, IH), 6.62 - 6.54 (m, IH), 3.17 - 3.00 (m, IH), 2.79 (t, J= 6.8 Hz, 5H), 2.69 (bs, 4H), 2.36 (s, 5H), 1.95 (t, J= 7.2 Hz, 4H), 1.81 - 1.74 (m, 3H), 1.58 (bs, IH), 1.04 (s, 3H); MS (ESI): m/z (%) = 418.21 (100%) (M+H)⁺.

Example-160 tert-butyl(S,E)-(3-(2-(2-(N-((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)sulfamoyl)vmyl)pyrrolidin-l-yl)propyl)(methyl)carbamate

’H NMR (400 MHz, DMSO-^): δ = 8.05 (s, 1H), 6.94 (s, 1H), 6.82 (d, J=15.2Hz, 1H), 6.62 6.57 (m, 1H), 3.26 - 3.22 (m, 1H), 3.30 - 2.94 (m, 1H), 2.82 - 2.65 (m, 13H), 2.20 - 2.18 (m, 2H), 2.03 - 1.92 (m, 5H), 1.77-1.71 (m, 3H), 1.59 - 1.48 (m, 3H), 1.40 - 1.37 (m, 9H); MS (ESI): m/z 5 (%) = 547.5 (100%) (M+H)⁺.

Example-161 tert-butyl (E)-(3-(2-(2-(N-((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)sulfamoyl)vinyl)-2-methylazetidin-l-yl)propyl)(methyl)carbamate

I I I

’H NMR (400 MHz, DMSO-^): Ô = 8.04 (s, 1H), 6.94 (s, 1H), 6.83 (d, J = 15.2 Hz, 1H), 6.77 (d, J= 15.2 Hz, 1H), 3.29 - 3.27 (m, 2H), 2.80 (t, J= 7.2 Hz, 4H), 2.75 - 2.72 (m, 1H), 2.68 (t, J = 7.2 Hz, 4H), 2.50 (s, 3H), 2.37 - 2.33 (m, 2H), 2.08 - 2.06 (m, 1H), 2.00 - 1.92 (m, 4H), 1.58 - 1.49 (m, 2H), 1.39 - 1.37 (m, 9H), 1.32 (s, 3H), 1.28 - 1.22 (m, 1H); MS (ESI): m/z (%) = 547.5 (100%) (M+H)⁺, 545.7 (100%) (M-l).

Example-162 tert-butyl(E)-(2-(2-(2-(N-((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)sulfamoyl)vinyl)-2-methylazetidin-l-yl)ethyl)(methyl)carbamate

100

I ι

I I

I

I I

I

I ι¹⁰

I

I ¹⁵

’H NMR (400 MHz, DMSO4): δ = 8.05 (s, 1H), 6.95 (s, 1H), 6.83 (d, J= 14.8 Hz, 1H), 6.75 6.68 (m, 1H), 3.32 - 3.23 (m, 1H), 3.09 - 3.02 (m, 1H), 2.80 (t, J= 7.2 Hz, 4H), 2.75 - 2.71 (m, 2H), 2.67 (t,J= 7.2 Hz, 4H), 2.56 -2.52 (m, 1H), 2.51 (s, 3H), 2.48 - 2.43 (m, 1H), 2.05-1.89 (m, 6H), 1.39 - 1.38 (m, 9H), 1.32 (s, 3H); MS (TOF): m/z (%) = 533.3222 (40%) (M+H)⁺, 531.3039(100%) (M-l).

Example-163 (E)-N-((l,2,3,5,6,7-hexahydro-s-mdacen-4-yl)carbamoyI)-2-(2-methyl-l-(2(methylthio)ethyl)azetidin-2-yl)ethene-l-sulfonamide

’H NMR (400 MHz, DMSO-rf«): δ = 10.36 (brs, 1H), 8.07 (s, 1H), 6.95 (s, 1H), 6.87 (d, J= 14.8 Hz, 1H), 6.83 (d, J = 14.8 Hz, 1H), 3.40 - 3.22 (m, 2H), 3.18 - 3.04 (m, 1H), 2.81 (t, J = 7.2 Hz, 4H), 2.68 (t, J= 7.2 Hz, 4H), 2.59 - 2.53 (m, 2H), 2.41- 2.38 (m, 2H), 2.08 - 1.88 (m, 8H), 1.32 (s, 3H); MS (TOF): m/z (%) = 450.1660 (100%) (M+H)\

Example-164 (E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yI)carbamoyI)-2-(2-methyl-l-(oxetan-3yl)azetidin-2-yl)ethene-l-sulfonamide

Ή NMR (400 MHz, DMSO-J₆): ô = 10.4 (brs, 1H), 8.13 (s, 1H), 6.96 (s, 1H), 6.84 (d, J= 15.2 Hz, 1H), 6.80 (d, J = 15.2 Hz, 1H), 4.56 (t, J = 6.0 Hz, 1H), 4.48 - 4.44 (m, 2H), 4.31 (t, J = 6.4 Hz, 1H), 3.93 - 3.87 (m, 1H), 3.38 - 3.28 (m, 3H), 2.81 (t, J= 7.2 Hz, 4H), 2.68 (t, J = 12 Hz, 4H), 2.12-2.06 (m, 1H), 2.01-1.97 (m, 5H), 1.24 (s, 3H); MS (TOF): m/z (%) = 432.1744 (80%) (M+H)⁺.

Example-165 tert-butyl(S)-2-(((S)-2-((E)-2-(N-((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)sulfamoyl)vinyl)-2-methylazetidin-l-yl)methyl)-2-methylpyrrolidine-lcarboxylate

H H

Ν-Boc

Ή NMR (400 MHz, DMSO-î/₆): δ = 10.4 (brs, 1H), 8.10 (s, 1H), 6.98 - 6.93 (m, 2H), 6.74 (dd, J= 15.6 Hz, J= 52 Hz, 1H), 3.30 - 3.27 (m, 2H), 3.20 - 3.16 (m, 2H), 2.80 (t, J= 12 Hz, 4H), 2.69 (t, J= 6.8 Hz, 4H), 2.04 - 1.91 (m, 7H), 1.75 - 1.46 (m, 3H), 1.39- 1.37 (m, 9H), 1.27 (s, 3H), 1.17 (s, 3H); MS (TOF): m/z (%) = 573.2813 (100%) (M+H)⁺;

Example-166 tert-butyl(S)-2-(((R)-2-((E)-2-(N-((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)sulfamoyl)vinyl)-2-methylazetidin-l-yl)methyl)-2-methylpyrrolidiiie-lcarboxylate

N N

H H

N—Boc

Ή NMR (400 MHz, DMSO-J₆): δ = 10.41 (brs, 1H), 8.10 (s, 1H), 6.96 (s, 1H), 6.77 - 6.73 (m, 2H), 3.41 - 3.34 (m, 1H), 3.26 - 3.15 (m, 3H), 2.81 (t, J = 12 Hz, 4H), 2.57 (t, J = 12 Hz, 4H), 102

I I

I

I I

I

1¹⁰

I I

I

I ι²⁰

I

2.16-1.89 (m, 7H), 1.79 - 1.47 (m, 3H), 1.40 - 1.37 (m, 9H), 1.30 - 1.28 (m, 3H), 1.21-1.20 (m, 3H); MS (TOF): m/z (%) = 573.2814 (80%) (M+H)⁺;

Example-167 (R,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l-(2sulfamoylethyl)pyrrolidin-2-yl)ethene-l-sulfonamide

’H NMR (400 MHz, DMSO-</₆): δ = 10.42 (br s, IH), 8.09 (s, IH), 6.95 (s, IH), 6.87 (d, J= 14.8 Hz, IH), 6.75 (s, 2H), 6.66 (dd, J= 14.8 Hz,J= 7.2 Hz, IH), 3.23 - 3.07 (m, 4H), 3.01 - 2.94 (m, IH), 2.80 (t, J = 7.2 Hz, 4H), 2.67 (t, J = 7.2 Hz, 4H), 2.63 - 2.56 (m, IH), 2.33- 2.27 (m, IH), 2.02- 1.93 (m, 5H), 1.73 - 1.70 (m, 2H), 1.55 - 1.50 (m, IH); MS (TOF): m/z (%) = 483.1490 (80%) (M+H)⁺.

Example-168 (S,E)-2-(2-ethyl-l-methylpyrrolidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)ethene-l-sulfonamide

IH NMR (400 MHz, DMSO-d6): δ =8.01 (s, IH), 6.93 (s, IH), 6.71 (d, J= 15.2 Hz, IH), 6.58 (d, J= 15.6 Hz, IH), 2.99 (m, IH), 2.80 (t, J= 7.2 Hz, 4H), 2.66 (t, J= 7.2 Hz, 4H) , 2.57 (m, IH), 2.24 (s, 3H), 1.95 (m, 4H), 1.85 (m, IH), 1.72 (m, 4H), 1.45 (m, IH), 0.8 (t, J =7.2 Hz, 3H); MS (ESI): m/z (%) = 418.19 (100%) (M+l);

Example -169 (R,E)-2-(l-(but-2-yn-l-yI)pyrrolidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)ethene-l-sulfonamide

103

’H NMR (400 MHz, DMSO-J₆): δ = 8.84 (s, IH), 7.03 (d, J= 15.6 Hz, IH), 6.91 (s, IH), 6.35 6.23 (m, IH), 4.31 - 4.03 (m, 3H), 3.26 - 3.07 (m, 2H), 2.82 - 2.67 (m, 8H), 2.20 - 2.05 (m, IH), 1.97 - 1.83 (m, 6H), 1.74 - 1.61 (m, 4H); MS (TOF): m/z (%) = 428.1884 (100%) (M+H)⁺.

Biological Activity:

In-vitro assay:

— THP1 monocytes were differentiated with PMA (lOOng/mL) and incubated at 37 degC for 20hrs in presence of 5% CO2. 2X10⁵ differentiated cells were plated per well of 96 well tissue culture

I plates. The cells were primed using 500 ng/mL Lipopolysaccharide and incubating for 4h under

0 the same condition. The cells were then treated with various concentrations of the compounds for 130 min followed by treatment with 5 mM ATP for Ihr. The supematants were collected and analyzed by IL-lb (Mabtech Cat # 3415-1H-20) or TNF-a (Mabtech; Cat # 3510-1H-20) détection kit. The data were analyzed using GraphPad Prism V7.0. Dose Response Curve (DRC) was constructed to détermine the IC50 value by fitting percentage cell survival data to the GraphPad

Prism using nonlinear régression analysis. The invitro IL-Ιβ inhibitory activity (IC50) for représentative compounds are listed in Table 1.

!

Table 1

Compound	IC50 (nM)
Example 4	7.4
Example 8	10.7
Example 10	64

104

I I

I I I

I I

I I I

I I

I

Example 13	9
Example 14	17
Example 21	2.4
Example 23	14
Example 56	8.8
Example 63	8
Example 71	87
Example 84	8.5
Example 90	16
Example 91	2.9
Example 100	70
Example 105	61
Example 111	4.3
Example 125	16.4
Example 127	5.6
Example 129	5.9
Example 131	16
Example 139	21
Example 144	8.6
Example 147	11
Example 149	11
Example 153	32

105

In-vivo efficacy studies:

Démonstration of in vivo efficacy of test compounds in rats mice, oral routes of administration.

Animais

Ail the animal experiments were carried out in female rats and mice, bred in-house. Animais were 5 housed in groups of 6 animais per cage, for a week, in order to habituate them to vivarium conditions (25 ± 4 °C, 60-65 % relative humidity, 12: 12 h light: dark cycle, with lights on at 7.30 am). Ail the animal experiments were carried out according to the intemationally valid guidelines following approval by the 'Zydus Research Center animal ethical committee'.

In-vivo LPS and ATP induced IL-Ιβ assay:

Female C57 mice (6-8 weeks) received intraperitoneal injection of 50 qg/mouse of lipopolysaccharide (LPS) in PBS. Animais were treated immediately with the test compounds or the vehicle. After 2h of LPS injection, animais were administered with ATP at 12.5 mg/mouse dissolved in PBS via intraperitoneal route. After 30 minutes of ATP injection, sérum was collected for IL-Ιβ estimation by ELISA.

I I

I I I I I I

I

The novel compounds of the présent invention can be formulated into suitable pharmaceutically acceptable compositions by combining with suitable excipients by techniques and processes and concentrations as are well known.

Représentative data of some of the test compounds are listed in Table-2:

Table 2

Compounds (Dose 10 mpk, po)	% IL-Ιβ inhibition in LPS+ATP challenged C57 mice
Example 4	90%
Example 5	70%
Example 22	83%
Example 40	86%
Example 55	82.5%
Example 69	84%

106

Example 73	80%
Example 77	47%
Example 101	82%
Example 102	74%

The compounds of formula (I) or pharmaceutical compositions containing them are useful as a médicament for the inhibition of NLRP3 activity and suitable for humans and other warm blooded animais, and may be administered either by oral, topical or parentéral administration.

Thus, a pharmaceutical composition comprising the compounds of the présent invention may comprise a suitable binder, suitable bulking agent &/or diluent and any other suitable agents as may be necessary. Optionally, the pharmaceutical composition may be suitabîy coated with suitable coating agents.

The compounds of the présent invention (I) are NLRP3 inhibitors and are useful in the treatment 10 of disease States mediated by NLRP3, preferably diseases or conditions in which interleukin 1 β activity is implicated and related disorders.

The quantity of active component, that is, the compounds of Formula (I) according to this invention, in the pharmaceutical composition and unit dosage form thereof may be varied or adjusted widely depending upon the particular application method, the potency of the particular 15 compound and the desired concentration. Generally, the quantity of active component will range between 0.5% to 90% by weight of the composition.

The compounds of the présent invention, formula (I), may be used alone or in any combination with one or more other therapeutic agents which a skilled medical practitioner can easily identify. Such other therapeutic agent may be selected depending on the type of disease being treated, the 20 severity, other médications being taken by the patients etc. Thus for example, for treatment of rheumatoid arthritis, one or more DMARDs may be used in combination with the compounds of the présent invention.

In one of the embodiments compound of formula (I) of the présent invention may be used in combination with one or more suitable pharmaceutically active agents selected from following therapeutic agents in any combination. Inhibitors of interleukin-1β (e.g. rilonacept, canakinumab, and anakinra); immune-suppressants (e.g., Methotrexate, mercaptopurine, cyclophosphamide), 107

I I * metabolic disorders drugs, glucocorticoids, non-steroidal anti-inflammatory drugs, Cox-2 spécifie inhibitors, TNF-α binding proteins (eg.,Infliximab, etanercept), interferon-13, interferon, * interleukin-2, antihistamines, beta-agonist, BTK inhibitors, anticolinergics, anti-cancer agents or

S their suitable pharmaceutically acceptable salts. Further examples for use in combination with * 5 Non-Alcoholic Steato- Hepatitis (NASH) and fibrosis drugs, anticancer antibiotics, hormones, * Aromatase inhibitors, antibodies, cytokines, vaccines, drug conjugates, inhibitors of mitogenactivated protein kinase signaling (ex: BAY 43-9006), Syk inhibitors, mTOR inhibitors, antibodies | (Rituxan), and BCR/AB L antagonist.

While the présent invention has been described in terms of its spécifie embodiments, certain 1 10 modifications and équivalents will be apparent to those skilled in the art and are intended to be included within the scope of the présent invention.

I I I I I 1 I 1 1 I

I I I

108

Claims

claim: Compound having the structure of general formula (I) Formula (I)

1-sulfonamide;

| 15 (S,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-methylpyrrolidin-2yl)ethene-1 -sulfonamide;

(S,E)-2-(l,2-dimethylpyrrolidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4| yl)carbamoyl)ethene-1 -sulfonamide;

(E)-N-(( 1,2,3,5,6,7-hexahydiO-s-indacen-4-yl)carbamoyl)-2-(indolin-2-yl)ethene-l| 20 sulfonamide;

| tert-butyl(E)-2-(2-(N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl) vinyl)indoline-1 -carboxylate;

| ((S,E)-2-(l-(cyclopropylmethyl)-2-methylpyrrolidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s। indacen-4-yl)carbamoyl)ethene-1 -sulfonamide;

25 (S,E)-2-(l-(cyclopropylsulfonyl)pynOlidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4| yl)carbamoyl)ethene-1 -sulfonamide;

— tert-butyl (S,E)-2-(2-(N-((l ,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)vinyl)-2-methylpyrrolidine-1 -carboxylate;

I

118 tert-butyl (R,E)-2-(2-(N-((2,6-diisopropylphenyl)carbamoyl) sulfamoyl) vinyl)-2methylpyrrolidine-1 -carboxylate;

(R,E)-N-((2,6-diisopropylphenyl)carbamoyl)-2-(2-methylpyrrolidin-2-yl)ethene-lsulfonamide 2,2,2-trifluoroacetate;

(S,E)-2-(l-ethyl-2-methylpynOlidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)ethene-1 -sulfonamide;

Bis sodium (R,E)-((2-(l,2-dimethylpyrrolidin-2-yl)vinyl)sulfonyl)((l,2,3,5,6,7hexahydro-s-indacen-4-yl)carbamoyl)amide;

Sodium (R,E)-((2-(l,2-dimethylpynOlidin-2-yl)vinyl)sulfonyl)((l,2,3,5,6,7-hexahydro-sindacen-4-yl)carbamoyl)amide;

tert-butyl (S,E)-2-(2-(N-((2,6-diisopropylphenyl)carbamoyl)sulfamoyl) vinyl)-2methylpyrrolidine-1 -carboxylate;

(S,E)-N-((2,6-diisopropylphenyl)carbamoyl)-2-(2-methylpyrrolidin-2-yl)ethene-lsulfonamide 2,2,2-trifluoroacetate;

(S,E)-N-((2,6-diisopropylphenyl)carbamoyl)-2-( 1,2-dimethylpyrrolidin-2-yl)ethene-1 sulfonamide;

(R,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-methyl-l-(oxetan-3yl)pyrrolidin-2-yl)ethene-1 -sulfonamide;

tert-butyl (S,E)-2-(2-(N-((4-fluoro-2,6-diisopropylphenyl)carbamoyl) sulfamoyl)vinyl)-2methylpyrrolidine-1 -carboxylate;

(S,E)-N-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)-2-(2-methylpyrrolidin-2-yl)ethene1 -sulfonamide 2,2,2-trifluoroacetate;

(S,E)-2-(l,2-dimethylpyrrolidin-2-yl)-N-((4-fluoro-2,6diisopropylphenyl)carbamoyl)ethene-1 -sulfonamide;

(E)-2-(l-acetylazetidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)ethene-1 -sulfonamide;

119 ί (S,E)-2-(l-allylpyrrolidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-l। sulfonamide;

(S,E)-2-(l-(lH-benzo[d]imidazole-6-carbonyl)pyrrolidin-2-yl)-N-((l,2,3,5,6,7| hexahydro-s-indacen-4-yl)carbamoyl)ethene-1 -sulfonamide;

15 (S,E)-2-(l-(cyclopropylsulfonyl)-2-methylpynOlidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-sindacen-4-yl)carbamoyl)ethene-1 -sulfonamide;

| (S,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l-(4methoxybenzyl)pyrrolidin-2-yl)ethene-1 -sulfonamide;

tert-butyl 5-((R)-2-((E)-2-(N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)

2. The compound as claimed in claim 1, wherein RI at each occurrence is selected from hydrogen, halogen, haloalkyl, optionally substituted groups selected from (Cl-C6)alkyl.

20

3. The compound as claimed in claim 1, wherein R2 at each occurrence is selected from | hydrogen, halogen, haloalkyl optionally substituted groups selected from (Cl-Cô)alkyl.

4. The compound as claimed in claim 1, wherein R³ and R⁴ at each occurrence is independently selected from hydrogen, halogen, haloalkyl, optionally substituted groups selected

25 from (Ci-Côjalkyl.

I

1³⁰

I

5 tert-butyl (R,E)-2-(3-(N-((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)sulfamoyl)allyl)-2-methylpyrrolidine-l-carboxylate;

tert-butyl (R,E)-(2-(2-(3-(N-((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)sulfamoyl)allyl)-2-methylpyrrolidin-l-yl)ethyl)(methyl)carbamate;

(R,E)-3-(l,2-dimethylpynOlidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-410 yl)carbamoyl)prop-1 -ene-1 -sulfonamide;

tert-butyl (S ,E)-(3 -(2-(2-(N-(( 1,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)sulfamoyl)vinyl)pyrrolidin-l-yl)propyl)(methyl)carbamate;

tert-butyl (E)-(3-(2-(2-(N-((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)sulfamoyl)vinyl)-2-methylazetidin-l-yl)propyl)(methyl)carbamate;

15 tert-butyl (E)-(2-(2-(2-(N-((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)sulfamoyl)vinyl)-2-methylazetidin-l-yl)ethyl)(methyl)carbamate;

(E)-N-((l, 2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-methyl-l-(2(methylthio)ethyl)azetidin-2-yl)ethene-1 -sulfonamide;

(E)-N-(( 1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-methyl-l-(oxetan-320 yl)azetidin-2-yl)ethene-1 -sulfonamide;

tert-butyl (S)-2-(((S)-2-((E)-2-(N-((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)sulfamoyl)vinyl)-2-methylazetidin-1 -yl)methyl)-2-methylpyrrolidine-1 -carboxylate;

tert-butyl (S)-2-(((R)-2-((E)-2-(N-((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)sulfamoyl)vinyl)-2-methylazetidin-1 -yl)methyl)-2-methylpyrrolidine-1 -carboxylate;

25 (R,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l-(2sulfamoylethyl)pyrrolidin-2-yl)ethene-1 -sulfonamide;

(S,E)-2-(2-ethyl-l-methylpynOlidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)ethene-1 -sulfonamide;

122 (R,E)-2-(l-(but-2-yn-l-yl)pyirolidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-

yl)carbamoyl)ethene-1 -sulfonamide;

5 potassium (R,E)-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)((2-(lmethylpyrrolidin-2-yl)vinyl)sulfonyl)amide;

sodium (S,E)-((2-(l ,2-dimethylpynOlidin-2-yl)vinyl)sulfonyl)((l ,2,3,5,6,7-hexahydro-sindacen-4-yl)carbamoyl)amide;

sodium (S,E)-((2-(l-ethylpyrrolidin-2-yl)vinyl)sulfonyl)((l,2,3,5,6,7-hexahydro-s10 indacen-4-yl)carbamoyl)amide;

(S,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l-(2-hydroxyethyl)pynOlidin-2yl)ethene-1 -sulfonamide;

tert-butyl (E)-2-(2-(N-(( 1,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)sulfamoyl)vinyl)-2-methylazetidine-l-carboxylate;

15 (E)-2-(l,2-dimethylazetidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)ethene-1 -sulfonamide;

tert-butyl (S,E)-2-ethyl-2-(2-(N-((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)sulfamoyl)vinyl)pyrrolidine-1 -carboxylate;

tert-butyl (S,E)-2-(2-(N-((l,2,3,6,7,8-hexahydro-as-indacen-420 yl)carbamoyl)sulfamoyl)vinyl)-2-methylpyrrolidine-1 -carboxylate;

(S,E)-2-(2-ethylpyrrolidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)ethene-l-sulfonamide 2,2,2-trifluoroacetate;

(S,E)-N-((l,2,3,6,7,8-hexahydro-as-indacen-4-yl)carbamoyl)-2-(2-methylpyrrolidin-2yl)ethene-1 -sulfonamide 2,2,2-trifluoroacetate;

25 (S,E)-2-(l,2-dimethylpyrrolidin-2-yl)-N-((l,2,3,6,7,8-hexahydro-as-indacen-4yl)carbamoyl)ethene-1 -sulfonamide;

tert-butyl (R,E)-2-(2-(N-((l,2,3,6,7,8-hexahydro-as-indacen-4yl)carbamoyl)sulfamoyl)vinyl)-2-methylpynOlidine-l-carboxylate;

121 (R,E)-N-((l,2,3,6,7,8-hexahydro-as-indacen-4-yl)carbamoyl)-2-(2-methylpyrrolidin-2yl)ethene-1 -sulfonamide 2,2,2-trifluoroacetate;

(R,E)-2-(l,2-dimethylpyrrolidin-2-yl)-N-((l,2,3,6,7,8-hexahydro-as-indacen-4yl)carbamoyl)ethene-1 -sulfonamide;

5 tert-butyl(E)-2-(2-(N-((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)sulfamoyl)vinyl)-azetidine-1 -carboxylate;

(E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l-methylazetidin-2yl)ethene-1 -sulfonamide;

(E)-2-(azetidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-l-

5 (R,E)-2-(l-(cyclopropylmethyl)-2-methylpyrrolidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-sindacen-4-yl)carbamoyl)ethene-1 -sulfonamide;

(S,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l-methylpyrrolidin-2-

5. The compound as claimed in claim 1, wherein each of R⁶, R⁷, R⁸, R⁹, R¹⁰ and R¹¹ at each occurrence is independently selected from hydrogen, halogen optionally substituted groups selected from (Ci-Côjalkyl, (Ci-Ce)haloalkyl.

5 their tautomeric forms, their stereoisomers, their enantiomers, their pharmaceutically acceptable salts, and pharmaceutical compositions containing them wherein, g R¹ at each occurrence is independently selected from hydrogen, halogen, haloalkyl, cyano, optionally substituted groups selected from (Ci-Côjalkyl, (Ci-Côjhaloalkyl, (C₂-Cô)alkenyl, (Ci| 10 C₆)alkoxy, (C₃-C₇)cycloalkyl, NH₂, NH(Ci-C₆)alkyl, N(C₃-C₇)cycloalkyl, N(Ci-C₆ alkyl)₂, aryl, heteroaryl, heterocyclyl, benzyl, thiol, mercapto alkyl, SO₂(Ci-Cô)alkyl, (Ci-Côjthio-alkoxy, | amide;

| X is N-R⁵; O, S, SO₂;

15 R⁵ at each occurrence is independently selected from hydrogen, halogen, haloalkyl, cyano, optionally substituted groups selected from (Ci-Côjalkyl, (Ci-Côjhaloalkyl, (C₂-C6)alkenyl, (C₂B Cô)alkynyl, (Ci-Cô)alkoxy, (C₃-C₇)cycloalkyl, (Ci-C6)alkylSO₂(Ci-Cô)alkyl, (Ci-C6)alkylN(Ci* Cô)alkyl, (Ci-Cô)alkylN(C₃-C₇)cycloalkyl, aryl, heteroaryl, heterocyclyl, benzyl, tert butyloxycarbonyl, thiol, mercaptoalkyl, SO₂(Ci-C6)alkyl, SO₂(C₃-C₇)cycloalkyl, SO₂-aryl, SO₂20 heterocyclyl, (Ci-Côjthioalkyl, (Ci-C6)thioalkoxy, (Ci-C6)alkylSO₂NH₂, -CONH₂, -CO(Ci| Cô)alkyl, -CO(Ci-C6)haloalkyl, -CO-aryl, -CO-heteroaryl, -CO-heterocyclyl, 4- to 7-membered heterocyclic ring, 7- to 14-membered bicyclic heterocyclic ring system, bridged or spiro ring | system having optionally one or more than one heteroatoms;

m and n is independently selected from integer 0-3;

। 25 q and r is independently selected from integer 1-4;

| R² at each occurrence is independently selected from hydrogen, halogen, cyano, optionally substituted groups selected from (Ci-Cô)alkyl, (C₂-Cô)alkenyl, (Ci-Cô)alkoxy, (C₃-C₇)cycloalkyl, | benzyl, aryl, heteroaryl, heterocyclyl, thiol, thioalkyl, , thio-alkoxy, SO₂(Ci-C6)alkyl, SO(CiCô)alkyl, bridged or spiro ring system having optionally one or more than one heteroatoms;

I

109 i 20271

I Each of R³ and R⁴ at each occurrence is independently selected from hydrogen, halogen, — haloalkyl, cyano, nitro, amide, sulphonamide, acyl, hydroxyl, optionally substituted groups I selected from (Ci-Cô)alkyl, (Ci-Côjhaloalkyl, (Ca-Côjcycloalkyl, (Ci-Cô)alkoxy, SO2(Ci-C6)alkyl, _ thiol, mercapto alkyl, benzyl, aryl, heteroaryl, heterocyclyl; Altematively R3 and R4 forms a bond; 5 ‘B’ is selected from the following ring system

I

1¹⁵

wherein X, Y, Z at each occurrence is independently selected from C, N, S, SO2 and O, which may, wherever possible be optionally substituted.

Each of R⁶, R⁷, R⁸, R⁹, R¹⁰ and R¹¹ at each occurrence are independently selected from hydrogen, halogen, cyano, amide, sulphonamide, acyl, hydroxyl, optionally substituted groups selected from (Ci-Cô)alkyl, (Ci-C6)haloalkyl, (C3-C6)cycloalkyl, (Ci-Cô)alkoxy, benzyl, aryl, heteroaryl, heterocyclyl; Altematively each of R⁷ and R⁸, R⁸ and R⁹, R⁹ and R¹⁰ or R¹⁰ and R¹¹wherever possible, together may form a 4 to 7 membered saturated or partially saturated ring containing from 0-2 additional heteroatoms selected from the group consisting of N, O, and S(O)_P; p= 1-2.

6. The compound as claimed in any preceding claim, wherein when any of the above group is substituted, the substitutions are selected from hydrogen, hydroxy, cyano, halo, haloalkyl,

110 haloalkyloxy, alkylthio (Ci-Cejalkyl, (C2-C6)alkenyl, (C2-Cô)alkynyl, (C3-C7)cycloalkyl, Ci-Cô alkoxy, aryl, heterocyclyl, heteroaryl, -COR12, -CSR12, C(O)ORi2, C(O)-Ri2, -C(O)-NRi2Ri3, C(S)-NRi2Ri3, -SO2R12 group, wherein each of R12 and R13 is independently selected from hydrogen, optionally substituted group selected from (Ci-Côjalkyl, (C2-C6)alkenyl, (C25 Côjalkynyl, (C3-C7)cycloalkyl, aryl, heteroaryl, heterocyclyl groups;

7. A compound as claimed in claim 1 selected from the group comprising of:

(R,E)-2-(l-ethylpyrrolidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethanesulfonamide ;

8. A pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) as claimed in any of the preceding claims and optionally one or more pharmaceutically acceptable carriers, diluents or excipients.

9. The pharmaceutical composition as claimed in claims 8 in combination with one or more suitable pharmaceutically active agents selected from Inhibitors of interleukin-ΐβ; immunesuppressants; metabolic disorders drugs, glucocorticoids, non-steroidal anti-inflammatory drugs, COX-2 specific inhibitors, anti-inflammatory drugs, TNF-α binding proteins, interferon-13, interferon, interleukin-2, antihistamines, beta-agonist, BTK inhibitors, anticolinergics, anti-cancer agents or their suitable pharmaceutically acceptable salts, Non-Alcoholic Steato- Hepatitis (NASH) and fibrosis drugs, anticancer drugs, antibiotics, hormones, aromatase inhibitors, inhibitors of mitogen-activated protein kinase signaling, Syk inhibitors, mTOR inhibitors, and BCR/ABL antagonists.

10. A process for the préparation of compound of formula (I) as claimed in claim 1, comprising the following steps:

(i) reacting compound of formula (5) with DMSO where ail symbols are as defined in claim 1 to obtain compound of formula (6)

(ii) reacting compound of formula (6) with isocyanato dérivative of compound of formula (7) where ail symbols are as defined in claim 1 to obtain compound of formula (I)

10 carbamoyl)sulfamoyl)vinyl)pyrrolidin-1 -yl)hexahydrocyclopenta[c]pyrrole-2( 1 H)-carboxylate;

(E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-((2R)-l-(octahydrocyclo| penta[c]pyrrol-5-yl)pyrrolidin-2-yl)ethene-1 -sulfonamide 2,2,2-trifluoroacetate;

(E)-2-(l-(cyclopropylsulfonyl)azetidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4| yl)carbamoyl)ethene-1 -sulfonamide;

15 (S,E)-N-((2,6-diisopropylphenyl)carbamoyl)-2-( 1 -(thiazol-2-yl)pyrrolidin-2-yl)ethene-1 - sulfonamide;

| tert-butyl (S,E)-(2-(2-(2-(N-((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)sulfamoyl)vinyl)-2-methylpyrrolidin-l-yl)ethyl)(methyl)carbamate;

potassium (R,E)-((2-(l,2-dimethylpynOlidin-2-yl)vinyl)sulfonyl)((l,2,3,5,6,7-hexahydro-s| 20 indacen-4-yl)carbamoyl)amide;

tert-butyl (E)-(2-(2-(2-(N-((l,2,3,5,6,7-hexahydro-s-indacen-4| yl)carbamoyl)sulfamoyl)vinyl)azetidin-1 -yl)ethyl)(methyl)carbamate;

| (S,E)-2-(l-(cyclohexylmethyl)-2-methylpynOlidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-sindacen-4-yl)carbamoyl)ethene-1 -sulfonamide;

I 25 Sodium (R,E)-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)((2-(l-(tetrahydro-2Hthiopyran-4-yl)pyrrolidin-2-yl)vinyl)sulfonyl)amide;

sodium (R,E)-((2-(l-cyclohexylpyrrolidin-2-yl)vinyl)sulfonyl)((l,2,3,5,6,7-hexahydro-s| indacen-4-yl)carbamoyl)amide;

I

120 sodium (S,E)-((2,6-diisopropylphenyl)carbamoyl)((2-(l,2-dimethylpynOlidin-2yl)vinyl)sulfonyl)amide;

sodium (R,E)-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)((2-(l-methylpyrrolidin2-yl)vinyl)sulfonyl)amide;

10 sulfonamide;

(R,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l-(tetrahydro-2H-pyran4-yl)pyrrolidin-2-yl)ethene-1 -sulfonamide;

(S,E)-2-(l-((5-chlorothiophen-2-yl)sulfonyl)pyrrolidin-2-yl)-N-((l,2,3,5,6,7-hexahydros-indacen-4-yl)carbamoyl)ethenesulfonamide;

15 (S,E)-2-(l-(benzylsulfonyl)pyrrolidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)ethenesulfonamide;

(S,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l-((4methoxyphenyl)sulfonyl) pyrrolidin-2-yl)ethenesulfonamide;

(S,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l-((4fluorophenyl)sulfonyl) pyrrolidin-2-yl)ethenesulfonamide;

(S,E)-2-(l-((2-cyanophenyl)sulfonyl)pynOlidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-sindacen-4-yl)carbamoyl)ethenesulfonamide;

25 (S,E)-2-(l-(4-fluorobenzyl)pyrrolidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)ethenesulfonamide;

(S,E)-2-(l-((4-cyanophenyl)sulfonyl)pyrrolidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-sindacen-4-yl)carbamoyl)ethene-1 -sulfonamide;

117

I

I (S,E)-2-(l-(4-cyanobenzyl)pynOlidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4I yl)carbamoyl)ethene-1 -sulfonamide;

(S,E)-N-((l,2,3,6,7,8-hexahydro-as-indacen-4-yl)carbamoyl)-2-(pynOlidin-2-yl)ethene-l| sulfonamide;

m 5 (E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(piperidin-2-yl)ethene-l- sulfonamide;

| (E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l-methylpiperidin-2yl)ethene-1 -sulfonamide;

(E)-N-(( 1,2,3,6,7,8-hexahydro-as-indacen-4-yl)carbamoyl)-2-( 1 -methylpyrrolidin-2| 10 yl)ethene-l-sulfonamide;

(E)-N-((l,2,3,6,7,8-hexahydro-as-indacen-4-yl)carbamoyl)-2-(l| (methylsulfonyl)pyrrolidin-2-yl)ethene-1 -sulfonamide;

((E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-(piperidin-2-yl)prop-l-ene-

10 yl)ethenesulfonamide;

(S,E)-tert-butyl2-(2-(N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl) vinyl)pyrrolidine-1 -carboxylate;

(S,E)-2-(l-(cyclopropylmethyl)pynOlidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)ethenesulfonamide;

15 (S,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l-(pyridin-3-ylsulfonyl)pyrrolidin-2-yl)ethenesulfonamide;

(S,E)-N-((2,6-diisopropylphenyl)carbamoyl)-2-(l-ethylpyrrolidin-2yl)ethenesulfonamide;

20 (S,E)-N-((2,6-diisopropylphenyl)carbamoyl)-2-(l-(methylsulfonyl) pyrrolidin-2yl)ethene-sulfonamide;

(S,E)-N-((2,6-diisopropylphenyl)carbamoyl)-2-(l-methylpyrrolidin-2yl)ethenesulfonamide;

(S,E)-2-(l-acetylpyrrolidin-2-yl)-N-((2,6-diisopropylphenyl) carbamoyl)ethenesulfonamide;

(S,E)-2-(l-acetylpyrrolidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethenesulfonamide;

115

(S,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l-(tetrahydro-2H-pyran4-carbonyl)pyrrolidin-2-yl)ethenesulfonamide;

(E)-N-((l,2,3,5,6,7-hexahydiO-s-indacen-4-yl)carbamoyl)-2-(tetrahydro-2H-pyran-4yl)ethenesulfonamide;

(S,E)-N-((l,2,3,5,6,7-hexahydro-s-mdacen-4-yl)carbamoyl)-2-(l-nicotinoylpyrrolidin-2yl)ethenesulfonamide;

(E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(tetrahydrofuran-2yl)ethene-1 -sulfonamide;

tert-butyl(S,E)-2-(2-(N-((4-fluoiO-2,6-diisopropylphenyl)carbamoyl) sulfamoyl) vinyl)pyrrolidine-1 -carboxylate;

(S,E)-N-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)-2-(pyrrolidin-2-yl)ethene-lsulfonamide;

(S,E)-N-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)-2-(l-methylpyrrolidin-2-yl) ethene-1 -sulfonamide;

(R,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l-isobutyl-2-methylpyrrolidin-2-yl)ethene-1 -sulfonamide;

(R, E)-N-(( 1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-methyl-1propylpyrrolidin-2-yl)ethene-1 -sulfonamide;

(S,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l-(thiazol-2-yl)pyrrolidin2-yl)ethene-1 -sulfonamide;

(E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(piperidin-3-yl)ethenesulfonamide;

(E)-2-(l-ethylpiperidin-3-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)ethene-sulfonamide;

(E)-tert-butyl 3-(2-(N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)vinyl)-piperidine-1 -carboxylate;

116 (E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l- (methylsulfonyl) piperidin-3-yl)ethenesulfonamide;

(E)-2-(l-acetylpiperidin-3-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)ethene-sulfonamide;

10 (S,E)-2-(l-ethylpyrrolidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethanesulfonamide ;

(R,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(pynOlidin-2-yl)ethene-lsulfonamide;

(R,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l-propylpynOlidin-215 yl)ethene-l-sulfonamide;

(R,E)-2-(l-(cyclopropylmethyl)pynOlidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)ethene-1 -sulfonamide;

(R,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l-methylpynOlidin-2yl)ethene-1 -sulfonamide;

20 (R,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l-(methylsulfonyl)pyrrolidin-2-yl)ethene-1 -sulfonamide;

(R,E)-2-(l-acetylpyrrolidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1 - sulfonamide;

(E)-2-(l-benzylpiperidin-4-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)25 ethanesulfonamide;

tert-butyl(R,E)-2-(2-(N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)vinyl)pyrrolidine-1 -carboxylate;

(R,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l-(2methoxyethyl)pyrrolidin-2-yl)ethenesulfonamide;

30 (R,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l(isopropylsulfonyl)pyrrolidin-2-yl)ethenesulfonamide;

(R,E)-2-(l-((3-fluorophenyl)sulfonyl)pyrrolidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-sindacen-4-yl)carbamoyl)ethenesulfonamide;

111

I

I (R,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l-(pyrazine-2carbonyl)pyrrolidin-2-yl)ethenesulfonamide;

(R,E)-2-(2-(N-((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)sulfamoyl)vinyl)pyrrolidine-1 -carboxamide;

(R,E)-2-(l-(cyclopropanecarbonyl)pyrrolidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen4-yl)carbamoyl)ethene-1 -sulfonamide;

(R,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l-(210 (methylthio)ethyl)pynOlidin-2-yl)ethene-1 -sulfonamide;

(R,E)-N-((l,2,3,5,6,7-hexahydiO-s-indacen-4-yl)carbamoyl)-2-(l-isobutylpynOlidin-2yl)ethene-1 -sulfonamide;

15 (R,E)-2-(l-(ethylsulfonyl)pyrrolidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)ethene-1 -sulfonamide;

(R,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l-(320 (methylsulfonyl)propyl)pyrrolidin-2-yl)ethenesulfonamide;

(R,E)-N-((2-(l-benzoylpyrrolidin-2-yl)vinyl)sulfonyl)-N-((l,2,3,5,6,7-hexahydro-sindacen-4-yl)carbamoyl)benzamide;

25 (R,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(pyrrolidin-2yl)ethenesulfonamide;

I

I I I

I 1

I I

I¹⁰

I I

1¹⁵

I I 1²⁰

I I !

I I (R,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(pyrrolidin-2-yl)ethene-lsulfonamide methane sulfonate;

(R,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(pynOlidin-2-yl)ethene-lsulfonamide maleate;

(R,Z)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(pynOlidin-2-yl)ethene-lsulfonamide;

(S,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-(pynOlidin-2-yl)prop-lene-1 -sulfonamide;

(R,E)-2-(l-(cyclohexylsulfonyl)pynOlidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)ethene-1 -sulfonamide;

(R,Z)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l-methylpynOlidin-2yl)ethene-1 -sulfonamide;

(R,E)-2-(l-(cyclohexylmethyl)pynOlidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)ethene-1 -sulfonamide;

(R,E)-2-(l-cyclohexylpynOlidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)ethene-1 -sulfonamide;

(R,E)-N-(( 1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-( 1 -( 1 -methylpiperidin-4yl)pyrrolidin-2-yl)ethene-1 -sulfonamide;

(R,E)-N-((l,2,3,5,6,7-hexahydiO-s-indacen-4-yl)carbamoyl)-2-(l-(oxetan-3yl)pyrrolidin-2-yl)ethene-1 -sulfonamide;

(R,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l-(tetrahydro-2Hthiopyran-4-yl)pyrrolidin-2-yl)ethene-1 -sulfonamide;

(R,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l-(thiazol-2ylmethyl)pyrrolidin-2-yl)ethene-1 -sulfonamide;

113 (E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(piperidin-4yl)ethenesulfonamide;

(E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l-methylpiperidin-4yl)ethenesulfonamide;

(E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(l(methylsulfonyl)piperidin-4-yl)ethenesulfonamide;

(E)-2-(l-acetylpiperidin-4-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)ethene-sulfonamide;

tert-butyl (E)-4-(2-(N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)vinyl)-piperidine-1 -carboxylate;

(E)-2-(l-ethylpiperidin-4-yl)-N-(( 1,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)ethene-1 -sulfonamide;

(R,E)-2-(l-ethylpynOlidin-3-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethenesulfonamide ;

(R,E)-l,l-diethyl-3-(2-(N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)pyrrolidin-1 -iumbromide;

(R,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-methylpyrrolidin-2yl)ethene-1 -sulfonamide;

tert-butyl (R,E)-2-(2-(N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) sulfamoyl)vinyl)-2-methylpyrrolidine-1 -carboxylate;

(R,E)-2-(l-acetyl-2-methylpyrrolidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)ethene-1 -sulfonamide;

(R,E)-1,1 -diethyl-2-(2-(N-(( 1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)-2-methylpyrrolidin-1 -ium bromide;

(R,E)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-methyl-l(methylsulfonyl)-pyrrolidin-2-yl)ethene-1 -sulfonamide; :

114

(R,E)-2-(l,2-dimethylpynOlidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)ethene-1 -sulfonamide;

(R,E)-2-(l-ethyl-2-methylpyrrolidin-2-yl)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl)ethene-1 -sulfonamide;

11. A process for the préparation of compound of formula (I) as claimed in claim 1, comprising the following steps:

(a) (i) reacting compound of formula (12) with compound of formula (3) where ail symbols are as defined in claim 1 to obtain compound of formula (13)

123

I I I I I I I I I I I 1 I I I I

I I

I

(ii) reacting compound of formula (13) with DMSO where ail symbols are as defined in claim 1 to obtain compound of formula (14).

Boc (iii) reacting compound of formula (14) with isocyanato dérivative of compound of formula (7) where ail symbols are as defined in claim 1 to obtain compound of formula (I)

Boc (R²)_r—(B)—NCO

TFA, R⁵-X

(I) (b) (i) reacting compound of formula (15) with isocyanato dérivative of compound of formula (7) where ail symbols are as defined in claim 1 to obtain compound of formula (16) o _n (R²)_r—(b>-nco

Ph NH₂ --------------►

R⁴

(ii) reacting compound of formula (16) with the compound of formula (4) where ail symbols are as defined in claim 1 to obtain compound of formula (I)

R³

12. An intermediate of Formula (5 ),

124

Formula (5) where ail symbols are as defined in claim 1.

13. An intermediate of Formula (6),

Where ail symbols are as defined in claim 1.

14. An intermediate of Formula (15),

Ph-p °Y^Z°

Ph NH₂

R⁴

Formula (15) where ail symbols are as defined in claim 1.

15. An intermediate of Formula (16),

O II

Ph À?

Ph

R⁴ o ^{0 p} A 'N^N

H H

Formula (16) where ail symbols are as defined in claim 1.

125