New substituted sulfonylurea derivatives

Abstract

The present invention relates to novel 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 said compounds, and the use of the compounds of the present invention as NLRP3 modulators belonging to the NOD-like receptor family (NLR) proteins. Accordingly, the present invention relates to novel NLRP3 modulators and to the use of novel inhibitor compounds in the treatment of diseases or disorders involving interleukin-1β activity.

Description

TECHNICAL FIELD

[0001] The present invention relates to novel 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 invention, pharmaceutical compositions comprising said compounds, and the use of the compounds of the invention belonging to the family of NLRP3 modulators of NOD-like receptor family (NLR) proteins. Accordingly, the present invention relates to novel NLRP3 modulators and to the use of novel inhibitor compounds in the treatment of diseases or disorders involving interleukin-1β activity. BACKGROUND ART

[0002] The NOD-like receptor family (NLR) protein NLRP3 is an intracellular signaling molecule that senses a variety of pathogen-derived, 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 to form 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).

[0003] 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 consecutive 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 "leaky" gut (PAMPs). This process leads to oligomerization of inflammasome components and cleavage of procaspase-1, resulting in the release of activated pro-inflammatory cytokines.

[0004] 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.a1., 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.)

[0005] 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, when inappropriately activated, also causes tissue damage. (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)

[0006] 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.

[0007] 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 treating 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.

[0008] We disclose herein novel heterocyclic compounds of general formula (I), which are NLRP3 modulators for the prevention and treatment of 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, hepatic 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, cancer 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 the prevention and treatment of NLRP3-mediated disease states and for treating diseases or conditions involving interleukin-1β activity. The compounds of the present invention are used for treating a human or animal body by inhibiting NLRP3. Thus, the compounds of the present invention are suitable for the prevention and treatment of NLRP3-mediated disease states.

[0011] Embodiments of the Present Invention

[0012] One embodiment of the present invention provides novel heterocyclic compounds represented by the 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.

[0013] 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.

[0014] 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.

[0015] 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.

[0016] In another embodiment, there is provided a method for preparing the novel compounds of the present invention.

[0017] Another object of the present invention is to provide novel intermediates involved in the said method.

[0018] 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

[0020] Accordingly, the present invention relates to compounds of general formula (I):

[0021]

[0022] their tautomeric forms, their stereoisomers, their enantiomers, their pharmaceutically acceptable salts and pharmaceutical compositions containing them, wherein,

[0023] R 1 independently represents, each time it appears, hydrogen, halogen, haloalkyl, cyano, a group optionally substituted and selected from the following: (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 2 -C 6 )alkenyl, (C 1 -C 6 )alkoxy, (C 3 -C 7 )cycloalkyl, NH 2 、NH(C 1 -C 6 )alkyl, N(C 3 -C 7 )cycloalkyl, N(C 1 -C 6 alkyl) 2 、aryl, heteroaryl, heterocyclic group, benzyl, thiol, mercaptoalkyl, SO 2 (C 1 -C 6 )alkyl, (C 1 -C 6 )thioalkoxy, amide;

[0024] m and n independently selected from the integers 0 to 3;

[0025] q and r independently selected from the integers 1 to 4;

[0026] X is N-R 5 、O、S、SO 2 ;

[0027] R 5 independently represents, each time it appears, hydrogen, halogen, haloalkyl, cyano, a group optionally substituted and selected from the following: (C 1 -C 6), alkyl, (C 1 -C 6 ), haloalkyl, (C 2 -C 6 ), alkenyl, (C 2 -C 6 ), alkynyl, (C 1 -C 6 ), alkoxy, (C 3 -C 7 ), cycloalkyl, (C 1 -C 6 ), alkylSO 2 (C 1 -C 6 ), alkyl, (C 1 -C 6 ), alkylN(C 1 -C 6 ), alkyl, (C 1 -C 6 ), alkylN(C 3 -C 7 ), cycloalkyl, aryl, heteroaryl, heterocyclic group, benzyl, tert-butoxycarbonyl, thiol, mercaptoalkyl, SO 2 (C 1 -C 6 ), alkyl, SO 2 (C 3 -C 7 ), cycloalkyl, SO 2 -aryl, SO 2 -heterocyclic group, (C 1 -C 6 ), thioalkyl, (C 1 -C 6 ), thioalkoxy, (C 1 -C 6 ), alkylSO 2 NH 2 , -CONH 2 , -CO(C 1 -C 6 ), alkyl, -CO(C 1 -C 6 ), 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;

[0028] R 2 independently represents, in each occurrence, hydrogen, halogen, haloalkyl, cyano, a group optionally substituted and selected from: (C 1 -C 6 ), alkyl, (C 1 -C6 )alkoxy, (C 2 -C 6 )alkenyl, (C 3 -C 7 )cycloalkyl, benzyl, aryl, heteroaryl, heterocyclic group, thiol, thioalkyl, thio-alkoxy, SO 2 (C 1 -C 6 )alkyl, SO(C 1 -C 6 )alkyl, a bridged or spirocyclic system optionally having one or more heteroatoms;

[0029] R 3 and R 4 each, upon each occurrence, represents hydrogen, halogen, haloalkyl, cyano, nitro, amide, sulfonamide, acyl, hydroxy, a group optionally substituted and selected from the following: (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkoxy, SO 2 (C 1 -C 6 )alkyl, thiol, mercaptoalkyl benzyl, aryl, heteroaryl, heterocyclic group; or R 3 and R 4 form a bond;

[0030] ‘B’ is selected from the following ring systems:

[0031]

[0032] wherein W, Y, Z each, upon each occurrence, independently represents C, N, S, SO 2 and O, which may be optionally substituted;

[0033] R 6 、R 7 、R 8 、R 9 、R 10 and R 11 each, upon each occurrence, independently is selected from hydrogen, halogen, cyano, amide, sulfonamide, acyl, hydroxy, a group optionally substituted and selected from the following: (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 3 -C 6)cycloalkyl, (C 1 -C 6 )alkoxy, benzyl, aryl, heteroaryl, heterocyclic group; or each of R 7 and R 8 , R 8 and R 9 , R 9 and R 10 and R 10 and R 11 in each 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.

[0034] When any of the above-defined groups are substituted, their substitution may be selected from those described above or may be selected from hydrogen, hydroxy, cyano, halo, haloalkyl, haloalkoxy, alkylthio(C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 7 )cycloalkyl, C 1 -C 6 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 , -SO 2 R 12 groups, where each of R 12 and R 13 is independently selected from hydrogen and an optionally substituted group selected from: (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 7 )cycloalkyl, aryl, heteroaryl, heterocyclic group;

[0035] In a preferred embodiment, each occurrence of R 1 independently represents hydrogen, halogen, haloalkyl, or an optionally substituted group selected from (C 1-C 6 ) an alkyl group;

[0036] In a preferred embodiment, R 2 independently represents, each time it appears, hydrogen, halogen, haloalkyl, optionally substituted with an optionally substituted group selected from (C 1 -C 6 ) an alkyl group;

[0037] In a preferred embodiment, R 3 and R 4 each independently represents, each time it appears, hydrogen, halogen, haloalkyl, an optionally substituted group selected from (C 1 -C 6 ) an alkyl group.

[0038] In a preferred embodiment, R 6 , R 7 , R 8 , R 9 , R 10 and R 11 each independently represents, each time it appears, an optionally substituted group selected from hydrogen, halogen, an optionally substituted group selected from (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl group;

[0039] In a preferred embodiment, the above groups, radicals may be selected from:

[0040] "alkyl" and other groups with 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 with an oxygen atom, which may be further 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, for example 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 expected. Substituted alkyl includes alkyl substituted with one or more moieties selected from halogenated (e.g., CI, F, Br, and I); haloalkylated (e.g., CF 3 , 2-Br-ethyl, CH 2 F, CH 2 CI, CH 2 CF 3 or CF 2 CF 3); hydroxyl; amino; carboxylate; formamide; alkylamino; arylamino; alkoxy; aryloxy; nitro; azide; cyano; thio; sulfonic acid; sulfate; phosphonic acid; phosphate and phosphonate and those described under the limitation of "optionally substituted".

[0041] "Alkenyl" means a carbon chain containing at least one carbon-carbon double bond, which can be straight-chain, branched-chain or a combination 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. When the specified number of carbon atoms permits, for example C 5-10 , the term alkenyl also includes cycloalkenyl groups and combinations of straight-chain, branched-chain and cyclic structures. When the number of carbon atoms is not specified, C 2-6 is intended.

[0042] "Alkynyl" means a carbon chain containing at least one carbon-carbon triple bond, which can be straight-chain, branched-chain or a combination thereof. Examples of alkynyl include ethynyl, propargyl, 3-methyl-1-pentynyl, etc. When the number of carbon atoms is not specified, it is intended.

[0043] 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.

[0044] As used herein, "carbocyclic" or "carbocyclic residue" is intended to mean any stable monocyclic, bicyclic or tricyclic ring, where any ring 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;

[0045] The terms "cycloalkyl" and "cycloalkenyl" refer to optionally substituted, saturated and unsaturated monocyclic, bicyclic or tricyclic carbon groups. Where appropriate, the cycloalkyl or cycloalkenyl group may have a specified number of carbon atoms, for example, C 3 -C 6A cycloalkyl or cycloalkenyl group includes a carbocyclic group having 3, 4, 5 or 6 carbon atoms in its ring. Examples of such substituents may be selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, etc. A substituted cycloalkyl or cycloalkenyl group includes having one or more moieties of substitution selected from halo (e.g., Cl, F, Br, and I); haloalkyl (e.g., CF 3 , 2-Br-ethyl, CH 2 F, CH 2 Cl, CH 2 CF 3 or CF 2 CF 3 ); 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 limitation of "optionally substituted".

[0046] "Alkoxy" refers to a straight-chain or branched-chain alkoxide of a specified number of carbon atoms.

[0047] "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.

[0048] "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, i.e., SO and SO 2 . The heterocyclic group system may be attached to another moiety through any number of carbon atoms or heteroatoms of the group and may be both saturated and unsaturated. Examples of heterocycles include tetrahydrofuran (THF), dihydrofuran, 1,4-dioxane, morpholine, 1,4-dithiane, piperazine, piperidine, 1,3-dioxolane, imidazoline, imidazolidine, pyrrolidine, pyrroline, tetrahydropyran, tetrahydro-2H-thiopyran, dihydropyran, oxathiolane, dithiolane, 1,3-dioxane, 1,3-dithiane, oxathiane, thiomorpholine, etc. The term "heterocycloalkyl" refers to a heterocyclic group as defined above attached to an alkyl as defined above;

[0049] "Heteroaryl" means an aromatic or partially aromatic heterocycle containing at least one ring heteroatom selected from O, S and N. Thus, heteroaryl includes heteroaryls 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, benzisoxazolyl, benzisoxazolyl, benzo benzoxazolyl, benzthiazolyl, benzothiadiazolyl, dihydrobenzofuryl, indolinyl, pyridazinyl, indazolyl, isoindolyl, dihydrobenzothienyl, indolinyl, pyridazinyl, indazolyl, isoindolyl, dihydrobenzothienyl, indolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, napthyridinyl, carbazolyl, benzodioxolyl, quinoxalinyl, purinyl, furazanyl, isobenzylfuryl, benzimidazolyl, benzofuranyl, benzothienyl, quinolinyl, indolyl, isoquinolinyl, dibenzofuranyl, etc. For heterocyclic and heteroaryl groups, including rings and ring systems containing 3 to 15 carbon atoms, 1 to 3 rings are formed.

[0050] 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 identical to each other.

[0051] The "haloalkoxy" group is selected from suitable haloalkyls as defined above directly connected to an oxygen atom, more preferably groups such as fluoromethoxy, chloromethoxy, fluoroethoxy, chloroethoxy, etc.;

[0052] In certain other embodiments in which two or more hydrogen atoms are replaced by halogen atoms, the halogen atoms are not identical to each other.

[0053] "Aryloxyalkyl" means an alkyl group substituted with an aryloxy group as defined herein.

[0054] "Aryloxyaryl" means an aryl group substituted with an aryloxy group as defined herein.

[0055] "Aryloxyheteroaryl" means a heteroaryl group substituted with an aryloxy group as defined herein.

[0056] "Halo / Halogen" refers to fluorine, chlorine, bromine, iodine. Chlorine and fluorine are generally preferred.

[0057] Suitable groups and substituents on the groups can be selected from those described anywhere in the specification.

[0058] 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.

[0059] "Pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds in which the parent compound is modified by preparing 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 acid, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, glycollyarsanilic acid, hexylresorcinol, 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.

[0060] 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, optionally substituted groups include unsubstituted groups.

[0061] 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.

[0062] Particularly useful compounds may be selected from, but are not limited to, the following:

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

[0064] (S,E)-2-(1-ethylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-ethanesulfonamide;

[0065] (R,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(pyrrolidin-2-yl)ethenesulfonamide;

[0066] (R,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-14-yl)carbamoyl)-2-(1-propylpyrrolidin-2-yl)ethenesulfonamide;

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

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

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

[0070] (R,E)-2-(1-acetylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-ethene-1-sulfonamide;

[0071] (E)-2-(1-benzylpiperidin-4-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-ethanesulfonamide;

[0072] (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;

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

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

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

[0076] (R,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(pyrazine-2-carbonyl)pyrrolidin-2-yl)ethenesulfonamide;

[0077] (R,E)-2-(2-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)pyrrolidine-1-carboxamide;

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

[0079] (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;

[0080] (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;

[0081] (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;

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

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

[0084] (R,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-isopropylpyrrolidin-2-yl)ethene-1-sulfonamide;

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

[0086] (R,E)-2-(1-benzoylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethenesulfonamide;

[0087] (R,E)-N-((2-(1-benzoylpyrrolidin-2-yl)vinyl)sulfonyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)benzamide;

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

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

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

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

[0092] (R,Z)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(pyrrolidin-2-yl)ethene-1-sulfonamide;

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

[0094] (R,E)-2-(1-(Cyclohexanesulfonyl)pyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide;

[0095] (R,Z)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-methylpyrrolidin-2-yl)ethene-1-sulfonamide;

[0096] (R,E)-2-(1-(Cyclohexylmethyl)pyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-41-yl)carbamoyl)ethene-1-sulfonamide;

[0097] (R,E)12-(1-Cyclohexylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide;

[0098] (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;

[0099] (R,Z)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-isopropylpyrrolidin-2-yl)ethene-1-sulfonamide;

[0100] (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;

[0101] (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;

[0102] (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;

[0103] (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;

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

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

[0106] (E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(methylsulfonyl)piperidin-4-yl)ethenesulfonamide;

[0107] (E)-2-(1-acetylpiperidin-4-yl)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)ethene-sulfonamide;

[0108] (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;

[0109] (E)-2-(1-ethylpiperidin-4-yl)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide;

[0110] (R,E)-2-(1-ethylpyrrolidin-3-yl)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-ethenesulfonamide;

[0111] (R,E)-1,1-diethyl-3-(2-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)aminosulfonyl)-vinyl)pyrrolidine-1-bromide ;

[0112] (E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(pyrrolidin-3-yl)ethene-sulfonamide;

[0113] (R,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-methylpyrrolidin-2-yl)ethene-1-sulfonamide;

[0114] (R,E)-2-(2-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)aminosulfonyl)vinyl)-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester;

[0115] (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;

[0116] (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 ;

[0117] (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;

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

[0119] (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;

[0120] (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;

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

[0122] (S,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-methylpyrrolidin-2-yl)ethene sulfonamide;

[0123] (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;

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

[0125] (S,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(pyridin-3-ylsulfonyl)pyrrolidin-2-yl)ethenesulfonamide;

[0126] (S,E)-N-((2,6-Diisopropylphenyl)carbamoyl)-2-(pyrrolidin-2-yl)ethenesulfonamide;

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

[0128] (S,E)-N-((2,6-Diisopropylphenyl)carbamoyl)-2-(1-(methylsulfonyl)pyrrolidin-2-yl)ethene-sulfonamide;

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

[0130] (S,E)-2-(1-acetylpyrrolidin-2-yl)-N-((2,6-diisopropylphenyl)carbamoyl)ethenesulfonamide;

[0131] (S,E)-2-(1-acetylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-ethenesulfonamide;

[0132] (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;

[0133] (E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(tetrahydro-2H-pyran-4-yl)ethenesulfonamide;

[0134] (S,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-nicotinoylpyrrolidin-2-yl)ethenesulfonamide;

[0135] (E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(tetrahydrofuran-2-yl)ethene-1-sulfonamide;

[0136] (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;

[0137] (S,E)-2-(2-(N-((4-Fluoro-2,6-diisopropylphenyl)carbamoyl)sulfamoyl)vinyl)-1-tert-butyl pyrrolidinecarboxylate;

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

[0139] (S,E)-N-((4-Fluoro-2,6-diisopropylphenyl)carbamoyl)-2-(1-methylpyrrolidin-2-yl)ethene-1-sulfonamide;

[0140] (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;

[0141] (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;

[0142] (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;

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

[0144] (E)-2-(1-Ethylpiperidin-3-yl)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)ethene-sulfonamide;

[0145] (E)-3-(2-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)-1-tert-butyl piperidinecarboxylate;

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

[0147] (E)-2-(1-Acetylpiperidin-3-yl)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)ethene-sulfonamide;

[0148] (E)-tert-Butyl 2-(2-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)azetidine-1-carboxylate;

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

[0150] (E)-2-(Azetidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide;

[0151] (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;

[0152] (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;

[0153] (S,E)-2-(1-(benzylsulfonyl)pyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethenesulfonamide;

[0154] (S,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-((4-methoxyphenyl)sulfonyl)pyrrolidin-2-yl)ethenesulfonamide;

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

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

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

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

[0159] (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;

[0160] (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;

[0161] (S,E)-N-((1,2,3,6,7,8-hexahydro-as-indacen-4-yl)carbamoyl)-2-(pyrrolidin-2-yl)ethene-1-sulfonamide;

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

[0163] (E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-methylpiperidin-2-yl)ethene-1-sulfonamide;

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

[0165] (E)-N-((1,2,3,6,7,8-hexahydro-as-indacen-4-yl)carbamoyl)-2-(1-(methylsulfonyl)pyrrolidin-2-yl)ethene-1-sulfonamide;

[0166] ((E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-(piperidin-2-yl)prop-1-ene-1-sulfonamide;

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

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

[0169] (E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(indolin-2-yl)ethene-1-sulfonamide;

[0170] (E)-tert-Butyl 2-(2-((N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)indoline-1-carboxylate;

[0171] ((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;

[0172] (S,E)-2-(1-(Cyclopropylsulfonyl)pyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide;

[0173] (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;

[0174] (R,E)-tert-Butyl 2-(2-((N-((2,6-diisopropylphenyl)carbamoyl)sulfamoyl)vinyl)-2-methylpyrrolidine-1-carboxylate;

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

[0176] (R,E)-N-((2,6-Diisopropylphenyl)carbamoyl)-2-(1,2-dimethylpyrrolidin-2-yl)ethene-1-sulfonamide;

[0177] (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;

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

[0179] Sodium (R,E)-((2-(1,2-Dimethylpyrrolidin-2-yl)vinyl)sulfonyl)((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)amide;

[0180] (S,E)-2-(2-(N-((2,6-Diisopropylphenyl)carbamoyl)sulfamoyl)vinyl)-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester;

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

[0182] (S,E)-N-((2,6-Diisopropylphenyl)carbamoyl)-2-(1,2-dimethylpyrrolidin-2-yl)ethene-1-sulfonamide;

[0183] (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;

[0184] (S,E)-2-(2-(N-((4-Fluoro-2,6-diisopropylphenyl)carbamoyl)sulfamoyl)vinyl)-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester;

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

[0186] (S,E)-2-(1,2-Dimethylpyrrolidin-2-yl)-N-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)ethene-1-sulfonamide;

[0187] (E)-2-(1-Acetylazetidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide;

[0188] (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;

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

[0190] (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;

[0191] (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;

[0192] (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;

[0193] 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;

[0194] (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;

[0195] (E)-2-(1-(cyclopropylsulfonyl)azetidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide;

[0196] (S,E)-N-((2,6-diisopropylphenyl)carbamoyl)-2-(1-(thiazol-2-yl)pyrrolidin-2-yl)ethene-1-sulfonamide;

[0197] (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;

[0198] Potassium (R,E)-((2-(1,2-dimethylpyrrolidin-2-yl)vinyl)sulfonyl)((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)amide;

[0199] (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;

[0200] (S,E)-2-(1-(Cyclohexylmethyl)-2-methylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)vinyl-1-sulfonamide;

[0201] 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;

[0202] Sodium (R,E)-((2-(1-Cyclohexylpyrrolidin-2-yl)vinyl)sulfonyl)((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)amide;

[0203] Sodium (S,E)-((2,6-Diisopropylphenyl)carbamoyl)((2-(1,2-dimethylpyrrolidin-2-yl)vinyl)sulfonyl)amide;

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

[0205] Potassium (R,E)-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)((2-(1-methylpyrrolidin-2-yl)vinyl)sulfonyl)amide;

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

[0207] Sodium (S,E)-((2-(1-Ethylpyrrolidin-2-yl)vinyl)sulfonyl)((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)amide;

[0208] (S,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(2-hydroxyethyl)pyrrolidin-2-yl)vinyl-1-sulfonamide;

[0209] (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;

[0210] (E)-2-(1,2-Dimethylazetidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide;

[0211] (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;

[0212] (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;

[0213] (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;

[0214] (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;

[0215] (S,E)-2-(1,2-Dimethylpyrrolidin-2-yl)-N-((1,2,3,6,7,8-hexahydro-as-indacen-4-yl)carbamoyl)ethene-1-sulfonamide;

[0216] (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;

[0217] (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;

[0218] (R,E)-2-(1,2-Dimethylpyrrolidin-2-yl)-N-((1,2,3,6,7,8-hexahydro-as-indacen-4-yl)carbamoyl)ethene-1-sulfonamide;

[0219] (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;

[0220] (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;

[0221] (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;

[0222] (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;

[0223] (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;

[0224] (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;

[0225] (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;

[0226] (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;

[0227] (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;

[0228] (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;

[0229] (R,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(2-sulfamoylethyl)pyrrolidin-2-yl)ethene-1-sulfonamide;

[0230] (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;

[0231] (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;

[0232] or a pharmaceutically acceptable salt of any of the above compounds.

[0233] The following is a list of abbreviations used in the description of the preparation of the compounds of the present invention:

[0234] μg: microgram

[0235] 1 H NMR: proton nuclear magnetic resonance

[0236] bs: broad singlet

[0237] CDC1 3 : deuterochloroform

[0238] CHC1 3 : chloroform

[0239] d: doublet

[0240] DAMP: damage-associated molecular pattern;

[0241] DCM: dichloromethane

[0242] dd: double doublet

[0243] DMAC: N,N-(dimethylacetamide)

[0244] DMAP: 4-(dimethylamino)pyridine

[0245] DMF: N,N-dimethylformamide

[0246] DMSO: dimethyl sulfoxide

[0247] dt: Double triplet

[0248] EDTA: Ethylenediaminetetraacetic acid

[0249] EtOAc: Ethyl acetate

[0250] EtOH: Ethanol

[0251] HCl(g): Hydrogen chloride (gas)

[0252] IL1β: Interleukin 1β

[0253] K2CO3: Potassium carbonate

[0254] LPS: Lipopolysaccharide

[0255] m: Multiplet

[0256] MeOH: Methanol

[0257] mmol: Millimole

[0258] MS: Mass spectrometry

[0259] N 2 : Nitrogen

[0260] Na 2 CO 3 : Sodium carbonate

[0261] ng: Nanogram

[0262] NIS: N-Iodosuccinimide

[0263] NLRP3: NOD-like receptor family, pyrin domain-containing protein 3

[0264] PAMP: Pathogen-associated molecular pattern;

[0265] PMA: Phorbol 12-myristate 13-acetate

[0266] POCI 3 : Phosphoryl chloride

[0267] RM: Reaction mixture

[0268] R.T; r.t: Room temperature

[0269] s: Singlet

[0270] t: Triplet

[0271] td: Triple doublet

[0272] THF: Tetrahydrofuran

[0273] TLC: Thin Layer Chromatography

[0274] TLR: Toll-like receptor.

[0275] TNFα: Tumor Necrosis Factor α

[0276] General preparation methods

[0277] The novel 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.

[0278] The reactions can be carried out in a solvent appropriate for the reagents and materials used and suitable for the transformation affected. Preferred methods include, but are not limited to, those described below, where all symbols are as defined above unless otherwise defined below.

[0279] 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.

[0280] Scheme 1

[0281]

[0282] Scheme 2

[0283]

[0284] Scheme 3

[0285]

[0286] wherein A, B, R 1 、R 2 、R 3 and R 4Each of the foregoing is as previously defined. 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.

[0287] 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.

[0288] The present invention is further illustrated by the following non - limiting examples that describe some preferred embodiments of the invention. The provision of these does not limit the scope of the invention in any way.

[0289] Those given in the examples 1 1H NMR spectral data (see below) were recorded using a 400 MHz spectrometer (Bruker AVANCE - 400) and reported on the δ scale. Unless otherwise stated, the solvent used for NMR was CDCl with TMS as the internal standard. 3 .

[0290] According to one feature of the present invention, there is provided the general structure of the intermediate of formula (5),

[0291]

[0292] wherein all symbols are as previously defined.

[0293] In another embodiment, there is provided the general structure of the intermediate of formula (6)

[0294]

[0295] wherein all symbols are as previously defined.

[0296] In another embodiment, there is provided the general structure of the intermediate of formula (15)

[0297]

[0298] wherein all symbols are as previously defined.

[0299] In another embodiment, a general structure of the intermediate of formula (16) is provided

[0300]

[0301] wherein all symbols are as defined above

[0302] In yet another embodiment, methods for preparing the intermediates of formulas (5), (6), (15) and (16) according to Schemes 1 and 3 disclosed in the specification are provided

[0303] Intermediate-1a: Preparation of (R,E)-2-(2-(N-(tert-butoxycarbonyl)-sulfamoyl)vinyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0304]

[0305] A 500 mL, three-necked, round-bottom 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)sulfamoyl carbamate (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)-2-formylpyrrolidine-1-carboxylic acid tert-butyl ester (Org. Lett. 2008, 10, 4, 3045 - 3048) (6.05 g, 30.3 mmol) in DMF (50 mL) was added dropwise over a 1-hour period 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)-2-(2-(N-(tert-butoxycarbonyl)sulfamoyl)vinyl)pyrrolidine-1-carboxylic acid tert-butyl ester (4.6 g, 12.22 mmol, 48% yield).

[0306] 1 H NMR (400 MHz, DMSO-d 6 ): 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 (br s, 1H), 1.79 - 1.71 (m, 3H), 1.44 - 1.35 (m, 18H); MS (ESI): m / z (%) = 375.30 (100%) (M - H)-.

[0307] Intermediate-1b: Preparation of tert-Butyl (S,E)-2-(2-(N-(tert-Butoxycarbonyl)sulfamoyl)vinyl)pyrrolidine-1-carboxylate

[0308]

[0309] Intermediate-1b was also prepared using (S)-2-Formylpyrrolidine-1-carboxylic acid tert-butyl ester according to the procedure described for the synthesis of Intermediate-1a.

[0310] Intermediate-2a: Preparation of tert-Butyl (R,E)-2-(2-Sulfamoylvinyl)pyrrolidine-1-carboxylate

[0311]

[0312] Compound [Intermediate 1a] (18 g) was dissolved in DMSO (180 mL) and heated to 85 °C (monitored by TLC for the disappearance of starting material). The reaction was cooled, poured into water (900 mL) and extracted with EtOAc (3 × 300 mL). The solvent was concentrated in vacuo and purified by column chromatography on silica gel (50% EtOAc: n-Hexane) to give the product tert-Butyl (R,E)-2-(2-Sulfamoylvinyl)pyrrolidine-1-carboxylate (14.3 g, 53.7 mmol, 67% yield).

[0313] 1 H NMR (400 MHz, DMSO-d 6 ): δ = 6.99 (s, 2H), 6.40 - 6.38 (m, 1H), 6.34 - 6.30 (m, 1H), 4.40 - 4.32 (m, 2H), 3.28 - 3.25 (m, 1H), 2.21 - 1.99 (m, 1H), 1.81 - 1.67 (m, 3H), 1.38 (m, 9H); MS (ESI): m / z (%) = 299.09 (50%) (M+Na) + , 275.09 (100%) (M-1).

[0314] Intermediate-2b: Preparation of tert-Butyl (S,E)-2-(2-Sulfamoylvinyl)pyrrolidine-1-carboxylate

[0315]

[0316] Intermediate-2b was also prepared using Intermediate 1b according to the procedure described for the synthesis of Intermediate-2a.

[0317] Intermediate-2c:(R,Z)-tert-Butyl 2-(2-sulfamoylvinyl)pyrrolidine-1-carboxylate Preparation

[0318]

[0319] Intermediate-2c was also obtained according to the procedure for synthesizing Intermediate-2a as described.

[0320] 1 H NMR(400MHz, DMSO-d 6 ): δ = 7.06(s, 2H), 6.22(d, J = 12Hz, 1H), (dd, J = 12Hz, J = 11.2Hz, 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) + .

[0321] Intermediate-2d: (S,Z)-tert-Butyl 2-(2-sulfamoylvinyl)pyrrolidine-1-carboxylate Preparation

[0322]

[0323] Intermediate-2d was also obtained according to the procedure for synthesizing Intermediate-2b as described.

[0324] Intermediate-3a (Example 10): (R,E)-tert-Butyl 2-(2-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-vinyl)pyrrolidine-1-carboxylate Preparation

[0325]

[0326] 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 in portions 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 solution, diluted with water (1500 mL), the precipitate was filtered and dried to give the product (38 g, 80 mmol, 100% yield).

[0327] 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).

[0328] Intermediate-3b (Example 61): (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 preparation

[0329]

[0330] Intermediate - 3b was also prepared according to the procedure for synthesizing Intermediate - 2b as described.

[0331] 1 1H NMR (400 MHz, DMSO): δ = 10.42 (bs, 1H), 8.09 (s, 1H), 6.96 (s, 1H), 6.71 - 6.67 (m, 1H), 6.6116.57 (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) + .

[0332] Intermediate-4a: (R)-2-Formyl-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester preparation

[0333]

[0334] 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 Na2SO 4 to obtain the product (83 g, 389 mmol, 97% yield).

[0335] 1 H NMR (400 MHz, DMSO-d 6 6): δ = 9.28 (m, 1H), 3.64 - 3.41 (m, 2H), 1.97 - 1.85 (m, 2H), 1.70 - 1.50 (m, 2H), 1.38 - 1.28 (m, 12H), rotamers: MS (ES1): m / z (%) = 214.3 (100%) (M + H) + .

[0336] Intermediate-4b: Preparation of (S)-2-formyl-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester

[0337]

[0338] Intermediate-4b was also prepared following the procedure described for the synthesis of Intermediate-4a using 1-(tert-butyl) 2-methyl (S)-2-methylpyrrolidine-1,2-dicarboxylate.

[0339] Intermediate-5a: Preparation of (R,E)-2-(2-(N-(tert-butoxycarbonyl)aminosulfonyl)vinyl)-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester

[0340]

[0341] NaH (60% dispersion in mineral oil) (34 gm, 851 mmol) was added to a solution of tert-butyl (((diphenylphosphoryl)methyl)sulfonyl)carbamate (153.0 gm, 387 mmol) in DMF (1530 mL) at 0 °C. The reaction was warmed to room temperature and stirred for 30 minutes. Aldehyde ((R)-tert-butyl 2-formyl-2-methylpyrrolidine-1-carboxylate) (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 with 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 Na 2 SO 4 dried, 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).

[0342] 1 1H NMR (400 MHz, DMSO-d 6 ) : 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),

[0343] 1.49 - 1.36 (m, 21H); MS (ESI) : m / z (%) = 413.15 (90%) (M+Na), 389.15 (100%) (M-1).

[0344] Intermediate-5b: Preparation of (S,E)-2-(2-(N-(tert-butoxycarbonyl)sulfamoyl)vinyl)-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester

[0345]

[0346] Intermediate-5b was also prepared following the procedure described for the synthesis of Intermediate-5a using (S)-tert-butyl 2-formyl-2-methylpyrrolidine-1-carboxylate.

[0347] Intermediate-6a: Preparation of (R,E)-tert-butyl 2-methyl-2-(2-sulfamoylvinyl)pyrrolidine-1-carboxylate

[0348]

[0349] Dissolve intermediate 5a (121 g) in DMSO (1200 mL) and heat to 85 °C (monitor the disappearance of the starting material by TLC). Cool the reaction, pour into water (3000 mL) and extract with EtOAc (2000 mL × 4) and dry with Na 2 SO 4 Dry. Concentrate the solvent in vacuo and purify by column chromatography on silica gel (50% EtOAc: n-hexane) to give the product (61.4 g, 211 mmol, 68.2% yield).

[0350] 1 1H NMR (400 MHz, DMSO-d 6 ) : δ = 6.98 (s, 2H), 6.61 - 6.49 (m, 1H), 6.25 (d, J = 15.2 Hz, 1H), 3.43 - 335 (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).

[0351] Intermediate-6b: Preparation of (S,E)-2-methyl-2-(2-sulfamoylethyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0352]

[0353] Intermediate-6b was also prepared using intermediate-5b according to the procedure described for the synthesis of intermediate-6a.

[0354] Intermediate-7a (Example 52): Preparation of (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

[0355]

[0356] 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).

[0357] 1 H NMR (400 MHz, DMSO-d 6 ): 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).

[0358] Intermediate-7b (Example 111): Preparation of (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

[0359]

[0360] Intermediate-7b (Example 111) was also synthesized according to the procedure for preparing Intermediate-7a using Intermediate-6b.

[0361] Intermediate-8: Preparation of (Diphenylphosphoryl)methanesulfonamide

[0362]

[0363] In N 2Under an atmosphere, dissolve tert-butyl (((diphenylphosphoryl)methyl)sulfonyl)carbamate (Synthesis 2003, 15, 2321 - 24) (10.0 g, 25.3 mmol) in DCM (100 mL). Cool it to 0 °C and add TFA (19.48 mL, 253 mmol) dropwise. After removing the added ice bath, stir the reaction mixture for 4 hours. 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 with P2O5 to give (diphenylphosphoryl)methanesulfonamide (7.3 g, 24.72 mmol, 98% yield).

[0364] NMR (400 MHz, DMSO-d 6 ): δ = 7.86 - 7.81 (m, 4H), 7.61 - 7.51 (m, 6H), 6.84 (s, 2H), 4.63 (d, J = 9.2 Hz, 2H); MS (ESI): m / z (%) = 296.05 (100%) (M + H) + .

[0365] Intermediate-9: Preparation of 1-(diphenylphosphoryl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)methanesulfonamide

[0366]

[0367] Under an N 2 atmosphere, introduce (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 at room temperature for 30 minutes. 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 further stir the reaction mixture at room temperature for 17 hours. 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).

[0368] 1 H NMR (400 MHz, DMSO-d 6δ = 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(ESI): m / z(%) 495.14 (100%)(M + H) + .

[0369] Intermediate-7b (Example 111): Preparation of tert - butyl (S,E)-2-(2-(N-((1,2,3,5,6,7 - hexahydro - s - indacen - 4 - yl)carbamoyl)sulfamoyl)vinyl)-2 - methylpyrrolidine - 1 - carboxylate

[0370]

[0371] 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 tert - butyl (S)-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 citric acid solution, a solid precipitated, the solid was filtered out and washed with water (15 mL), and dried with P 2 O 5 The crude product was purified by column chromatography using 40% EtOAc:hexane to give tert - butyl (S,E)-2-(2-(N-((1,2,3,5,6,7 - hexahydro - s - indacen - 4 - yl)carbamoyl)sulfamoyl)vinyl)-2 - methylpyrrolidine - 1 - carboxylate (0.125 g, 0.255 mmol, 25.3% yield).

[0372] Intermediate-7a (Example 52) was also prepared according to the procedure for synthesizing Intermediate - 7b (Example 111) using (R)-2 - formyl - 2 - methylpyrrolidine - 1 - carboxylate tert - butyl ester.

[0373] Intermediate-3a(Example 10) was also prepared using tert-butyl (R)-2-formylpyrrolidine-1-carboxylate according to the procedure for synthesizing Intermediate-7b as described.

[0374] Intermediate-3b (Example 61) was also prepared using tert-butyl (S)-2-formylpyrrolidine-1-carboxylate according to the procedure for synthesizing Intermediate-7b as described.

[0375] Intermediate-10a: Preparation of tert-butyl 2-formylazetidine-1-carboxylate

[0376]

[0377] 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 gm, 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), and dried over Na2SO 4 and the solvent was evaporated to obtain the product tert-butyl 2-formylazetidine-1-carboxylate (3.4 gm, 18.36 mmol, 93% yield).

[0378] Intermediate-10b: Preparation of tert-butyl 2-formyl-2-methylazetidine-1-carboxylate

[0379]

[0380] 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.

[0381] Intermediate-11a: Preparation of tert-butyl (E)-2-(2-(N-(tert-butoxycarbonyl)sulfamoyl)vinyl)azetidine-1-carboxylate

[0382]

[0383] 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 with 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 Na2SO 4 dried, 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).

[0384] 1 1H NMR (400 MHz, DMSO-d 6 6): δ = 11.36 (s, 1H), 6.86 (d, J = 15.2 Hz, J = 5.6 Hz, 1H), 6.65 (d, J = 14.8 Hz, 1H), 4.88 - 4.83 (m, 1H), 3.84 - 3.72 (m, 2H), 2.46 - 2.40 (m, 1H), 2.02 - 1.96 (m, 1H), 1.44 (s, 9H), 1.41 (s, 9H); MS (TOF): m / z (%) = 385.2035 (100%) (M+Na), 361.1853 (100%) (M-1).

[0385] Intermediate-11: (E)-2-(2-Sulfamoylvinyl)azetidine-1-carboxylic acid tert-butyl ester Preparation of tert-butyl

[0386]

[0387] tert-Butyl (E)-2-(2-(N-(tert-butoxycarbonyl)sulfamoyl)vinyl)azetidine-1-carboxylate (Intermediate 11a) (1.8 g, 4.97 mmol) was dissolved in DMSO (18 mL) and heated to 85 °C (monitored by TLC for disappearance of starting material). The reaction was cooled, poured into water (90 mL) and extracted with EtOAc (40 ml × 4) and washed with Na2 SO 4 Dry. The solvent was concentrated in vacuo and purified by column chromatography (60% EtOAc: n - hexane) on silica gel to afford tert - butyl (E) - 2 - (2 - sulfamoylvinyl)azetidine - 1 - carboxylate (2.02 g, 3.74 mmol, 83% yield).

[0388] 1 H NMR (400 MHz, DMSO - d 6 ): 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).

[0389] Intermediate-12a: Preparation of tert - butyl (E) - 2 - (2 - (N - (tert - butoxycarbonyl)sulfamoyl)vinyl) - 2 - methylazetidine - 1 - carboxylate

[0390]

[0391] To a solution of tert - butyl (((diphenylphosphoryl)methyl)sulfonyl)carbamate (4.5 g, 11.38 mmol) in DMF (45 mL) was added NaH (60% dispersion in mineral oil) (1.00 g, 25.04 mmol) at 0 °C. The reaction was warmed to room temperature and stirred for 30 min. 2 - Formyl - 2 - methylazetidine - 1 - carboxylate (Journal of Medicinal Chemistry, 2014, 57(23), 10044 - 10057) (2.72 g, 13.66 mmol) in DMF (30 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 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), and dried over Na 2 SO 4Dry, concentrate and dry to obtain the crude product. Purify the residue by column chromatography on silica gel using 30% EtOAC: n-hexane to obtain tert-butyl (E)-2-(2-(N-(tert-butoxycarbonyl)sulfamoyl)vinyl)-2-methylazetidine-1-carboxylate (3.73 g, 9.91 mmol, 87% yield).

[0392] 1 H NMR (400 MHz, DMSO-d 6 ): 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).

[0393] Intermediate-12: Preparation of tert-butyl (E)-2-methyl-2-(2-sulfamoylvinyl)azetidine-1-carboxylate

[0394]

[0395] 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 with Na 2 SO 4 Dry. Concentrate the solvent in vacuo and purify by column chromatography on silica gel (60% EtOAc: n-hexane) to obtain tert-butyl (E)-2-methyl-2-(2-sulfamoylvinyl)azetidine-1-carboxylate (2.52 g, 9.12 mmol, 92% yield).

[0396] 1 H NMR (400 MHz, DMSO-d 6δ = 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).

[0397] Example - 1

[0398] (R,E)-2-(1 - ethylpyrrolidin - 2 - yl)-N-((1,2,3,5,6,7 - hexahydro - s - indacen - 4 - yl)carbamoyl)-ethanesulfonamide

[0399]

[0400] At 0 °C, TFA (1 equivalent) was added to a solution of intermediate 3a (1 equivalent) in DCM (2.5 mL). The reaction was warmed to room temperature and further stirred for 3 hours. The reaction mixture was concentrated in vacuo and purified by preparative HPLC to obtain the product. At room temperature, NaHCO 3 (1.2 equivalents) was added to a solution of the product (1 equivalent) in MeOH (7.0 mL) and stirred for 5 minutes. Acetaldehyde (5 equivalents) was added at room temperature and stirred for 2 hours. Thereafter, the reaction mixture was treated portionwise with NaBH 4 (1.5 equivalents) at 0 °C, then the reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was purified by preparative HPLC to obtain the pure product (Example 1).

[0401] Alternatively: At 0 °C, TFA (1 equivalent) was added to a solution of intermediate 3 (1 equivalent) in DCM (2.5 mL). The reaction was warmed to room temperature and further stirred for 3 hours. The reaction mixture was concentrated in vacuo and purified by preparative HPLC to obtain the product. At 0 °C, NaH (1.2 equivalents) was added to a solution of the product (1 equivalent) in anhydrous THF (5.0 mL) and stirred for 5 minutes. Ethyl bromide (1.6 equivalents) was added and stirred at room temperature for 14 hours. The reaction mixture was purified by preparative HPLC to obtain the pure product (Example 1).

[0402] 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 the mixture was stirred at room temperature for 1 hour. DCM was distilled off and to the reaction mixture at 0 °C was added an excess of trimethylamine (5.23 g, 7.2 mL, 53.1 mmol), followed by addition of 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 a nitrogen atmosphere, 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 portionwise sodium hydride (60% in mineral oil) (0.5 g, 12.39 mmol). The resulting suspension was further stirred at room temperature for 1 hour. 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 hours. 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).

[0403] 1 H NMR(400MHz, DMSO-d 6 ): 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) + .

[0404] 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.

[0405] Example - 2

[0406] (S,E)-2-(1-ethylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-ethanesulfonamide

[0407]

[0408] 1 H NMR (400 MHz, DMSO-d 6 ):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) + .

[0409] Example - 3

[0410] (R, E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(pyrrolidin-2-yl)ethene-1-sulfonamide

[0411]

[0412] 1 H NMR (400 MHz, DMSO-d 6 ):δ = 9.71 (brs, 1H), 7.49 (s, 1H), 6.95 (d, J = 15.2 Hz, 1H), 6.80 (s, 1H), 6.36 (dd, J = 7.2 Hz, J = 15.2 Hz, 1H), 4.08 - 4.02 (m, 1H), 3.18 - 3.03 (m, 2H), 2.77 (t, J = 7.2 Hz, 4H), 2.70 (t, J = 7.2 Hz, 4H), 2.14 - 2.07 (m, 4H), 2.03 - 1.80 (m, 6H), 1.70 - 1.60 (m, 1H); MS (ESI): m / z (%) = 376.10 (100%) (M + H) + , 374.05 (100%) (M - 1).

[0413] Example - 4

[0414] (R, E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-propylpyrrolidin-2-yl)ethene-1-sulfonamide

[0415]

[0416] 1 1H NMR (400 MHz, DMSO-d 6 6): δ = 8.00 (s, 1H), 6.93 (s, 1H), 6.84 (d, J = 14.8 Hz, 1H), 6.58 (dd, J = 7.6 Hz, J = 15.2 Hz, 1H), 3.15 (s, 1H), 2.80 (t, J = 7.2 Hz, 4H), 2.67 (t, J = 7.2 Hz, 4H), 2.33 - 2.22 (m, 2H), 2.09 - 1.91 (m, 6H), 1.78 - 1.73 (m, 2H), 1.62 - 1.50 (m, 1H), 1.46 - 1.33 (m, 2H), 0.82 (t, J = 7.2 Hz, 3H); MS (ESI): m / z (%) = 418.22 (100%) (M + H) + .

[0417] Example - 5

[0418] (R,E)-2-(1-(Cyclopropylmethyl)pyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide

[0419]

[0420] 1 1H NMR (400 MHz, DMSO-d 6 6): 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).

[0421] Example - 6

[0422] (R,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-methylpyrrolidin-2-yl)ethene-1-sulfonamide

[0423]

[0424] 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 give the product. Solid NaHCO 3 (1.2 equiv) was added to a solution of this product (1 equiv) in MeOH (7.0 mL) 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 NaBH 4 (1.5 equiv) at 0 °C, then the reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was purified by preparative HPLC to give the pure product.

[0425] Alternatively, Example 6 was also prepared using intermediate 9 and (R)-1-methylpyrrolidine-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).

[0426] 1 H NMR (400 MHz, DMSO-d 6 6): 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)

[0427] Example - 7

[0428] (R,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(methylsulfonyl)-pyrrolidin-2-yl)ethene-1-sulfonamide

[0429]

[0430] 1 H NMR (400 MHz, DMSO-d 6 ): 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), 2.11H2.07 (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) + .

[0431] Example - 8

[0432] (R,E)-2-(1-Acetylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide

[0433]

[0434] 1 H NMR (400 MHz, DMSO-d 6 ): 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) + .

[0435] Example - 9

[0436] (E)-2-(1-Benzylpiperidin-4-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethanesulfonamide

[0437]

[0438] 1 1H NMR (400 MHz, DMSO-d 6 ):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) + .

[0439] Example - 10

[0440] (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

[0441]

[0442] 1H NMR (400 MHz, DMSO-d6): δ = 1042 (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).

[0443] Example - 11

[0444] (R,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(2-methoxyethyl)pyrrolidin-2-yl)ethenesulfonamide

[0445]

[0446] 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)+.

[0447] Example - 12

[0448]

[0449] (R,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(isopropylsulfonyl)pyrrolidin-2-yl)ethenesulfonamide

[0450] 1 1H NMR(400MHz, DMSO-d 6 ): 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) + ;

[0451] Example - 13

[0452] (R,E)-2-(1-((3-Fluorophenyl)sulfonyl)pyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethenesulfonamide

[0453]

[0454] 1 H NMR (400 MHz, DMSO-d 6 );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, J 1 = 5.6 Hz, J 2 = 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 (ES1) m / z (%) = 534.18 (100%) (M + H) + ;

[0455] Example - 14

[0456] (R,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(pyrazine-2-carbonyl)pyrrolidin-2-yl)ethenesulfonamide

[0457]

[0458] 1 H NMR (400 MHz, DMSO-d 6 ):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) + .

[0459] Example - 15

[0460] (R,E)-2-(2-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)pyrrolidine-1-carboxamide

[0461]

[0462] 1 H NMR(400MHz, DMSO-d 6 ): 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), 325 - 3.21(m, 1H), 2.80(t, J = 7, 2Hz, 4H), 2.68(t, J = 6.8Hz, 4H), 2.00 - 1.91(m, 6H), 1.81 - 1.69(m, 3H); MS(ESI): m / z(%) = 419.16(100%)(M + H) + .

[0463] Example 16

[0464] (R,E)-2-(1-(Cyclopropanecarbonyl)pyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide

[0465]

[0466] 1 H NMR(400MHz, DMSO-d 6 ): δ = 10.45(s, 1H), 8.11(d, J = 14.4Hz, 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 = 7.2Hz, 4H), 2.67(q, J = 6.0Hz, 4H), 2.17 - 216(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) + .

[0467] Example - 17

[0468] (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

[0469]

[0470] 1 H NMR(400MHz, DMSO-d 6 ): 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 = 7.6Hz, 4H), 2.67(t, J = 6.4Hz, 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) + .

[0471] Example - 18

[0472] (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

[0473]

[0474] 1 H NMR(400MHz, DMSO-d 6 ): δ = 10.38(s, 1H), 8.06(s, 1H), 6.95(s, 1H), 6.91(d, J = 14.8Hz, 1H), 6.68(d, J = 15.2Hz, 1H), 3.21 - 3.12(m, 2H), 2.81(t, J = 7.2Hz, 5H), 2.68(t, J = 7.2Hz, 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) + .

[0475] Example - 19

[0476] (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

[0477]

[0478] 1 H NMR(400MHz, DMSO-d 6 ): δ = 7.91(s, 1H), 6.88(s, 1H), 6.76(d, J = 15.2Hz, 1H), 6.41(dd, J 1 = 7.2Hz, J 2 , 14.8, 1H), 3.34 - 3.21(m, 1H), 3.16 - 3.09(m, 2H), 2.78(t, J = 7.2Hz, 4H), 2.67(t, J = 7.2Hz, 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) + .

[0479] Example - 20

[0480] (R,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-isobutylpyrrolidin-2-yl)ethene-1-sulfonamide

[0481]

[0482] 1 H NMR(400MHz, DMSO-d 6 ): δ = 10.4(brs, 1H), 8.00(s, 1H), 6.92(s, 1H), 6.80(d, J = 15.2Hz, 1H), 6.56(dd, J = 15.2Hz, J = 6.8Hz, 1H), 3.12 - 3.00(m, 3H), 2.80(t, J = 7.2Hz, 4H), 2.68(t, J = 7.2Hz, 4H), 2.25 - 2.14(m, 2H), 2.10 - 204(m, 2H), 1.99 - 1.91(m, 4H), 1.76 - 1.65(m, 2H), 1.55 - 1.48(m, 1H), 0.85(t, J = 6.8Hz, 3H), 0.79(d, J = 6.4Hz, 3H); MS(ES1): m / z(%) = 432.21(100%)(M + H) + .

[0483] Example - 21

[0484] (R,E)-2-(1-(ethylsulfonyl)pyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide

[0485]

[0486] 1 H NMR(400MHz, DMSO-d 6 ): δ = 10.39(brs, 1H), 8.01(s, 1H), 7.38(s, 1H), 6.77(d, J = 15.2Hz, 1H), 6.68(dd, J = 15.2Hz, J = 5.2Hz, 1H), 4.63 - 4.39(m, 1H), 3.38 - 3.33(m, 2H), 3.09 - 2.97(m, 2H), 2.80(t, J = 7.2Hz, 4H), 2.68(t, J = 7.2Hz, 4H), 2.15 - 2.04(m, 1H), 2.00 - 1.91(m, 4H), 1.88 - 1.77(m, 3H), 1.19(t, J = 72Hz, 3H); MS(ESI): m / z(%) = 468.12(100%)(M + H) + .

[0487] Example - 22

[0488] (R,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-isopropylpyrrolidin-2-yl)ethene-1-sulfonamide

[0489]

[0490] 1 H NMR(400MHz, DMSO-d 6):δ = 10.23 (brs, 1H), 7.96 (s, 1H), 6.92 (s, 1H), 6.89 (d, J = 15.2 Hz, 1H), 6.61 (d, J = 15.2 Hz, J = 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).

[0491] Example - 23

[0492] (R,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(3-(methylsulfonyl)propyl)pyrrolidin-2-yl)ethenesulfonamide

[0493]

[0494] 1 H NMR(400 MHz, DMSO-d 6 ): 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).

[0495] Example - 24

[0496] (R,E)-2-(1-Benzoylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethenesulfonamide

[0497]

[0498] 1 H NMR(400 MHz, DMSO-d 6 ):δ = 10.41 (brs, 1H), 8.03 (s, 1H), 7.54 - 7.30 (m, 5H), 6.93 (s, 1H), 6.80 - 6.50 (m, 2H), 4.85 - 4.49 (m, 1H), 3.62 - 3.36 (m, 2H), 2.78 (t, J = 6.8 Hz, 4H), 2.66 (t, J = 6.8 Hz, 4H), 2.19 - 2.08 (m, 1H), 1.94 - 1.90 (m, 4H), 1.82 - 1.76 (m, 3H); MS(ESI): m / z(%) = 480.17 (100%)(M + H) + , 478.15 (100%)(M - 1).

[0499] Example - 25

[0500] (R,E)-N-((2-(1-Benzoylpyrrolidin-2-yl)vinyl)sulfonyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)benzamide

[0501]

[0502] 1 H NMR(400 MHz, DMSO-d 6 ):δ = 7.61 - 7.52 (m, 2H), 7.47 - 7.32 (m, 8H), 7.22 - 7.09 (m, 1H), 6.97 (s, 1H), 6.56 (d, J = 14.4 Hz, 1H), 6.31 (d, J = 14.4 Hz, 1H), 4.76 - 4.37 (m, 1H), 3.78 - 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).

[0503] Example - 26

[0504] (R,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(pyrrolidin-2-yl)ethenesulfonamide

[0505]

[0506] 1 H NMR(400MHz, DMSO-d 6 ): 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).

[0507] Example - 27

[0508] (R,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(thiophene-3-carbonyl)pyrrolidin-2-yl)ethenesulfonamide

[0509]

[0510] 1 H NMR(400MHz, DMSO-d 6 ): 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), 378 - 3.67(m, 1H), 3.66 - 352(m, 1H), 2.79(t, J = 72Hz, 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).

[0511] Example - 28

[0512] (R,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(pyrrolidin-2-yl)vinyl-1-sulfonamide mesylate

[0513]

[0514] 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 give the product.

[0515] 1 H NMR (400 MHz, DMSO-d 6 ): 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) + .

[0516] Example - 29

[0517] (R,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(pyrrolidin-2-yl)vinyl-1-sulfonamide maleate

[0518]

[0519] 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 give the product.

[0520] 1 1H NMR (400 MHz, DMSO-d 6 6): 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) + .

[0521] Example - 30

[0522] (R,Z)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(pyrrolidin-2-yl)ethene-1-sulfonamide

[0523]

[0524] 1 1H NMR (400 MHz, DMSO-d 6 6): 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) + .

[0525] Example - 31

[0526] (S,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-3-(pyrrolidin-2-yl)prop-1-ene-1-sulfonamide

[0527]

[0528] 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 for a further 3 h. The reaction mixture was concentrated in vacuo and purified by preparative HPLC to give the product.

[0529] 1 1H NMR (400 MHz, DMSO-d 6 6): 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 - 344 (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) + .

[0530] Example - 32

[0531] (R,E)-2-(1-(Cyclohexylsulfonyl)pyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide

[0532]

[0533] 1 1H NMR (400 MHz, DMSO-d 6 6): 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).

[0534] Example - 33

[0535] (R,Z)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-methylpyrrolidin-2-yl)ethene-1-sulfonamide

[0536]

[0537] 1 H NMR(400MHz, DMSO-d 6 ): 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), 233 - 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).

[0538] Example - 34

[0539] (R,E)-2-(1-(Cyclohexylmethyl)pyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide

[0540]

[0541] 1 H NMR(400MHz, DMSO-d 6):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) + .

[0542] Example - 35

[0543] (R,E)-2-(1-Cyclohexylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide

[0544]

[0545] 1 H NMR(400 MHz, DMSO-d 6 ):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) + .

[0546] Example - 36

[0547] (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

[0548]

[0549] 1 H NMR (400 MHz, DMSO-d 6 ):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), 1.05 - 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) + 。

[0550] Example - 37

[0551] (R,Z)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-isopropylpyrrolidin-2-yl)ethene-1-sulfonamide

[0552]

[0553] 1 H NMR (400 MHz, DMSO-d 6 ):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, = 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).

[0554] Example - 38

[0555] (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

[0556]

[0557] 1 H NMR(400MHz, DMSO-d 6 ): 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) + .

[0558] Example - 39

[0559] (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

[0560]

[0561] 1 H NMR(400MHz, DMSO-d 6δ = 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) + .

[0562] Example - 40

[0563] (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

[0564]

[0565] 1 H NMR(400 MHz, DMSO-d 6 ):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) + .

[0566] Example - 41

[0567] (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

[0568]

[0569] 1 H NMR(400MHz, DMSO-d 6 ): 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) +

[0570] Example - 42

[0571] (E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(piperidin-4-yl)ethene sulfonamide

[0572]

[0573] 1 H NMR(400MHz, DMSO-d 6 ): ε = 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) + .

[0574] Example - 43

[0575] (E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-methylpiperidin-4-yl)ethenesulfonamide

[0576]

[0577] 1 H NMR(400MHz, DMSO-d 6 ): δ = 7.80(s, 1H), 6.86(s, 1H), 6.64(s, 1H), 6.60(d, J = 16.4Hz, 1H), 6.48(dd, J 1 = 6.0Hz, J 2 = 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) + .

[0578] Example - 44

[0579] (E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(methylsulfonyl)piperidin-4-yl)ethenesulfonamide

[0580]

[0581] 1 H NMR(400MHz, DMSO-d 6 ): 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) + .

[0582] Example - 45

[0583] (E)-2-(1-Acetylpiperidin-4-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)vinyl-sulfonamide

[0584]

[0585] 1 H NMR(400MHz, DMSO-d 6 ): δ = 10.38(bs, 1H), 8.04(s, 1H), 6.94(s, 1H), 6.64(dd, J I = 5.6Hz, J 2 = 15.6Hz, 1H), 6.68(d, J = 15.6Hz, 1H), 4.33(d, J = 13.3Hz, 1H), 3.81(d, J = 14.4Hz, 1H), 3.06(t, J = 12.0Hz, 1H), 2.80(t, J = 7.2Hz, 4H), 2.67(t, J = 7.2Hz, 4H), 2.63 - 2.56(m, 2H), 2.00 - 1.91(m, 7H), 1.72(t, J = 15.6Hz, 2H), 1.35 - 1.24(m, 1H), 1.21 - 1.11(m, 1H); MS(ESI): m / z(%) = 432.17(J00%)(M + H) + .

[0586] Example - 46

[0587] (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

[0588]

[0589] 1 H NMR(400MHz, DMSO-d 6 ): δ = 10.37(bs, 1H), 8.05(s, 1H), 6.96(s, 1H), 6.8(dd, J 1 = 6.0Hz, J 2= 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) + .

[0590] Example - 47

[0591] (E)-2-(1 - ethylpiperidin - 4 - yl)-N - ((1,2,3,5,6,7 - hexahydro - s - indacen - 4 - yl)carbamoyl)ethen - 1 - sulfonamide

[0592]

[0593] 1 H NMR(400 MHz, DMSO - d 6 ): δ = 7.87 (s, 1H), 6.94 (s, 1H), 6.65 (d, J = 15.6 Hz, 1H), 6.52 (dd, J 1 = 6.0 Hz, J 2 = 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) - .

[0594] Example - 48

[0595] (R,E)-2-(1 - ethylpyrrolidin - 3 - yl)-N - ((1,2,3,5,6,7 - hexahydro - s - indacen - 4 - yl)carbamoyl)ethenesulfonamide

[0596]

[0597] 1 H NMR(400 MHz, MSO - d 6δ = 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) + .

[0598] Example - 49

[0599] (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

[0600]

[0601] 1 H NMR(400 MHz, DMSO - d 6 ):δ = 7.27 (s, 1H), 6.77 (s, 1H), 6.73 (s, 1H), 6.27 (dd, J 1 = 6.8 Hz, J 2 = 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) + .

[0602] Example - 50

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

[0604]

[0605] 11H NMR (400 MHz, DMSO-d 6 ): δ = 7.41 (s, 1H), 6.78 (s, 1H), 6.64 (d, J = 15.6 Hz, 1H), 6.23 (dd, J 1 = 7.6 Hz, J 2 = 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) + .

[0606] Example - 51

[0607] (R,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-methylpyrrolidin-2-yl)ethene-1-sulfonamide

[0608]

[0609] 1 1H NMR (400 MHz, DMSO-d 6 ) : δ = 7.56 (s, 1H), 6.91 (d, J = 156 Hz, 1H), 6.82 (s, 1H), 6.52 (d, J = 152 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 / Hz (%) = 390.14 (100%) (M + H) + .

[0610] Example - 52

[0611] (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

[0612]

[0613] 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) + .

[0614] Example - 53

[0615] (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

[0616]

[0617] 1 H NMR(400MHz, DMSO - d 6 ):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) + .

[0618] Example - 54

[0619] (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 - bromide

[0620]

[0621] 1 H NMR(400MHz, DMSO - d 6):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) + .

[0622] Example - 55

[0623] (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;

[0624]

[0625] 1 H NMR(400MHz, DMSO-d 6 ): 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) + .

[0626] Example - 56

[0627] (R,E)-2-(1,2-Dimethylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide

[0628]

[0629] 1 H NMR(400MHz, DMSO-d 6):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) + .

[0630] 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.

[0631] Example - 57

[0632] (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

[0633]

[0634] 1 H NMR(400 MHz, DMSO - d 6 ):δ = 8.82 (bs, 1H), 6.96 (s, 1H), 6.92 (d, J = 9.6 Hz, 1H), 6.41 (m, 1H), 3.60 - 3.51 (m, 2H), 3.22 - 3.17 (m, 2H), 2.80 - 2.73 (m, 5H), 2.61 (t, J = 7.2 Hz, 4H), 1.97 - 1.93 (m, 6H), 1.84 - 1.80 (m, 1H), 1.53 (s, 3H), 0.90 (t, J = 6.4 Hz, 3H); MS(ESI): m / z(%) = 418.18 (100%)(M + H) + ;

[0635] Example - 58

[0636] (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

[0637]

[0638] 1 1H NMR (400 MHz, DMSO-d 6 6): δ = 10.39 (s, 1H), 8.06 (s, 1H), 6.94 (s, 1H), 6.75 (d, J = 15.6 Hz, 1H), 6.69 (d, J = 15.6 Hz, 1H), 3.18 - 3.13 (m, 1H), 2.80 (t, J = 7.2 Hz, 5H), 2.67 (t, J = 7.2 Hz, 4H), 2.33 - 2.11 (m, 2H), 1.94 (t, J = 7.2 Hz, 4H), 1.80 - 1.71 (m, 4H), 1.12 (s, 3H), 0.86 - 0.79 (m, 1H), 0.42 (quintet, J = 8.8 Hz, 2H), 0.05 - 0.04 (m, 2H); MS (ESI): m / z (%) = 444.17 (100%) (M + H).

[0639] Example - 59

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

[0641]

[0642] 1 1H 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) + .

[0643] Example - 60

[0644] (S,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-methylpyrrolidin-2-yl)ethenesulfonamide

[0645]

[0646] 11H 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 - 2.31 (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) + .

[0647] Example - 61

[0648] (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

[0649]

[0650] 1 1H 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) + .

[0651] Example - 62

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

[0653]

[0654] 1 1H NMR (400 MHz, DMSO-d 6):δ = 10.32 (bs, 1H), 8.02 (bs, 1H), 6.93 (s, 1H), 6.86 (d, J = 14.8Hz, 1H), 6.64 - 6.50 (m, 1H), 3.50 - 3.20 (m, 3H), 2.80 (t, J = 7.2Hz, 4H), 2.67 (t, J = 7.2Hz, 4H), 2.61 - 2.56 (m, 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) + .

[0655] Example - 63

[0656] (S,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(pyridin-3-ylsulfonyl)pyrrolidin-2-yl)ethenesulfonamide

[0657]

[0658] 1 H NMR(400MHz, DMSO-d 6 ):δ = 10.40 (bs, 1H), 9.02 (d, = 2.0Hz, 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 = 7.2Hz, 4H), 2.69 (t, J = 7.2Hz, 4H), 1.99 - 1.91 (m, 4H), 1.76 - 1.65 (m, 4H); MS(ESI): m / z(%) = 51711 (100%)(M + H) + .

[0659] Example - 64

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

[0661]

[0662] 11H 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) + .

[0663] Example - 65

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

[0665]

[0666] 1 1H NMR (400 MHz, DMSO - d 6 ): 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) + .

[0667] Example - 66

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

[0669]

[0670] 1 1H NMR (400 MHz, DMSO - d 6):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) + .

[0671] Example - 67

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

[0673]

[0674] 1 H NMR(400MHz, DMSO-d 6 ):δ = 7.69 (s, 1H), 7.22 - 7.18 (m, 1H), 7.11 - 7.09 (m, 2H), 6.75 (d, J = 15.2Hz, 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) + .

[0675] Example - 68

[0676] (S,E)-2-(1-Acetylpyrrolidin-2-yl)-N-((2,6-diisopropylphenyl)carbamoyl)ethenesulfonamide

[0677]

[0678] 1 H NMR(400MHz, DMSO-d 6):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) + .

[0679] Example - 69

[0680] (S,E)-2-(1-Acetylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethenesulfonamide

[0681]

[0682] 1 H NMR(400MHz, DMSO-d 6 ):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 = 7.2Hz, 4H), 2.67 (q, J = 7.2Hz, 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) + .

[0683] Example - 70

[0684] (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

[0685]

[0686] 1 H NMR(400MHz, DMSO-d 6):δ=10.40(bs, 1H), 8.03(s, 1H), 6.94 - 6.93(m, 1H), 6.74 - 6.49(m, 2H), 6.64 - 6.50(m, 1H), 4.84 - 4.65(m, 1H), 3.87 - 3.78(m, 2H), 3.64 - 3.52(m, 1H), 3.50 - 3.25(m, 2H), 2.81(t, J = 7.6Hz, 4H), 2.73 - 2.67(m, 5H), 2.01 - 1.89(m, 5H), 1.82 - 1.72(m, 3H), 1.61 - 1.49(m, 4H); MS(ESI): m / z(%) = 488.21(100%)(M + H) + .

[0687] Example - 71

[0688] (E)-N-((1,2,3,5,6,7 - hexahydro - s - indacen - 4 - yl)carbamoyl)-2-(tetrahydro - 2H - pyran - 4 - yl)ethenesulfonamide

[0689]

[0690] 1 H NMR(400MHz, DMSO - d 6 ):δ=10.33(bs, 1H), 8.07(s, 1H), 6.96(s, 1H), 6.80 - 6.74(m, 1H), 6.69 - 6.65(m, 1H), 3.87 - 3.83(m, 2H), 3.37 - 3.34(m, 3H), 2.81(t, J = 7.6Hz, 4H), 2.67(t, J = 7.6Hz, 4H), 2.08 - 1.94(m, 4H), 1.65 - 1.62(m, 2H), 1.55 - 1.30(m, 2H); MS(ESI): m / z(%) = 391.15(100%)(M + H) + .

[0691] Example - 72

[0692] (S,E)-N-((1,2,3,5,6,7 - hexahydro - s - indacen - 4 - yl)carbamoyl)-2-(1 - nicotinoylpyrrolidin - 2 - yl)ethenesulfonamide

[0693]

[0694] 1 H NMR(400MHz, DMSO - d 6):δ = 10.35 (bs, 1H), 8.76 - 8.59 (m, 2H), 8.05 (s, 1H), 6.72 (d, = 8Hz, 0.72H), 7.77 (d, J 8Hz, 0.23H), 7.48 - 7.40 (m, 1H), 6.94 (s, 1H), 6.84 (s, 1H), 6.57 - 6.55 (m, 1H), 4.86 - 4.50 (m, 1H), 3.65 - 3.59 (m, 1H), 3.41 - 3.37 (m, 1H), 2.78 (t, J = 7.6Hz, 4H), 2.65 (t, J = 7.6Hz, 4H), 2.20 - 2.13 (m, 1H), 1.96 - 1.84 (m, 7H); MS(ESI): m / z(%) = 481.18 (100%)(M + H) + .

[0695] Example - 73

[0696] (E)-N-((1,2,3,5,6,7 - hexahydro - s - indacen - 4 - yl)carbamoyl)-2-(tetrahydrofuran - 2 - yl)ethene - 1 - sulfonamide

[0697]

[0698] 1 H NMR(400MHz, DMSO - d 6 ):δ = 10.40 (bs, 1H), 8.11 (s, 1H), 6.96 (s, 1H), 6.81 (dd, J = 4.0Hz, J = 14.8Hz, 1H), 6.74 (dd, J = 1.2Hz, J = 15.2Hz, 1H), 4.57 - 4.53 (m, 1H), 3.86 - 3.81 (m, 1H), 3.76 - 3.70 (m, 1H), 2.8l (t, J = 7.2Hz, 4H), 2.67 (t, J = 7.2Hz, 4H), 2.16 - 2.07 (m, 1H), 2.01 - 1.94 (m, 4H), 1.90 - 1.79 (m, 2H), 1.67 - 1.62 (m, 1H); MS(ESI): m / z(%) = 377.15 (100%)(M + H) + .

[0699] Example - 74

[0700] (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

[0701]

[0702] 1 1H NMR (400 MHz, DMSO-d 6 ): 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 - 324 (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) + .

[0703] Example - 75

[0704] (S,E)-2-(2-(N-((4-Fluoro-2,6-diisopropylphenyl)carbamoyl)sulfamoyl)vinyl)-pyrrolidine-1-carboxylic acid tert-butyl ester

[0705]

[0706] 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) + .

[0707] Example - 76

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

[0709]

[0710] 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) + .

[0711] Example - 77

[0712] (S,E)-N-((4-Fluoro-2,6-diisopropylphenyl)carbamoyl)-2-(1-methylpyrrolidin-2-yl)ethene-1-sulfonamide.

[0713]

[0714] 1 1H NMR (400 MHz, DMSO-d 6 ) : 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 = 6.8 Hz, 12H); MS (ESI): m / z (%) = 412.26 (100%) (M + H) + .

[0715] Example - 78

[0716] (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

[0717]

[0718] 1 1H NMR (400 MHz, DMSO-d 6δ = 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) + .

[0719] Example - 79

[0720] (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

[0721]

[0722] 1 H NMR(400MHz, DMSO-d 6 ):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) + .

[0723] Example - 80

[0724] (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

[0725]

[0726] 1 H NMR(400MHz,) MSO-d 6δ = 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) + .

[0727] Example - 81

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

[0729]

[0730] 1 H NMR(400MHz, DMSO-d 6 ):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) + .

[0731] Example - 82

[0732] (E)-2-(1-Ethylpiperidin-3-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)vinyl-sulfonamide

[0733]

[0734] 1 H NMR(400MHz, DMSO-d 6):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), 268 (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) + .

[0735] Example - 83

[0736] (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

[0737]

[0738] 1 H NMR(400MHz, DMSO-d 6 ):δ = 10.4 (brs, 1H), 7.93 (s, 1H), 6.93 (s, 1H), 6.74 (d, J = 15.2 Hz, 1H), 6.61 (dd, J = 15.2 Hz, J = 6.8 Hz, 1H), 3.75 - 3.64 (m, 2H), 2.93 - 2.88 (m, 2H), 2.80 (t, 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).

[0739] Example - 84

[0740] (E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(methylsulfonyl)piperidin-3-yl)ethenesulfonamide

[0741]

[0742] 1 H NMR (400 MHz, DMSO-d 6 ):δ = 10.4 (brs, 1H), 7.98 (s, 1H), 6.93 (s, 1H), 6.79 (d 4J = 15.2 Hz, 1H), 6.66 (dd, J = 15.2 Hz, J = 6.4 Hz, 1H), 3.47 - 3.39 (N, 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).

[0743] Example - 85

[0744] (E)-2-(1 - Acetylpiperidin - 3 - yl)-N - ((1,2,3,5,6,7 - hexahydro - s - indacen - 4 - yl)carbamoyl)vinyl - sulfonamide

[0745]

[0746] 1 H NMR (400 MHz, DMSO-d 6 ):δ = 8.00 (s, 1H), 6.94 (s, 1H), 6.80 - 6.65 (m, 2H), 4.16 - 4.10 (m, 1H), 3.77 - 3.63 (m, 1H), 3.09 - 2.93 (m, 1H), 2.80 (t, J = 7.2 Hz, 4H), 2.75 - 2.64 (m, 5H), 2.39 - 2.26 (m, 1H), 2.00 - 1.91 (m, 7H), 1.90 - 1.77 (m, 1H), 1.74 - 1.57 (m, 1H), 1.54 - 1.28 (m, 2H); MS (ESI): m / z (%) = 468.14 (100%) (M + H) + , 490.40 (50%) (M + Na), 466.11 (100%) (M - 1).

[0747] Example - 86

[0748] (E)-tert-Butyl 2-(2-((N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)azetidine-1-carboxylate

[0749]

[0750] Example 86 was prepared using Intermediate-11 according to the procedure for synthesizing Intermediate-3a as described.

[0751] 1 H NMR(400MHz, DMSO-d 6 ): 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).

[0752] Example - 87

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

[0754]

[0755] 1 H NMR(400MHz, DMSO-d 6 ): 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).

[0756] Example - 88

[0757] (E)-2-(Azetidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide

[0758]

[0759] 1 H NMR (400 MHz, DMSO-d 6 ): δ = 7.51 (s, 1H), 6.94 (d, J = 15.2 Hz, 1H), 6.80 (s, 1H), 6.55 (dd, J = 15.2 Hz, J = 7.2 Hz, 1H), 5.01 - 4.95 (m, 1H), 3.89 - 3.82 (m, 1H), 3.72 - 3.62 (m, 1H), 2.77 (t, J = 7.2 Hz, 4H), 2.70 (t, J = 6.8 Hz, 4H), 2.50 - 2.33 (m, 1H), 1.96 - 1.88 (m, 5H); MS (ESI): m / z (%) = 362.24 (100%) (M + H) + .

[0760] Example - 89

[0761] (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

[0762]

[0763] 1 H NMR (400 MHz, DMSO-d 6):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 / z(%) = 416.29 (100%)(M + H) + .

[0764] Example - 90

[0765] (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

[0766]

[0767] 1 H NMR(400MHz, DMSO-d 6 ):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).

[0768] Example - 91

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

[0770]

[0771] 11H NMR (400 MHz, DMSO-d 6 ):δ = 7.86 (s, 1H), 7.42 (m, 2H), 7.34 (t, J = 4.0 Hz, 3H), 6.87 (s, 1H), 6.71 (s, 1H), 6.45 (m, 1H), 4.46 (s, 2H), 4.37 (d, J = 8.0 Hz, 1H), 3.22 (s, 1H), 2.78 (t, J = 7.6 Hz, 4H), 2.66 (t, J = 7.2 Hz, 4H), 1.99 (m, 1H), 1.95 (m, 4H), 1.74 (m, 3H); MS (ESI): m / z (%) = 530 (100%) (M+1).

[0772] Example - 92

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

[0774]

[0775] 1 1H NMR (400 MHz, DMSO-d 6 ):δ = 7.93 (s, 1H), 7.79 (d, J = 2.8 Hz, 2H), 7.12 (d, J = 2.0 Hz, 2H), 6.90 (s, 1H), 6.85 (s, 1H), 6.66 (s, 1H), 6.60 (d, J = 5.6 Hz, 1H), 6.57 (d, J = 4.4 Hz, 1H), 4.4 (m, 1H), 3.84 (s, 3H), 3.22 (m, 1H), 2.78 (t, J = 7.2 Hz, 4H), 2.70 (t, J = 7.2 Hz, 4H), 1.99 (m, 4H), 1.68 (m, 3H), 1.60 (m, 1H); MS (ESI): m / z (%) = 546 (100%) (M+1).

[0776] Example - 93

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

[0778]

[0779] 1 1H NMR (400 MHz, DMSO-d 6):δ = 8.02 (s, 1H), 7.94 (d, J = 2.0 Hz, 2H), 7.47 (d, J = 3.6 Hz, 2H), 6.90 (s, 1H), 6.87 (s, 1H), 6.68 (d, J = 9.6 Hz, 1H), 4.41 (m, 1H), 3.36 (m, 1H), 2.78 (t, J = 7.2 Hz, 4H), 2.69 (t, J = 7.2 Hz, 4H), 1.99 (m, 4H), 1.68 (m, 3H), 1.60 (m, 1H); MS(ESI): m / z(%) = 534 (100%)(M + 1).

[0780] Example - 94

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

[0782]

[0783] 1 H NMR(400MHz, DMSO-d 6 ):δ = 8.11 (d, J = 1.2 Hz, 2H), 7.90 (d, J = 1.2 Hz, 2H), 7.83 (s, 1H), 6.82 (s, 1H), 6.70 (d, J = 14.8 Hz, 1H), 6.30 (s, 1H), 4.51 (s, 1H), 3.32 (s, 2H), 2.77 (t, J = 7.2 Hz, 4H), 2.70 (t, J = 7.2 Hz, 4H), 1.92 (m, 4H), 1.80 (m, 2H), 1.74 (m, 2H); MS(ESI): m / z(%) = 541.14 (100%)(M + 1).

[0784] Example - 95

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

[0786]

[0787] 1 H NMR(400MHz, DMSO-d 6):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, J = 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).

[0788] Example - 96

[0789] (S,E)-2-(1-(4-Fluorobenzyl)pyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethenesulfonamide

[0790]

[0791] 1 H NMR(400MHz, DMSO-d 6 ):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).

[0792] Example - 97

[0793] (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

[0794]

[0795] 1 H NMR(400MHz, DMSO-d 6):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, J = 7.2 Hz, 4H), 2.70 (t, J = 72 Hz, 4H), 1.92 (m, 4H), 1.67 (m, 3H), 1.56 (m, 1H); MS(ESI): m / z(%) = 541.15 (100%)(M + 1).

[0796] Example - 98

[0797] (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

[0798]

[0799] 1 H NMR(400 MHz, DMSO - d 6 ):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).

[0800] Example - 99

[0801] (S,E)-N-((1,2,3,6,7,8 - hexahydro - as - indacen - 4 - yl)carbamoyl)-2-(pyrrolidin - 2 - yl)ethene - 1 - sulfonamide

[0802]

[0803] 1 H NMR(400 MHz, DMSO - d 6):δ=8.90(s, 1H), 7.59(s, 1H), 7.26(s, 1H), 6.98(d, J1 = 0.8Hz, 1H), 6.98(t, J2 = 1.2Hz, 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).

[0804] Example - 100

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

[0806]

[0807] 1 H NMR(400MHz, DMSO-d 6 ):δ=7.41(s, 1H), 6.86(d, J = 15.6Hz, 1H), 6.79(s, 1H), 6.28(d, J = 6.0Hz, 1H), 3.61(s, 2H), 3.14(d, J = 12.8Hz, 1H), 2.81(t, J = 7.2Hz, 4H), 2.70(t, J = 7.2Hz, 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).

[0808] Example - 101

[0809] (E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-methylpiperidin-2-yl)ethene-1-sulfonamide

[0810]

[0811] 1 H NMR(400MHz, DMSO-d 6):δ=7.92(s, 1H), 6.89(s, 1H), 6.80(d, J = 14.8Hz, 1H), 6.42(d, J = 8.4Hz, 1H), 2.92(t, J = 5.2Hz, 2H), 2.82(t, J = 7.2Hz, 4H), 2.72(t, J = 7.2Hz, 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).

[0812] Example - 102

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

[0814]

[0815] 1H NMR(400MHz, DMSO-d6): δ = 7.83(s, 1H), 744(s, 1H), 6.88(d, J = 14.8Hz, 1H), 6.53(d, J = 8.0Hz, 1H), 3.13(s, 3H), 2.82(t, J = 7.2Hz, 4H), 2.72(t, J = 7.2Hz, 4H), 2.39(s, 2H), 2.33(d, J = 2.0Hz, 3H), 2.11(m, 5H), 1.81(m, 2H), 1.78(m, 1H); MS(ESI): m / z(%) = 390.14(100%)(M + 1).

[0816] Example - 103

[0817] (E)-N-((1,2,3,6,7,8-Hexahydro-as-indacen-4-yl)carbamoyl)-2-(1-(methylsulfonyl)pyrrolidin-2-yl)ethene-1-sulfonamide

[0818]

[0819] 1 H NMR(400MHz, DMSO-d 6):δ=7.87(s, 1H), 7.45(s, 1H), 6.77(d, J = 14.8Hz, 1H), 6.68(d, J = 4.8Hz, 1H), 4.48(t, J = 4.0Hz, 1H), 2.99(s, 3H), 2.82(t, J = 7.2Hz, 4H), 2.72(t, J = 7.2Hz, 4H), 2.11(m, 5H), 1.81(m, 3H); MS(ESI): m / z(%) = 454.09(100%)(M + 1).

[0820] Example - 104

[0821] ((E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-3-(piperidin-2-yl)prop-1-ene-1-sulfonamide

[0822]

[0823] 1 H NMR(400MHz, DMSO-d 6 ):δ=7.44(s, 1H), 6.79(s, 1H), 6.47(d, J = 15.2Hz, 1H), 6.20(m, 1H), 2.85(t, J = 7.2Hz, 5H), 2.70(t, J = 7.2Hz, 4H), 2.33(t, J = 1.6Hz, 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).

[0824] Example - 105

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

[0826]

[0827] 1 H NMR(400MHz, DMSO-d 6):δ=7.52(s, 1H), 6.88(d, J=15.6Hz, 1H), 6.81(s, 1H), 6.46(d, J=15.6Hz, 1H), 3.21(m, 2H), 3.12(m, 1H), 2.75(t, J=7.2Hz, 4H), 2.69(t, J=7.2Hz, 4H), 1.98(m, 7H), 1.78(s, 2H), 1.38(s, 3H); MS(ESI): m / z(%)=390.24(100%)(M + 1).

[0828] Example - 106

[0829] (S, E)-2-(1,2 - dimethylpyrrolidin - 2 - yl)-N-((1,2,3,5,6,7 - hexahydro - s - indacen - 4 - yl)carbamoyl)ethene - 1 - sulfonamide

[0830]

[0831] 1H NMR(400MHz, DMSO - d6): δ=8.04(s, 1H), 6.93(s, 1H), 6.73(d, J=15.2Hz, 1H), 6.65(d, J=15.2Hz, 1H), 2.80(t, J=7.2Hz, 4H), 2.68(t, J=7.2Hz, 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).

[0832] Alternatively, Example 106 can also be prepared according to the procedure for synthesizing Intermediate - 7b (Example 111) using Intermediate 9 and (S)-1,2 - dimethylpyrrolidine - 2 - carbaldehyde together with conventional techniques known to those skilled in the art of organic synthesis.

[0833] Example - 107

[0834] (E)-N-((1,2,3,5,6,7 - hexahydro - s - indacen - 4 - yl)carbamoyl)-2-(indolin - 2 - yl)ethene - 1 - sulfonamide

[0835]

[0836] 1 H NMR(400MHz, DMSO - d 6):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, = 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).

[0837] Example - 108

[0838] (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

[0839]

[0840] 1 H NMR(400MHz, DMSO-d 6 ):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, = 15.6 Hz, 1H-H), 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).

[0841] Example - 109

[0842] ((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

[0843]

[0844] 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).

[0845] Example - 110

[0846] (S,E)-2-(1-(Cyclopropylsulfonyl)pyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)vinyl-1-sulfonamide

[0847]

[0848] 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), 268 (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).

[0849] Example - 111

[0850] (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

[0851]

[0852] 1 1H 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).

[0853] Example - 112

[0854] (R,E)-2-(2-(N-((2,6-Diisopropylphenyl)carbamoyl)sulfamoyl)vinyl)-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester

[0855]

[0856] 1 H NMR(400MHz, DMSO-d 6 ):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), 169 - 1.64 (m, 1H), 1.44 (s, 3H), 1.37 (s, 9H), 1.13 (d, / = 6.8 Hz, 12H); MS(ESI): m / z(%) = 492.24 (100%)(M - 1) - .

[0857] Example - 113

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

[0859]

[0860] 1 H NMR(400MHz, DMSO-d 6):δ = 11.10 (bs, 1H), 9.08 (bs, 2H), 8.24 (s, 1H), 7.27 (t, J = 7.6 Hz, 1H), 7.16 (d, J = 7.6 Hz, 2H), 7.11 (d, J = 15.6 Hz, 1H), 7.05 (d, J = 15.2 Hz, 1H), 3.33 - 3.29 (m, 2H), 3.07 - 3.00 (m, 2H), 2.13 - 1.83 (m, 4H), 1.46 (s, 3H), 1.12 (d, J = 6.8 Hz, 12H); MS(ESI): m / z(%) = 392.22 (100%)(M - TFA) + ;

[0861] Example - 114

[0862] (R,E)-N-((2,6 - Diisopropylphenyl)carbamoyl)-2-(1,2 - dimethylpyrrolidin - 2 - yl)ethene - 1 - sulfonamide

[0863]

[0864] 1 H NMR(400 MHz, DMSO - d 6 ):δ = 10.45 (bs, 1H), 7.83 (s, 1H), 7.25 (t, J = 7.6 Hz, 1H), 7.15 (d, J = 8.0 Hz, 2H), 6.73 (d, J = 15.2 Hz, 1H), 6.68 (d, J = 15.6 Hz, 1H), 3.33 - 3.22 (m, 2H), 2.83 - 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) + .

[0865] Example - 115

[0866] (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

[0867]

[0868] 1 H NMR(400 MHz, DMSO - d 6):δ = 10.45 (bs, 1H), 8.05 (bs, 1H), 6.93 (s, 1H), 6.74 (d, J = 15.2Hz, 1H), 6.68 (d, J = 15.6Hz, 1H), 2.96 - 2.89 (m, 2H), 2.80 (t, J = 7.2Hz, 4H), 2.67 (1, J = 7.6Hz, 6H), 1.96 (quintet, J = 7.2Hz, 4H), 1.79 - 1.72 (m, 4H), 1.14 (s, 3H), 1.02 (t, J = 6.4Hz, 3H); MS(ESI): m / z(%) = 418.16 (100%)(M + H )+ .

[0869] Example - 116

[0870] Disodium (R,E)-((2-(1,2-dimethylpyrrolidin-2-yl)vinyl)sulfonyl)((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)amide

[0871]

[0872] 1 H NMR(400MHz, DMSO-d 6 ):δ = 6.76 (s, 1H), 6.56 (d, J = 15.6Hz, 1H), 6.20 (d, J = 15.6(Hz, 1H), 2.75 (t, J = 7.6Hz, 5H), 2.69 (t, J = 7.2Hz, 4H), 2.64 - 2.59 (m, 1H), 2.08 (s, 3H), 1.90 (quintet, J = 7.2Hz, 4H),.74 - 1.68 (m, 3H), 1.62 - 1.61 (m, 1H), 1.01 (s, 3H); MS(ESI) m / z(%) = 404.17 (100%)(M - 2Na) + .

[0873] Example - 117

[0874] Sodium (R,E)-((2-(1,2-dimethylpyrrolidin-2-yl)vinyl)sulfonyl)((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)amide

[0875]

[0876] 1 H NMR(400MHz, DMSO-d 6):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 = 72 Hz, 5H), 2.69 (t, J = 7.21 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) + .

[0877] Example - 118

[0878] (S,E)-2-(2-(N-((2,6-Diisopropylphenyl)carbamoyl)sulfamoyl)vinyl)-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester

[0879]

[0880] 1 H NMR(400MHz, DMSO-d 6 ):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, J = 6.8 Hz, 12H); MS(ESI): m / z(%) = 494.31 (10%)(M + 1) + .

[0881] Example - 119

[0882] (S,E)-N-((2,6-Diisopropylphenyl)carbamoyl)-2-(2-methylpyrrolidin-2-yl)ethene-1-sulfonamide 2,2,2-trifluoroacetate

[0883]

[0884] 1 H NMR(400MHz, DMSO-d 6):δ=11.10(bs, 1H), 9.10(bs, 2H), 8.28(s, 1H), 7.27(t, J = 7.6Hz, 1H), 7.16(d, J = 7.6Hz, 2H), 7.12(d, J = 15.6Hz, 1H), 7.00(d, J = 15.2Hz, 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 = 6.8Hz, 12H); MS(ESI): m / z(%) = 394.27(100%)(M - TFA) + .

[0885] Example - 120

[0886] (S, E)-N-((2,6 - Diisopropylphenyl)carbamoyl)-2-(1,2 - dimethylpyrrolidin - 2 - yl)ethene - 1 - sulfonamide

[0887]

[0888] 1 H NMR(400MHz, DMSO - d 6 ):δ=10.10(bs, 1H), 7.92(s, 1H), 7.25(t, J = 7.6Hz, 1H), 7.13(d, J = 7.6Hz, 2H), 6.68(d, J = 14.8Hz, 1H), 6.61(d, J = 15.6Hz, 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) + .

[0889] Example - 121

[0890] (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

[0891]

[0892] 1 H NMR(400MHz, DMSO - d 6δ = 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) + .

[0893] Example - 122

[0894] (S,E)-2-(2-(N-((4-Fluoro-2,6-diisopropylphenyl)carbamoyl)sulfamoyl)vinyl)-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester

[0895]

[0896] 1 H NMR(400MHz, DMSO-d 6 ):δ = 10.61 (bs, 1H), 7.89 - 7.85 (m, 1H), 6.97 (d, J = 10Hz, 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 = 7.2Hz, 12H); MS(ESI): m / z(%) = 512.30 (8%)(M + H) + , 534.29 (8%)(M + Na) + .

[0897] Example - 123

[0898] (S,E)-N-((4-Fluoro-2,6-diisopropylphenyl)carbamoyl)-2-(2-methylpyrrolidin-2-yl)ethene-1-sulfonamide 2,2,2-trifluoroacetate

[0899]

[0900] 1 H NMR(400MHz, DMSO-d 6):δ=11.11(bs, 1H), 9.08(bs, 2H), 8.25(s, 1H), 7.09(d, J=15.6Hz, 1H); 7.00 - 6.95(m, 3H), 3.42 - 3.40(m, 1H), 3.21 - 3.17(m, 1H), 3.06 - 2.99(m, 2H), 2.10 - 1.83(m, 4H), 1.45(s, 3H), 1.11(d, J=5.6Hz, 12H); MS(ESI): m / z(%)=412.23(100%)(M + H) + ;

[0901] Example - 124

[0902] (S,E)-2-(1,2 - dimethylpyrrolidin - 2 - yl)-N-((4 - fluoro - 2,6 - diisopropylphenyl)carbamoyl)ethene - 1 - sulfonamide

[0903]

[0904] 1 H NMR(400MHz, DMSO - d 6 ):δ=7.87(s, 1H), 6.93(d, J=10Hz, 2H); 6.66 - 6.92(m, 2H), 3.10 - 3.04(m, 2H), 2.83 - 2.67(m, 2H), 2.15(s, 3H), 1.76 - 1.69(m, 4H), 1.11 - 1.09(m, 15H); MS(ESI): m / z(%)=426.29(100%)(M + H) + ;

[0905] Example - 125

[0906] (E)-2-(1 - acetylazetidin - 2 - yl)-N-((1,2,3,5,6,7 - hexahydro - s - indacen - 4 - yl)carbamoyl)ethene - 1 - sulfonamide

[0907]

[0908] 1 H NMR(400MHz, DMSO - d 6):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) + .

[0909] Example - 126

[0910] (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

[0911]

[0912] 1 H NMR(400MHz, DMSO-d 6 ):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) + .

[0913] Example - 127

[0914] (S,E)-2-(1-allylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide

[0915]

[0916] 1 H NMR(400MHz, DMSO-d 6δ = 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) + .

[0917] Example - 128

[0918] (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

[0919]

[0920] 1 H NMR(400 MHz, DMSO - d 6 ):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 - 342 (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) + .

[0921] Example - 129

[0922] (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

[0923]

[0924] 1 H NMR (400 MHz, DMSO-d 6 ): δ = 8.01 (s, 1H), 6.94 (s, 1H), 6.86 (d, J = 15.2 Hz, 1H), 6.71 (dd, J = 14.8 Hz, J = 6.4 Hz, 1H), 3.46 (t, J = 6.8 Hz, 2H), 2.80 (t, J = 7.2 Hz, 4H), 2.68 (t, J = 7.2 Hz, 4H), 2.63 - 2.56 (m, 2H), 2.07 - 1.91 (m, 6H), 1.90 - 1.74 (m, 1H), 1.57 (s, 3H), 0.97 - 0.89 (m, 4H); MS (ESI): m / z (%) = 494.22 (100%) (M + H) + .

[0925] Example - 130

[0926] (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

[0927]

[0928] 1 H NMR (400 MHz, DMSO-d 6 ): 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).

[0929] Example - 131

[0930] 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

[0931]

[0932] 1 H NMR (400 MHz, DMSO-d 6 ):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), 131 - 1.08 (m, 2H); MS(ESI): m / z(%) = 585.29 (100%)(M + H) + .

[0933] Example - 132

[0934] (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

[0935]

[0936] 1 H NMR (400 MHz, DMSO-d 6 ):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) + .

[0937] Example - 133

[0938] (E)-2-(1-(Cyclopropylsulfonyl)azetidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide

[0939]

[0940] 1 H NMR(400MHz, DMSO-d 6 ): 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) + .

[0941] Example - 134

[0942] (S,E)-N-((2,6-Diisopropylphenyl)carbamoyl)-2-(1-(thiazol-2-yl)pyrrolidin-2-yl)ethene-1-sulfonamide

[0943]

[0944] 1 H NMR(400MHz, DMSO-d 6 ): 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) + .

[0945] Example - 135

[0946] (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

[0947]

[0948] 1 H NMR(400MHz, DMSO-d 6 ): 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 = 6.8(Hz, 4H), 2.68 2.65(m, 8H), 2.43 - 2.42(m, 1H), 1.96(pentet, J = 7.2(Hz, 4H), 1.75 - 1.65(m, 4H), 1.41 - 1.37(m, 12H), 1.1(s, 3H); MS(ESI) m / z(%) = 547.32(100%)(M + H) + .

[0949] Example - 136

[0950] Potassium (R,E)-((2-(1,2-dimethylpyrrolidin-2-yl)vinyl)sulfonyl)((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)amide

[0951]

[0952] 1 H NMR(400MHz, DMSO-d 6 ): 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, 5(H), 2.69(t, J = 7.2Hz, 4H), 2.64 - 2.58(m, 1H), 2.08(s, 3H), 1.90(pentet, J = 7.6Hz, H), 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) + .

[0953] Example - 137

[0954] (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

[0955]

[0956] 1 H NMR(400MHz, DMSO-d 6 ): δ = 8.03(s, 1H), 6.94(m, 1H), 6.85 - 6.64(m, 2H), 3.88 - 3.72(m, 1H), 2.96 - 2.88(m, 1H), 2.80(t, J = 7.2Hz, 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).

[0957] Example - 138

[0958] (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

[0959]

[0960] 1 H NMR(400MHz, DMSO-d 6):δ = 10.36 (brs, 1H), 8.04 (s, 1H), 6.95 (m, 1H), 6.78 - 6.62 (m, 2H), 2.81 (t, J = 7.2 Hz, 4H), 2.68 (t, J = 7.2 Hz, 4H),), 2.65 - 2.55 (m, 1H), 2.26 - 2.02 (m, 2H), 2.00 - 1.91 (m, 5H), 1.86 - 1.71 (m, 4H), 1.70 - 1.50 (m, 5H), 1.43 - 1.24 (m, 1H), 1.23 - 1.13 (m, 2H), 1.12 - 1.00 (m, 4H), 0.86 - 0.67 (m, 2H); MS(TOF): m / z(%) ) +486.2891(100%)(M + H) + , 484.2571(100%)(M - 1).

[0961] Example - 139

[0962] 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

[0963]

[0964] 1 H NMR(400MHz, DMSO - d 6 ): δ = 7.31 (s, 1H), 6.76 (s, 1H), 6.63 (d, J = 15.2 Hz, 1H), 6.06 (dd, J = 15.2 Hz, J = 7.6 Hz, 1H), 3.43 - 3.36 (m, 1H), 2.87 - 2.64 (m, 10H), 2.65 - 2.42 (m, 5H), 2.03 - 1.84 (m, 7H), 1.68 - 1.43 (m, 5H); MS(ESI): m / z(%) = 476.25(100%)(M + H) + , 474.20(100%)(M - 1).

[0965] Example - 140

[0966] Sodium (R,E)-((2-(1 - cyclohexylpyrrolidin - 2 - yl)vinyl)sulfonyl)((1,2,3,5,6,7 - hexahydro - s - indacen - 4 - yl)carbamoyl)amide

[0967]

[0968] 1 H NMR(400MHz, DMS0 - d6 ):δ = 7.33 (s, 1H), 6.77 (s, 1H), 6.63 (d, J = 15.2 Hz, 1H), 6.09 (dd, J = 15.2 Hz, J = 7.6 Hz, 1H), 3.34 - 3.42 (m, 1H), 2.84 - 2.79 (m, 1H), 2.76 (t, J = 7.2 Hz, 4H), 2.70 (t, J = 7.2 Hz, 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) + .

[0969] Example - 141

[0970] Sodium (S,E)-((2,6 - diisopropylphenyl)carbamoyl)((2-(1,2 - dimethylpyrrolidin - 2 - yl)vinyl)sulfonyl)amide

[0971]

[0972] 1 H NMR(400MHz, DMSO - d 6 ):δ = 7.24 (s, 1H), 7.11 (t, J = 8.4 Hz, 1H), 7.04 (d, J = 7.6 Hz, 2H), 6.54 (d, J = 15.6 Hz, 1H), 6.21 (d, J = 16.0 Hz, 1H), 3.23 - 3.16 (m, 2H), 2.74 - 2.67 (m, 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 = 6.4 Hz, 12H), 1.0 (s, 3H); MS(ESI): m / z(%) = 408.25(100%)(M - Na) + .

[0973] Example - 142

[0974] Sodium (R,E)-((1,2,3,5,6,7 - hexahydro - s - indacen - 4 - yl)carbamoyl)((2-(1 - methylpyrrolidin - 2 - yl)vinyl)sulfonyl)amide

[0975]

[0976] 1 H NMR(400MHz, DMSO - d 6):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(quintet, 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) + .

[0977] Example - 143

[0978] Potassium (R,E)-((1,2,3,5,6,7 - hexahydro - s - indacen - 4 - yl)carbamoyl)((2-(1 - methylpyrrolidin - 2 - yl)vinyl)sulfonyl)amide

[0979]

[0980] 1 H NMR(400MHz, DMSO - d 6 ): 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) + .

[0981] Example - 144

[0982] Sodium (S,E)-((2-(1,2 - dimethylpyrrolidin - 2 - yl)vinyl)sulfonyl)((1,2,3,5,6,7 - hexahydro - s - indacen - 4 - yl)carbamoyl)amide

[0983]

[0984] 1H NMR (400 MHz, DMSO-d6): δ = 7.33 (s, 1H), 6.77 (s, 1H), 6.56 (d, J = 15.2 Hz, H), 6.16 (d, J = 16 Hz, 1H), 2.76 (t, J = 7.2 Hz, 4H), 2.69 (t, J = 7.2 Hz, 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).

[0985] Example - 145

[0986] Sodium (S,E)-((2-(1-ethylpyrrolidin-2-yl)vinyl)sulfonyl)((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)amide

[0987]

[0988] 1 1H NMR (400 MHz, DMSO-d 6 6): 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) + .

[0989] Example - 146

[0990] (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

[0991]

[0992] 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).

[0993] Example - 147

[0994] (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

[0995]

[0996] 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.

[0997] 1 H NMR (400 MHz, DMSO-d 6 ): 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).

[0998] Example - 148

[0999] (E)-2-(1,2-Dimethylazetidin-2-yl)-N-((1,2,3,50,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide

[1000]

[1001] 1 H NMR (400 MHz, DMSO-d 6 ):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).

[1002] Example - 149

[1003] (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

[1004]

[1005] 1 H NMR (400 MHz, DMSO-d 6 ):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).

[1006] Example - 150

[1007] (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

[1008]

[1009] 1 H NMR (400 MHz, DMSO-d 6 ):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), 280 (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).

[1010] Example - 151

[1011] (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

[1012]

[1013] 1 H NMR (400 MHz, DMSO-d 6 ):δ = 9.19 (s, 1H), 90.6 (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).

[1014] Example - 152

[1015] (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

[1016]

[1017] 1 H NMR (400 MHz, DMSO-d6 ):δ=7.39(s, 1H), 7.11(d, J=15.6Hz, 1H), 7.02(d, J=15.6Hz, 1H), 2.79(q, J=7.6Hz, 5H), 2.71(t, J=7.2Hz, 4H), 2.01(m, 9H), 1.47(q, J=7.2Hz, 3H), 1.04(d, J=6.0Hz, 2H); MS(ESI): m / z(%)=390.24(100%)(M + 1).

[1018] Example - 153

[1019] (S, E)-2-(1,2 - dimethylpyrrolidin - 2 - yl)-N-((1,2,3,6,7,8 - hexahydro - as - indacen - 4 - yl)carbamoyl)ethene - 1 - sulfonamide

[1020]

[1021] 1H NMR(400MHz, DMSO - d6): δ=7.88(s, 1H), 7.43(s, 1H), 6.72(d, J=15.2Hz, 1H), 6.62(d, J=15.2Hz, 1H), 3.09(q, J=7.2Hz, 4H), 2.75(m, 4H), 2.60(t, J=6.8Hz, 4H), 2.21(s, 3H), 1.95(m, 4H), 1.78(t, J=10Hz, 4H), 1.17(m, 8H); MS(ESI): m / z(%)=404.30(100%)(M + 1).

[1022] Example - 154

[1023] (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

[1024]

[1025] 1 H NMR(400MHz, DMSO - d 6):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)-.

[1026] Example - 155

[1027] (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

[1028]

[1029] 1 H NMR(400MHz, DMSO-d 6 ): 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) + .

[1030] Example - 156

[1031] (R,E)-2-(1,2-Dimethylpyrrolidin-2-yl)-N-((1,2,3,6,7,8-hexahydro-as-indacen-4-yl)carbamoyl)ethene-1-sulfonamide

[1032]

[1033] 1 H NMR(400MHz, DMSO-d 6):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) + .

[1034] Example - 157

[1035] (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

[1036]

[1037] 1 H NMR(400MHz, DMSO-d 6 ): δ = 10.38 (s, 1H), 8.07 (d, J = 72Hz, 1H), 6.95 (s, 1H), 6.81 (q, J = 15.2 Hz, 1H), 6.64 (dd, J I = 8.0Hz, J 2 = 15.2Hz, 1H), 3.19 - 3.17 (m, 1H), 2.91 - 2.86 (m, 1H), 2.81 (t, J = 7.2Hz, 4H), 2.67 (t, J = 7.2Hz, 5H), 2.63 - 2.58 (m, 1H), 1.97 (quintet, J = 7.2Hz, 4H), 1.88 - 1.83 (m, 1H), 1.70 - 1.62 (m, 3H), 1.41 (d, J = 6.8Hz, 9H), 1.30 (s, 3H); MS(ES1): m / z(%) = 526.28 (50%)(M + Na) - ; 502.28 (100%)(M - H) - .

[1038] Example - 158

[1039] (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

[1040]

[1041] 1 H NMR (400 MHz, DMSO-d 6 ): 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 = 68 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) - .

[1042] Example - 159

[1043] (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

[1044]

[1045] 1 H NMR (400 MHz, DMSO-d 6 ): 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 = 6.8 Hz, 5H), 2.69 (bs, 4H), 2.36 (s, 5H), 1.95 (t, J = 7.2 Hz, 4H), 1.81 - 1.74 (m, 3H), 1.58 (bs, 1H), 1.04 (s, 3H); MS (ESI): m / z (%) = 418.21 (100%) (M + H) + .

[1046] Example - 160

[1047] (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

[1048]

[1049] 1 H NMR (400 MHz, DMSO-d 6 ):δ = 8.05 (s, 1H), 6.94 (s, 1H), 6.82 (d, J = 15.2 Hz, 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) + .

[1050] Example - 161

[1051] (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

[1052]

[1053] 1 H NMR (400 MHz, DMSO-d 6 ):δ = 8.04 (s, 1H), 6.94 (s, 1H), 6.83 (d, J = 15.2 Hz, 1H), 6.77 (d, J = 15.2 Hz, 1H), 3.29 - 3.27 (m, 2H), 2.80 (t, J = 7.2 Hz, 4H), 2.75 - 2.72 (m, 1H), 2.68 (t, J = 7.2 Hz, 4H), 2.50 (s, 3H), 2.37 - 2.33 (m, 2H), 2.08 - 2.06 (m, 1H), 2.00 - 1.92 (m, 4H), 1.58 - 1.49 (m, 2H), 1.39 - 1.37 (m, 9H), 1.32 (s, 3H), 1.28 - 1.22 (m, 1H); MS (ESI): m / z (%) = 547.5 (100%) (M + H) + , 545.7 (100%) (M - 1).

[1054] Example - 162

[1055] (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

[1056]

[1057] 1 H NMR(400MHz, DMSO-d 6 ): δ = 8.05(s, 1H), 6.95(s, 1H), 6.83(d, J = 14.8Hz, 1H), 6.75 - 6.68(m, 1H), 3.32 - 3,23(m, 1H), 3.09 - 3.02(m, 1H), 2.80(t, J = 7.2Hz, 4H), 2.75 - 2.71(m, 2H), 2.67(t, J = 7.2Hz, 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).

[1058] Example - 163

[1059] (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

[1060]

[1061] 1 H NMR(400MHz, DMSO-d 6 ): δ = 10.36(brs, 1H), 8.07(s, 1H), 6.95(s, 1H), 6.87(d, J = 14.8Hz, 1H), 6.83(d, J = 14.8Hz, 1H), 3.40 - 3.22(m, 2H), 3.18 - 3.04(m, 1H), 2.81(t, J = 7.2Hz, 4H), 2.68(t, J = 7.2Hz, 4H), 2.59 - 2.53(m, 2H), 241 - 2.38(m, 2H), 2.08 - 1.88(m, 8H), 1.32(s, 3H); MS(TOF): m / z(%) = 450.1660(100%)(M + H) + .

[1062] Example - 164

[1063] (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

[1064]

[1065] 1 H NMR(400MHz, DMSO-d 6 ): δ = 10.4(brs, 1H), 8.13(s, 1H), 6.96(s, 1H), 6.84(d, J = 15.2Hz, 1H), 6.80(d, J = 15.2Hz, 1H), 4.56(t, J = 6.0Hz, 1H), 4.48 - 4.44(m, 2H), 4.31(t, J = 6.4Hz, 1H), 3.93 - 3.87(m, 1H), 3.38 - 3.28(m, 3H), 2.81(t, J = 7.2Hz, 4H), 2.68(t, J = 7.2Hz, 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) + .

[1066] Example - 165

[1067] (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

[1068]

[1069] 1 H NMR(400MHz, DMSO-d 6):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) + ;

[1070] Example - 166

[1071] (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

[1072]

[1073] 1 H NMR(400 MHz, DMSO-d 6 ):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 = 7.2 Hz, 4H), 2.57 (t, J = 7.2 Hz, 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) + ;

[1074] Example - 167

[1075] (R,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(2-sulfamoylethyl)pyrrolidin-2-yl)ethene-1-sulfonamide

[1076]

[1077] 11H NMR (400 MHz, DMSO-d 6 ):δ = 10.42 (br s, 1H), 8.09 (s, 1H), 6.95 (s, 1H), 6.87 (d, J = 14.8 Hz, 1H), 6.75 (s, 2H), 6.66 (dd, J = 14.8 Hz, J = 7.2 Hz, 1H), 3.23 - 3.07 (m, 4H), 3.01 - 2.94 (m, 1H), 2.80 (t, J = 7.2 Hz, 4H), 2.67 (t, J = 7.2 Hz, 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) + .

[1078] Example - 168

[1079] (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

[1080]

[1081] 1H NMR (400 MHz, DMSO-d6): δ = 8.01 (s, 1H), 6.93 (s, 1H), 6.71 (d, J = 15.2 Hz, 1H), 6.58 (d, J = 15.6 Hz, 1H), 2.99 (m, 1H), 2.80 (t, J = 7.2 Hz, 4H), 2.66 (t, J = 7.2 Hz, 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 = 7.2 Hz, 3H); MS (ESI): m / z (%) = 418.19 (100%) (M + 1);

[1082] Example - 169

[1083] (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

[1084]

[1085] 11H NMR (400 MHz, DMSO-d 6 6): δ = 8.84 (s, 1H), 7.03 (d, J = 15.6 Hz, 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) + .

[1086] Biological activity:

[1087] In vitro assay:

[1088] Differentiate THP1 monocytes with PMA (100 ng / mL) and incubate at 37 °C for 20 h in the presence of 5% CO2. In a 96-well tissue culture plate, seed 2 × 10 5 differentiated cells per well. 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 to fit the percentage cell survival data to GraphPad Prism. The in vitro IL-1β inhibitory activity (IC 50 ) of representative compounds is listed in Table 1.

[1089] Table 1

[1090]

[1091]

[1092] In vivo potency study:

[1093] Demonstration of the in vivo potency of the test compound in rats and mice, via oral administration route.

[1094] Animal

[1095] All animal experiments were conducted in female rats and mice bred in-house. 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, lights on at 7:30 am). All animal experiments were conducted in accordance with internationally valid guidelines approved by the "Zydus Research Centre Animal Ethics Committee" as described below.

[1096] In vivo LPS and ATP-induced IL-1β assay:

[1097] Female C57 mice (6 to 8 weeks old) received an intraperitoneal injection of lipopolysaccharide (LPS) at 50 μg / mouse in PBS. Animals were immediately treated with the test compound or vehicle. Two hours after LPS injection, ATP dissolved in PBS was administered to the animals at 12.5 mg / mouse via the intraperitoneal route. Thirty minutes after ATP injection, serum was collected for the estimation of IL-1β by ELISA.

[1098] The novel compounds of the present invention can be formulated into suitable pharmaceutically acceptable compositions by known techniques and methods and at concentrations by combination with suitable excipients.

[1099] Representative data for some of the test compounds are listed in Table 2:

[1100] Table 2

[1101]

[1102] 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.

[1103] Accordingly, the pharmaceutical compositions containing the compounds of the present invention may 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.

[1104] The compounds (I) of the present invention are NLRP3 inhibitors and can be used for the treatment of disease states mediated by NLRP3, preferably diseases or disorders involving interleukin 1β activity and related disorders.

[1105] 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 depending on the specific method of administration, the potency of the specific compound and the desired concentration. Generally, the amount of the active ingredient will range between 0.5% and 90% by weight of the composition.

[1106] The compound 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 readily identified by a skilled physician. Such other therapeutic agents can be selected based on the type of disease being treated, its severity, other medications 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 compound of the present invention.

[1107] In one embodiment, the compound of formula (I) of the present invention can be used in any combination with one or more suitable pharmaceutically active agents selected from the following therapeutic agents. Interleukin-1β inhibitors (e.g., rilonacept, canakinumab, and anakinra); immunosuppressants (e.g., methotrexate, mercaptopurine, cyclophosphamide), metabolic disorder drugs, glucocorticoids, non-steroidal anti-inflammatory drugs, Cox-2 specific inhibitors, TNF-α binding proteins (e.g., infliximab, etanercept), interferon-13, interferons, interleukin-2, antihistamines, β-agonists, BTK inhibitors, anticholinergics, anticancer agents, or their suitable pharmaceutically acceptable salts. 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 (e.g.: BAY 43-9006), Syk inhibitors, mTOR inhibitors, antibodies (rituximab), and BCR / ABL antagonists.

[1108] Although the present invention has been described in terms of specific embodiments thereof, 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.

Claims

1. A compound selected from the following: (R,E)-2-(1,2-Dimethylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide.

2. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to claim 1 and optionally one or more pharmaceutically acceptable carriers or excipients.

3. The pharmaceutical composition according to claim 2, wherein the excipient is a diluent.

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