Substituted sulfonylurea derivatives

Abstract

The invention relates to a substituted sulfonylurea derivative. The present invention relates to heterocyclic compounds of general formula (I), pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers and polymorphs thereof. The invention also relates to a method for preparing the compound disclosed by the invention, a pharmaceutical composition containing the compound and application of the compound disclosed by the invention, which belongs to the NOD-like receptor family (NLR) protein NLRP3 regulator family. Thus, the present invention relates to NLRP3 modulators and to the use of inhibitor compounds in the treatment of diseases or conditions in which interleukin 1 [beta] activity is implicated. # imgabs0 #

Description

[0001] This application is a divisional application of a Chinese patent application with an application date of January 13, 2020, an application number of "202080017147.5", and an invention title of "Novel Substituted Sulfonylurea Derivatives". The original application is the Chinese national phase application of international application PCT / IB2020 / 050216. Technical Field

[0002] The present invention relates to heterocyclic compounds of general formula (I), their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers, and polymorphs. The present invention also relates to methods for preparing the compounds of the present invention, pharmaceutical compositions comprising the compounds, and the use of the compounds of the present invention belonging to the family of NLRP3 modulators of NOD-like receptor (NLR) proteins. Accordingly, the present invention relates to NLRP3 modulators and to the use of inhibitor compounds in the treatment of diseases or disorders involving interleukin-1β activity. Background Art

[0003] The NOD-like receptor family (NLR) protein NLRP3 is an intracellular signaling molecule that senses a variety of pathogen-, environmental-, and host-derived factors (Wen., et al., Immunity. 2013; 39:432–441). Activation of NLRP3 leads to binding to apoptosis associated speck-like protein containing a CARD (ASC). ASC in turn interacts with the cysteine protease caspase-1, forming a complex called the inflammasome. This results in the activation of caspase-1, which cleaves the pro-inflammatory cytokines IL-1β and IL-18 into their active forms and mediates a type of inflammatory cell death called pyroptosis. Other intracellular pattern recognition receptors (PRRs) are also capable of forming inflammasomes. These include other NLR family members such as NLRP1 and NLRC4, as well as non-NLR PRRs such as the double-stranded DNA (dsDNA) sensor absent in melanoma 2 (AIM2) and interferon gamma inducible protein 16 (IFI16) (Latz, et al., Nat Rev Immunol. 2013; 13:397–411). NLRP3-dependent IL-1β processing can also be activated by an indirect, non-canonical pathway downstream of caspase-1 (Lamkanfi, et al., Cell. 2014; 157:1013–1022).

[0004] Inflammasome components such as NLRP3, ASC, and caspase-1 are expressed in immune cells of the liver, including Kupffer cells, infiltrating macrophages, hepatocytes, and hepatic stellate cells. Activation of the inflammasome depends on two sequential signals. Signal 1 is driven by TLR and IL-1R signaling and includes the expression of component proteins including NLRP3, ASC, procaspase-1, pro-IL-1β, and pro-IL-18. Signal 2 is provided by danger signals (DAMPS), which during the development of NASH are mainly released by stressed or dying hepatocytes or through the “leaky” gut (PAMP). This process leads to oligomerization of inflammasome components and cleavage of procaspase-1, resulting in the release of activated pro-inflammatory cytokines.

[0005] The NLRP3 inflammasome acts as a key mediator of the inflammatory response by activating caspase-1, leading to the processing and release of the pro-inflammatory cytokines interleukin-1β (IL-1β) and interleukin-18 (IL-18). The NLRP3 inflammasome is an integral part of the inflammatory process, and its aberrant activation is pathogenic in genetic disorders (such as rare periodic fever syndromes, cryopyrin associated periodic syndrome (CAPS), tumor necrosis factor receptor-associated periodic syndrome (TRAPS)) and complex diseases (such as multiple sclerosis, inflammatory bowel disease (IBD), type 2 diabetes, atherosclerosis, asthma, gouty arthritis, and inflammatory central nervous system (CNS) diseases including Parkinson's disease, Alzheimer's disease, 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.)

[0006] Inflammation is a fundamental host response to infection and injury. Regulation of the pro-inflammatory cytokine interleukin-1β (IL-1β) is central to the host response to infection and also causes tissue damage when inappropriately activated. (Dinarello, et.al., Nat. Rev. Drug Discovery 2012, 11, 633-652.) NLRP3 inflammasome activation plays a key role in each component including induction of pro-inflammatory signaling, hepatocyte injury and cell death, and activation of hepatic stellate cells (HSCs) responsible for collagen deposition and liver fibrosis. In particular, the transition from NAFLD to NASH is associated with NLRP3-inflammasome activation and 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), 1037-1046)

[0007] Current treatments for NLRP3-related diseases include biologics targeting IL-1. These are the recombinant IL-1 receptor antagonist anakinra, the neutralizing IL-1β antibody canakinumab, and the soluble decoy IL-1 receptor rilonacept.

[0008] Wipo patent applications WO98 / 32733, WO2001 / 019390, WO2014 / 190015, WO2016 / 123229, WO2016 / 131098 disclose sulfonylurea derivatives and related compounds as NLRP3 inflammasome inhibitors. WO2017 / 017469 discloses certain cyclic diarylboron derivatives as NLRP3 inflammasome inhibitors for the treatment of diseases or disorders involving interleukin 1β activity. Some recent patent applications, such as WO2017 / 031161, WO2017 / 079352, WO2017 / 129897, WO2017 / 184623, WO2018 / 225018, WO2019 / 043610, WO2019 / 023147, WO2019 / 008029, WO2019 / 068772, also disclose certain classes of compounds as NLRP3 inhibitors.

[0009] We disclose in this article heterocyclic compounds of general formula (I), which are NLRP3 modulators for preventing and treating NLRP3-mediated disease states or conditions involving interleukin-1β activity, including inflammation, cryopyrin-associated periodic syndromes (CAPS), gouty arthritis, multiple sclerosis, inflammatory bowel disease (IBD), type 2 diabetes, atherosclerosis, liver fibrosis, inflammatory central nervous system (CNS) diseases such as Parkinson's disease, Alzheimer's disease and other brain diseases mediated by the NLRP3 pathway. More particularly, embodiments of the present invention can be used as therapeutic agents for treating a variety of pathological conditions, including (but not limited to) lymphoma, autoimmune diseases, alloimmune diseases, inflammatory diseases, cancers and neurodegenerative diseases or conditions. Summary of the Invention

[0010] The present invention discloses heterocyclic compounds defined by general formula (I), which are NLRP3 modulators for preventing and treating NLRP3-mediated disease states and for treating diseases or conditions involving interleukin-1β activity. The compounds of the present invention are used for treating humans or animals by inhibiting NLRP3. Accordingly, the compounds of the present invention are suitable for preventing and treating NLRP3-mediated disease states. Detailed Description of the Invention

[0011] One embodiment of the present invention provides heterocyclic compounds represented by said general formula (I), their tautomeric forms, their enantiomers, their diastereomers, their stereoisomers, their pharmaceutically acceptable salts and pharmaceutical compositions containing them or mixtures thereof.

[0012] In another embodiment of the present invention, there is provided a pharmaceutical composition containing a compound of general formula (I), their tautomeric forms, their enantiomers, their diastereomers, their stereoisomers, their pharmaceutically acceptable salts or mixtures thereof, which is combined with a suitable carrier, solvent, diluent and other media commonly used for preparing such compositions.

[0013] In another embodiment, there is provided the use of the heterocyclic compounds of the present invention as NLRP3 modulators by administering to a mammal a therapeutically effective and non-toxic amount of a compound of general formula (I) or a pharmaceutically acceptable composition thereof.

[0014] In yet another embodiment, the compounds of formula (I) of the present invention can be used in combination with one or more suitable pharmaceutical active agents.

[0015] In another embodiment, there is provided a method for preparing the compounds of the present invention.

[0016] Another object of the present invention is to provide the intermediates involved in the said method.

[0017] Another object of the present invention is to provide a method for preparing the intermediates involved in the said method. DETAILED DESCRIPTION OF THE INVENTION

[0019] Accordingly, the present invention relates to compounds of general formula (I):

[0020]

[0021] their tautomeric forms, their stereoisomers, their enantiomers, their pharmaceutically acceptable salts and pharmaceutical compositions containing them, wherein,

[0022] R 1 independently represents, each time it appears, hydrogen, halogen, haloalkyl, cyano, a group optionally substituted and selected from the following: (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C1-C6)alkoxy, (C3-C7)cycloalkyl, NH2, NH(C1-C6)alkyl, N(C3-C7)cycloalkyl, N(C1-C6alkyl)2, aryl, heteroaryl, heterocyclic group, benzyl, thiol, mercaptoalkyl, SO2(C1-C6)alkyl, (C1-C6)thioalkoxy, amide;

[0023] m and n independently selected from the integers 0 to 3;

[0024] q and r independently selected from the integers 1 to 4;

[0025] X is N-R 5 , O, S, SO2;

[0026] R 5 independently represents, each time it appears, hydrogen, halogen, haloalkyl, cyano, a group optionally substituted and selected from the following: (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C3-C7)cycloalkyl, (C1-C6)alkylSO2(C1-C6)alkyl, (C1-C6)alkylN(C1-C6)alkyl, (C1-C6)alkylN(C3-C7)cycloalkyl, aryl, heteroaryl, heterocyclic group, benzyl, tert-butoxycarbonyl, thiol, mercaptoalkyl, SO2(C1-C6)alkyl, SO2(C3-C7)cycloalkyl, SO2-aryl, SO2-heterocyclic group, (C1-C6)thioalkyl, (C1-C6)thioalkoxy, (C1-C6)alkylSO2NH2, -CONH2, -CO(C1-C6)alkyl, -CO(C1-C6)haloalkyl, -CO-aryl, -CO-heteroaryl, -CO-heterocyclic group, 4- to 7-membered heterocycle, 7- to 14-membered bicyclic heterocyclic system, bridged or spirocyclic system having optionally one or more heteroatoms;

[0027] R 2 independently represents, each time it appears, hydrogen, halogen, haloalkyl, cyano, an optionally substituted group selected from the following: (C1-C6)alkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, (C3-C7)cycloalkyl, benzyl, aryl, heteroaryl, heterocyclic group, thiol, thioalkyl, thio-alkoxy, SO2(C1-C6)alkyl, SO(C1-C6)alkyl, a bridged or spirocyclic system having optionally one or more heteroatoms;

[0028] R 3 and each R 4 represents, each time it appears, hydrogen, halogen, haloalkyl, cyano, nitro, amide, sulfonamide, acyl, hydroxy, an optionally substituted group selected from the following: (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, SO2(C1-C6)alkyl, thiol, mercaptoalkylbenzyl, aryl, heteroaryl, heterocyclic group; or R3 and R4 form a bond;

[0029] ‘B’ is selected from the following ring systems:

[0030]

[0031] wherein W, Y, Z independently represent, each time they appear, C, N, S, SO2 and O, which may optionally be substituted;

[0032] R 6 、R 7 、R 8 、R 9 、R 10 and R 11 each independently represents, each time it appears, hydrogen, halogen, cyano, amide, sulfonamide, acyl, hydroxy, an optionally substituted group selected from the following: (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, benzyl, aryl, heteroaryl, heterocyclic group; or R 7 and R 8 、R 8 and R 9 、R 9 and R 10 and R 10 and R 11 in any possible case, may together form a 4- to 7-membered saturated or partially saturated ring containing 0 to 2 additional heteroatoms selected from N, O and S(O) p ; p = 1 to 2.

[0033] When any of the above-defined groups is substituted, the substitution thereof may be selected from those described above or may be selected from hydrogen, hydroxy, cyano, halo, haloalkyl, haloalkoxy, alkylthio (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C7) cycloalkyl, C1-C6 alkoxy, aryl, heterocyclic group, heteroaryl, -COR 12 、-CSR 12 、C(O)OR 12 、C(O)-R 12 、-C(O)-NR 12 R 13 、-C(S)-NR 12 R 13 、-SO2R 12 group, where each of R 12 and R 13 is independently selected from hydrogen and optionally substituted groups selected from the following: (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C7) cycloalkyl, aryl, heteroaryl, heterocyclic group;

[0034] In a preferred embodiment, R 1 independently represents, each time it appears, hydrogen, halogen, haloalkyl, an optionally substituted group selected from (C1-C6) alkyl;

[0035] In a preferred embodiment, R 2 independently represents, each time it appears, hydrogen, halogen, haloalkyl, an optionally substituted group selected from (C1-C6) alkyl;

[0036] In a preferred embodiment, each of R 3 and R 4 independently represents, each time it appears, hydrogen, halogen, haloalkyl, an optionally substituted group selected from (C1-C6) alkyl.

[0037] In a preferred embodiment, each of R 6 、R 7 、R 8 、R 9 、R 10 and R 11 is independently selected, each time it appears, from hydrogen, halogen, an optionally substituted group selected from (C1-C6) alkyl, (C1-C6) haloalkyl;

[0038] In a preferred embodiment, the above groups, radicals may be selected from:

[0039] "Alkyl" and other groups having the prefix "alk", such as alkoxy and alkanoyl, as is well known to those skilled in the art, mean a carbon chain that may be further substituted by an oxygen atom, which may further be straight-chain or branched-chain, and combinations thereof, unless the carbon chain is otherwise defined. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, hexyl, etc. Where the specified number of carbon atoms permits, e.g., C 3-10 , the term alkyl also includes cycloalkyl groups, and combinations of straight-chain or branched-chain alkyl chains combined with cycloalkyl structures. When no number of carbon atoms is specified, C 1-6 is intended. Substituted alkyl includes alkyl substituted by one or more moieties selected from halo (e.g., Cl, F, Br, and I); haloalkyl (e.g., CF3, 2-Br-ethyl, CH2F, CH2Cl, CH2CF3, or CF2CF3); hydroxy; amino; carboxylate; formamide; alkylamino; arylamino; alkoxy; aryloxy; nitro; azido; cyano; thio; sulfonic acid; sulfate; phosphonic acid; phosphate, and phosphonate, and those described under the limitation of "optionally substituted".

[0040] "Alkenyl" means a carbon chain containing at least one carbon-carbon double bond, which may be straight-chain or branched-chain or combinations thereof, unless the carbon chain is otherwise defined. Examples of alkenyl include, but are not limited to, vinyl, allyl, isopropenyl, hexenyl, pentenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl, etc. Where the specified number of carbon atoms permits, e.g., C 5-10 , the term alkenyl also includes cycloalkenyl groups and combinations of straight-chain, branched-chain, and cyclic structures. When no number of carbon atoms is specified, C 2-6 is intended.

[0041] "Alkynyl" means a carbon chain containing at least one carbon-carbon triple bond, which may be straight-chain or branched-chain or combinations thereof. Examples of alkynyl include ethynyl, propargyl, 3-methyl-1-pentynyl, etc. When no number of carbon atoms is specified, it is intended.

[0042] The "thioalkyl" group, used alone or in combination with other groups, represents an alkyl group as defined above linked to a group of the formula -SR' (sulfur and its oxidized forms), where R' represents hydrogen, an alkyl, or an aryl group, such as thiomethyl, methylthiomethyl, phenylthiomethyl, etc., which may be optionally substituted.

[0043] As used herein, "carbocyclic" or "carbocyclic residue" is intended to mean any stable monocyclic, bicyclic, or tricyclic ring, where any of the rings can 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 (decahydronaphthalene), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetrahydronaphthalene). From a broader perspective, the term carbocyclic is intended to include (where applicable) groups representing cycloalkyl, phenyl, and other saturated, partially saturated, or aromatic residues;

[0044] The terms "cycloalkyl" and "cycloalkenyl" refer to optionally substituted, saturated and unsaturated monocyclic, bicyclic, or tricyclic carbon groups. Where appropriate, a cycloalkyl or cycloalkenyl group can have a specified number of carbon atoms; for example, C3-C6 cycloalkyl or cycloalkenyl includes carbocyclic groups having 3, 4, 5, or 6 carbon atoms in their range. Examples of such substituents can be selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, etc. Substituted cycloalkyl or cycloalkenyl includes having one or more moieties of substitution selected from halo (e.g., Cl, F, Br, and I); haloalkyl (e.g., CF3, 2-Br-ethyl, CH2F, CH2Cl, CH2CF3, or CF2CF3); hydroxy; amino; carboxylate; formamide; alkylamino; arylamino; alkoxy; aryloxy; nitro; azide; cyano; thio; sulfonic acid; sulfate; phosphonic acid; phosphate; and phosphonate, as well as those described under the definition of "optionally substituted".

[0045] "Alkoxy" refers to a straight-chain or branched-chain alkoxide of a specified number of carbon atoms.

[0046] "Aryl" means a monocyclic or polycyclic aromatic ring system containing carbocyclic atoms. Preferred aryls are monocyclic or bicyclic 6- to 10-membered aromatic ring systems. Phenyl and naphthyl are preferred aryls.

[0047] "Heterocyclic group" means a saturated, partially saturated or unsaturated aromatic or non-aromatic mono-, bi- or tricyclic group containing one or more heteroatoms selected from nitrogen, sulfur and oxygen, further optionally including oxidized forms of sulfur, namely SO and SO2. The heterocyclic group system can be linked to another moiety through any number of carbon atoms or heteroatoms of the group and can 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 linked to an alkyl group as defined above;

[0048] "Heteroaryl" means an aromatic or partially aromatic heterocycle containing at least one ring heteroatom selected from O, S and N. Thus, heteroaryl includes heteroaryl fused to other types of rings, such as aryl, cycloalkyl and non-aromatic heterocycles. Examples of heteroaryl groups include: pyrrolyl, iso azolyl, isothiazolyl, pyrazolyl, pyridyl, azolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, triazinyl, thienyl, pyrimidinyl, benzoiso oxazolyl (benzisoxazolyl), benzo oxazolyl (benzoxazolyl), benzothiazolyl, benzothiadiazolyl, dihydrobenzofuranyl, indolinyl, pyridazinyl, indazolyl, isoindolyl, dihydrobenzothienyl, indolinyl, pyridazinyl, indazolyl, isoindolyl, dihydrobenzothienyl, indolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, napthyridinyl, carbazolyl, benzodioxolyl, quinoxalinyl, purinyl, furazanyl, isobenzylfuranyl, benzimidazolyl, benzofuranyt, benzothienyl, quinolinyl, indolyl, isoquinolinyl, dibenzofuranyl, etc. For heterocyclic and heteroaryl groups, rings and ring systems containing 3 to 15 carbon atoms are included, forming 1 to 3 rings.

[0049] The term "haloalkyl" means an alkyl structure in which at least one hydrogen is replaced by a halogen atom. In certain embodiments in which two or more hydrogen atoms are replaced by halogen atoms, the halogen atoms are completely identical to each other.

[0050] The "haloalkoxy" group is selected from suitable haloalkyls as defined above that are directly connected to an oxygen atom, more preferably groups such as fluoromethoxy, chloromethoxy, fluoroethoxy, chloroethoxy, etc.;

[0051] In certain other embodiments in which two or more hydrogen atoms are replaced by halogen atoms, the halogen atoms are not completely identical to each other.

[0052] "Aryloxyalkyl" means an alkyl group substituted with an aryloxy group as defined herein.

[0053] "Aryloxyaryl" means an aryl group substituted with an aryloxy group as defined herein.

[0054] "Aryloxyheteroaryl" means a heteroaryl group substituted with an aryloxy group as defined herein.

[0055] "Halo / Halogen" refers to fluorine, chlorine, bromine, iodine. Chlorine and fluorine are generally preferred.

[0056] Suitable groups and substituents on the groups can be selected from those described anywhere in the specification.

[0057] As used herein, the term "substituted" means that any one or more hydrogens on a specified atom are replaced by a selection from the indicated groups, provided that the normal valence of the specified atom is not exceeded and the substitution results in a stable compound. As used herein, the term "substituted" means that any one or more hydrogens on a specified atom are replaced by a selection from the indicated groups, provided that the normal valence of the specified atom is not exceeded and the substitution results in a stable compound.

[0058] "Pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds in which the parent compound is modified by formation of its acid or base salts. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of 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 acid, 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonic, carbonic, citric acid, edetic acid, ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, glycollyarsanilic acid, hexylresorcinolic acid, hydrabamic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxymaleic acid, hydroxynaphthoic acid, hydroxyethanesulfonic acid, lactic acid, lactobionic acid, -laurylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, napsylic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, subacetic acid, succinic acid, aminosulfonic acid, sulfanilic acid, sulfuric acid, tannic acid, tartaric acid, and toluenesulfonic acid.

[0059] The term "optional" or "optionally" means that the subsequent described event or circumstance may or may not occur, and the description includes both the case where the event or circumstance occurs and the case where it does not occur. For example, "optionally substituted alkyl" means "alkyl" or "substituted alkyl". Additionally, an optionally substituted group includes the unsubstituted group.

[0060] Unless otherwise indicated in the specification, the structures described herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms.

[0061] Particularly useful compounds may be selected from, but are not limited to, the following:

[0062] (R,E)-2-(1-ethylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-ethanesulfonamide;

[0063] (S,E)-2-(1-ethylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-ethanesulfonamide;

[0064] (R,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(pyrrolidin-2-yl)ethene-1-sulfonamide;

[0065] (R,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-propylpyrrolidin-2-yl)ethene-1-sulfonamide;

[0066] (R,E)-2-(1-(Cyclopropylmethyl)pyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide;

[0067] (R,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-methylpyrrolidin-2-yl)ethene-1-sulfonamide;

[0068] (R,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(methylsulfonyl)pyrrolidin-2-yl)ethene-1-sulfonamide;

[0069] (R,E)-2-(1-acetylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide;

[0070] (E)-2-(1-benzylpiperidin-4-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethanesulfonamide;

[0071] (R,E)-2-(2-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)aminosulfonyl)vinyl)pyrrolidine-1-carboxylic acid tert-butyl ester;

[0072] (R,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(2-methoxyethyl)pyrrolidin-2-yl)ethenesulfonamide;

[0073] (R,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(isopropylsulfonyl)pyrrolidin-2-yl)ethenesulfonamide;

[0074] (R,E)-2-(1-((3-fluorophenyl)sulfonyl)pyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethenesulfonamide;

[0075] (R,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(pyrazine-2-carbonyl)pyrrolidin-2-yl)ethenesulfonamide;

[0076] (R,E)-2-(2-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)pyrrolidine-1-carboxamide;

[0077] (R,E)-2-(1-(cyclopropanecarbonyl)pyrrolidin-2-yl)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide;

[0078] (R,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(2,2,2-trifluoroacetyl)pyrrolidin-2-yl)ethene-1-sulfonamide;

[0079] (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;

[0080] (R,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(2,2,2-trifluoroethyl)pyrrolidin-2-yl)ethene-1-sulfonamide;

[0081] (R,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-isobutylpyrrolidin-2-yl)ethene-1-sulfonamide;

[0082] (R,E)-2-(1-(ethylsulfonyl)pyrrolidin-2-yl)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide;

[0083] (R,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-isopropylpyrrolidin-2-yl)ethene-1-sulfonamide;

[0084] (R,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(3-(methylsulfonyl)propyl)pyrrolidin-2-yl)ethenesulfonamide;

[0085] (R,E)-2-(1-Benzoyl pyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)vinylsulfonamide;

[0086] (R,E)-N-((2-(1-Benzoyl pyrrolidin-2-yl)vinyl)sulfonyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)benzamide;

[0087] (R,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(pyrrolidin-2-yl)vinylsulfonamide;

[0088] (R,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(thiophene-3-carbonyl)pyrrolidin-2-yl)vinylsulfonamide;

[0089] (R,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(pyrrolidin-2-yl)vinyl-1-sulfonamide mesylate;

[0090] (R,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(pyrrolidin-2-yl)vinyl-1-sulfonamide maleate;

[0091] (R,Z)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(pyrrolidin-2-yl)vinyl-1-sulfonamide;

[0092] (S,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-(pyrrolidin-2-yl)prop-1-ene-1-sulfonamide;

[0093] (R,E)-2-(1-(Cyclohexylsulfonyl)pyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)vinyl-1-sulfonamide;

[0094] (R,Z)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-methylpyrrolidin-2-yl)vinyl-1-sulfonamide;

[0095] (R,E)-2-(1-(Cyclohexylmethyl)pyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)vinyl-1-sulfonamide;

[0096] (R,E)-2-(1-Cyclohexylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide;

[0097] (R,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(1-methylpiperidin-4-yl)pyrrolidin-2-yl)ethene-1-sulfonamide;

[0098] (R,Z)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-isopropylpyrrolidin-2-yl)ethene-1-sulfonamide;

[0099] (R,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-2-yl)ethene-1-sulfonamide;

[0100] (R,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(oxetan-3-yl)pyrrolidin-2-yl)ethene-1-sulfonamide;

[0101] (R,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(tetrahydro-2H-thiopyran-4-yl)pyrrolidin-2-yl)ethene-1-sulfonamide;

[0102] (R,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(thiazol-2-ylmethyl)pyrrolidin-2-yl)ethene-1-sulfonamide;

[0103] (E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(piperidin-4-yl)ethenesulfonamide;

[0104] (E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-methylpiperidin-4-yl)ethenesulfonamide;

[0105] (E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(methylsulfonyl)piperidin-4-yl)ethenesulfonamide;

[0106] (E)-2-(1-Acetylpiperidin-4-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)vinyl-sulfonamide;

[0107] (E)-4-(2-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)-piperidine-1-carboxylic acid tert-butyl ester;

[0108] (E)-2-(1-Ethylpiperidin-4-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)vinyl-1-sulfonamide;

[0109] (R,E)-2-(1-Ethylpyrrolidin-3-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-vinylsulfonamide;

[0110] (R,E)-1,1-Diethyl-3-(2-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-vinyl)pyrrolidine-1-bromide

[0111] (E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(pyrrolidin-3-yl)vinyl-sulfonamide;

[0112] (R,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-methylpyrrolidin-2-yl)vinyl-1-sulfonamide;

[0113] (R,E)-2-(2-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester;

[0114] (R,E)-2-(1-Acetyl-2-methylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)vinyl-1-sulfonamide;

[0115] (R,E)-1,1-Diethyl-2-(2-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-vinyl)-2-methylpyrrolidine-1-bromide

[0116] (R,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-methyl-1-(methylsulfonyl)pyrrolidin-2-yl)ethene-1-sulfonamide;

[0117] (R,E)-2-(1,2-Dimethylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide;

[0118] (R,E)-2-(1-Ethyl-2-methylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide;

[0119] (R,E)-2-(1-(Cyclopropylmethyl)-2-methylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide;

[0120] (S,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(pyrrolidin-2-yl)ethene-sulfonamide;

[0121] (S,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-methylpyrrolidin-2-yl)ethene sulfonamide;

[0122] (S,E)-2-(2-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)pyrrolidine-1-carboxylic acid tert-butyl ester;

[0123] (S,E)-2-(1-(Cyclopropylmethyl)pyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene sulfonamide;

[0124] (S,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(pyridin-3-ylsulfonyl)pyrrolidin-2-yl)ethene sulfonamide;

[0125] (S,E)-N-((2,6-Diisopropylphenyl)carbamoyl)-2-(pyrrolidin-2-yl)ethene sulfonamide;

[0126] (S,E)-N-((2,6-Diisopropylphenyl)carbamoyl)-2-(1-ethylpyrrolidin-2-yl)ethene sulfonamide;

[0127] (S,E)-N-((2,6-Diisopropylphenyl)carbamoyl)-2-(1-(methylsulfonyl)pyrrolidin-2-yl)ethenesulfonamide;

[0128] (S,E)-N-((2,6-Diisopropylphenyl)carbamoyl)-2-(1-methylpyrrolidin-2-yl)ethenesulfonamide;

[0129] (S,E)-2-(1-Acetylpyrrolidin-2-yl)-N-((2,6-diisopropylphenyl)carbamoyl)ethenesulfonamide;

[0130] (S,E)-2-(1-Acetylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-ethenesulfonamide;

[0131] (S,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(tetrahydro-2H-pyran-4-carbonyl)pyrrolidin-2-yl)ethenesulfonamide;

[0132] (E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(tetrahydro-2H-pyran-4-yl)ethenesulfonamide;

[0133] (S,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-nicotinoylpyrrolidin-2-yl)ethenesulfonamide;

[0134] (E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(tetrahydrofuran-2-yl)ethene-1-sulfonamide;

[0135] (S,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(thiophen-2-ylmethyl)-pyrrolidin-2-yl)ethene-1-sulfonamide;

[0136] (S,E)-2-(2-(N-((4-Fluoro-2,6-diisopropylphenyl)carbamoyl)aminosulfonyl)vinyl)-pyrrolidine-1-carboxylic acid tert-butyl ester;

[0137] (S,E)-N-((4-Fluoro-2,6-diisopropylphenyl)carbamoyl)-2-(pyrrolidin-2-yl)ethene-1-sulfonamide;

[0138] (S,E)-N-((4-Fluoro-2,6-diisopropylphenyl)carbamoyl)-2-(1-methylpyrrolidin-2-yl)ethene-1-sulfonamide;

[0139] (R,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-isobutyl-2-methylpyrrolidin-2-yl)ethene-1-sulfonamide;

[0140] (R,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-methyl-1-propylpyrrolidin-2-yl)ethene-1-sulfonamide;

[0141] (S,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(thiazol-2-yl)pyrrolidin-2-yl)ethene-1-sulfonamide;

[0142] (E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(piperidin-3-yl)ethene-sulfonamide;

[0143] (E)-2-(1-ethylpiperidin-3-yl)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)ethene-sulfonamide;

[0144] (E)-3-(2-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)aminosulfonyl)vinyl)piperidine-1-carboxylic acid tert-butyl ester;

[0145] (E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(methylsulfonyl)piperidin-3-yl)ethenesulfonamide;

[0146] (E)-2-(1-acetylpiperidin-3-yl)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)ethene-sulfonamide;

[0147] (E)-2-(2-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)aminosulfonyl)vinyl)azetidine-1-carboxylic acid tert-butyl ester;

[0148] (E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-methylazetidin-2-yl)ethene-1-sulfonamide;

[0149] (E)-2-(azetidin-2-yl)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide;

[0150] (R,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-2-yl)ethene-1-sulfonamide;

[0151] (S,E)-2-(1-((5-chlorothiophen-2-yl)sulfonyl)pyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide;

[0152] (S,E)-2-(1-(benzylsulfonyl)pyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide;

[0153] (S,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-((4-methoxyphenyl)sulfonyl)pyrrolidin-2-yl)ethene-1-sulfonamide;

[0154] (S,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-((4-fluorophenyl)sulfonyl)pyrrolidin-2-yl)ethene-1-sulfonamide;

[0155] (S,E)-2-(1-((2-cyanophenyl)sulfonyl)pyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide;

[0156] (S,E)-2-(1-(cyclohexylsulfonyl)pyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide;

[0157] (S,E)-2-(1-(4-fluorobenzyl)pyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide;

[0158] (S,E)-2-(1-((4-cyanophenyl)sulfonyl)pyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide;

[0159] (S,E)-2-(1-(4-cyanobenzyl)pyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide;

[0160] (S,E)-N-((1,2,3,6,7,8-Hexahydro-as-indacen-4-yl)carbamoyl)-2-(pyrrolidin-2-yl)ethene-1-sulfonamide;

[0161] (E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(piperidin-2-yl)ethene-1-sulfonamide;

[0162] (E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-methylpiperidin-2-yl)ethene-1-sulfonamide;

[0163] (E)-N-((1,2,3,6,7,8-Hexahydro-as-indacen-4-yl)carbamoyl)-2-(1-methylpyrrolidin-2-yl)ethene-1-sulfonamide;

[0164] (E)-N-((1,2,3,6,7,8-Hexahydro-as-indacen-4-yl)carbamoyl)-2-(1-(methylsulfonyl)pyrrolidin-2-yl)ethene-1-sulfonamide;

[0165] ((E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-3-(piperidin-2-yl)prop-1-ene-1-sulfonamide;

[0166] (S,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-methylpyrrolidin-2-yl)ethene-1-sulfonamide;

[0167] (S,E)-2-(1,2-dimethylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide;

[0168] (E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(indolin-2-yl)ethene-1-sulfonamide;

[0169] (E)-2-(2-((N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)aminosulfonyl)vinyl)indoline-1-carboxylic acid tert-butyl ester;

[0170] ((S,E)-2-(1-(cyclopropylmethyl)-2-methylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide;

[0171] (S,E)-2-(1-(Cyclopropylsulfonyl)pyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide;

[0172] (S,E)-2-(2-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester;

[0173] (R,E)-2-(2-(N-((2,6-Diisopropylphenyl)carbamoyl)sulfamoyl)vinyl)-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester;

[0174] (R,E)-N-((2,6-Diisopropylphenyl)carbamoyl)-2-(2-methylpyrrolidin-2-yl)ethene-1-sulfonamide 2,2,2-trifluoroacetate;

[0175] (R,E)-N-((2,6-Diisopropylphenyl)carbamoyl)-2-(1,2-dimethylpyrrolidin-2-yl)ethene-1-sulfonamide;

[0176] (S,E)-2-(1-Ethyl-2-methylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide;

[0177] Disodium (R,E)-((2-(1,2-dimethylpyrrolidin-2-yl)vinyl)sulfonyl)((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)amide;

[0178] Sodium (R,E)-((2-(1,2-dimethylpyrrolidin-2-yl)vinyl)sulfonyl)((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)amide;

[0179] (S,E)-2-(2-(N-((2,6-Diisopropylphenyl)carbamoyl)sulfamoyl)vinyl)-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester;

[0180] (S,E)-N-((2,6-Diisopropylphenyl)carbamoyl)-2-(2-methylpyrrolidin-2-yl)ethene-1-sulfonamide 2,2,2-trifluoroacetate;

[0181] (S,E)-N-((2,6-Diisopropylphenyl)carbamoyl)-2-(1,2-dimethylpyrrolidin-2-yl)ethene-1-sulfonamide;

[0182] (R,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-methyl-1-(oxetan-3-yl)pyrrolidin-2-yl)ethene-1-sulfonamide;

[0183] (S,E)-tert-Butyl 2-(2-((N-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)sulfamoyl)vinyl)-2-methylpyrrolidine-1-carboxylate;

[0184] (S,E)-N-((4-Fluoro-2,6-diisopropylphenyl)carbamoyl)-2-(2-methylpyrrolidin-2-yl)ethene-1-sulfonamide 2,2,2-trifluoroacetate;

[0185] (S,E)-2-(1,2-Dimethylpyrrolidin-2-yl)-N-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)ethene-1-sulfonamide;

[0186] (E)-2-(1-Acetylazetidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide;

[0187] (R,E)-tert-Butyl (2-(2-(2-((N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)pyrrolidin-1-yl)ethyl)(methyl)carbamate;

[0188] (S,E)-2-(1-Allylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide;

[0189] (S,E)-2-(1-(1H-Benzimidazole-6-carbonyl)pyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide;

[0190] (S,E)-2-(1-(Cyclopropylsulfonyl)-2-methylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide;

[0191] (S,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(4-methoxybenzyl)pyrrolidin-2-yl)ethene-1-sulfonamide;

[0192] tert-Butyl 5-((R)-2-((E)-2-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)pyrrolidin-1-yl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate;

[0193] (E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-((2R)-1-(octahydrocyclopenta[c]pyrrol-5-yl)pyrrolidin-2-yl)ethene-1-sulfonamide 2,2,2-trifluoroacetate;

[0194] (E)-2-(1-(Cyclopropylsulfonyl)azetidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide;

[0195] (S,E)-N-((2,6-Diisopropylphenyl)carbamoyl)-2-(1-(thiazol-2-yl)pyrrolidin-2-yl)ethene-1-sulfonamide;

[0196] (S,E)-(2-(2-(2-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)-2-methylpyrrolidin-1-yl)ethyl)(methyl)carbamic acid tert-butyl ester;

[0197] Potassium (R,E)-((2-(1,2-dimethylpyrrolidin-2-yl)vinyl)sulfonyl)((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)amide;

[0198] (E)-(2-(2-(2-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)azetidin-1-yl)ethyl)(methyl)carbamic acid tert-butyl ester;

[0199] (S,E)-2-(1-(Cyclohexylmethyl)-2-methylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide;

[0200] Sodium (R,E)-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)((2-(1-(tetrahydro-2H-thiopyran-4-yl)pyrrolidin-2-yl)vinyl)sulfonyl)amide;

[0201] Sodium (R,E)-((2-(1-cyclohexylpyrrolidin-2-yl)vinyl)sulfonyl)((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)amide;

[0202] Sodium (S,E)-((2,6-diisopropylphenyl)carbamoyl)((2-(1,2-dimethylpyrrolidin-2-yl)vinyl)sulfonyl)amide;

[0203] Sodium (R,E)-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)((2-(1-methylpyrrolidin-2-yl)vinyl)sulfonyl)amide;

[0204] Potassium (R,E)-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)((2-(1-methylpyrrolidin-2-yl)vinyl)sulfonyl)amide;

[0205] Sodium (S,E)-((2-(1,2-dimethylpyrrolidin-2-yl)vinyl)sulfonyl)((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)amide;

[0206] Sodium (S,E)-((2-(1-ethylpyrrolidin-2-yl)vinyl)sulfonyl)((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)amide;

[0207] (S,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(2-hydroxyethyl)pyrrolidin-2-yl)ethene-1-sulfonamide;

[0208] (E)-2-(2-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)-2-methylazetidine-1-carboxylic acid tert-butyl ester;

[0209] (E)-2-(1,2-dimethylazetidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide;

[0210] (S,E)-2-ethyl-2-(2-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)pyrrolidine-1-carboxylic acid tert-butyl ester;

[0211] (S,E)-tert-Butyl 2-(2-(N-((1,2,3,6,7,8-hexahydro-as-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)-2-methylpyrrolidine-1-carboxylate;

[0212] (S,E)-2-(2-Ethylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide 2,2,2-trifluoroacetate;

[0213] (S,E)-N-((1,2,3,6,7,8-hexahydro-as-indacen-4-yl)carbamoyl)-2-(2-methylpyrrolidin-2-yl)ethene-1-sulfonamide 2,2,2-trifluoroacetate;

[0214] (S,E)-2-(1,2-Dimethylpyrrolidin-2-yl)-N-((1,2,3,6,7,8-hexahydro-as-indacen-4-yl)carbamoyl)ethene-1-sulfonamide;

[0215] (R,E)-tert-Butyl 2-(2-(N-((1,2,3,6,7,8-hexahydro-as-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)-2-methylpyrrolidine-1-carboxylate;

[0216] (R,E)-N-((1,2,3,6,7,8-hexahydro-as-indacen-4-yl)carbamoyl)-2-(2-methylpyrrolidin-2-yl)ethene-1-sulfonamide 2,2,2-trifluoroacetate;

[0217] (R,E)-2-(1,2-Dimethylpyrrolidin-2-yl)-N-((1,2,3,6,7,8-hexahydro-as-indacen-4-yl)carbamoyl)ethene-1-sulfonamide;

[0218] (R,E)-tert-Butyl 2-(3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)allyl)-2-methylpyrrolidine-1-carboxylate;

[0219] (R,E)-tert-Butyl ((2-(2-(3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)allyl)-2-methylpyrrolidin-1-yl)ethyl)(methyl)carbamate;

[0220] (R,E)-3-(1,2-Dimethylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)prop-1-ene-1-sulfonamide;

[0221] (S,E)-(3-(2-(2-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)pyrrolidin-1-yl)propyl)(methyl)carbamic acid tert-butyl ester;

[0222] (E)-(3-(2-(2-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)-2-methylazetidin-1-yl)propyl)(methyl)carbamic acid tert-butyl ester;

[0223] (E)-(2-(2-(2-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)-2-methylazetidin-1-yl)ethyl)(methyl)carbamic acid tert-butyl ester;

[0224] (E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-methyl-1-(2-(methylthio)ethyl)azetidin-2-yl)ethene-1-sulfonamide;

[0225] (E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-methyl-1-(oxetan-3-yl)azetidin-2-yl)ethene-1-sulfonamide;

[0226] (S)-2-(((S)-2-((E)-2-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)-2-methylazetidin-1-yl)methyl)-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester;

[0227] (S)-2-(((R)-2-((E)-2-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)-2-methylazetidin-1-yl)methyl)-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester;

[0228] (R,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(2-sulfonylethyl)pyrrolidin-2-yl)ethene-1-sulfonamide;

[0229] (S,E)-2-(2-ethyl-1-methylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide;

[0230] (R,E)-2-(1-(but-2-yn-1-yl)pyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide;

[0231] or a pharmaceutically acceptable salt of any of the above compounds.

[0232] The following is a list of abbreviations used in the description of the preparation of the compounds of the present invention:

[0233] μg: microgram

[0234] 1 1H NMR: proton nuclear magnetic resonance

[0235] bs: broad singlet

[0236] CDCl3: deuterated chloroform

[0237] CHCl3: chloroform

[0238] d: doublet

[0239] DAMP: damage-associated molecular pattern;

[0240] DCM: dichloromethane

[0241] dd: double doublet

[0242] DMAC: N,N-(dimethylacetamide)

[0243] DMAP: 4-(dimethylamino)pyridine

[0244] DMF: N,N-dimethylformamide

[0245] DMSO: dimethyl sulfoxide

[0246] dt: double triplet

[0247] EDTA: ethylenediaminetetraacetic acid

[0248] EtOAc: ethyl acetate

[0249] EtOH: ethanol

[0250] HCl(g): hydrogen chloride (gas)

[0251] IL1β: interleukin 1β

[0252] K2CO3: potassium carbonate

[0253] LPS: lipopolysaccharide

[0254] m: multiplet

[0255] MeOH: methanol

[0256] mmol: millimole

[0257] MS: mass spectrometry

[0258] N2: nitrogen

[0259] Na2CO3: sodium carbonate

[0260] ng: nanogram

[0261] NIS: N-iodosuccinimide

[0262] NLRP3: NOD-like receptor family, pyrin domain-containing protein 3

[0263] PAMP: pathogen-associated molecular pattern;

[0264] PMA: phorbol 12-myristate 13-acetate

[0265] POCI3: phosphoryl chloride

[0266] RM: reaction mixture

[0267] R.T; r.t: room temperature

[0268] s: singlet

[0269] t: triplet

[0270] td: triple doublet

[0271] THF: tetrahydrofuran

[0272] TLC: thin layer chromatography

[0273] TLR: Toll-like receptor.

[0274] TNFα: tumor necrosis factor α

[0275] General preparation methods

[0276] The compounds of the present invention can be prepared using the following reactions and techniques, together with conventional techniques known to those skilled in the art of organic synthesis, or variations thereof as understood by those skilled in the art.

[0277] The reactions can be carried out in a solvent suitable for the reagents and materials used and appropriate for the affected transformation. Preferred methods include, but are not limited to, those described below, where all symbols are as defined above unless otherwise defined below.

[0278] The compounds of general formula (I) can be prepared as described in the following scheme, together with suitable modifications / variations that are entirely within the scope of those skilled in the art.

[0279] Scheme 1

[0280]

[0281] Scheme 2

[0282]

[0283] Scheme 3

[0284]

[0285] wherein A, B, R 1 , R 2 , R 3 and R 4 are each as defined above. Compound (2) can be prepared from commercially available methanesulfonamide (1) using a reagent such as Boc anhydride by various methods familiar to those skilled in the art. Compound (2) is treated with diphenylphosphinous chloride under suitable conditions and in a suitable solvent to give compound 3 (Reference: Synthesis 2003, 15, 2321 - 24). Compound 3 is treated with an aldehyde or ketone derivative (4) in the presence of a base (such as sodium hydride) and a suitable solvent under suitable conditions to give compound (5), which can be deprotected under suitable conditions to give compound (6). Compound (3) is treated with an isocyanate derivative (7) in the presence of a base (such as sodium hydride) and a suitable solvent under suitable conditions to give the compound of formula (I) (Scheme 1). Alternatively, the compound of formula (I) can also be prepared as depicted in Schemes 2 and 3.

[0286] The specific reaction conditions, solvents and other parameters necessary to carry out the above method steps are entirely within the capabilities of those skilled in the art.

[0287] The present invention is further illustrated by the following non - limiting examples which describe some preferred embodiments of the invention. The provision of these does not in any way limit the scope of the invention.

[0288] The 1 1H NMR spectral data given in the examples (see below) were recorded using a 400 MHz spectrometer (Bruker AVANCE - 400) and reported on a δ scale. Unless otherwise stated, the solvent used for NMR was CDCl3 with TMS as the internal standard.

[0289] According to a feature of the present invention, there is provided the general structure of the intermediate of formula (5),

[0290]

[0291] All symbols are as defined above.

[0292] In another embodiment, a general structure of the intermediate of formula (6) is provided

[0293]

[0294] All symbols are as defined above.

[0295] In another embodiment, a general structure of the intermediate of formula (15) is provided

[0296]

[0297] All symbols are as defined above.

[0298] In another embodiment, a general structure of the intermediate of formula (16) is provided

[0299]

[0300] All symbols are as defined above.

[0301] In yet another embodiment, a method for preparing the intermediates of formulae (5), (6), (15) and (16) according to Schemes 1 and 3 disclosed in the specification is provided.

[0302] Intermediate-1a: Preparation of (R,E)-2-(2-(N-(tert-butoxycarbonyl)-sulfamoyl)-vinyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0303]

[0304] A 500 mL, three-necked, round-bottomed flask was equipped with a magnetic stirrer, an N2 balloon, a heat-insulating bag, and a dry-ice bath. Under a nitrogen atmosphere, ((diphenylphosphoryl)methyl)sulfonylcarbamic acid tert-butyl ester (3) (10 g, 25.3 mmol) was dissolved in DMF (100 mL). It was cooled to -20 °C and NaH (2.023 g, 50.6 mmol) was added. It was gradually warmed to 25 °C and stirred for 30 minutes. It was cooled again to -20 °C, and a solution of (R)-tert-butyl 2-formylpyrrolidine-1-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 1 hour at -20 °C. After the addition, the reaction mixture was warmed to room temperature and further stirred for 17 hours. The reaction mixture was cooled to 0 °C and acidified with saturated citric acid solution (30 mL) and water (200 mL), and a solid precipitated. It was filtered, washed, and dried to give (R,E)-tert-butyl 2-(2-(N-(tert-butoxycarbonyl)aminosulfonyl)vinyl)pyrrolidine-1-carboxylate (4.6 g, 12.22 mmol, 48% yield).

[0305] 1 H NMR (400 MHz, DMSO-d6): 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); MS (ESI): m / z (%) = 375.30 (100%) (M - H) - .

[0306] Intermediate-1b: Preparation of (S,E)-tert-butyl 2-(2-(N-(tert-butoxycarbonyl)-aminosulfonyl)-vinyl)pyrrolidine-1-carboxylate

[0307]

[0308] Intermediate-1b was also prepared using (S)-tert-butyl 2-formylpyrrolidine-1-carboxylate according to the procedure described for the synthesis of Intermediate-1a.

[0309] Intermediate-2a: Preparation of (R,E)-tert-butyl 2-(2-aminosulfonylvinyl)pyrrolidine-1-carboxylate

[0310]

[0311] Dissolve the compound [Intermediate 1a] (18 g) in DMSO (180 mL) and heat to 85 °C (monitor the disappearance of the starting material by TLC). Cool the reaction, pour into water (900 mL) and extract with EtOAc (3 × 300 mL). Concentrate the solvent in vacuo and purify by column chromatography on silica gel (50% EtOAc: n - hexane) to give the product (R,E)-tert - butyl 2-(2 - sulfamoylethylidene)pyrrolidine - 1 - carboxylate (14.3 g, 53.7 mmol, 67% yield).

[0312] 1 H NMR (400 MHz, DMSO - d6): 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 - 1).

[0313] Intermediate-2b: Preparation of (S,E)-tert - butyl 2-(2 - sulfamoylethylidene)pyrrolidine - 1 - carboxylate

[0314]

[0315] Intermediate - 2b was also prepared using Intermediate 1b according to the procedure described for the synthesis of Intermediate - 2a.

[0316] Intermediate-2c: Preparation of (R,Z)-tert - butyl 2-(2 - sulfamoylethylidene)pyrrolidine - 1 - carboxylate

[0317]

[0318] Intermediate - 2c was also obtained according to the procedure described for the synthesis of Intermediate - 2a.

[0319] 1 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)+ .

[0320] Intermediate-2d: Preparation of (S,Z)-2-(2-sulfamoylvinyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0321]

[0322] Intermediate-2d was also obtained according to the procedure for synthesizing Intermediate-2b as described.

[0323] Intermediate-3a (Example 10): Preparation of (R,E)-2-(2-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0324]

[0325] NaH (60% dispersion in mineral oil) (3.82 gm, 96 mmol) was added to a solution of sulfonamide [Intermediate 2a] (22.0 gm, 80 mmol) in DMF (220 mL) at 0 °C. The reaction was warmed to room temperature and stirred for 30 minutes. 4-Isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (19.03 gm, 96 mmol) was added portionwise at 0 °C, and the reaction was warmed to room temperature and stirred overnight. The reaction was acidified to pH = 2.0 with 50% aqueous citric acid, diluted with water (1500 mL), the precipitate was filtered and dried to give the product (38 g, 80 mmol, 100% yield).

[0326] 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), 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 - 1).

[0327] Intermediate-3b (Example 61): Preparation of (S,E)-2-(2-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0328]

[0329] Intermediate-3b was also prepared according to the procedure for preparing Intermediate-2b as described.

[0330] 1 H 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 = 7.2 Hz, 4H), 2.67 (t, J = 7.2 Hz, 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) + .

[0331] Intermediate-4a: Preparation of (R)-tert-butyl 2-formyl-2-methylpyrrolidine-1-carboxylate

[0332]

[0333] To a solution of 1-(tert-butyl) 2-methyl (R)-2-methylpyrrolidine-1,2-dicarboxylate (Singh et.al., RSC Adv., 2013, 3, 19533–19544) (98 g, 403 mmol) in anhydrous DCM (2000 mL) to obtain a solution. DIBAL-H (806 mL, 1.5 M in toluene, 537 mmol) was added dropwise at -78 °C. The reaction mixture was stirred at -78 °C for 2 h and then quenched with methanol (100 mL) at -78 °C. The reaction mixture was acidified with 50% citric acid solution until pH = 4.0. Water (1000 mL) and DCM (1000 mL) were added. The aqueous layer was extracted with DCM (2 × 1500 mL). The combined organic layers were washed with water (1500 mL), brine (1000 mL), and dried over Na2SO4. The solvent was removed to obtain the product (83 g, 389 mmol, 97% yield).

[0334] 1 H NMR (400 MHz, DMSO-d6): 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), rotamer: MS (ESI): m / z (%) = 214.3 (100%) (M + H)+ .

[0335] Intermediate-4b: Preparation of tert-butyl (S)-2-formyl-2-methylpyrrolidine-1-carboxylate

[0336]

[0337] Intermediate-4b was also prepared according to the procedure for synthesizing Intermediate-4a using 1-(tert-butyl) 2-methyl (S)-2-methylpyrrolidine-1,2-dicarboxylate.

[0338] Intermediate-5a: Preparation of tert-butyl (R,E)-2-(2-(N-(tert-butoxycarbonyl)sulfamoyl)vinyl)-2-methylpyrrolidine-1-carboxylate

[0339]

[0340] NaH (60% dispersion in mineral oil) (34 gm, 851 mmol) was added at 0 °C to a solution of tert-butyl (((diphenylphosphoryl)methyl)sulfonyl)carbamate (153.0 gm, 387 mmol) in DMF (1530 mL). The reaction was warmed to room temperature and stirred for 30 minutes. Aldehyde ((R)-2-formyl-2-methylpyrrolidine-1-carboxylate tert-butyl ester) (83 gm, 387 mmol) in DMF (830 mL) was added dropwise at -20 °C, and the reaction was warmed to room temperature and stirred overnight. The reaction was acidified to pH = 2.0 using 50% aqueous citric acid (ca. 500 mL), diluted with water (3000 mL) and extracted with EtOAc (2000 mL × 2). The combined organic layers were washed with water (2000 mL × 3), brine (1000 mL), dried over Na2SO4, concentrated and dried to give the crude product. The residue was purified by column chromatography on silica gel using 25% EtOAC: n-hexane to afford the title compound (121 g, 310 mmol, 80% yield).

[0341] 1 H NMR (400 MHz, DMSO-d6): δ = 11.35 (s, 1H), 6.78 (d, J = 15.2 Hz, 1H), 6.44 (d, J = 15.6 Hz, 1H), 3.42 - 3.36 (m, 2H), 1.99 - 1.92 (m, 1H), 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-1).

[0342] Intermediate-5b:(S,E)-tert-Butyl 2-(2-(N-(tert-butoxycarbonyl)sulfamoyl)vinyl)-2-methylpyrrolidine-1-carboxylate Preparation

[0343]

[0344] Intermediate-5b was also prepared following the procedure for synthesizing Intermediate-5a using (S)-tert-butyl 2-formyl-2-methylpyrrolidine-1-carboxylate.

[0345] Intermediate-6a: (R,E)-tert-Butyl 2-methyl-2-(2-sulfamoylvinyl)pyrrolidine-1-carboxylate Preparation

[0346]

[0347] Intermediate 5a (121 g) was dissolved in DMSO (1200 mL) and heated to 85 °C (monitored by TLC for the disappearance of starting material). The reaction was cooled, poured into water (3000 mL) and extracted with EtOAc (2000 mL × 4) and dried over Na2SO4. The solvent was concentrated in vacuo and purified by column chromatography on silica gel (50% EtOAc: n-hexane) to afford the product (61.4 g, 211 mmol, 68.2% yield).

[0348] 1 1H NMR (400 MHz, DMSO-d6): 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 - 1).

[0349] Intermediate-6b: (S,E)-tert-Butyl 2-methyl-2-(2-sulfamoylvinyl)pyrrolidine-1-carboxylate Preparation

[0350]

[0351] Intermediate-6b was also prepared following the procedure for synthesizing Intermediate-6a using Intermediate-5b.

[0352] Intermediate-7a (Example 52): (R,E)-tert-Butyl 2-(2-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)-2-methylpyrrolidine-1-carboxylate Preparation

[0353]

[0354] NaH (60% dispersion in mineral oil) (10.08 gm, 252 mmol) was added to a solution of (R,E)-tert-butyl 2-methyl-2-(2-sulfamoylvinyl)pyrrolidine-1-carboxylate (Intermediate 6a) (61.0 gm, 210 mmol) in DMF (610 mL) at 0 °C. The reaction was warmed to room temperature and stirred for 30 minutes. 4-Isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (50.2 gm, 252 mmol) was added portionwise at 0 °C, and the reaction was warmed to room temperature and stirred overnight. The reaction was acidified to pH = 2.0 with 50% aqueous citric acid at 0 °C and diluted with cold water (3000 mL). The precipitate was filtered through a Buchner funnel and dried to give the product (100 g, 204 mmol, 97% yield).

[0355] 1 H NMR (400 MHz, DMSO-d6): 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 - 1).

[0356] Intermediate-7b (Example 111): (S,E)-tert-butyl 2-(2-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)-2-methylpyrrolidine-1-carboxylate Preparation

[0357]

[0358] Intermediate-7b (Example 111) was also synthesized following the procedure for preparing Intermediate-7a using Intermediate-6b.

[0359] Intermediate-8: (Diphenylphosphoryl)methanesulfonamide Preparation

[0360]

[0361] Dissolve tert-butyl (((diphenylphosphoryl)methyl)sulfonyl)carbamate (Synthesis 2003, 15, 2321 - 24) (10.0 g, 25.3 mmol) in DCM (100 mL) under N2 atmosphere. Cool it to 0 °C and add TFA (19.48 mL, 253 mmol) dropwise, and stir the reaction mixture for a further 4 h after removing the ice bath. Check TLC and no starting material was observed. Concentrate the reaction mixture under reduced pressure, add water (50 mL), a solid precipitated, filter and wash with water (25 mL×2), and dry over P2O5 to give (diphenylphosphoryl)methanesulfonamide (7.3 g, 24.72 mmol, 98% yield).

[0362] 1 H NMR (400 MHz, DMSO-d6): 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 (ES1): m / z (%) = 296.05 (100%) (M + H) + .

[0363] Intermediate-9: Preparation of 1-(diphenylphosphoryl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)methanesulfonamide

[0364]

[0365] Under N2 atmosphere, bring (diphenylphosphoryl)methanesulfonamide [Intermediate 8] (6.0 g, 20.32 mmol) into DMF (60 mL). Cool it to 0 °C and add NaH (1.170 g, 24.38 mmol) and stir the reaction mixture for 30 min at room temperature. Then add a solution of 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (4.86 g, 24.38 mmol) in DMF (15 mL), and stir the reaction mixture for a further 17 h at room temperature. Check TLC and no starting material was observed. Pour the reaction mixture into ice-cold water (180 mL) and acidify with saturated citric acid, stir and filter to obtain the crude product. Purify the crude product by trituration in ethyl acetate to give 1-(diphenylphosphoryl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)methanesulfonamide (9.1 g, 18.40 mmol, 91% yield).

[0366] 11H NMR (400 MHz, DMSO-d6): δ = 10.4 (bs, 1H), 8.14 (s, 1H), 7.88 - 7.83 (m, 4H), 7.63 - 7.53 (m, 6H), 6.96 (s, 1H), 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 (ES): m / z (%) = 495.14 (100%) (M + H) + .

[0367] Intermediate-7b (Example 111): (S,E)-2-(2-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester Preparation

[0368]

[0369] Under N2 atmosphere, 1-(diphenylphosphoryl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)methanesulfonamide [Intermediate 9] (0.5 g, 1.011 mmol) was dissolved in DMF (5 mL). It was cooled to 0 °C and NaH (0.089 g, 2.224 mmol) was added under N2 atmosphere at 0 °C. After that, the ice bath was removed and the RM was stirred at room temperature for 30 minutes. Then a solution of (S)-tert-butyl 2-formyl-2-methylpyrrolidine-1-carboxylate (0.259 g, 1.213 mmol) in DMF (2.5 mL) was added dropwise to the above suspension at -20 °C. Then the RM was warmed to room temperature and further stirred for 18 hours. TLC was checked and a small amount of starting material was observed. The RM was diluted with water (15 mL), the aqueous layer was acidified with a citric acid solution, a solid precipitated, the solid was filtered out and washed with water (15 mL), and dried over P2O5. The crude product was purified by column chromatography using 40% EtOAc:hexane to give (S,E)-2-(2-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester (0.125 g, 0.255 mmol, 25.3% yield).

[0370] Intermediate-7a (Example 52) It was also prepared using (R)-tert-butyl 2-formyl-2-methylpyrrolidine-1-carboxylate according to the procedure described for synthesizing Intermediate-7b (Example 111).

[0371] Intermediate-3a(Example 10) was also prepared using (R)-tert-butyl 2-formylpyrrolidine-1-carboxylate according to the procedure for synthesizing Intermediate-7b as described.

[0372] Intermediate-3b (Example 61) was also prepared using (S)-tert-butyl 2-formylpyrrolidine-1-carboxylate according to the procedure for synthesizing Intermediate-7b as described.

[0373] Intermediate-10a: Preparation of tert-butyl 2-formylazetidine-1-carboxylate

[0374]

[0375] To a solution of 1-(tert-butyl) 2-methylazetidine-1,2-dicarboxylate (European Journal of Medicinal Chemistry, 2000, 35(11), 979-988; Journal of the American Chemical Society (2010), 132(40), 14027-14029) (4.26 g, 19.79 mmol) in anhydrous DCM (86 mL) to obtain a solution. DIBAL-H (26.4 mL, 1.5 M, in toluene solution, 39.6 mmol) was added dropwise at -78 °C. The reaction mixture was stirred at -78 °C for 2 hours and then quenched with methanol (5 mL) at -78 °C. The reaction mixture was acidified with 50% citric acid solution until pH = 4.0. Water (100 mL) and DCM (50 mL) were added. The aqueous layer was extracted with DCM (2 × 80 mL). The combined organic layers were washed with water (150 mL), brine (10 mL), dried over Na2SO4 and the solvent was evaporated to obtain the product tert-butyl 2-formylazetidine-1-carboxylate (3.4 g, 18.36 mmol, 93% yield).

[0376] Intermediate-10b: Preparation of tert-butyl 2-formyl-2-methylazetidine-1-carboxylate

[0377]

[0378] Intermediate-10b was also prepared using 1-(tert-butyl) 2-methyl 2-methylazetidine-1,2-dicarboxylate according to the procedure for synthesizing Intermediate-10a as described.

[0379] Intermediate-11a: Preparation of (E)-tert-butyl 2-(2-(N-(tert-butoxycarbonyl)sulfamoyl)vinyl)azetidine-1-carboxylate

[0380]

[0381] NaH (60% dispersion in mineral oil) (1.34 gm, 33.4 mmol) was added to a solution of tert-butyl (((diphenylphosphoryl)methyl)sulfonyl)carbamate (6.0 gm, 15.17 mmol) in DMF (60 mL) at 0 °C. The reaction was warmed to room temperature and stirred for 30 minutes. tert-Butyl 2-formylazetidine-1-carboxylate (3.37 g, 18.21 mmol) in DMF (35 mL) was added dropwise at -20 °C, and the reaction was warmed to room temperature and stirred overnight. The reaction was acidified to pH = 2.0 using 50% aqueous citric acid (ca. 10 mL), diluted with water (200 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with water (150 mL × 3), brine (80 mL), dried over Na2SO4, concentrated and dried to give the crude product. The residue was purified by column chromatography on silica gel using 30% EtOAC: n-hexane to afford tert-butyl (E)-2-(2-(N-(tert-butoxycarbonyl)sulfamoyl)vinyl)azetidine-1-carboxylate (1.8 g, 4.97 mmol, 33% yield).

[0382] 1 1H NMR (400 MHz, DMSO-d6): 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-1).

[0383] Intermediate-11: (E)-2-(2-Sulfamoylvinyl)azetidine-1-carboxylate tert-butyl

[0384]

[0385] Dissolve tert-butyl (E)-2-(2-(N-(tert-butoxycarbonyl)sulfamoyl)vinyl)azetidine-1-carboxylate (Intermediate 11a) (1.8 g, 4.97 mmol) in DMSO (18 mL) and heat to 85 °C (monitor the disappearance of the starting material by TLC). Cool the reaction, pour into water (90 mL) and extract with EtOAc (40 ml × 4) and dry over Na2SO4. Concentrate the solvent in vacuo and purify by column chromatography (60% EtOAc: n-hexane) on silica gel to give tert-butyl (E)-2-(2-sulfamoylvinyl)azetidine-1-carboxylate (2.02 g, 3.74 mmol, 83% yield).

[0386] 1 H NMR (400 MHz, DMSO-d6): 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-1).

[0387] Intermediate-12a: Preparation of tert-butyl (E)-2-(2-(N-(tert-butoxycarbonyl)sulfamoyl)vinyl)-2-methylazetidine-1-carboxylate

[0388]

[0389] At 0 °C, NaH (60% dispersion in mineral oil) (1.00 gm, 25.04 mmol) was added to a solution of tert-butyl (((diphenylphosphoryl)methyl)sulfonyl)carbamate (4.5 gm, 11.38 mmol) in DMF (45 mL). The reaction was warmed to room temperature and stirred for 30 minutes. At -20 °C, tert-butyl 2-formyl-2-methylazetidine-1-carboxylate (Journal of Medicinal Chemistry, 2014, 57(23), 10044–10057) (2.72 gm, 13.66 mmol) in DMF (30 mL) was added dropwise. The reaction was warmed to room temperature and stirred overnight. The reaction was acidified to pH = 2.0 with 50% aqueous citric acid, diluted with water (100 mL) and extracted with EtOAc (80 mL × 3). The combined organic layers were washed with water (100 mL × 3), brine (50 mL), dried over Na2SO4, concentrated and dried to give the crude product. The residue was purified by column chromatography on silica gel using 30% EtOAC: n-hexane to afford tert-butyl (E)-2-(2-(N-(tert-butoxycarbonyl)sulfamoyl)vinyl)-2-methylazetidine-1-carboxylate (3.73 g, 9.91 mmol, 87% yield).

[0390] 1 H NMR (400 MHz, DMSO-d6): 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 - 1.36 (m, 9H); MS (ESI): m / z (%) = 399.20 (100%) (M+Na), 375.20 (100%) (M-1).

[0391] Intermediate-12: Preparation of tert-butyl (E)-2-methyl-2-(2-sulfamoylvinyl)azetidine-1-carboxylate

[0392]

[0393] Dissolve tert-butyl (E)-2-(2-(N-(tert-butoxycarbonyl)sulfamoyl)vinyl)-2-methylazetidine-1-carboxylate (Intermediate-12a) (3.73 g, 9.91 mmol) in DMSO (20 mL) and heat to 85 °C (monitor the disappearance of the starting material by TLC). Cool the reaction, pour into water (70 mL) and extract with EtOAc (30 mL × 4) and dry over Na2SO4. Concentrate the solvent in vacuo and purify by column chromatography (60% EtOAc: n-hexane) on silica gel to afford tert-butyl (E)-2-methyl-2-(2-sulfamoylvinyl)azetidine-1-carboxylate (2.52 g, 9.12 mmol, 92% yield).

[0394] 1 H NMR (400 MHz, DMSO-d6): 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-1).

[0395] Example-1

[0396] (R,E)-2-(1-Ethylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-ethanesulfonamide

[0397]

[0398] Add TFA (1 equiv) to a solution of Intermediate 3a (1 equiv) in DCM (2.5 mL) at 0 °C. Warm the reaction to room temperature and stir for a further 3 h. Concentrate the reaction mixture in vacuo and purify by preparative HPLC to afford the product. Add NaHCO3 (1.2 equiv) to a solution of this product (1 equiv) in MeOH (7.0 mL) at room temperature and stir for 5 min. Add acetaldehyde (5 equiv) at room temperature and stir for 2 h. Thereafter, treat the reaction mixture with NaBH4 (1.5 equiv) portionwise at 0 °C, then warm the reaction mixture to room temperature and stir overnight. Purify the reaction mixture by preparative HPLC to afford the pure product (Example 1).

[0399] Alternatively: To a solution of intermediate 3 (1 equiv) in DCM (2.5 mL) at 0 °C was added TFA (1 equiv). The reaction was warmed to room temperature and further stirred for 3 h. The reaction mixture was concentrated in vacuo and purified by preparative HPLC to give the product. To a solution of this product (1 equiv) in anhydrous THF (5.0 mL) at 0 °C was added NaH (1.2 equiv) and stirred for 5 min. Ethyl bromide (1.6 equiv) was added and stirred at room temperature for 14 h. The reaction mixture was purified by preparative HPLC to give the pure product (Example 1).

[0400] Alternatively: To a solution of (R,E)-tert-butyl 2-(2-(N-(tert-butoxycarbonyl)sulfamoyl)vinyl)pyrrolidine-1-carboxylate (3.4 g, 9.04 mmol) in DCM was added trifluoroacetic acid (15.3 mL) and stirred at room temperature for 1 h. DCM was distilled off and at 0 °C, excess trimethylamine (5.23 g, 7.2 mL, 53.1 mmol) was added to the reaction mixture, followed by ethyl bromide (1.35 g, 0.926 mL, 12.74 mmol). The crude mixture gave (R,E)-2-(1-ethylpyrrolidin-2-yl)ethene-1-sulfonamide. Under nitrogen atmosphere conditions, to a solution of (R,E)-2-(1-ethylpyrrolidin-2-yl)ethene-1-sulfonamide (2.11 g, 10.33 mmol) in DMF (50 mL) was added sodium hydride (60% in mineral oil) (0.5 g, 12.39 mmol) in one portion. The resulting suspension was further stirred at room temperature for 1 h. 4-Isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (2 g, 10.05 mmol) was further added and the reaction mixture (RM) was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure and acidified with citric acid. The crude product was purified by preparative HPLC to give the pure product (Example 1).

[0401] 1 H NMR (400 MHz, DMSO-d6): δ = 8.03 (s, 1H), 6.92 (s, 1H), 6.87 (d, J = 14.8 Hz, 1H), 6.60 - 6.54 (m, 1H), 3.27 - 3.16 (m, 3H), 2.80 (t, J = 7.2 Hz, 4H), 2.67 (t, J = 7.2 Hz, 4H), 2.35 - 2.33 (m, 2H), 2.09 - 1.94 (m, 6H), 1.81 - 1.73 (m, 2H), 1.03 (t, J = 7.2 Hz, 3H); MS (ESI): m / z (%) = 404.20 (100%) (M+H) + .

[0402] Using appropriate starting materials and suitable modifications to the method described in Example 1, including suitable additions and / or deletions to the steps that may be necessary, which are entirely within the scope of those skilled in the art, the following compounds were prepared in a similar manner.

[0403] Example - 2

[0404] (S,E)-2-(1-Ethylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-ethanesulfonamide

[0405]

[0406] 1 H NMR(400MHz,DMSO-d6):δ=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,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) + .

[0407] Example - 3

[0408] (R,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(pyrrolidin-2-yl)ethene-1-sulfonamide

[0409]

[0410] 1 H NMR(400MHz,DMSO-d6):δ=9.71(brs,1H),7.49(s,1H),6.95(d,J=15.2Hz,1H),6.80(s,1H),6.36(dd,J=7.2Hz,J=15.2Hz,1H),4.08 - 4.02(m,1H),3.18 - 3.03(m,2H),2.77(t,J=7.2Hz,4H),2.70(t,J=7.2Hz,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 - 1).

[0411] Example - 4

[0412] (R,E)-N-((1,2,3,5,6,7 - hexahydro - s - indacen - 4 - yl)carbamoyl)-2-(1 - propylpyrrolidin - 2 - yl)ethene - 1 - sulfonamide

[0413]

[0414] 1 H NMR(400MHz, DMSO - d6): δ = 8.00(s, 1H), 6.93(s, 1H), 6.84(d, J = 14.8Hz, 1H), 6.58(dd, J = 7.6Hz, J = 15.2Hz, 1H), 3.15(s, 1H), 2.80(t, J = 7.2Hz, 4H), 2.67(t, J = 7.2Hz, 4H), 2.33 - 2.22(m, 2H), 2.09 - 1.91(m, 6H), 1.78 - 1.73(m, 2H), 1.62 - 1.50(m, 1H), 1.46 - 1.33(m, 2H), 0.82(t, J = 7.2Hz, 3H); MS(ESI): m / z(%) = 418.22(100%)(M + H) + .

[0415] Example - 5

[0416] (R,E)-2-(1-(cyclopropylmethyl)pyrrolidin - 2 - yl)-N-((1,2,3,5,6,7 - hexahydro - s - indacen - 4 - yl)carbamoyl)ethene - 1 - sulfonamide

[0417]

[0418] 11H NMR (400 MHz, DMSO-d6): δ = 10.42 (brs, 1H), 8.03 (s, 1H), 6.93 (s, 1H), 6.87 (d, J = 15.2 Hz, 1H), 6.62 (dd, J = 7.2 Hz, J = 15.2 Hz, 1H), 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, 1H), 2.30 - 2.05 (m, 1H), 2.04 - 1.91 (m, 5H), 1.87 - 1.71 (m, 2H), 1.70 - 1.50 (m, 1H), 0.91 - 0.67 (m, 1H), 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 - 1).

[0419] Example - 6

[0420] (R,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-methylpyrrolidin-2-yl)ethene-1-sulfonamide

[0421]

[0422] To a solution of Intermediate 3a (1 equiv) in DCM (2.5 mL) at 0 °C was added TFA (1 equiv). The reaction was warmed to room temperature and stirred for a further 3 h. The reaction mixture was concentrated in vacuo and purified by preparative HPLC to afford the product. To a solution of the product (1 equiv) in MeOH (7.0 mL) at room temperature was added solid NaHCO3 (1.2 equiv) and stirred for 5 min. Formaldehyde (37% solution) (5 equiv) was added at room temperature and stirred for 2 h. Thereafter, the reaction mixture was treated portionwise with NaBH4 (1.5 equiv) at 0 °C and then the reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was purified by preparative HPLC to afford the pure product.

[0423] Alternatively, Example 6 was also prepared according to the procedure for synthesizing Intermediate - 7b (Example 111) using Intermediate 9 and (R)-1-methylpyrrolidine-2-carbaldehyde together with conventional techniques known to those skilled in the art of organic synthesis.

[0424] 11H NMR (400 MHz, DMSO-d6): δ = 10.53 (brs, 1H), 7.97 (s, 1H), 6.92 (s, 1H), 6.84 (d, J = 15.2 Hz, 1H), 6.53 (dd, J = 7.6 Hz, J = 15.2 Hz, 1H), 3.13 - 3.04 (m, 1H), 3.05 - 2.92 (m, 1H), 2.80 (t, J = 7.2 Hz, 4H), 2.67 (t, J = 7.2 Hz, 4H), 2.33 - 2.28 (m, 1H), 2.26 (s, 3H), 2.05 - 1.91 (m, 5H), 1.79 - 1.72 (m, 2H), 1.59 - 1.54 (m, 1H); MS (ESI): m / z (%) = 390.17 (100%) (M + H) + , 388.07 (30%) (M - 1).

[0425] Example - 7

[0426] (R,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(methylsulfonyl)pyrrolidin-2-yl)ethene-1-sulfonamide

[0427]

[0428] 1 1H NMR (400 MHz, DMSO-d6): δ = 10.55 (bs, 1H), 8.06 (s, 1H), 6.94 (s, 1H), 6.79 - 6.69 (m, 2H), 4.50 - 4.47 (m, 1H), 3.34 - 3.33 (m, 1H), 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 (quintet, J = 7.6 Hz, 4H), 1.88 - 1.85 (m, 1H), 1.80 - 1.79 (m, 2H); MS (ESI): m / z (%) = 454.17 (100%) (M + H) + .

[0429] Example - 8

[0430] (R,E)-2-(1-Acetylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide

[0431]

[0432] 11H NMR (400 MHz, DMSO-d6): δ = 10.25 (bs, 1H), 8.07 (s, 1H), 6.95 (s, 1H), 6.73 - 6.67 (m, 1H), 6.63 (d, J = 15.2 Hz, 1H), 4.69 - 4.62 (m, 1H), 3.55 - 3.42 (m, 1H), 2.83 (t, J = 7.2 Hz, 4H), 2.69 (q, J = 7.2 Hz, 4H), 2.21 - 2.09 (m, 1H), 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) + .

[0433] Example - 9

[0434] (E)-2-(1-Benzylpiperidin-4-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-ethanesulfonamide

[0435]

[0436] 1 1H NMR (400 MHz, DMSO-d6): δ = 10.23 (br s, 1H), 8.02 (s, 1H), 7.35 - 7.25 (s, 5H), 6.94 (s, 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) + .

[0437] Example - 10

[0438] (R,E)-2-(2-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)aminosulfonyl)-vinyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0439]

[0440] 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), 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 - 1).

[0441] Example - 11

[0442] (R,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(2-methoxyethyl)pyrrolidin-2-yl)ethenesulfonamide

[0443]

[0444] 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, J1 = 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), 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, 1H); MS (ESI): m / z (%) = 434.19 (100%) (M + H)+.

[0445] Example - 12

[0446]

[0447] (R,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(isopropylsulfonyl)pyrrolidin-2-yl)ethenesulfonamide

[0448] 11H NMR (400 MHz, DMSO-d6): δ = 7.34 (s, 1H), 6.77 (s, 1H), 6.67 (d, J = 15.2 Hz, 1H), 6.20 - 6.19 (m, 1H), 4.39 (bs, 1H), 3.46 (q, J = 9.6 Hz, 1H), 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, 1H), 1.93 (t, J = 7.2 Hz, 4H), 1.87 (t, J = 8.4 Hz, 4H), 1.73 - 1.69 (m, 1H), 1.19 (d, J = 6.4 Hz, 6H); MS (ESI): m / z (%) = 482.13 (65%) (M + H) + , 504.10 (100%) (M + Na) + ;

[0449] Example - 13

[0450] (R,E)-2-(1-((3-Fluorophenyl)sulfonyl)pyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethenesulfonamide

[0451]

[0452] 1 1H NMR (400 MHz, DMSO-d6): δ = 10.46 (s, 1H), 8.07 (s, 1H), 7.71 - 7.70 (m, 3H), 7.62 - 7.58 (m, 1H), 6.95 (s, 1H), 6.90 (d, J = 14.8 Hz, 1H), 6.74 (dd, J1 = 5.6 Hz, J2 = 15.2 Hz 1H), 4.49 (t, J = 5.6 Hz, 1H), 3.42 - 3.38 (m, 1H), 3.18 - 3.14 (m, 1H), 2,80 (t, J = 7.6 Hz, 4H), 2.69 (t, J = 7.2 Hz, 4H), 1.96 (quintet, J = 7.2 Hz, 4H), 1.76 - 1.60 (m, 3H), 1.55 - 1.52 (m, 1H); MS (ESI): m / z (%) = 534.18 (100%) (M + H) + ;

[0453] Example - 14

[0454] (R,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(pyrazine-2-carbonyl)pyrrolidin-2-yl)ethenesulfonamide

[0455]

[0456] 1 1H NMR (400 MHz, DMSO-d6): 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 (t, 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) + .

[0457] Example - 15

[0458] (R,E)-2-(2-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)pyrrolidine-1-carboxamide

[0459]

[0460] 1 1H NMR (400 MHz, DMSO-d6): 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 = 7.2 Hz, 4H), 2.68 (t, J = 6.8 Hz, 4H), 2.00 - 1.91 (m, 6H), 1.81 - 1.69 (m, 3H); MS (ESI): m / z (%) = 419.16 (100%) (M + H) + .

[0461] Example - 16

[0462] (R,E)-2-(1-(Cyclopropanecarbonyl)pyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide

[0463]

[0464] 1 1H NMR (400 MHz, DMSO-d6): 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 = 7.2 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) + .

[0465] Example - 17

[0466] (R, E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(2,2,2-trifluoroacetyl)pyrrolidin-2-yl)ethene-1-sulfonamide

[0467]

[0468] 1 1H NMR (400 MHz, DMSO-d6): 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%) (M - H) + .

[0469] Example - 18

[0470] (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

[0471]

[0472] 11H NMR (400 MHz, DMSO-d6): 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) + .

[0473] Example - 19

[0474] (R,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(2,2,2-trifluoroethyl)pyrrolidin-2-yl)ethene-1-sulfonamide

[0475]

[0476] 1 1H NMR (400 MHz, DMSO-d6): δ = 7.91 (s, 1H), 6.88 (s, 1H), 6.76 (d, J = 15.2 Hz, 1H), 6.41 (dd, J1 = 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) + .

[0477] Example - 20

[0478] (R,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-isobutylpyrrolidin-2-yl)ethene-1-sulfonamide

[0479]

[0480] 11H NMR (400 MHz, DMSO-d6): δ = 10.4 (brs, 1H), 8.00 (s, 1H), 6.92 (s, 1H), 6.80 (d, J = 15.2 Hz, 1H), 6.56 (dd, J = 15.2 Hz, J = 6.8 Hz, 1H), 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, 1H), 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) + .

[0481] Example - 21

[0482] (R,E)-2-(1-(Ethylsulfonyl)pyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide

[0483]

[0484] 1 1H NMR (400 MHz, DMSO-d6): δ = 10.39 (brs, 1H), 8.01 (s, 1H), 7.38 (s, 1H), 6.77 (d, J = 15.2 Hz, 1H), 6.68 (dd, J = 15.2 Hz, J = 5.2 Hz, 1H), 4.63 - 4.39 (m, 1H), 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, 1H), 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) + .

[0485] Example - 22

[0486] (R,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-isopropylpyrrolidin-2-yl)ethene-1-sulfonamide

[0487]

[0488] 1 1H NMR (400 MHz, DMSO-d6): 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 = 7.2 Hz, 1H), 2.98 - 2.85 (m, 2H), 2.80 (t, J = 7.2 Hz, 4H), 2.67 (t, J = 7.2 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 - 1).

[0489] Example - 23

[0490] (R,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(3-(methylsulfonyl)propyl)pyrrolidin-2-yl)ethenesulfonamide

[0491]

[0492] 1 1H NMR (400 MHz, DMSO-d6): 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 - 1).

[0493] Example - 24

[0494] (R,E)-2-(1-benzoylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethenesulfonamide

[0495]

[0496] 1 H NMR(400MHz, DMSO-d6): 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 = 6.8Hz, 4H), 2.66(t, J = 6.8Hz, 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 - 1).

[0497] Example - 25

[0498] (R,E)-N-((2-(1-benzoylpyrrolidin-2-yl)vinyl)sulfonyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)benzamide

[0499]

[0500] 1 H NMR(400MHz, DMSO-d6): 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 = 14.4Hz, 1H), 6.31(d, J = 14.4Hz, 1H), 4.76 - 4.37(m, 1H), 3.78 - 3.42(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 - 1).

[0501] Example - 26

[0502] (R,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(pyrrolidin-2-yl)ethenesulfonamide

[0503]

[0504] 1 H NMR(400MHz,DMSO-d6):δ=7.54(s,1H),6.81(s,1H),6.70(d,J=15.2Hz,1H),6.33 - 6.26(m,1H),3.53 - 3.46(m,2H),3.15 - 3.00(m,3H),2.77(t,J=7.2Hz,4H),2.70(t,J=7.2Hz,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 - 1).

[0505] Example - 27

[0506] (R,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(thiophene-3-carbonyl)pyrrolidin-2-yl)ethenesulfonamide

[0507]

[0508] 1 H NMR(400MHz,DMSO-d6):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 - 3.52(m,1H),2.79(t,J=7.2Hz,4H),2.66(t,J=6.8Hz,4H),2.15 - 1.76(m,8H);MS(ESI):m / z(%)=486.13(100%)(M + H) + ,484.11(100%)(M - 1).

[0509] Example - 28

[0510] (R,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(pyrrolidin-2-yl)ethene-1-sulfonamide mesylate

[0511]

[0512] Procedure: To a solution of (R,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(pyrrolidin-2-yl)vinyl-1-sulfonamide (0.105 g, 0.28 mmol) in EtOH (2.0 mL) at room temperature was added methanesulfonic acid (27 mg, 0.280 mmol). The reaction was refluxed for 1 h, then cooled to room temperature, a precipitate formed, which was then filtered through a Buchner funnel and dried in vacuo to obtain the product.

[0513] 1 H NMR (400 MHz, DMSO-d6): δ = 10.59 (brs, 1H), 9.05 (brs, 2H), 8.27 (s, 1H), 7.13 (d, J = 15.2 Hz, 1H), 6.97 (s, 1H), 6.90 - 6.85 (m, 1H), 4.32 - 4.30 (m, 1H), 3.32 - 3.12 (m, 2H), 3.99 - 3.78 (m, 4H), 3.75 - 3.66 (m, 4H), 2.37 (s, 1H), 2.28 - 2.12 (m, 1H), 2.10 - 1.88 (m, 6H), 1.27 - 1.22 (m, 1H); MS (ESI): m / z (%) = 376.10 (100%) (M + H) + .

[0514] Example - 29

[0515] (R,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(pyrrolidin-2-yl)vinyl-1-sulfonamide maleate

[0516]

[0517] Procedure: To a solution of (R,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(pyrrolidin-2-yl)vinyl-1-sulfonamide (0.2 g, 0.533 mmol) in EtOH (4.0 mL) at room temperature was added maleic acid (0.124 g, 1.07 mmol). The reaction was refluxed for 30 min. Then it was cooled to room temperature, a precipitate formed, which was then filtered through a Buchner funnel and dried in vacuo to obtain the product. 11H NMR (400 MHz, DMSO-d6): δ = 9.06 (brs, 1H), 8.15 (s, 1H), 7.12 (d, J = 15.6 Hz, 1H), 6.96 (s, 1H), 6.87 - 6.82 (m, 1H), 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, 1H), 2.09 - 1.83 (m, 6H), 1.82 - 1.63 (m, 1H); MS (ESI): m / z (%) = 376.15 (100%) (M+H) + .

[0518] Example - 30

[0519] (R,Z)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(pyrrolidin-2-yl)ethene-1-sulfonamide

[0520]

[0521] 1 1H NMR (400 MHz, DMSO-d6): δ = 9.70 (brs, 1H), 7.94 (s, 1H), 6.83 (s, 1H), 6.36 (dd, J = 11.6 Hz, J = 1.6 Hz, 1H), 5.82 (dd, J = 11.2 Hz, J = 6.0 Hz, 1H), 4.95 - 4.94 (m, 1H), 3.17 - 3.03 (m, 1H), 2.99 - 2.89 (m, 1H), 2.79 - 2.63 (m, 9H), 2.03 - 1.76 (m, 8H); MS (ESI): m / z (%) = 376.16 (60%) (M+H) + .

[0522] Example - 31

[0523] (S,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-3-(pyrrolidin-2-yl)prop-1-ene-1-sulfonamide

[0524]

[0525] Procedure: To a solution of the corresponding N-Boc derivative (0.20 g, 0.408 mmol) in DCM (2.5 mL) was added TFA (0.315 mL, 4.08 mmol) at 0 °C. The reaction was warmed to room temperature and stirred further for 3 h. The reaction mixture was concentrated in vacuo and purified by preparative HPLC to afford the product.

[0526] 1 1H NMR (400 MHz, DMSO-d6): δ = 7.54 (s, 1H), 6.80 (s, 1H), 6.69 (d, J = 15.2 Hz, 1H), 6.29 - 6.25 (m, 1H), 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 Hz, 4H), 2.01 - 1.76 (m, 8H), 1.53 - 1.50 (m, 1H); MS (ESI): m / z (%) = 390.16 (100%) (M + H) + .

[0527] Example - 32

[0528] (R,E)-2-(1-(Cyclohexylsulfonyl)pyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide

[0529]

[0530] 1 1H NMR (400 MHz, DMSO-d6): 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 - 1).

[0531] Example - 33

[0532] (R,Z)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-methylpyrrolidin-2-yl)ethene-1-sulfonamide

[0533]

[0534] 1 H NMR(400MHz,DMSO-d6):δ=7.85(s,1H),6.84(s,1H),6.52(dd,J=11.2Hz,J=1.2Hz,1H),5.84(dd,J=11.2Hz,J=8.0Hz,1H),4.54-4.53(m,1H),3.24-3.18(m,2H),2.77(t,J=7.2Hz,4H),2.70(t,J=7.2Hz,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-1).

[0535] Example - 34

[0536] (R,E)-2-(1-(Cyclohexylmethyl)pyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide

[0537]

[0538] 11H NMR (400 MHz, DMSO-d6): 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) + .

[0539] Example - 35

[0540] (R,E)-2-(1-Cyclohexylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide

[0541]

[0542] 1 1H NMR (400 MHz, DMSO-d6): 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 = 7.2 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) + .

[0543] Example - 36

[0544] (R,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(1-methylpiperidin-4-yl)pyrrolidin-2-yl)ethene-1-sulfonamide

[0545]

[0546] 1 H NMR(400 MHz, DMSO-d6): δ = 7.46 (s, 1H), 7.29 (s, 1H), 6.77 (s, 1H), 6.64 (d, J = 15.2 Hz, 1H), 6.11 (dd, 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 = 7.2 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 - 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) + .

[0547] Example - 37

[0548] (R,Z)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-isopropylpyrrolidin-2-yl)ethene-1-sulfonamide

[0549]

[0550] 1 H NMR(400 MHz, DMSO-d6): 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), 3.17 - 3.01 (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 - 1).

[0551] Example - 38

[0552] (R,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-2-yl)ethene-1-sulfonamide

[0553]

[0554] 1 H NMR(400MHz,DMSO-d6):δ=10.30(brs,1H),8.05(s,1H),6.95(s,1H),6.85(d,J=15.2Hz,1H),6.70(dd,J=14.8Hz,J=6.4Hz,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=7.2Hz,4H),2.67(t,J=7.2Hz,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(ESI):m / z(%)=460.30(100%)(M+H) + .

[0555] Example-39

[0556] (R,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(oxetan-3-yl)pyrrolidin-2-yl)ethene-1-sulfonamide

[0557]

[0558] 11H NMR (400 MHz, DMSO-d6): δ = 10.41 (brs, 1H), 8.10 (s, 1H), 6.96 (s, 1H), 6.83 (d, J = 14.8 Hz, 1H), 6.61 (dd, J = 15.2 Hz, J = 8.0 Hz, 1H), 4.51 - 4.44 (m, 2H), 4.43 - 4.38 (m, 2H), 3.81 - 3.74 (m, 1H), 3.23 - 3.17 (m, 1H), 3.00 - 2.95 (m, 1H), 2.81 (t, J = 7.2 Hz, 4H), 2.68 (t, J = 7.2 Hz, 4H), 2.41 - 2.33 (m, 1H), 2.01 - 1.91 (m, 5H), 1.78 - 1.71 (m, 2H), 1.62 - 1.55 (m, 1H); MS (ESI): m / z (%) = 432.22 (100%) (M + H) + .

[0559] Example - 40

[0560] (R,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(tetrahydro-2H-thiopyran-4-yl)pyrrolidin-2-yl)ethen-1-sulfonamide

[0561]

[0562] 1 1H NMR (400 MHz, DMSO-d6): δ = 10.32 (brs, 1H), 8.06 (s, 1H), 6.95 (s, 1H), 6.84 (d, J = 14.8 Hz, 1H), 6.64 (dd, J = 14.8 Hz, J = 6.4 Hz, 1H), 3.71 - 3.58 (m, 1H), 2.98 - 2.87 (m, 1H), 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, 1H), 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) + .

[0563] Example - 41

[0564] (R,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(thiazol-2-ylmethyl)pyrrolidin-2-yl)ethene-1-sulfonamide

[0565]

[0566] 1 H NMR(400MHz,DMSO-d6):δ=10.33(brs,1H),8.08(s,1H),7.71(d,J=3.2Hz,1H),6.41(d,J=3.2Hz,1H),6.92-6.86(m,2H),6.70(dd,J=15.2Hz,J=6.8Hz,1H),4.04(d,J=14.8Hz,1H),3.78(d,J=14.8Hz,1H),3.44-3.39(m,1H),3.07-3.02(m,1H),2.77(t,J=6.8Hz,4H),2.61(t,J=6.8Hz,4H),2.43-2.33(m,1H),2.08-1.97(m,1H),1.96-1.87(m,4H),1.80-1.74(m,2H),1.63-1.57(m,1H);MS(ESI):m / z(%)=473.19(100%)(M+H) +

[0567] Example - 42

[0568] (E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(piperidin-4-yl)ethene sulfonamide

[0569]

[0570] 1 H NMR(400MHz,DMSO-d6):δ=10.55(s,1H),8.78(s,1H),8.26(s,2H),6.95(s,1H),6.79-6.70(m,2H),3.29(d,J=11.2Hz,2H),2.80(t,J=6.8Hz,4H),2.66(t,J=6.4Hz,4H),1.95(t,J=6.8Hz,4H),1.90(d,J=13.2Hz,2H);MS(ESI):m / z(%)=390.20(100%)(M+H) + .

[0571] Example - 43

[0572] (E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-methylpiperidin-4-yl)ethenesulfonamide

[0573]

[0574] 1 H NMR(400MHz,DMSO-d6):δ=7.80(s,1H),6.86(s,1H),6.64(s,1H),6.60(d,J=16.4Hz,1H),6.48(dd,J1=6.0Hz,J2=15.2Hz 1H),3.03-2.99(m,3H),2.78(t,J=7.6Hz,4H),2.68(t,J=7.6Hz,4H),2.38(s,3H),2.36-2.24(m,2H),1.94(t,J=7.2Hz,4H),1.77-1.74(m,2H),1.47-1.37(m,2H);MS(ESI):m / z(%)=404.20(100%)(M+H) + .

[0575] Example - 44

[0576] (E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(methylsulfonyl)piperidin-4-yl)ethenesulfonamide

[0577]

[0578] 1 H NMR(400MHz,DMSO-d6):δ=10.37(bs,1H),8.11(s,1H),6.96(s,1H),6.78-6.7(m,2H),3.57(d,J=12.0Hz,2H),2.85(s,3H),2.81(t,J=7.2Hz,4H),2.75-2.67(m,6H),1.97(t,J=7.2Hz,4H),1.82(d,J=11.6Hz,2H),1.45-1.37(m,2H);MS(ESI):m / z(%)=468.12(100%)(M+H) + .

[0579] Example - 45

[0580] (E)-2-(1-acetylpiperidin-4-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-sulfonamide

[0581]

[0582] 1 1H NMR (400 MHz, DMSO-d6): δ = 10.38 (bs, 1H), 8.04 (s, 1H), 6.94 (s, 1H), 6.64 (dd, J1 = 5.6 Hz, J2 = 15.6 Hz, 1H), 6.68 (d, J = 15.6 Hz, 1H), 4.33 (d, J = 13.3 Hz, 1H), 3.81 (d, J = 14.4 Hz, 1H), 3.06 (t, J = 12.0 Hz, 1H), 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, 1H), 1.21 - 1.11 (m, 1H); MS (ESI): m / z (%) = 432.17 (100%) (M + H) + .

[0583] Example - 46 (E)-4-(2-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)-piperidine-1-carboxylic acid tert-butyl ester

[0584]

[0585] 1 1H NMR (400 MHz, DMSO-d6): δ = 10.37 (bs, 1H), 8.05 (s, 1H), 6.96 (s, 1H), 6.8 (dd, J1 = 6.0 Hz, J2 = 15.2 Hz, 1H), 6.69 (d, J = 15.6 Hz, 1H), 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) + .

[0586] Example - 47

[0587] (E)-2-(1-Ethylpiperidin-4-yl)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide

[0588]

[0589] 1 1H NMR (400 MHz, DMSO-d6): δ = 7.87 (s, 1H), 6.94 (s, 1H), 6.65 (d, J = 15.6 Hz, 1H), 6.52 (dd, J1 = 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 = 7.2 Hz, 3H), MS (ESI): m / z (%) = 418.18 (100%) (M + H) + , 416.17 (100%) (M - 1) - .

[0590] Example - 48

[0591] (R,E)-2-(1-Ethylpyrrolidin-3-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethenesulfonamide

[0592]

[0593] 1 1H NMR (400 MHz, DMSO-d6): 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 = 4.8 Hz, 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) + .

[0594] Example - 49

[0595] (R,E)-1,1-Diethyl-3-(2-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)aminosulfonyl)vinyl)pyrrolidin-1-ium bromide

[0596]

[0597] 1 1H NMR (400 MHz, DMSO-d6): δ = 7.27 (s, 1H), 6.77 (s, 1H), 6.73 (s, 1H), 6.27 (dd, J1 = 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 = 7.6 Hz, 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) + .

[0598] Example - 50

[0599] (E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(pyrrolidin-3-yl)ethene-sulfonamide

[0600]

[0601] 1 1H NMR (400 MHz, DMSO-d6): δ = 7.41 (s, 1H), 6.78 (s, 1H), 6.64 (d, J = 15.6 Hz, 1H), 6.23 (dd, J1 = 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) + .

[0602] Example - 51

[0603] (R,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-methylpyrrolidin-2-yl)ethene-1-sulfonamide

[0604]

[0605] 11H NMR (400 MHz, DMSO-d6): 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) + .

[0606] Example - 52

[0607] (R,E)-2-(2-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester

[0608]

[0609] 1 1H 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) + .

[0610] Example - 53

[0611] (R,E)-2-(1-Acetyl-2-methylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide

[0612]

[0613] 11H NMR (400 MHz, DMSO-d6): δ = 10.40 (s, 1H), 8.06 (s, 1H), 6.96 (s, 1H), 6.91 (d, J = 15.6 Hz, 1H), 6.58 (d, J = 15.2 Hz, 1H), 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) + .

[0614] Example - 54

[0615] (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

[0616]

[0617] 1 1H NMR (400 MHz, DMSO-d6): δ = 6.88 (s, 1H), 6.65 (d, J = 15.6 Hz, 1H), 6.21 - 6.15 (m, 1H), 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) + .

[0618] Example - 55

[0619] (R,E)-N - ((1,2,3,5,6,7 - hexahydro - s - indacen - 4 - yl)carbamoyl)-2-(2 - methyl - 1-(methylsulfonyl)pyrrolidin - 2 - yl)ethene - 1 - sulfonamide;

[0620]

[0621] 11H NMR (400 MHz, DMSO-d6): δ = 10.43 (bs, 1H), 8.09 (s, 1H), 6.96 (s, 1H), 6.90 (d, J = 15.2 Hz, 1H), 6.72 (d, J = 15.2 Hz, 1H), 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, 1H), 1.24 (s, 3H), MS (ESI): m / z (%) = 468.11 (100%) (M+H) + .

[0622] Example - 56

[0623] (R,E)-2-(1,2-Dimethylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide

[0624]

[0625] 1 1H NMR (400 MHz, DMSO-d6): 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 = 7.2 Hz, 4H), 2.67 (t, J = 7.2 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) + .

[0626] Alternatively, Example 56 was also prepared according to the procedure for synthesizing Intermediate - 7b (Example 111) using Intermediate 9 and (R)-1,2-dimethylpyrrolidine-2-carbaldehyde together with conventional techniques known to those skilled in the art of organic synthesis.

[0627] Example - 57

[0628] (R,E)-2-(1-Ethyl-2-methylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide

[0629]

[0630] 1 1H NMR (400 MHz, DMSO-d6): δ = 8.82 (broad singlet, 1H), 6.96 (singlet, 1H), 6.92 (doublet, J = 9.6 Hz, 1H), 6.41 (multiplet, 1H), 3.60 - 3.51 (multiplet, 2H), 3.22 - 3.17 (multiplet, 2H), 2.80 - 2.73 (multiplet, 5H), 2.61 (triplet, J = 7.2 Hz, 4H), 1.97 - 1.93 (multiplet, 6H), 1.84 - 1.80 (multiplet, 1H), 1.53 (singlet, 3H), 0.90 (triplet, J = 6.4 Hz, 3H); MS (ESI): m / z (%) = 418.18 (100%) (M + H) + ;

[0631] Example - 58

[0632] (R,E)-2-(1-(Cyclopropylmethyl)-2-methylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide

[0633]

[0634] 1 1H NMR (400 MHz, DMSO-d6): δ = 10.39 (singlet, 1H), 8.06 (singlet, 1H), 6.94 (singlet, 1H), 6.75 (doublet, J = 15.6 Hz, 1H), 6.69 (doublet, J = 15.6 Hz, 1H), 3.18 - 3.13 (multiplet, 1H), 2.80 (triplet, J = 7.2 Hz, 5H), 2.67 (triplet, J = 7.2 Hz, 4H), 2.33 - 2.11 (multiplet, 2H), 1.94 (triplet, J = 7.2 Hz, 4H), 1.80 - 1.71 (multiplet, 4H), 1.12 (singlet, 3H), 0.86 - 0.79 (multiplet, 1H), 0.42 (quintet, J = 8.8 Hz, 2H), 0.05 - 0.04 (multiplet, 2H); MS (ESI): m / z (%) = 444.17 (100%) (M + H) + .

[0635] Example - 59

[0636] (S,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(pyrrolidin-2-yl)ethene-sulfonamide

[0637]

[0638] 11H NMR (400 MHz, DMSO): δ = 8.75 (bs, 1H), 7.50 (s, 1H), 6.95 (d, J = 15.6 Hz, 1H), 6.80 (s, 1H), 6.39 - 6.33 (m, 1H), 4.08 - 4.02 (m, 1H), 3.16 - 4.11 (m, 2H), 2.77 (t, J = 7.2 Hz, 4H), 2.71 (t, J = 7.2 Hz, 4H), 2.12 - 2.08 (m, 1H), 1.96 - 1.85 (m, 6H), 1.68 - 1.62 (m, 1H); MS (ESI): m / z (%) = 376.16 (100%) (M+H) + .

[0639] Example - 60

[0640] (S,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-methylpyrrolidin-2-yl)ethenesulfonamide

[0641]

[0642] 1 1H NMR (400 MHz, DMSO): δ = 8.00 (s, 1H), 6.93 (s, 1H), 6.85 (d, J = 15.2 Hz, 1H), 6.58 - 6.52 (m, 1H), 3.12 - 3.04 (m, 2H), 2.80 (t, J = 7.2 Hz, 4H), 2.67 (t, J = 7.2 Hz, 4H), 2.36 - 2.01 (m, 1H), 2.27 (s, 3H), 2.08 - 1.91 (m, 5H), 1.80 - 1.72 (m, 2H), 1.70 - 1.50 (m, 1H); MS (ESI): m / z (%) = 390.17 (100%) (M+H) + .

[0643] Example - 61

[0644] (S,E)-2-(2-((N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0645]

[0646] 11H 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 = 7.2 Hz, 4H), 2.67 (t, J = 7.2 Hz, 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) + .

[0647] Example - 62

[0648] (S,E)-2-(1-(Cyclopropylmethyl)pyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethenesulfonamide

[0649]

[0650] 1 1H NMR (400 MHz, DMSO-d6): δ = 10.32 (bs, 1H), 8.02 (bs, 1H), 6.93 (s, 1H), 6.86 (d, J = 14.8 Hz, 1H), 6.64 - 6.50 (m, 1H), 3.50 - 3.20 (m, 3H), 2.80 (t, J = 7.2 Hz, 4H), 2.67 (t, J = 7.2 Hz, 4H), 2.61 - 2.56 (m, 1H), 2.15 - 1.91 (m, 6H), 1.85 - 1.78 (m, 2H), 1.62 - 1.53 (m, 1H), 0.86 - 0.80 (m, 1H), 0.50 - 0.30 (m, 2H), 0.15 - 0.14 (m, 2H); MS (ESI): m / z (%) = 430.19 (100%) (M + H) + .

[0651] Example - 63

[0652] (S,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(pyridin-3-ylsulfonyl)pyrrolidin-2-yl)ethenesulfonamide

[0653]

[0654] 11H NMR (400 MHz, DMSO-d6): δ = 10.40 (bs, 1H), 9.02 (d, J = 2.0 Hz, 1H), 8.90 - 8.88 (m, 1H), 8.29 - 8.26 (m, 1H), 8.04 (s, 1H), 7.68 - 7.65 (m, 1H), 6.94 - 6.87 (m, 2H), 6.72 - 6.67 (m, 1H), 4.52 - 4.49 (m, 1H), 3.44 - 3.42 (m, 1H), 3.21 - 3.15 (m, 1H), 2.80 (t, J = 7.2 Hz, 4H), 2.69 (t, J = 7.2 Hz, 4H), 1.99 - 1.91 (m, 4H), 1.76 - 1.65 (m, 4H); MS (ESI): m / z (%) = 517.11 (100%) (M+H) + .

[0655] Example - 64

[0656] (S,E)-N-((2,6-Diisopropylphenyl)carbamoyl)-2-(pyrrolidin-2-yl)ethenesulfonamide

[0657]

[0658] 1 1H 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) + .

[0659] Example - 65

[0660] (S,E)-N-((2,6-Diisopropylphenyl)carbamoyl)-2-(1-ethylpyrrolidin-2-yl)ethenesulfonamide

[0661]

[0662] 11H 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 = 15.2 Hz, 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 = 7.2 Hz, 3H); MS (ESI): m / z (%) = 408.19 (100%) (M + H) + .

[0663] Example - 66

[0664] (S,E)-N-((2,6-Diisopropylphenyl)carbamoyl)-2-(1-(methylsulfonyl)pyrrolidin-2-yl)ethenesulfonamide

[0665]

[0666] 1 1H 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 (100%) (M + H) + .

[0667] Example - 67

[0668] (S,E)-N-((2,6-Diisopropylphenyl)carbamoyl)-2-(1-methylpyrrolidin-2-yl)ethenesulfonamide

[0669]

[0670] 11H NMR (400 MHz, DMSO-d6): δ = 7.69 (s, 1H), 7.22 - 7.18 (m, 1H), 7.11 - 7.09 (m, 2H), 6.75 (d, J = 15.2 Hz, 1H), 6.55 - 6.30 (m, 1H), 3.12 - 2.99 (m, 3H), 2.79 - 2.76 (m, 1H), 2.23 - 2.18 (m, 4H), 2.00 - 1.95 (m, 1H), 1.76 - 1.68 (m, 2H), 1.54 - 1.49 (m, 1H), 1.11 - 1.09 (m, 12H); MS (ESI): m / z (%) = 394.19 (100%) (M + H) + .

[0671] Example - 68

[0672] (S,E)-2-(1-Acetylpyrrolidin-2-yl)-N-((2,6-diisopropylphenyl)carbamoyl)ethenesulfonamide

[0673]

[0674] 1 1H NMR (400 MHz, DMSO-d6): δ = 10.55 (bs, 1H), 7.89 - 7.86 (m, 1H), 7.28 - 7.23 (m, 1H), 7.15 - 7.13 (m, 2H), 6.76 - 6.69 (m, 1H), 6.63 - 6.53 (m, 1H), 4.68 - 4.61 (m, 1H), 3.52 - 3.39 (m, 1H), 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) + .

[0675] Example - 69

[0676] (S,E)-2-(1-Acetylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethenesulfonamide

[0677]

[0678] 11H NMR (400 MHz, DMSO-d6): δ = 10.30 (bs, 1H), 8.11 - 8.05 (m, 1H), 6.95 (s, 1H), 6.78 - 6.56 (m, 2H), 4.72 - 4.62 (m, 1H), 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) + .

[0679] Example - 70

[0680] (S,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(tetrahydro-2H-pyran-4-carbonyl)pyrrolidin-2-yl)ethenesulfonamide

[0681]

[0682] 1 1H 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 = 7.6 Hz, 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) + .

[0683] Example - 71

[0684] (E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(tetrahydro-2H-pyran-4-yl)ethenesulfonamide

[0685]

[0686] 11H 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 = 7.6 Hz, 4H), 2.67 (t, J = 7.6 Hz, 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) + .

[0687] Example - 72

[0688] (S,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-nicotinoylpyrrolidin-2-yl)ethenesulfonamide

[0689]

[0690] 1 1H NMR (400 MHz, DMSO-d6): δ = 10.35 (bs, 1H), 8.76 - 8.59 (m, 2H), 8.05 (s, 1H), 6.72 (d, J = 8 Hz, 0.72H), 7.77 (d, J = 8 Hz, 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 = 7.6 Hz, 4H), 2.65 (t, J = 7.6 Hz, 4H), 2.20 - 2.13 (m, 1H), 1.96 - 1.84 (m, 7H); MS (ESI): m / z (%) = 481.18 (100%) (M+H) + .

[0691] Example - 73

[0692] (E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(tetrahydrofuran-2-yl)ethene-1-sulfonamide

[0693]

[0694] 11H NMR (400 MHz, DMSO-d6): δ = 10.40 (bs, 1H), 8.11 (s, 1H), 6.96 (s, 1H), 6.81 (dd, J = 4.0 Hz, J = 14.8 Hz, 1H), 6.74 (dd, J = 1.2 Hz, J = 15.2 Hz, 1H), 4.57 - 4.53 (m, 1H), 3.86 - 3.81 (m, 1H), 3.76 - 3.70 (m, 1H), 2.81 (t, J = 7.2 Hz, 4H), 2.67 (t, J = 7.2 Hz, 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) + .

[0695] Example - 74

[0696] (S,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(thiophen-2-ylmethyl)pyrrolidin-2-yl)ethen-1-sulfonamide

[0697]

[0698] 1 1H 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 = 14 Hz, 1H), 3.58 (d, J = 14 Hz, 1H), 3.28 - 3.24 (m, 1H), 2.97 - 2.92 (m, 1H), 2.77 (t, J = 7.2 Hz, 4H), 2.63 (t, J = 7.2 Hz, 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) + .

[0699] Example - 75

[0700] (S,E)-2-(2-(N-((4-Fluoro-2,6-diisopropylphenyl)carbamoyl)sulfamoyl)vinyl)-pyrrolidine-1-carboxylic acid tert-butyl ester

[0701]

[0702] 1 1H 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 = 6.8 Hz, 12H); MS (ESI): m / z (%) = 398.29 (100%) (M - 100) + ; 520.36 (15%) (M + Na) + ; 496.32 (100%) (M - H) + .

[0703] Example - 76

[0704] (S,E)-N-((4-Fluoro-2,6-diisopropylphenyl)carbamoyl)-2-(pyrrolidin-2-yl)ethene-1-sulfonamide

[0705]

[0706] 1 1H NMR (400 MHz, DMSO): δ = 9.40 (bs, 1H), 7.39 (bs, 1H), 7.02 - 6.76 (m, 3H), 6.39 - 6.22 (m, 1H), 4.05 - 4.04 (m, 1H), 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) + .

[0707] Example - 77

[0708] (S,E)-N-((4-Fluoro-2,6-diisopropylphenyl)carbamoyl)-2-(1-methylpyrrolidin-2-yl)ethene-1-sulfonamide.

[0709]

[0710] 11H NMR (400 MHz, DMSO-d6): δ = 10.90 (bs, 1H), 7.84 (bs, 1H), 6.94 (d, J = 9.6 Hz, 2H), 6.90 (d, J = 15.2 Hz, 1H), 6.58 - 6.53 (m, 1H), 3.08 - 2.95 (m, 4H), 2.33 - 2.27 (m, 1H), 2.23 (s, 3H), 2.07 - 1.97 (m, 1H), 1.78 - 1.73 (m, 2H), 1.59 - 1.50 (m, 1H), 6.75 (d, J = 68 Hz, 12H); MS (ESI): m / z (%) = 412.26 (100%) (M+H) + .

[0711] Example - 78

[0712] (R,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-isobutyl-2-methyl-pyrrolidin-2-yl)ethene-1-sulfonamide

[0713]

[0714] 1 1H NMR (400 MHz, DMSO-d6): δ = 8.03 (bs, 1H), 6.89 (s, 1H), 6.88 (d, J = 15.6 Hz, 1H), 6.54 (d, J = 15.6 Hz, 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) + .

[0715] Example - 79

[0716] (R,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-methyl-1-propylpyrrolidin-2-yl)ethene-1-sulfonamide

[0717]

[0718] 11H NMR (400 MHz, DMSO-d6): δ = 7.99 (bs, 1H), 6.90 (s, 1H), 6.67 (d, J = 15.6 Hz, 1H), 6.57 (d, J = 16.0 Hz, 1H), 2.93 - 2.87 (m, 1H), 2.79 (t, J = 7.2 Hz, 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 = 7.6 Hz, 3H); MS (ESI): m / z (%) = 432.25 (100%) (M+H) + .

[0719] Example - 80

[0720] (S,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(thiazol-2-yl)pyrrolidin-2-yl)ethene-1-sulfonamide

[0721]

[0722] 1 1H NMR (400 MHz, DMSO-d6): δ = 10.4 (bs, 1H), 8.09 (s, 1H), 7.14 (d, J = 3.6 Hz, 1H), 6.96 (s, 1H), 6.84 - 6.79 (m, 1H), 6.75 (d, J = 3.6 Hz, 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 = 7.2 Hz, 4H), 2.64 (t, J = 7.2 Hz, 4H), 2.30 - 2.18 (m, 1H), 2.04 - 1.87 (m, 7H); MS (ESI): m / z (%) = 459.17 (100%) (M+H) + .

[0723] Example - 81

[0724] (E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(piperidin-3-yl)ethene-sulfonamide

[0725]

[0726] 11H NMR (400 MHz, DMSO-d6): 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) + .

[0727] Example - 82

[0728] (E)-2-(1-Ethylpiperidin-3-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)vinyl-sulfonamide

[0729]

[0730] 1 1H NMR (400 MHz, DMSO-d6): 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) + .

[0731] Example - 83

[0732] (E)-3-(2-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)-piperidine-1-carboxylic acid tert-butyl ester

[0733]

[0734] 11H NMR (400 MHz, DMSO-d6): 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, 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 - 1).

[0735] Example - 84

[0736] (E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(methylsulfonyl)piperidin-3-yl)ethenesulfonamide

[0737]

[0738] 1 1H NMR (400 MHz, DMSO-d6): 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 - 1).

[0739] Example - 85

[0740] (E)-2-(1-Acetylpiperidin-3-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)vinyl-sulfonamide

[0741]

[0742] 1 H NMR(400MHz, DMSO-d6): 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 = 7.2Hz, 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%)(M - 1).

[0743] Example - 86

[0744] (E)-2-(2-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)-azetidine-1-carboxylic acid tert-butyl ester

[0745]

[0746] Example 86 was prepared using Intermediate - 11 according to the procedure for synthesizing Intermediate - 3a as described.

[0747] 1 H NMR(400MHz, DMSO-d6): δ = 10.57(brs, 1H), 7.83(s, 1H), 6.89(s, 1H), 6.73(d, J = 15.2Hz, 1H), 6.66(dd, J = 15.2Hz, J = 4.4Hz, 1H), 4.73 - 4.84(m, 1H), 3.80 - 3.70(m, 2H), 2.79(t, J = 7.2Hz, 4H), 2.69(t, J = 7.2Hz, 4H), 2.46 - 2.33(m, 1H), 2.04 - 1.97(m, 5H), 1.35(s, 9H); MS(ESI): m / z(%) = 484.84(90%)(M + H) + , 460.23(100%)(M - 1).

[0748] Example - 87

[0749] (E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-methylazetidin-2-yl)ethene-1-sulfonamide

[0750]

[0751] 1 H NMR(400MHz, DMSO-d6): δ = 10.45(brs, 1H), 7.98(s, 1H), 6.92(s, 1H), 6.84(d, J = 14.8Hz, 1H), 6.72(dd, J = 15.2Hz, J = 5.2Hz 1H), 3.95 - 3.82(m, 1H), 3.44 - 3.36(m, 2H), 3.09 - 2.95(m, 1H), 2.80(t, J = 7.2Hz, 4H), 2.68(t, J = 6.8Hz, 4H), 2.30(s, 3H), 2.26 - 2.20(m, 1H), 2.03 - 1.89(m, 4H); MS(ESI): m / z(%) = 376.19(100%)(M + H) + , 374.16(100%)(M - 1).

[0752] Example - 88

[0753] (E)-2-(Azetidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide

[0754]

[0755] 1 H NMR(400MHz, DMSO-d6): δ = 7.51(s, 1H), 6.94(d, J = 15.2Hz, 1H), 6.80(s, 1H), 6.55(dd, J = 15.2Hz, J = 7.2Hz, 1H), 5.01 - 4.95(m, 1H), 3.89 - 3.82(m, 1H), 3.72 - 3.62(m, 1H), 2.77(t, J = 7.2Hz, 4H), 2.70(t, J = 6.8Hz, 4H), 2.50 - 2.33(m, 1H), 1.96 - 1.88(m, 5H); MS(ESI): m / z(%) = 362.24(100%)(M + H) + .

[0756] Example - 89

[0757] (R,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-2-yl)ethenesulfonamide

[0758]

[0759] 1 H NMR(400MHz, DMSO-d6): δ = 10.36(brs, 1H), 7.99(s, 1H), 6.94 - 6.90(m, 2H), 6.77(dd, J = 14.8Hz, J = 5.2Hz, 1H), 3.99 - 3.86(m, 1H), 3.46 - 3.39(m, 2H), 3.13 - 2.96(m, 1H), 2.80(t, J = 7.2Hz, 4H), 2.66(t, J = 7.2Hz, 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 / t(%) = 416.29(100%)(M + H) + .

[0760] Example - 90

[0761] (S,E)-2-(1-((5-chlorothiophen-2-yl)sulfonyl)pyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethenesulfonamide

[0762]

[0763] 1 H NMR(400MHz, DMSO-d6): δ = 8.01(s, 1H), 7.68(t, J = 1.2Hz, 1H), 7.36(d, J = 4.0Hz, 1H), 6.90(s, 1H), 6.85(s, 1H), 6.82(s, 1H), 4.40(d, J = 5.2Hz, 1H), 3.43(t, J = 6.8Hz, 1H), 3.32(s, 1H), 3.20(d, J = 7.6Hz, 1H), 2.80(t, J = 7.2Hz, 4H), 2.69(t, J = 8.8Hz, 4H), 1.95(m, 4H), 1.74(m, 3H), 1.64(s, 1H); MS(ESI): m / z(%) = 556(100%)(M + 1).

[0764] Example - 91

[0765] (S,E)-2-(1-(Benzylsulfonyl)pyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethenesulfonamide

[0766]

[0767] 1 H NMR(400MHz, DMSO-d6): δ = 7.86(s, 1H), 7.42(m, 2H), 7.34(t, J = 4.0Hz, 3H), 6.87(s, 1H), 6.71(s, 1H), 6.45(m, 1H), 4.46(s, 2H), 4.37(d, J = 8.0Hz, 1H), 3.22(s, 1H), 2.78(t, J = 7.6Hz, 4H), 2.66(t, J = 7.2Hz, 4H), 1.99(m, 1H), 1.95(m, 4H), 1.74(m, 3H); MS(ESI): m / z(%) = 530(100%)(M + 1).

[0768] Example - 92

[0769] (S,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-((4-methoxyphenyl)sulfonyl)pyrrolidin-2-yl)ethenesulfonamide

[0770]

[0771] 1 H NMR(400MHz, DMSO-d6): δ = 7.93(s, 1H), 7.79(d, J = 2.8Hz, 2H), 7.12(d, J = 2.0Hz, 2H), 6.90(s, 1H), 6.85(s, 1H), 6.66(s, 1H), 6.60(d, J = 5.6Hz, 1H), 6.57(d, J = 4.4Hz, 1H), 4.4(m, 1H), 3.84(s, 3H), 3.22(m, 1H), 2.78(t, J = 7.2Hz, 4H), 2.70(t, J = 7.2Hz, 4H), 1.99(m, 4H), 1.68(m, 3H), 1.60(m, 1H); MS(ESI): m / z(%) = 546(100%)(M + 1).

[0772] Example - 93

[0773] (S,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-((4-fluorophenyl)sulfonyl)pyrrolidin-2-yl)ethenesulfonamide

[0774]

[0775] 1 H NMR(400MHz, DMSO-d s ):δ=8.02(s, 1H), 7.94(d, J=2.0Hz, 2H), 7.47(d, J=3.6Hz, 2H), 6.90(s, 1H), 6.87(s, 1H), 6.68(d, J=9.6Hz, 1H), 4.41(m, 1H), 3.36(m, 1H), 2.78(t, J=7.2Hz, 4H), 2.69(t, J=7.2Hz, 4H), 1.99(m, 4H), 1.68(m, 3H), 1.60(m, 1H); MS(ESI): m / z(%)=534(100%)(M + 1).

[0776] Example - 94

[0777] (S,E)-2-(1-((2-cyanophenyl)sulfonyl)pyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethenesulfonamide

[0778]

[0779] 1 H NMR(400MHz, DMSO-d6): δ=8.11(d, J=1.2Hz, 2H), 7.90(d, J=1.2Hz, 2H), 7.83(s, 1H), 6.82(s, 1H), 6.70(d, J=14.8Hz, 1H), 6.30(s, 1H), 4.51(s, 1H), 3.32(s, 2H), 2.77(t, J=7.2Hz, 4H), 2.70(t, J=7.2Hz, 4H), 1.92(m, 4H), 1.80(m, 2H), 1.74(m, 2H); MS(ESI): m / z(%)=541.14(100%)(M + 1).

[0780] Example - 95

[0781] (S,E)-2-(1-(cyclohexylsulfonyl)pyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethenesulfonamide

[0782]

[0783] 1 1H NMR (400 MHz, DMSO-d6): δ = 7.78 (s, 1H), 6.85 (s, 1H), 6.70 (d, J = 14.8 Hz, 1H), 6.41 (s, 1H), 4.46 (s, 1H), 3.42 (m, 1H), 3.08 (s, 1H), 2.78 (t, J = 7.6 Hz, 4H), 2.70 (t, J = 7.2 Hz, 4H), 2.09 (d, = 4.8 Hz, 1H) 1.94 (m, 7H), 1.83 (m, 3H), 1.72 (m, 1H), 1.52 (s, 1H), 1.32 (m, 3H), 1.24 (s, 2H), 1.08 (s, 1H); MS (ESI): m / z (%) = 522.19 (100%) (M+1).

[0784] Example - 96

[0785] (S,E)-2-(1-(4-Fluorobenzyl)pyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethenesulfonamide

[0786]

[0787] 1 1H NMR (400 MHz, DMSO-d6): δ = 8.03 (s, 1H), 7.28 (t, J = 6.0 Hz, 2H), 7.06 (t, J = 8.8 Hz, 2H), 6.89 (s, 1H), 6.86 (s, 1H), 6.62 (m, 1H), 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, 1H), 1.90 (m, 1H), 1.85 (m, 4H), 1.70 (m, 2H), 1.55 (m,.1H); MS (ESI): m / z (%) = 484.19 (100%) (M+1).

[0788] Example - 97

[0789] (S,E)-2-(1-((4-Cyanophenyl)sulfonyl)pyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide

[0790]

[0791] 11H NMR (400 MHz, DMSO-d6): δ = 8.06 (d, J = 8.4 Hz, 2H), 8.01 (t, J = 8.6 Hz, 2H), 7.86 (s, 1H), 6.87 (s, 1H), 6.80 (d, J = 14.8 Hz, 1H), 6.42 (d, J = 9.6 Hz, 1H), 4.44 (t, J = 5.6 Hz, 1H), 3.36 (m, 2H), 3.18 (m, 1H), 2.78 (t, = 7.2 Hz, 4H), 2.70 (t, J = 7.2 Hz, 4H), 1.92 (m, 4H), 1.67 (m, 3H), 1.56 (m, 1H); MS (ESI): m / z (%) = 541.15 (100%) (M+1).

[0792] Example - 98

[0793] (S,E)-2-(1-(4-Cyanobenzyl)pyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide

[0794]

[0795] 1 1H NMR (400 MHz, DMSO-d6): δ = 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+1).

[0796] Example - 99

[0797] (S,E)-N-((1,2,3,6,7,8-hexahydro-as-indacen-4-yl)carbamoyl)-2-(pyrrolidin-2-yl)ethene-1-sulfonamide

[0798]

[0799] 11H NMR (400 MHz, DMSO-d6): 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, 1H), 1.56 (m, 1H); MS (ESI): m / z (%) = 372.87 (100%) (M - 1).

[0800] Example - 100

[0801] (E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(piperidin-2-yl)ethene-1-sulfonamide

[0802]

[0803] 1 1H NMR (400 MHz, DMSO-d6): δ = 7.41 (s, 1H), 6.86 (d, J = 15.6 Hz, 1H), 6.79 (s, 1H), 6.28 (d, J = 6.0 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 + 1).

[0804] Example - 101

[0805] (E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-methylpiperidin-2-yl)ethene-1-sulfonamide

[0806]

[0807] 11H NMR (400 MHz, DMSO-d6): δ = 7.92 (s, 1H), 6.89 (s, 1H), 6.80 (d, J = 14.8 Hz, 1H), 6.42 (d, J = 8.4 Hz, 1H), 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+1).

[0808] Example - 102

[0809] (E)-N-((1,2,3,6,7,8-Hexahydro-as-indacen-4-yl)carbamoyl)-2-(1-methylpyrrolidin-2-yl)ethene-1-sulfonamide

[0810]

[0811] 1H NMR (400 MHz, DMSO-d6): δ = 7.83 (s, 1H), 7.44 (s, 1H), 6.88 (d, J = 14.8 Hz, 1H), 6.53 (d, J = 8.0 Hz, 1H), 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, 1H); MS (ESI): m / z (%) = 390.14 (100%) (M+1).

[0812] Example - 103

[0813] (E)-N-((1,2,3,6,7,8-Hexahydro-as-indacen-4-yl)carbamoyl)-2-(1-(methylsulfonyl)pyrrolidin-2-yl)ethene-1-sulfonamide

[0814]

[0815] 11H NMR (400 MHz, DMSO-d6): δ = 7.87 (s, 1H), 7.45 (s, 1H), 6.77 (d, J = 14.8 Hz, 1H), 6.68 (d, J = 4.8 Hz, 1H), 4.48 (t, J = 4.0 Hz, 1H), 2.99 (s, 3H), 2.82 (t, J = 7.2 Hz, 4H), 2.72 (t, J = 7.2 Hz, 4H), 2.11 (m, 5H), 1.81 (m, 3H); MS (ESI): m / z (%) = 454.09 (100%) (M+1).

[0816] Example - 104

[0817] ((E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-3-(piperidin-2-yl)prop-1-ene-1-sulfonamide

[0818]

[0819] 1 1H NMR (400 MHz, DMSO-d6): δ = 7.44 (s, 1H), 6.79 (s, 1H), 6.47 (d, J = 15.2 Hz, 1H), 6.20 (m, 1H), 2.85 (t, J = 7.2 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+1).

[0820] Example - 105

[0821] (S,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-methylpyrrolidin-2-yl)ethene-1-sulfonamide

[0822]

[0823] 11H NMR (400 MHz, DMSO-d6): 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, 1H), 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+1).

[0824] Example - 106

[0825] (S,E)-2-(1,2-Dimethylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide

[0826]

[0827] 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+1).

[0828] Alternatively, Example 106 can also be prepared using Intermediate 9 and (S)-1,2-dimethylpyrrolidine-2-carbaldehyde together with conventional techniques known to those skilled in the art of organic synthesis according to the procedure for synthesizing Intermediate - 7b (Example 111).

[0829] Example - 107

[0830] (E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(indolin-2-yl)ethene-1-sulfonamide

[0831]

[0832] 11H NMR (400 MHz, DMSO-d6): δ = 7.89 (s, 1H), 7.04 (d, J = 3.2 Hz, 1H), 6.99 (d, J = 6.8 Hz, 1H), 6.93 (d, J = 8.0 Hz, 1H), 6.82 (d, J = 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 (%) = 424.20 (100%) (M+1).

[0833] Example - 108

[0834] (E)-2-(2-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)indoline-1-carboxylic acid tert-butyl ester

[0835]

[0836] 1 1H NMR (400 MHz, DMSO-d6): δ = 8.11 (s, 1H), 7.71 (s, 1H), 7.20 (d, J = 8.8 Hz, 1H), 7.17 (s, 1H), 6.99 (d, J1 = 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, J = 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-1).

[0837] Example - 109

[0838] ((S,E)-2-(1-(Cyclopropylmethyl)-2-methylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide

[0839]

[0840] 11H NMR (400 MHz, DMSO-d6): δ = 7.42 (s, 1H), 6.78 (s, 1H), 6.57 (d, J = 15.6 Hz, 1H), 6.21 (d, J = 15.2 Hz, 1H), 2.93 (t, J = 6.4 Hz, 1H), 2.76 (t, J = 7.2 Hz, 4H), 2.69 (t, J = 7.2 Hz, 4H), 2.33 (t, J = 1.62 Hz, 1H), 2.27 (t, J = 6.8 Hz, 1H), 2.01 (m, 1H), 1.93 (m, 4H), 1.76 (d, J = 5.62 Hz, 1H), 1.68 (d, J = 8.0 Hz, 1H), 1.60 (d, J = 4.4 Hz, 1H), 1.0 (s, 2H), 0.38 (t, J = 7.6 Hz, 2H); MS (ESI): m / z (%) = 444.26 (100%) (M+1).

[0841] Example - 110

[0842] (S,E)-2-(1-(Cyclopropylsulfonyl)pyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide

[0843]

[0844] 1 1H NMR (400 MHz, DMSO-d6): δ = 8.05 (s, 1H), 6.94 (s, 1H), 6.81 (d, J = 0.8 Hz, 1H), 6.77 (d, J = 1.2 Hz, 1H), 6.68 (d, J = 15.2 Hz, 1H), 4.57 (m, 1H), 3.43 (m, 1H), 2.80 (t, J = 7.2 Hz, 1H), 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+1).

[0845] Example - 111

[0846] (S,E)-2-(2-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester

[0847]

[0848] 11H NMR (400 MHz, DMSO-d6): δ = 7.97 (s, 1H), 6.91 (s, 1H), 6.72 (d, J = 15.2 Hz, 1H), 6.54 (d, J = 7.68 Hz, 1H), 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%) (M - 1).

[0849] Example - 112

[0850] (R,E)-2-(2-(N-((2,6-Diisopropylphenyl)carbamoyl)sulfamoyl)vinyl)-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester

[0851]

[0852] 1 1H NMR (400 MHz, DMSO-d6): δ = 10.55 (s, 1H), 7.89 (d, J = 16.0 Hz, 1H), 7.27 (t, J = 7.6 Hz, 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 - 1) - .

[0853] Example - 113

[0854] (R,E)-N-((2,6-Diisopropylphenyl)carbamoyl)-2-(2-methylpyrrolidin-2-yl)ethene-1-sulfonamide 2,2,2-trifluoroacetate

[0855]

[0856] 11H NMR (400 MHz, DMSO-d6): 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) + ;

[0857] Example - 114

[0858] (R,E)-N-((2,6 - Diisopropylphenyl)carbamoyl)-2-(1,2 - dimethylpyrrolidin - 2 - yl)ethene - 1 - sulfonamide

[0859]

[0860] 1 1H NMR (400 MHz, DMSO-d6): 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 - 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) + .

[0861] Example - 115 (S,E)-2-(1 - Ethyl - 2 - methylpyrrolidin - 2 - yl)-N-((1,2,3,5,6,7 - hexahydro - s - indacen - 4 - yl)carbamoyl)ethene - 1 - sulfonamide

[0862]

[0863] 11H 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 (quintet, 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) + .

[0864] Example - 116

[0865] Disodium (R,E)-((2-(1,2-dimethylpyrrolidin-2-yl)vinyl)sulfonyl)((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)amide

[0866]

[0867] 1 1H NMR (400 MHz, DMSO-d6): 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 (quintet, 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) + .

[0868] Example - 117

[0869] Sodium (R,E)-((2-(1,2-dimethylpyrrolidin-2-yl)vinyl)sulfonyl)((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)amide

[0870]

[0871] 11H NMR (400 MHz, DMSO-d6): 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 = 7.2 Hz, 4H), 2.64 - 2.59 (m, 1H), 2.08 (s, 3H), 1.91 (quintet, J = 7.6 Hz, 4H), 1.74 - 1.68 (m, 3H), 1.62 - 1.60 (m, 1H), 1.01 (s, 3H); MS (ESI): m / z (%) = 404.17 (100%) (M - Na) + .

[0872] Example - 118

[0873] (S,E)-2-(2-(N-((2,6-Diisopropylphenyl)carbamoyl)sulfamoyl)vinyl)-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester

[0874]

[0875] 1 1H NMR (400 MHz, DMSO-d6): δ = 10.55 (s, 1H), 7.89 (s, 1H), 7.27 (t, J = 7.6 Hz, 1H), 7.16 (d, J = 7.6 Hz, 2H), 6.84 (d, J = 15.6 Hz, 1H), 6.56 (d, J = 15.6 Hz, 1H), 3.37 (t, J = 6.4 Hz, 2H), 3.03 (t, J = 6.4 Hz, 2H), 1.91 - 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, = 6.8 Hz, 12H); MS (ESI): m / z (%) = 494.31 (10%) (M + 1) + .

[0876] Example - 119

[0877] (S,E)-N-((2,6-Diisopropylphenyl)carbamoyl)-2-(2-methylpyrrolidin-2-yl)ethene-1-sulfonamide 2,2,2-trifluoroacetate

[0878]

[0879] 11H NMR (400 MHz, DMSO-d6): δ = 11.10 (bs, 1H), 9.10 (bs, 2H), 8.28 (s, 1H), 7.27 (t, J = 7.6 Hz, 1H), 7.16 (d, J = 7.6 Hz, 2H), 7.12 (d, J = 15.6 Hz, 1H), 7.00 (d, J = 15.2 Hz, 1H), 3.35 - 3.30 (m, 1H), 3.24 - 3.20 (m, 1H), 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) + .

[0880] Example - 120

[0881] (S,E)-N-((2,6 - Diisopropylphenyl)carbamoyl)-2-(1,2 - dimethylpyrrolidin - 2 - yl)ethene - 1 - sulfonamide

[0882]

[0883] 1 1H NMR (400 MHz, DMSO-d6): δ = 10.10 (bs, 1H), 7.92 (s, 1H), 7.25 (t, J = 7.6 Hz, 1H), 7.13 (d, J = 7.6 Hz, 2H), 6.68 (d, J = 14.8 Hz, 1H), 6.61 (d, J = 15.6 Hz, 1H), 3.07 - 3.02 (m, 2H), 2.85 - 2.83 (m, 1H), 2.69 - 2.67 (m, 1H), 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) + .

[0884] Example - 121

[0885] (R,E)-N-((1,2,3,5,6,7 - Hexahydro - s - indacen - 4 - yl)carbamoyl)-2-(2 - methyl - 1 - (oxetan - 3 - yl)pyrrolidin - 2 - yl)ethene - 1 - sulfonamide

[0886]

[0887] 11H NMR (400 MHz, DMSO-d6): δ = 10.39 (bs, 1H), 8.14 (s, 1H), 6.95 (s, 1H), 6.71 - 6.59 (m, 2H), 4.65 (t, J = 6.4 Hz, 1H), 4.55 (t, J = 6.8 Hz, 1H), 4.45 - 4.39 (m, 2H), 4.05 - 3.98 (m, 1H), 3.13 - 3.07 (m, 1H), 3.02 - 2.99 (m, 1H), 2.81 (t, J = 7.2 Hz, 4H), 2.69 (t, J = 7.2 Hz, 4H), 2.01 - 1.63 (m, 8H), 1.03 (s, 3H); MS (ESI): m / z (%) = 446.24 (100%) (M + H) + .

[0888] Example - 122

[0889] (S,E)-2-(2-(N-((4-Fluoro-2,6-diisopropylphenyl)carbamoyl)sulfamoyl)vinyl)-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester

[0890]

[0891] 1 1H NMR (400 MHz, DMSO-d6): δ = 10.61 (bs, 1H), 7.89 - 7.85 (m, 1H), 6.97 (d, J = 10 Hz, 2H), 6.90 - 6.79 (m, 1H), 6.55 - 6.49 (m, 1H), 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 = 7.2 Hz, 12H); MS (ESI): m / z (%) = 512.30 (8%) (M + H) + , 534.29 (8%) (M + Na) + .

[0892] Example - 123

[0893] (S,E)-N-((4-Fluoro-2,6-diisopropylphenyl)carbamoyl)-2-(2-methylpyrrolidin-2-yl)ethene-1-sulfonamide 2,2,2-trifluoroacetate

[0894]

[0895] 11H NMR (400 MHz, DMSO-d6): δ = 11.11 (bs, 1H), 9.08 (bs, 2H), 8.25 (s, 1H), 7.09 (d, J = 15.6 Hz, 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 = 5.6 Hz, 12H); MS (ESI): m / z (%) = 412.23 (100%) (M+H) + ;

[0896] Example - 124

[0897] (S,E)-2-(1,2-Dimethylpyrrolidin-2-yl)-N-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)ethene-1-sulfonamide

[0898]

[0899] 1 1H NMR (400 MHz, DMSO-d6): δ = 7.87 (s, 1H), 6.93 (d, J = 10 Hz, 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) + ;

[0900] Example - 125

[0901] (E)-2-(1-Acetylazetidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide

[0902]

[0903] 11H NMR (400 MHz, DMSO-d6): δ = 10.40 (br s, 1H), 8.15 - 8.09 (m, 1H), 6.96 - 6.71 (m, 3H), 5.14 - 4.87 (m, 1H), 2.81 (t, J = 7.2 Hz, 4H), 2.77 - 2.64 (m, 4H), 2.60 - 2.56 (m, 1H), 2.01 - 1.94 (m, 5H), 1.78 (s, 2H), 1.66 (s, 1H); MS (ESI): m / z (%) = 404.11 (100%) (M + H) + .

[0904] Example - 126

[0905] (R,E)-(2-(2-(2-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)pyrrolidin-1-yl)ethyl)(methyl)carbamic acid tert-butyl ester

[0906]

[0907] 1 1H NMR (400 MHz, DMSO-d6): δ = 10.38 (br s, 1H), 8.05 (s, 1H), 6.95 (s, 1H), 6.80 (d, J = 14.4 Hz, 1H), 6.63 (dd, J = 14.8 Hz J = 6.8 Hz, 1H), 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, 1H), 1.37 (s, 9H); MS (ESI): m / z (%) = 533.21 (100%) (M + H) + .

[0908] Example - 127

[0909] (S,E)-2-(1-allylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide

[0910]

[0911] 11H NMR (400 MHz, DMSO-d6): δ = 8.07 (s, 1H), 6.95 (s, 1H), 6.84 (d, J = 15.2 Hz, 1H), 6.64 (dd, J = 15.2 Hz, J = 7.2 Hz, 1H), 5.85 - 5.80 (m, 1H), 5.19 - 5.14 (m, 1H), 5.09 - 5.07 (m, 1H), 3.28 - 3.27 (m, 1H), 3.21 - 3.15 (m, 1H), 3.05 - 3.01 (m, 1H), 2.86 - 2.78 (m, 4H), 2.73 - 2.64 (m, 4H), 2.60 - 2.56 (m, 1H), 2.30 - 2.23 (m, 1H), 2.07 - 1.97 (m, 5H), 1.80 - 1.70 (m, 2H), 1.59 - 1.50 (m, 1H); MS (ESI): m / z (%) = 416.14 (100%) (M + H) + .

[0912] Example - 128

[0913] (S,E)-2-(1-(1H - Benzo[d]imidazole - 6 - carbonyl)pyrrolidin - 2 - yl)-N - ((1,2,3,5,6,7 - hexahydro - s - indacen - 4 - yl)carbamoyl)ethene - 1 - sulfonamide

[0914]

[0915] 1 1H NMR (400 MHz, DMSO-d6): δ = 12.65 (brs, 1H), 8.40 (s, 1H), 8.04 (s, 1H), 7.85 - 7.69 (m, 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) + .

[0916] Example - 129

[0917] (S,E)-2-(1-(Cyclopropylsulfonyl)-2 - methylpyrrolidin - 2 - yl)-N - ((1,2,3,5,6,7 - hexahydro - s - indacen - 4 - yl)carbamoyl)ethene - 1 - sulfonamide

[0918]

[0919] 1 1H NMR (400 MHz, DMSO-d6): 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 - 1.01 (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) + .

[0920] Example - 130

[0921] (S,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(4-methoxybenzyl)pyrrolidin-2-yl)ethene-1-sulfonamide

[0922]

[0923] 1 1H NMR (400 MHz, DMSO-d6): δ = 8.01 (s, 1H), 7.20 (d, J = 8.4 Hz, 2H), 7.16 (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), 2.80 (t, J = 7.2 Hz, 1H), 2.68 (t, J = 7.2 Hz, 4H), 2.12 (m, 1H), 1.98 (m, 4H), 1.72 (m, 2H), 1.76 (m, 1H); MS (ESI): m / z (%) = 496.33 (100%) (M + 1).

[0924] Example - 131

[0925] tert-Butyl 5-((R)-2-((E)-2-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)pyrrolidin-1-yl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

[0926]

[0927] 1 H NMR (400 MHz, DMSO-d6): δ = 10.34 (brs, 1H), 8.03 (s, 1H), 6.94 (s, 1H), 6.84 (d, J = 14.8 Hz, 1H), 6.66 (dd, J = 14.8 Hz, J = 7.6 Hz, 1H), 3.48 - 3.35 (m, 1H), 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) + .

[0928] Example - 132

[0929] (E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-((2R)-1-(Octahydro-cyclopenta[c]pyrrol-5-yl)pyrrolidin-2-yl)ethene-1-sulfonamide 2,2,2-trifluoroacetate

[0930]

[0931] 1 H NMR (400 MHz, DMSO-d6): δ = 10.54 (brs, 1H), 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) + .

[0932] Example - 133

[0933] (E)-2-(1-(Cyclopropylsulfonyl)azetidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethenesulfonamide

[0934]

[0935] 1 H NMR(400MHz, DMSO-d6): δ = 10.54(brs, 1H), 8.12(s, 1H), 6.97 - 6.93(m, 2H), 6.86(dd, J = 15.2Hz, J = 4.8Hz, 1H), 5.08 - 5.02(m, 1H), 4.05 - 3.99(m, 1H), 3.66 - 3.61(m, 1H), 2.81(t, J = 7.2Hz, 4H), 2.78 - 2.73(m, 1H), 2.68(t, J = 7.2Hz, 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) + .

[0936] Example - 134

[0937] (S,E)-N-((2,6-Diisopropylphenyl)carbamoyl)-2-(1-(thiazol-2-yl)pyrrolidin-2-yl)ethenesulfonamide

[0938]

[0939] 1 H NMR(400MHz, 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) + .

[0940] Example - 135

[0941] (S,E)-(2-(2-(2-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)-2-methylpyrrolidin-1-yl)ethyl)(methyl)carbamic acid tert-butyl ester

[0942]

[0943] 1 H NMR(400MHz,DMSO-d6):δ=10.37(bs,1H),8.06(s,1H),6.95(s,1H),6.72(d,J=15.6Hz,1H),6.66(d,J=15.6Hz,1H),3.2-3.17(m,1H),2.81(t,J=6.8Hz,4H),2.68-2.65(m,8H),2.43-2.42(m,1H),1.96(pentet,J=7.2Hz,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) + .

[0944] Example-136

[0945] Potassium (R,E)-((2-(1,2-dimethylpyrrolidin-2-yl)vinyl)sulfonyl)((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)amide

[0946]

[0947] 1 H NMR(400MHz,DMSO-d6):δ=7.33(s,1H),6.77(s,1H),6.58(d,J=15.6Hz,1H),6.18(d,J=15.6Hz,1H),2.77-2.72(m,5H),2.69(t,J=7.2Hz,4H),2.64-2.58(m,1H),2.08(s,3H),1.90(pentet,J=7.6Hz,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) + .

[0948] Example-137

[0949] (E)-(2-(2-(2-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)azetidin-1-yl)ethyl)(methyl)carbamic acid tert-butyl ester

[0950]

[0951] 1 H NMR(400MHz,DMSO-d6):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=7.2Hz,4H),2.75 - 2.71(m,4H),2.67(t,J=7.2Hz,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 - 1).

[0952] Example - 138

[0953] (S,E)-2-(1-(Cyclohexylmethyl)-2-methylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide

[0954]

[0955] 1 H NMR(400MHz,DMSO-d6):δ=10.36(brs,1H),8.04(s,1H),6.95(m,1H),6.78 - 6.62(m,2H),2.81(t,J=7.2Hz,4H),2.68(t,J=7.2Hz,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 - 1).

[0956] Example - 139

[0957] Sodium (R,E)-((1,2,3,5,6,7 - hexahydro - s - indacen - 4 - yl)carbamoyl)((2-(1-(tetrahydro - 2H - thiopyran - 4 - yl)pyrrolidin - 2 - yl)vinyl)sulfonyl)amide

[0958]

[0959] 1 H NMR(400MHz, DMSO - d6): δ = 7.31(s, 1H), 6.76(s, 1H), 6.63(d, J = 15.2Hz, 1H), 6.06(dd, J = 15.2Hz, J = 7.6Hz, 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 - 1).

[0960] Example - 140

[0961] Sodium (R,E)-((2-(1 - cyclohexylpyrrolidin - 2 - yl)vinyl)sulfonyl)((1,2,3,5,6,7 - hexahydro - s - indacen - 4 - yl)carbamoyl)amide

[0962]

[0963] 1 H NMR(400MHz, DMSO - d6): δ = 7.33(s, 1H), 6.77(s, 1H), 6.63(d, J = 15.2Hz, 1H), 6.09(dd, J = 15.2Hz, J = 7.6Hz, 1H), 3.34 - 3.42(m, 1H), 2.84 - 2.79(m, 1H), 2.76(t, J = 7.2Hz, 4H), 2.70(t, J = 7.2Hz, 4H), 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) + .

[0964] Example - 141

[0965] Sodium (S,E)-((2,6-diisopropylphenyl)carbamoyl)((2-(1,2-dimethylpyrrolidin-2-yl)vinyl)sulfonyl)amide

[0966]

[0967] 1 H NMR(400MHz,DMSO-d6):δ=7.24(s,1H),7.11(t,J=8.4Hz,1H),7.04(d,J=7.6Hz,2H),6.54(d,J=15.6Hz,1H),6.21(d,J=16.0Hz,1H),3.23-3.16(m,2H),2.74-2.67(m,1H),2.65-2.59(m,1H),2.08(s,3H),1.75-1.71(m,3H),1.61-1.59(m,1H),1.1(d,J=6.4Hz,12H),1.0(s,3H); MS(ESI):m / z(%)=408.25(100%)(M-Na) + .

[0968] Example - 142

[0969] Sodium (R,E)-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)((2-(1-methylpyrrolidin-2-yl)vinyl)sulfonyl)amide

[0970]

[0971] 1 H NMR(400MHz,DMSO-d6):δ=7.37(s,1H),6.77(s,1H),6.64(d,J=15.2Hz,1H),6.07(d,J=15.2Hz,1H),3.0-2.95(m,1H),2.76(t,J=7.2Hz,4H),2.69(t,J=7.2Hz,4H),2.59-2.53(m,1H),2.14(s,3H),2.13-2.06(m,2H),1.91(pentet,J=7.2Hz,4H),1.73-1.60(m,3H),1.54-1.49(m,1H); MS(ESI):m / z(%)=390.20(100%)(M-Na) + .

[0972] Example - 143

[0973] Potassium (R,E)-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)((2-(1-methylpyrrolidin-2-yl)vinyl)sulfonyl)amide

[0974]

[0975] 1 H NMR(400MHz,DMSO-d6):δ=7.31(s,1H),6.76(s,1H),6.67(d,J=15.2Hz,1H),6.03-6.01(m,1H),2.97(bs,1H),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,1H);MS(ESI):m / z(%)=390.20(100%)(M-K) + .

[0976] Example-144

[0977] Sodium (S,E)-((2-(1,2-dimethylpyrrolidin-2-yl)vinyl)sulfonyl)((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)amide

[0978]

[0979] 1H NMR(400MHz,DMSO-d6):δ=7.33(s,1H),6.77(s,1H),6.56(d,J=15.2Hz,1H),6.16(d,J=16Hz,1H),2.76(t,J=7.2Hz,4H),2.69(t,J=7.2Hz,4H),2.62(m,1H),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+1).

[0980] Example-145

[0981] Sodium (S,E)-((2-(1-ethylpyrrolidin-2-yl)vinyl)sulfonyl)((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)amide

[0982]

[0983] 11H NMR (400 MHz, DMSO-d6): δ = 7.36 (s, 1H), 6.77 (s, 1H), 6.61 (d, J = 15.2 Hz, 1H); 6.05 (dd, J = 8.0 Hz, J = 15.2 Hz, 1H); 3.10 - 3.05 (m, 1H), 2.78 - 2.65 (m, 10H), 2.12 - 1.85 (m, 7H), 1.71 - 1.66 (m, 2H), 1.49 - 1.44 (m, 1H), 0.98 (t, J = 7.2 Hz, 3H); MS (ESI): m / z (%) = 426.20 (50%) (M + H) + .

[0984] Example - 146

[0985] (S,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(2-hydroxyethyl)pyrrolidin-2-yl)ethene-1-sulfonamide

[0986]

[0987] 1H NMR (400 MHz, DMSO-d6): δ = 7.90 (s, 1H), 6.90 (s, 1H), 6.84 (d, J = 15.8 Hz, 1H), 6.51 (d, J = 14.8 Hz, 1H), 4.57 (s, 1H), 3.57 (d, J = 8.8 Hz, 2H), 3.17 (s, 2H), 2.80 (t, J = 7.2 Hz, 1H), 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 (m, 1H); MS (ESI): m / z (%) = 420.23 (100%) (M + 1).

[0988] Example - 147

[0989] (E)-2-(2-((N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)aminosulfonyl)vinyl)-2-methylazetidine-1-carboxylic acid tert-butyl ester

[0990]

[0991] Example 147 was prepared using Intermediate - 12 together with conventional techniques known to those skilled in the art of organic synthesis according to the procedure for synthesizing Intermediate - 3a as described.

[0992] 11H NMR (400 MHz, DMSO-d6): δ = 10.47 (br s, 1H), 8.12 (s, 1H), 6.96 (s, 1H), 6.92 (d, J = 15.2 Hz, 1H), 6.70 (d, J = 15.2 Hz, 1H), 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 - 1).

[0993] Example - 148

[0994] (E)-2-(1,2-Dimethylazetidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide

[0995]

[0996] 1 1H NMR (400 MHz, DMSO-d6): δ = 7.91 (s, 1H), 6.91 (s, 1H), 6.79 (d, J = 14.8 Hz, 1H), 6.72 (d, J = 15.2 Hz, 1H), 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, 1H), 2.00 - 1.91 (m, 5H), 1.34 (s, 3H); MS (TOF): m / z (%) = 390.2279 (70%) (M + H) + , 388.2130 (100%) (M - 1).

[0997] Example - 149

[0998] (S,E)-2-Ethyl-2-(2-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0999]

[1000] 11H NMR (400 MHz, DMSO-d6): δ = 10.38 (s, 1H), 8.0 (d, J = 4.4 Hz, 1H), 6.99 (s, 1H), 6.89 (d, J = 15.2 Hz, 1H), 6.50 (d, J = 15.2 Hz, 1H), 3.50 (m, 1H), 3.25 (m, 1H), 2.81 (t, J = 7.2 Hz, 4H), 2.65 (t, J = 7.2 Hz, 5H), 1.95 (m, 4H), 1.77 (s, 3H), 1.80 (m, 4H), 1.58 (m, 1H), 1.36 (d, J = 10 Hz, 9H), 0.81 (m, 3H), MS (ESI): m / z (%) = 502.23 (100%) (M - 1).

[1001] Example - 150

[1002] (S,E)-2-(2-(N-((1,2,3,6,7,8-Hexahydro-as-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester

[1003]

[1004] 1 1H NMR (400 MHz, DMSO-d6): δ = 7.95 (s, 1H), 7.42 (d, J = 15.2 Hz, 1H), 6.79 (d, J = 7.68 Hz, 1H), 6.55 (d, J = 15.2 Hz, 1H), 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, 1H), 1.46 (d, J = 10 Hz, 3H), 1.38 (s, 3H), 1.32 (s, 7H); MS (ESI): m / z (%) = 488.24 (100%) (M - 1).

[1005] Example - 151

[1006] (S,E)-2-(2-Ethylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide 2,2,2-trifluoroacetate

[1007]

[1008] 11H NMR (400 MHz, DMSO-d6): δ = 9.19 (s, 1H), 9.06 (s, 1H), 8.39 (s, 1H), 7.56 (s, 1H), 7.11 (s, 1H), 6.97 (s, 1H), 6.84 (d, J = 15.6 Hz, 1H), 3.32 (s, 1H), 3.17 (s, 1H), 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+1).

[1009] Example - 152

[1010] (S,E)-N-((1,2,3,6,7,8-Hexahydro-as-indacen-4-yl)carbamoyl)-2-(2-methylpyrrolidin-2-yl)ethene-1-sulfonamide 2,2,2-trifluoroacetate

[1011]

[1012] 1 1H NMR (400 MHz, DMSO-d6): δ = 7.39 (s, 1H), 7.11 (d, J = 15.6 Hz, 1H), 7.02 (d, J = 15.6 Hz, 1H), 2.79 (q, J = 7.6 Hz, 5H), 2.71 (t, J = 7.2 Hz, 4H), 2.01 (m, 9H), 1.47 (q, J = 7.2 Hz, 3H), 1.04 (d, J = 6.0 Hz, 2H); MS (ESI): m / z (%) = 390.24 (100%) (M+1).

[1013] Example - 153

[1014] (S,E)-2-(1,2-Dimethylpyrrolidin-2-yl)-N-((1,2,3,6,7,8-hexahydro-as-indacen-4-yl)carbamoyl)ethene-1-sulfonamide

[1015]

[1016] 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+1).

[1017] Example - 154

[1018] (R,E)-2-(2-(N-((1,2,3,6,7,8-Hexahydro-as-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester

[1019]

[1020] 1 1H NMR (400 MHz, DMSO-d6): 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+Na) + , 502.28 (100%) (M-H) - .

[1021] Example - 155

[1022] (R,E)-N-((1,2,3,6,7,8-Hexahydro-as-indacen-4-yl)carbamoyl)-2-(2-methylpyrrolidin-2-yl)ethene-1-sulfonamide 2,2,2-trifluoroacetate

[1023]

[1024] 11H NMR (400 MHz, DMSO-d6): δ = 9.09 (bs, 2H), 8.21 (s, 1H), 7.39 (s, 1H), 7.13 (d, J = 15.6 Hz, 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) + .

[1025] Example - 156

[1026] (R,E)-2-(1,2-Dimethylpyrrolidin-2-yl)-N-((1,2,3,6,7,8-hexahydro-as-indacen-4-yl)carbamoyl)ethene-1-sulfonamide

[1027]

[1028] 1 1H NMR (400 MHz, DMSO-d6): 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 (quintet, 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 - 1) - .

[1029] Example - 157

[1030] (R,E)-2-(3-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)allyl)-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester

[1031]

[1032] 11H 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, J = 15.2 Hz, 1H), 6.64 (dd, J1 = 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 (quintet, 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) - .

[1033] Example - 158

[1034] (R,E)-(2-(2-(3-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)allyl)-2-methylpyrrolidin-1-yl)ethyl)(methyl)carbamic acid tert-butyl ester

[1035]

[1036] 1 1H NMR (400 MHz, DMSO-d6): δ = 10.37 (bs, 1H), 8.03 (s, 1H), 6.95 (s, 1H), 6.74 (d, J = 8.0 Hz, 2H), 3.12 (q, J = 7.2 Hz, 2H), 2.90 (bs, 1H), 2.80 (t, J = 7.2 Hz, 6H), 2.67 (t, J = 6.8 Hz, 5H), 2.29 - 2.26 (m, 2H), 1.96 (quintet, 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 - 1) - .

[1037] Example - 159

[1038] (R,E)-3-(1,2-Dimethylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)prop-1-ene-1-sulfonamide

[1039]

[1040] 1 H NMR(400MHz,DMSO-d6):δ=8.04(s,1H),6.90(s,1H),6.75 - 6.72(m,1H),6.62 - 6.54(m,1H),3.17 - 3.00(m,1H),2.79(t,J=6.8Hz,5H),2.69(bs,4H),2.36(s,5H),1.95(t,J=7.2Hz,4H),1.81 - 1.74(m,3H),1.58(bs,1H),1.04(s,3H);MS(ESI):m / z(%)=418.21(100%)(M + H) + .

[1041] Example - 160

[1042] (S,E)-(3-(2-(2-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)pyrrolidin-1-yl)propyl)(methyl)carbamic acid tert-butyl ester

[1043]

[1044] 1 H NMR(400MHz,DMSO-d6):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(%)=547.5(100%)(M + H) + .

[1045] Example - 161

[1046] (E)-(3-(2-(2-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)-2-methylazetidin-1-yl)propyl)(methyl)carbamic acid tert-butyl ester

[1047]

[1048] 1 H NMR(400MHz,DMSO-d6):δ=8.04(s,1H),6.94(s,1H),6.83(d,J=15.2Hz,1H),6.77(d,J=15.2Hz,1H),3.29-3.27(m,2H),2.80(t,J=7.2Hz,4H),2.75-2.72(m,1H),2.68(t,J=7.2Hz,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-1).

[1049] Example-162

[1050] (E)-(2-(2-(2-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)-2-methylazetidin-1-yl)ethyl)(methyl)carbamic acid tert-butyl ester

[1051]

[1052] 11H NMR (400 MHz, DMSO-d6): 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 - 1).

[1053] Example - 163

[1054] (E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-methyl-1-(2-(methylthio)ethyl)azetidin-2-yl)ethene-1-sulfonamide

[1055]

[1056] 1 1H NMR (400 MHz, DMSO-d6): 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) + .

[1057] Example - 164

[1058] (E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-methyl-1-(oxetan-3-yl)azetidin-2-yl)ethene-1-sulfonamide

[1059]

[1060] 1 1H NMR (400 MHz, DMSO-d6): δ = 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 = 7.2 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) + .

[1061] Example - 165

[1062] (S)-2-(((S)-2-((E)-2-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)-2-methylazetidin-1-yl)methyl)-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester

[1063]

[1064] 1 1H NMR (400 MHz, DMSO-d6): δ = 10.4 (brs, 1H), 8.10 (s, 1H), 6.98 - 6.93 (m, 2H), 6.74 (dd, J = 15.6 Hz, J = 5.2 Hz, 1H), 3.30 - 3.27 (m, 2H), 3.20 - 3.16 (m, 2H), 2.80 (t, J = 7.2 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) + ;

[1065] Example - 166

[1066] (S)-2-(((R)-2-((E)-2-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)-2-methylazetidin-1-yl)methyl)-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester

[1067]

[1068] 1 H NMR(400MHz, DMSO-d6): 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 = 7.2Hz, 4H), 2.57(t, J = 7.2Hz, 4H), 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) + ;

[1069] Example - 167

[1070] (R,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(2-sulfonylethyl)pyrrolidin-2-yl)ethene-1-sulfonamide

[1071]

[1072] 1 H NMR(400MHz, DMSO-d6): δ = 10.42(br s, 1H), 8.09(s, 1H), 6.95(s, 1H), 6.87(d, J = 14.8Hz, 1H), 6.75(s, 2H), 6.66(dd, J = 14.8Hz, J = 7.2Hz, 1H), 3.23 - 3.07(m, 4H), 3.01 - 2.94(m, 1H), 2.80(t, J = 7.2Hz, 4H), 2.67(t, J = 7.2Hz, 4H), 2.63 - 2.56(m, 1H), 2.33 - 2.27(m, 1H), 2.02 - 1.93(m, 5H), 1.73 - 1.70(m, 2H), 1.55 - 1.50(m, 1H); MS(TOF): m / z(%) = 483.1490(80%)(M + H) + .

[1073] Example - 168

[1074] (S,E)-2-(2-Ethyl-1-methylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide

[1075]

[1076] 1H NMR(400MHz, DMSO-d6); δ = 8.01(s, 1H), 6.93(s, 1H), 6.71(d, J = 15.2Hz, 1H), 6.58(d, J = 15.6Hz, 1H), 2.99(m, 1H), 2.80(t, J = 7.2Hz, 4H), 2.66(t, J = 7.2Hz, 4H), 2.57(m, 1H), 2.24(s, 3H), 1.95(m, 4H), 1.85(m, 1H), 1.72(m, 4H), 1.45(m, 1H), 0.8(t, J = 7.2Hz, 3H); MS(ESI): m / z(%) = 418.19(100%)(M + 1);

[1077] Example - 169

[1078] (R,E)-2-(1-(But-2-yn-1-yl)pyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide

[1079]

[1080] 1 1H NMR(400MHz, DMSO-d6): δ = 8.84(s, 1H), 7.03(d, J = 15.6Hz, 1H), 6.91(s, 1H), 6.35 - 6.23(m, 1H), 4.31 - 4.03(m, 3H), 3.26 - 3.07(m, 2H), 2.82 - 2.67(m, 8H), 2.20 - 2.05(m, 1H), 1.97 - 1.83(m, 6H), 1.74 - 1.61(m, 4H); MS(TOF): m / z(%) = 428.1884(100%)(M + H) + .

[1081] Biological Activity:

[1082] In Vitro Assay:

[1083] Differentiate THP1 monocytes with PMA (100 ng / mL) and incubate at 37 °C for 20 h in the presence of 5% CO2. Seed 2×10 5 differentiated cells per well in a 96-well tissue culture plate. Sensitize the cells with 500 ng / mL lipopolysaccharide and incubate for 4 h under the same conditions. Then treat the cells with different concentrations of the compound for 30 min, followed by treatment with 5 mM ATP for 1 h. Collect the supernatant and analyze it using an IL-1β (Mabtech Cat#3415-1H-20) or TNF-α (Mabtech; Cat#3510-1H-20) detection kit. Analyze the data using GraphPad Prism V7.0. Determine the IC 50 value by constructing a dose-response curve (DRC) using non-linear regression analysis by fitting the percentage cell survival data to GraphPad Prism. The in vitro IL-1β inhibitory activities (IC 50 ) of representative compounds are listed in Table 1.

[1084] Table 1

[1085]

[1086]

[1087] In vivo potency study:

[1088] Demonstration of the in vivo potency of the test compound in rats and mice, oral administration route.

[1089] Animals

[1090] All animal experiments were conducted in female rats and mice bred in-house. The animals were housed in groups of six per cage for one week to acclimatize them to the chamber environment (25 ± 4 °C, 60% to 65% relative humidity, 12:12 h light:dark cycle, light on at 7:30 am). All animal experiments were conducted in accordance with internationally valid guidelines approved by the "Zydus Research Center Animal Ethics Committee" as described below.

[1091] In vivo LPS- and ATP-induced IL-1β assay:

[1092] Female C57 mice (6 to 8 weeks) received an intraperitoneal injection of lipopolysaccharide (LPS) at 50 μg / mouse in PBS. Treat the animals immediately with the test compound or vehicle. Two hours after LPS injection, administer ATP dissolved in PBS to the animals at 12.5 mg / mouse via the intraperitoneal route. Thirty minutes after ATP injection, collect the serum for the estimation of IL-1β by ELISA.

[1093] The novel compounds of the present invention can be formulated into suitable pharmaceutically acceptable compositions by known techniques and methods and concentrations in combination with suitable excipients.

[1094] Representative data for some of the test compounds are listed in Table 2:

[1095] Table 2

[1096]

[1097] The compounds of formula (I) or pharmaceutical compositions containing them can be used as drugs for inhibiting NLRP3 activity and are suitable for humans and other warm-blooded animals, and can be administered by oral, topical or parenteral administration.

[1098] Accordingly, the pharmaceutical compositions containing the compounds of the present invention can contain suitable binders, suitable fillers and / or diluents and any other suitable pharmaceutical agents that may be necessary. Optionally, the pharmaceutical compositions can be suitably coated with a suitable coating agent.

[1099] The compounds (I) of the present invention are NLRP3 inhibitors and can be used for treating disease states mediated by NLRP3, preferably diseases or disorders involving interleukin 1β activity and related disorders.

[1100] The amount of the active ingredient (i.e., the compound of formula (I) according to the present invention) in the pharmaceutical composition and its unit dosage form can vary or be adjusted widely according to the specific administration method, the potency of the specific compound and the desired concentration. Generally speaking, the amount of the active ingredient will range between 0.5% and 90% by weight of the composition.

[1101] The compounds of formula (I) of the present invention can be used alone or in any combination with one or more other therapeutic agents that can be easily identified by a skilled physician. Such other therapeutic agents can be selected according to the type of disease being treated, its severity, other drugs the patient is taking, etc. Thus, for example, for the treatment of rheumatoid arthritis, one or more DMARDs can be used in combination with the compounds of the present invention.

[1102] In one of the embodiments, the compound of formula (I) of the present invention can be used in combination with one or more suitable pharmaceutically active agents selected from the following therapeutic agents in any combination. Interleukin-1β inhibitors (such as rilonacept, canakinumab, and anakinra); immunosuppressants (such as methotrexate, mercaptopurine, cyclophosphamide), metabolic disorder drugs, glucocorticoids, non-steroidal anti-inflammatory drugs, Cox-2 specific inhibitors, TNF-α binding proteins (such as infliximab, etanercept), interferon-13, interferons, interleukin-2, antihistamines, β-agonists, BTK inhibitors, anticholinergics, anticancer agents, or suitable pharmaceutically acceptable salts thereof. Other examples are for use in combination with: Non-Alcoholic Steato-Hepatitis (NASH) and fibrosis drugs, anticancer antibiotics, hormones, aromatase inhibitors, antibodies, cytokines, vaccines, drug conjugates, mitogen-activated protein kinase signaling inhibitors (such as: BAY 43-9006), Syk inhibitors, mTOR inhibitors, antibodies (rituximab), and BCR / ABL antagonists.

[1103] Although the present invention has been described in accordance with specific embodiments of the present invention, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

[1104] This application also relates to the following embodiments:

[1105] 1. Compounds having the structure of general formula (I):

[1106]

[1107] Their tautomeric forms, their stereoisomers, their enantiomers, their pharmaceutically acceptable salts, and pharmaceutical compositions containing them, wherein,

[1108] R 1 is independently selected from hydrogen, halogen, haloalkyl, cyano, and optionally substituted groups selected from the following: (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C1-C6) alkoxy, (C3-C7) cycloalkyl, NH2, NH(C1-C6) alkyl, N(C3-C7) cycloalkyl, N(C1-C6 alkyl)2, aryl, heteroaryl, heterocyclic group, benzyl, thiol, mercaptoalkyl, SO2(C1-C6) alkyl, (C1-C6) thioalkoxy, amide;

[1109] X is N-R 5 , O, S, SO2;

[1110] R 5 independently selected from hydrogen, halogen, haloalkyl, cyano, and optionally substituted groups selected from the following at each occurrence: (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C3-C7)cycloalkyl, (C1-C6)alkylSO2(C1-C6)alkyl, (C1-C6)alkylN(C1-C6)alkyl, (C1-C6)alkylN(C3-C7)cycloalkyl, aryl, heteroaryl, heterocyclic group, benzyl, tert-butoxycarbonyl, thiol, mercaptoalkyl, SO2(C1-C6)alkyl, SO2(C3-C7)cycloalkyl, SO2-aryl, SO2-heterocyclic group, (C1-C6)thioalkyl, (C1-C6)thioalkoxy, (C1-C6)alkylSO2NH2, -CONH2, -CO(C1-C6)alkyl, -CO(C1-C6)haloalkyl, -CO-aryl, -CO-heteroaryl, -CO-heterocyclic group, 4- to 7-membered heterocycle, 7- to 14-membered bicyclic heterocyclic system, bridged or spirocyclic system having optionally one or more heteroatoms;

[1111] m and n are independently selected from the integers 0 to 3;

[1112] q and r are independently selected from the integers 1 to 4;

[1113] R 2 independently selected from hydrogen, halogen, cyano, and optionally substituted groups selected from the following at each occurrence: (C1-C6)alkyl, (C2-C6)alkenyl, (C1-C6)alkoxy, (C3-C7)cycloalkyl, benzyl, aryl, heteroaryl, heterocyclic group, thiol, thioalkyl, thio-alkoxy, SO2(C1-C6)alkyl, SO(C1-C6)alkyl, bridged or spirocyclic system having optionally one or more heteroatoms;

[1114] R 3 and R 4 each of which is independently selected from hydrogen, halogen, haloalkyl, cyano, nitro, amide, sulfonamide, acyl, hydroxy, and optionally substituted groups selected from the following at each occurrence: (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, SO2(C1-C6)alkyl, thiol, mercaptoalkyl, benzyl, aryl, heteroaryl, heterocyclic group; or R3 and R4 form a bond;

[1115] ‘B’ is selected from the following ring systems:

[1116]

[1117] Wherein X, Y, and Z are each independently selected from C, N, S, SO2, and O at each occurrence, and may optionally be substituted whenever possible;

[1118] R 6 , R 7 , R 8 , R 9 , R 10 and R 11 each, at each occurrence, is independently selected from hydrogen, halogen, cyano, amide, sulfonamide, acyl, hydroxy, a group optionally substituted from the group consisting of: (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, benzyl, aryl, heteroaryl, heterocyclic; or R 7 and R 8 , R 8 and R 9 , R 9 and R 10 or R 10 and R 11 each, whenever possible, may together form a 4- to 7-membered saturated or partially saturated ring containing 0 to 2 additional heteroatoms selected from N, O, and S(O) p ; p = 1 to 2.

[1119] 2. The compound according to embodiment 1, wherein R1 is selected from hydrogen, halogen, haloalkyl, and a group optionally substituted from (C1-C6)alkyl at each occurrence.

[1120] 3. The compound according to embodiment 1, wherein R2 is selected from hydrogen, halogen, haloalkyl, and a group optionally substituted from (C1-C6)alkyl at each occurrence.

[1121] 4. The compound according to embodiment 1, wherein R 3 and R 4 are each independently selected from hydrogen, halogen, haloalkyl, and a group optionally substituted from (C1-C6)alkyl at each occurrence.

[1122] 5. The compound according to embodiment 1, wherein R 6 , R 7 , R 8 , R 9 , R 10 and R 11 each, at each occurrence, is independently selected from hydrogen, halogen, a group optionally substituted from (C1-C6)alkyl, and (C1-C6)haloalkyl.

[1123] 6. A compound according to any one of the foregoing embodiments, wherein when any of the above groups is substituted, the substitution is selected from hydrogen, hydroxy, cyano, halo, haloalkyl, haloalkoxy, alkylthio (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C7) cycloalkyl, C1-C6 alkoxy, aryl, heterocyclic group, heteroaryl, -COR 12 、-CSR 12 、C(O)OR 12 、C(O)-R 12 、-C(O)-NR 12 R 13 、-C(S)-NR 12 R 13 、-SO2R 12 group, wherein each of R 12 and R 13 is independently selected from hydrogen and an optionally substituted group selected from the following: (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C7) cycloalkyl, aryl, heteroaryl, heterocyclic group.

[1124] 7. A compound according to embodiment 1, the compound being selected from:

[1125] (R,E)-2-(1-Ethylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethanesulfonamide;

[1126] (S,E)-2-(1-Ethylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethanesulfonamide;

[1127] (R,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(pyrrolidin-2-yl)ethene-1-sulfonamide;

[1128] (R,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-propylpyrrolidin-2-yl)ethene-1-sulfonamide;

[1129] (R,E)-2-(1-(Cyclopropylmethyl)pyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide;

[1130] (R,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-methylpyrrolidin-2-yl)ethene-1-sulfonamide;

[1131] (R,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(methylsulfonyl)pyrrolidin-2-yl)ethene-1-sulfonamide;

[1132] (R,E)-2-(1-acetylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide;

[1133] (E)-2-(1-benzylpiperidin-4-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethanesulfonamide;

[1134] (R,E)-2-(2-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)pyrrolidine-1-carboxylic acid tert-butyl ester;

[1135] (R,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(2-methoxyethyl)pyrrolidin-2-yl)ethenesulfonamide;

[1136] (R,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(isopropylsulfonyl)pyrrolidin-2-yl)ethenesulfonamide;

[1137] (R,E)-2-(1-((3-fluorophenyl)sulfonyl)pyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethenesulfonamide;

[1138] (R,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(pyrazine-2-carbonyl)pyrrolidin-2-yl)ethenesulfonamide;

[1139] (R,E)-2-(2-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)pyrrolidine-1-carboxamide;

[1140] (R,E)-2-(1-(cyclopropanecarbonyl)pyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide;

[1141] (R,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(2,2,2-trifluoroacetyl)pyrrolidin-2-yl)ethenesulfonamide;

[1142] (R,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(2-(methylthio)ethyl)pyrrolidin-2-yl)ethenesulfonamide;

[1143] (R,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(2,2,2-trifluoroethyl)pyrrolidin-2-yl)ethenesulfonamide;

[1144] (R,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-isobutylpyrrolidin-2-yl)ethenesulfonamide;

[1145] (R,E)-2-(1-(ethylsulfonyl)pyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethenesulfonamide;

[1146] (R,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-isopropylpyrrolidin-2-yl)ethenesulfonamide;

[1147] (R,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(3-(methylsulfonyl)propyl)pyrrolidin-2-yl)ethenesulfonamide;

[1148] (R,E)-2-(1-benzoylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethenesulfonamide;

[1149] (R,E)-N-((2-(1-benzoylpyrrolidin-2-yl)vinyl)sulfonyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)benzamide;

[1150] (R,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(pyrrolidin-2-yl)ethenesulfonamide;

[1151] (R,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(thiophene-3-carbonyl)pyrrolidin-2-yl)ethenesulfonamide;

[1152] (R,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(pyrrolidin-2-yl)ethene-1-sulfonamide mesylate;

[1153] (R,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(pyrrolidin-2-yl)ethene-1-sulfonamide maleate;

[1154] (R,Z)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(pyrrolidin-2-yl)ethene-1-sulfonamide;

[1155] (S,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-3-(pyrrolidin-2-yl)prop-1-ene-1-sulfonamide;

[1156] (R,E)-2-(1-(cyclohexylsulfonyl)pyrrolidin-2-yl)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide;

[1157] (R,Z)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-methylpyrrolidin-2-yl)ethene-1-sulfonamide;

[1158] (R,E)-2-(1-(cyclohexylmethyl)pyrrolidin-2-yl)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide;

[1159] (R,E)-2-(1-cyclohexylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide;

[1160] (R,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(1-methylpiperidin-4-yl)pyrrolidin-2-yl)ethene-1-sulfonamide;

[1161] (R,Z)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-isopropylpyrrolidin-2-yl)ethene-1-sulfonamide;

[1162] (R,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-2-yl)ethene-1-sulfonamide;

[1163] (R,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(oxetan-3-yl)pyrrolidin-2-yl)ethene-1-sulfonamide;

[1164] (R,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(tetrahydro-2H-thiopyran-4-yl)pyrrolidin-2-yl)ethene-1-sulfonamide;

[1165] (R,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(thiazol-2-ylmethyl)pyrrolidin-2-yl)ethene-1-sulfonamide;

[1166] (E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(piperidin-4-yl)ethene-1-sulfonamide;

[1167] (E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-methylpiperidin-4-yl)ethene-1-sulfonamide;

[1168] (E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(methylsulfonyl)piperidin-4-yl)ethene-1-sulfonamide;

[1169] (E)-2-(1-acetylpiperidin-4-yl)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide;

[1170] (E)-4-(2-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)aminosulfonyl)vinyl)-piperidine-1-carboxylic acid tert-butyl ester;

[1171] (E)-2-(1-ethylpiperidin-4-yl)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide;

[1172] (R,E)-2-(1-Ethylpyrrolidin-3-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethenesulfonamide;

[1173] (R,E)-1,1-Diethyl-3-(2-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)pyrrolidin-1-ium bromide ;

[1174] (E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(pyrrolidin-3-yl)ethenesulfonamide;

[1175] (R,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-methylpyrrolidin-2-yl)ethen-1-esulfonamide;

[1176] (R,E)-2-(2-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester;

[1177] (R,E)-2-(1-Acetyl-2-methylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethen-1-esulfonamide;

[1178] (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 ;

[1179] (R,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-methyl-1-(methylsulfonyl)pyrrolidin-2-yl)ethen-1-esulfonamide;

[1180] (R,E)-2-(1,2-Dimethylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethen-1-esulfonamide;

[1181] (R,E)-2-(1-Ethyl-2-methylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethen-1-esulfonamide;

[1182] (R,E)-2-(1-(Cyclopropylmethyl)-2-methylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide;

[1183] (S,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(pyrrolidin-2-yl)ethene-sulfonamide;

[1184] (S,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-methylpyrrolidin-2-yl)ethene sulfonamide;

[1185] (S,E)-2-(2-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)pyrrolidine-1-carboxylic acid tert-butyl ester;

[1186] (S,E)-2-(1-(Cyclopropylmethyl)pyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene sulfonamide;

[1187] (S,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(pyridin-3-ylsulfonyl)-pyrrolidin-2-yl)ethene sulfonamide;

[1188] (S,E)-N-((2,6-diisopropylphenyl)carbamoyl)-2-(pyrrolidin-2-yl)ethene sulfonamide;

[1189] (S,E)-N-((2,6-diisopropylphenyl)carbamoyl)-2-(1-ethylpyrrolidin-2-yl)ethene sulfonamide;

[1190] (S,E)-N-((2,6-diisopropylphenyl)carbamoyl)-2-(1-(methylsulfonyl)pyrrolidin-2-yl)ethene-sulfonamide;

[1191] (S,E)-N-((2,6-diisopropylphenyl)carbamoyl)-2-(1-methylpyrrolidin-2-yl)ethene sulfonamide;

[1192] (S,E)-2-(1-acetylpyrrolidin-2-yl)-N-((2,6-diisopropylphenyl)carbamoyl)ethene sulfonamide;

[1193] (S,E)-2-(1-acetylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-ethene sulfonamide;

[1194] (S,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(tetrahydro-2H-pyran-4-carbonyl)pyrrolidin-2-yl)ethenesulfonamide;

[1195] (E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(tetrahydro-2H-pyran-4-yl)ethenesulfonamide;

[1196] (S,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-nicotinoylpyrrolidin-2-yl)ethenesulfonamide;

[1197] (E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(tetrahydrofuran-2-yl)ethene-1-sulfonamide;

[1198] (S,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(thiophen-2-ylmethyl)-pyrrolidin-2-yl)ethene-1-sulfonamide;

[1199] (S,E)-2-(2-(N-((4-Fluoro-2,6-diisopropylphenyl)carbamoyl)aminosulfonyl)vinyl)-pyrrolidine-1-carboxylic acid tert-butyl ester;

[1200] (S,E)-N-((4-Fluoro-2,6-diisopropylphenyl)carbamoyl)-2-(pyrrolidin-2-yl)ethene-1-sulfonamide;

[1201] (S,E)-N-((4-Fluoro-2,6-diisopropylphenyl)carbamoyl)-2-(1-methylpyrrolidin-2-yl)ethene-1-sulfonamide;

[1202] (R,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-isobutyl-2-methyl-pyrrolidin-2-yl)ethene-1-sulfonamide;

[1203] (R,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-methyl-1-propylpyrrolidin-2-yl)ethene-1-sulfonamide;

[1204] (S,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(thiazol-2-yl)pyrrolidin-2-yl)ethene-1-sulfonamide;

[1205] (E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(piperidin-3-yl)ethenesulfonamide;

[1206] (E)-2-(1-Ethylpiperidin-3-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethenesulfonamide;

[1207] (E)-3-(2-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)-piperidine-1-carboxylic acid tert-butyl ester;

[1208] (E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(methylsulfonyl)piperidin-3-yl)ethenesulfonamide;

[1209] (E)-2-(1-Acetylpiperidin-3-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethenesulfonamide;

[1210] (E)-2-(2-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)-azetidine-1-carboxylic acid tert-butyl ester;

[1211] (E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-methylazetidin-2-yl)ethene-1-sulfonamide;

[1212] (E)-2-(Azetidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide;

[1213] (R,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-2-yl)ethene-1-sulfonamide;

[1214] (S,E)-2-(1-((5-Chlorothiophen-2-yl)sulfonyl)pyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethenesulfonamide;

[1215] (S,E)-2-(1-(Benzylsulfonyl)pyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethenesulfonamide;

[1216] (S,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-((4-methoxyphenyl)sulfonyl)pyrrolidin-2-yl)ethenesulfonamide;

[1217] (S,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-((4-fluorophenyl)sulfonyl)pyrrolidin-2-yl)ethenesulfonamide;

[1218] (S,E)-2-(1-((2-cyanophenyl)sulfonyl)pyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethenesulfonamide;

[1219] (S,E)-2-(1-(Cyclohexylsulfonyl)pyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethenesulfonamide;

[1220] (S,E)-2-(1-(4-fluorobenzyl)pyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethenesulfonamide;

[1221] (S,E)-2-(1-((4-cyanophenyl)sulfonyl)pyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide;

[1222] (S,E)-2-(1-(4-cyanobenzyl)pyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide;

[1223] (S,E)-N-((1,2,3,6,7,8-hexahydro-as-indacen-4-yl)carbamoyl)-2-(pyrrolidin-2-yl)ethene-1-sulfonamide;

[1224] (E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(piperidin-2-yl)ethene-1-sulfonamide;

[1225] (E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-methylpiperidin-2-yl)ethene-1-sulfonamide;

[1226] (E)-N-((1,2,3,6,7,8-Hexahydro-as-indacen-4-yl)carbamoyl)-2-(1-methylpyrrolidin-2-yl)ethene-1-sulfonamide;

[1227] (E)-N-((1,2,3,6,7,8-Hexahydro-as-indacen-4-yl)carbamoyl)-2-(1-(methylsulfonyl)pyrrolidin-2-yl)ethene-1-sulfonamide;

[1228] ((E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-3-(piperidin-2-yl)prop-1-ene-1-sulfonamide;

[1229] (S,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-methylpyrrolidin-2-yl)ethene-1-sulfonamide;

[1230] (S,E)-2-(1,2-dimethylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide;

[1231] (E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(indolin-2-yl)ethene-1-sulfonamide;

[1232] (E)-2-(2-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)indoline-1-carboxylic acid tert-butyl ester;

[1233] ((S,E)-2-(1-(cyclopropylmethyl)-2-methylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide;

[1234] (S,E)-2-(1-(cyclopropylsulfonyl)pyrrolidin-2-yl)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide;

[1235] (S,E)-2-(2-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester;

[1236] (R,E)-tert-Butyl 2-(2-((N-((2,6-diisopropylphenyl)carbamoyl)sulfamoyl)vinyl)-2-methylpyrrolidine-1-carboxylate;

[1237] (R,E)-N-((2,6-Diisopropylphenyl)carbamoyl)-2-(2-methylpyrrolidin-2-yl)ethene-1-sulfonamide 2,2,2-trifluoroacetate;

[1238] (R,E)-N-((2,6-Diisopropylphenyl)carbamoyl)-2-(1,2-dimethylpyrrolidin-2-yl)ethene-1-sulfonamide;

[1239] (S,E)-2-(1-Ethyl-2-methylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide;

[1240] Disodium (R,E)-((2-(1,2-dimethylpyrrolidin-2-yl)vinyl)sulfonyl)((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)amide;

[1241] Sodium (R,E)-((2-(1,2-dimethylpyrrolidin-2-yl)vinyl)sulfonyl)((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)amide;

[1242] (S,E)-tert-Butyl 2-(2-((N-((2,6-diisopropylphenyl)carbamoyl)sulfamoyl)vinyl)-2-methylpyrrolidine-1-carboxylate;

[1243] (S,E)-N-((2,6-Diisopropylphenyl)carbamoyl)-2-(2-methylpyrrolidin-2-yl)ethene-1-sulfonamide 2,2,2-trifluoroacetate;

[1244] (S,E)-N-((2,6-Diisopropylphenyl)carbamoyl)-2-(1,2-dimethylpyrrolidin-2-yl)ethene-1-sulfonamide;

[1245] (R,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-methyl-1-(oxetan-3-yl)pyrrolidin-2-yl)ethene-1-sulfonamide;

[1246] (S,E)-tert-Butyl 2-(2-((N-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)sulfamoyl)vinyl)-2-methylpyrrolidine-1-carboxylate;

[1247] (S,E)-N-((4-Fluoro-2,6-diisopropylphenyl)carbamoyl)-2-(2-methylpyrrolidin-2-yl)ethene-1-sulfonamide 2,2,2-trifluoroacetate;

[1248] (S,E)-2-(1,2-Dimethylpyrrolidin-2-yl)-N-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)ethene-1-sulfonamide;

[1249] (E)-2-(1-Acetylazetidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide;

[1250] (R,E)-(2-(2-(2-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)pyrrolidin-1-yl)ethyl)(methyl)carbamic acid tert-butyl ester;

[1251] (S,E)-2-(1-Allylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide;

[1252] (S,E)-2-(1-(1H-Benzimidazole-6-carbonyl)pyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide;

[1253] (S,E)-2-(1-(Cyclopropylsulfonyl)-2-methylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide;

[1254] (S,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(4-methoxybenzyl)pyrrolidin-2-yl)ethene-1-sulfonamide;

[1255] 5-((R)-2-((E)-2-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)pyrrolidin-1-yl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester;

[1256] (E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-((2R)-1-(octahydrocyclopenta[c]pyrrol-5-yl)pyrrolidin-2-yl)ethene-1-sulfonamide 2,2,2-trifluoroacetate;

[1257] (E)-2-(1-(Cyclopropylsulfonyl)azetidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide;

[1258] (S,E)-N-((2,6-Diisopropylphenyl)carbamoyl)-2-(1-(thiazol-2-yl)pyrrolidin-2-yl)ethene-1-sulfonamide;

[1259] (S,E)-(2-(2-(2-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)-2-methylpyrrolidin-1-yl)ethyl)(methyl)carbamic acid tert-butyl ester;

[1260] Potassium (R,E)-((2-(1,2-dimethylpyrrolidin-2-yl)vinyl)sulfonyl)((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)amide;

[1261] (E)-(2-(2-(2-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)azetidin-1-yl)ethyl)(methyl)carbamic acid tert-butyl ester;

[1262] (S,E)-2-(1-(Cyclohexylmethyl)-2-methylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide;

[1263] Sodium (R,E)-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)((2-(1-(tetrahydro-2H-thiopyran-4-yl)pyrrolidin-2-yl)vinyl)sulfonyl)amide;

[1264] Sodium (R,E)-((2-(1-cyclohexylpyrrolidin-2-yl)vinyl)sulfonyl)((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)amide;

[1265] Sodium (S,E)-((2,6-Diisopropylphenyl)carbamoyl)((2-(1,2-dimethylpyrrolidin-2-yl)vinyl)sulfonyl)amide;

[1266] Sodium (R,E)-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)((2-(1-methylpyrrolidin-2-yl)vinyl)sulfonyl)amide;

[1267] Potassium (R,E)-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)((2-(1-methylpyrrolidin-2-yl)vinyl)sulfonyl)amide;

[1268] Sodium (S,E)-((2-(1,2-dimethylpyrrolidin-2-yl)vinyl)sulfonyl)((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)amide;

[1269] Sodium (S,E)-((2-(1-ethylpyrrolidin-2-yl)vinyl)sulfonyl)((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)amide;

[1270] (S,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(2-hydroxyethyl)pyrrolidin-2-yl)ethene-1-sulfonamide;

[1271] (E)-2-(2-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)aminosulfonyl)vinyl)-2-methylazetidine-1-carboxylic acid tert-butyl ester;

[1272] (E)-2-(1,2-dimethylazetidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide;

[1273] (S,E)-2-ethyl-2-(2-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)aminosulfonyl)vinyl)pyrrolidine-1-carboxylic acid tert-butyl ester;

[1274] (S,E)-2-(2-(N-((1,2,3,6,7,8-hexahydro-as-indacen-4-yl)carbamoyl)aminosulfonyl)vinyl)-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester;

[1275] (S,E)-2-(2-ethylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide 2,2,2-trifluoroacetate;

[1276] (S,E)-N-((1,2,3,6,7,8-hexahydro-as-indacen-4-yl)carbamoyl)-2-(2-methylpyrrolidin-2-yl)ethene-1-sulfonamide 2,2,2-trifluoroacetate;

[1277] (S,E)-2-(1,2-Dimethylpyrrolidin-2-yl)-N-((1,2,3,6,7,8-hexahydro-as-indacen-4-yl)carbamoyl)ethene-1-sulfonamide;

[1278] (R,E)-tert-Butyl 2-(2-(N-((1,2,3,6,7,8-hexahydro-as-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)-2-methylpyrrolidine-1-carboxylate;

[1279] (R,E)-N-((1,2,3,6,7,8-hexahydro-as-indacen-4-yl)carbamoyl)-2-(2-methylpyrrolidin-2-yl)ethene-1-sulfonamide 2,2,2-trifluoroacetate;

[1280] (R,E)-2-(1,2-Dimethylpyrrolidin-2-yl)-N-((1,2,3,6,7,8-hexahydro-as-indacen-4-yl)carbamoyl)ethene-1-sulfonamide;

[1281] (R,E)-tert-Butyl 2-(3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)allyl)-2-methylpyrrolidine-1-carboxylate;

[1282] (R,E)-tert-Butyl (2-(2-(3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)allyl)-2-methylpyrrolidin-1-yl)ethyl)(methyl)carbamate;

[1283] (R,E)-3-(1,2-Dimethylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)prop-1-ene-1-sulfonamide;

[1284] (S,E)-tert-Butyl (3-(2-(2-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)pyrrolidin-1-yl)propyl)(methyl)carbamate;

[1285] (E)-tert-Butyl (3-(2-(2-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)-2-methylazetidin-1-yl)propyl)(methyl)carbamate;

[1286] (E)-(2-(2-(2-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)-2-methylazetidin-1-yl)ethyl)(methyl)carbamic acid tert-butyl ester;

[1287] (E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-methyl-1-(2-(methylthio)ethyl)azetidin-2-yl)ethene-1-sulfonamide;

[1288] (E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-methyl-1-(oxetan-3-yl)azetidin-2-yl)ethene-1-sulfonamide;

[1289] (S)-2-(((S)-2-((E)-2-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)-2-methylazetidin-1-yl)methyl)-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester;

[1290] (S)-2-(((R)-2-((E)-2-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)-2-methylazetidin-1-yl)methyl)-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester;

[1291] (R,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(2-sulfonatoethyl)pyrrolidin-2-yl)ethene-1-sulfonamide;

[1292] (S,E)-2-(2-ethyl-1-methylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide;

[1293] (R,E)-2-(1-(but-2-yn-1-yl)pyrrolidin-2-yl)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide.

[1294] 8. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) according to any one of the foregoing embodiments and optionally one or more pharmaceutically acceptable carriers, diluents or excipients.

[1295] 9. A method for treating a disease with an NLRP3 modulator as a drug and treating a disease or disorder involving interleukin-1β activity and interleukin-18 (IL-18), which comprises administering to a patient in need thereof an effective amount of a compound of formula (I) or a suitable pharmaceutical composition according to any one of the foregoing embodiments.

[1296] 10. Use of a compound of formula (I) or a pharmaceutical composition thereof according to any one of the foregoing embodiments for treating a disease in which an NLRP3 modulator has a pathophysiological function.

[1297] 11. The pharmaceutical composition according to embodiment 8, which is combined with one or more suitable pharmaceutical active agents selected from the following: interleukin-1β inhibitor; immunosuppressant; metabolic disorder drug, glucocorticoid, non-steroidal anti-inflammatory drug, COX-2 specific inhibitor, anti-inflammatory drug, TNF-α binding protein, interferon-13, interferon, interleukin-2, antihistamine, β-agonist, BTK inhibitor, anticholinergic agent, anticancer agent, or a suitable pharmaceutically acceptable salt thereof, non-alcoholic steatohepatitis (NASH) and fibrosis drug, anticancer drug, antibiotic, hormone, aromatase inhibitor, mitogen-activated protein kinase signal transduction inhibitor, Syk inhibitor, mTOR inhibitor and BCR / ABL antagonist.

[1298] 12. A method for preparing a compound of formula (I) according to embodiment 1, the method comprising the following steps:

[1299] (i) Reacting a compound of formula (5) with DMSO to obtain a compound of formula (6), wherein all symbols are as defined in embodiment 1:

[1300]

[1301] (ii) Reacting a compound of formula (6) with an isocyanate derivative of a compound of formula (7) to obtain a compound of formula (I), wherein all symbols are as defined in embodiment 1:

[1302]

[1303] 13. A method for preparing a compound of formula (I) according to embodiment 1, the method comprising the following steps:

[1304] (a)(i) Reacting a compound of formula (12) with a compound of formula (3) to obtain a compound of formula (13), wherein all symbols are as defined in embodiment 1:

[1305]

[1306] (ii) React the compound of formula (13) with DMSO to obtain the compound of formula (14), wherein all symbols are as defined in Embodiment 1:

[1307]

[1308] (iii) React the compound of formula (14) with the isocyanate derivative of the compound of formula (7) to obtain the compound of formula (I), wherein all symbols are as defined in Embodiment 1:

[1309]

[1310] (b)(i) React the compound of formula (15) with the isocyanate derivative of the compound of formula (7) to obtain the compound of formula (16), wherein all symbols are as defined in Embodiment 1:

[1311]

[1312] (ii) React the compound of formula (16) with the compound of formula (4) to obtain the compound of formula (I), wherein all symbols are as defined in Embodiment 1:

[1313]

[1314] 14. Intermediate of formula (5),

[1315]

[1316]

[1317] wherein all symbols are as defined in Embodiment 1.

[1318] 15. Intermediate of formula (6),

[1319]

[1320] wherein all symbols are as defined in Embodiment 1.

[1321] 16. Intermediate of formula (15),

[1322]

[1323] wherein all symbols are as defined in Embodiment 1.

[1324] 17. Intermediate of formula (16),

[1325]

[1326] wherein all symbols are as defined in Embodiment 1.

Claims

1. A compound having the structure of general formula (I): Its tautomeric forms, its stereoisomers, its enantiomers, its pharmaceutically acceptable salts and pharmaceutical compositions comprising the same, wherein, R 1 independently selected from hydrogen and substituted or unsubstituted (C1-C6) alkyl each time it appears; X is N-R 5 , O; R 5 independently selected from hydrogen and, in each occurrence, a substituted or unsubstituted group selected from the following: (C1-C6)alkyl, (C2-C6)alkenyl, (C1-C6)alkylSO2(C1-C6)alkyl, heterocyclic group, tert-butoxycarbonyl, unsubstituted or aryl-substituted SO2(C1-C6)alkyl, SO2(C3-C7)cycloalkyl, SO2-aryl, SO2-heterocyclic group, -CO(C1-C6)alkyl, -CO-heteroaryl, 4- to 7-membered heterocycle, 7- to 14-membered bicyclic heterocyclic system; m is 0; and n is selected from the integers 0 to 3; q and r are independently selected from the integers 1 to 4; R 2 independently, at each occurrence, is hydrogen; R 3 and R 4 each of which, each time it appears, is independently hydrogen; ‘B’ is selected from the following ring systems: wherein X, Y, Z are independently C at each occurrence and may optionally be substituted in any possible case; R 6 Each occurrence is independently selected from hydrogen, halogen, and optionally substituted (C1-C6) alkyl.

2. The compound according to claim 1, wherein when any of the above groups is substituted, the substitution is selected from hydrogen, hydroxy, cyano, halo, haloalkyl, haloalkoxy, alkylthio (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C7) cycloalkyl, C1-C6 alkoxy, aryl, heterocyclic group, heteroaryl, -COR 12 , -CSR 12 , C(O)OR 12 , C(O)-R 12 , -C(O)-NR 12 R 13 , -C(S)-NR 12 R 13 , -SO2R 12 group, wherein each of R 12 and R 13 is independently selected from hydrogen and a group optionally substituted and selected from the following: (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C7) cycloalkyl, aryl, heteroaryl, heterocyclic group.

3. A compound selected from the following: (R,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-propylpyrrolidin-2-yl)ethene-1-sulfonamide; (R,E)-2-(1-((3-Fluorophenyl)sulfonyl)pyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene sulfonamide; (R,E)-2-(1-(Ethylsulfonyl)pyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide; (R,E)-2-(1,2-Dimethylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide; (S,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(pyridin-3-ylsulfonyl)-pyrrolidin-2-yl)ethene sulfonamide; (E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(methylsulfonyl)piperidin-3-yl)ethene sulfonamide; (S,E)-2-(1-(Benzylsulfonyl)pyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene sulfonamide; (S,E)-2-(2-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester; (S,E)-2-(1-Allylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide; (S,E)-2-(1-(Cyclopropylsulfonyl)-2-methylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide; Sodium (S,E)-((2-(1,2-Dimethylpyrrolidin-2-yl)vinyl)sulfonyl)((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)amide.

4. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of the preceding claims and optionally one or more pharmaceutically acceptable carriers, diluents or excipients.

5. Use of a compound or a suitable pharmaceutical composition according to any one of the preceding claims in the manufacture of a medicament for the treatment of a disease or disorder mediated by an NLRP3 modulator, wherein the NLRP3 modulator has a pathophysiological function.

6. The pharmaceutical composition according to claim 4, in combination with one or more suitable pharmaceutical active agents selected from: interleukin-1β inhibitors; immunosuppressants; metabolic disorder drugs, glucocorticoids, non-steroidal anti-inflammatory drugs, COX-2 specific inhibitors, anti-inflammatory drugs, TNF-α binding proteins, interferon-13, interferons, interleukin-2, antihistamines, β-agonists, BTK inhibitors, anticholinergics, anticancer agents, or suitable pharmaceutically acceptable salts thereof, non-alcoholic steatohepatitis (NASH) and fibrosis drugs, anticancer drugs, antibiotics, hormones, aromatase inhibitors, mitogen-activated protein kinase signaling inhibitors, Syk inhibitors, mTOR inhibitors and BCR / ABL antagonists.

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