New substituted sulfonylurea and sulfonylimide urea derivatives

Abstract

The present invention relates to a novel compound of general formula (I), its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers and polymorphs. The present invention also relates to a method for preparing the compound of the present invention, a pharmaceutical composition comprising the compound, and the use of the compound of the present invention belonging to the family of NOD-like receptor family (NLR) protein NLRP3 regulators. Therefore, the present invention relates to the use of novel NLRP3 regulators and novel inhibitor compounds in the treatment of diseases or conditions involving interleukin 1β activity.

Description

Field of the Invention

[0001] The present invention relates to a novel compound of general formula (I), its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers and polymorphs. The present invention also relates to a method for preparing the compound of the present invention, a pharmaceutical composition comprising the compound, and the use of the compound of the present invention belonging to the family of NOD-like receptor family (NLR) protein NLRP3 regulators. Therefore, the present invention relates to the use of novel NLRP3 regulators and novel inhibitor compounds in the treatment of diseases or conditions 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 pathogens, environmental and host-derived factors. (Wen et al., Immunity. 2013; 39: 432–441). Activation of NLRP3 leads to binding to the apoptosis-associated speck-like protein (ASC) containing CARD. ASC in turn interacts with the cysteine ​​protease caspase-1 to form a complex called inflammasome. This leads to the activation of caspase-1, which cleaves the proinflammatory cytokines IL-1β and IL-18 into their activated forms and mediates a type of inflammatory cell death called pyroptosis. Other intracellular pattern recognition receptors (PRRs) can also form inflammasomes. These include other NLR family members, such as NLRP1 and NLRC4, and non-NLR PRRs, such as the double-stranded DNA (dsDNA) sensor melanoma deficiency factor 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 through 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 liver immune cells, including Kupffer cells, infiltrating macrophages, hepatocytes and hepatic stellate cells. The activation of inflammasomes depends on two consecutive signals. Signal 1 is driven by TLR and IL-1R signaling, including the expression of component proteins including NLRP3, ASC, caspase-1, IL-1β and IL-18. Signal 2 is provided by danger signals (DAMPS), which are mainly released by stressed or dying hepatocytes or via "leaky" intestines (PAMPs) during the occurrence of NASH. This process leads to oligomerization of inflammasome components and cleavage of caspase-1, leading to the release of activated proinflammatory 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 proinflammatory cytokines interleukin-1β (IL-1β) and interleukin-18 (IL-18). The NLRP3 inflammasome is an integral part of the inflammatory process, and its abnormal activation is pathogenic in inherited disorders (e.g., rare periodic fever syndromes, cold pyrin-associated periodic syndrome (CAPS), tumor necrosis factor receptor-associated periodic syndrome (TRAPS)) and complex diseases (e.g., multiple sclerosis, type 2 diabetes, atherosclerosis, asthma, gouty arthritis, and inflammatory central nervous system (CNS) diseases including Alzheimer's disease and other brain diseases). (Masters et al., Annu Rev Immunol. 2009; 27: 621–668; Strowig et al., Nature 2012, 481, 278-286; Guo et al., Nat. Med. 2015, 21, 677; Ising et al., Nature 2019, 575, 669–673)

[0005] Inflammation is a basic host response to infection and injury. Regulation of the proinflammatory cytokine interleukin-1β (IL-1β) is the core of the host's response to infection, and also causes tissue damage when it is improperly activated. (Dinarello et al., Nat. Rev. Drug Discovery 2012, 11, 633-652.) NLRP3 inflammasome activation plays a key role in each component of the activation of hepatic stellate cells (HSC) including the induction of proinflammatory signaling, hepatocyte injury and cell death, and collagen deposition and liver fibrosis. In particular, the conversion from NAFLD to NASH is associated with NLRP3-inflammasome activation and increased expression of inflammasome-related components including apoptosis-related speck-like protein (ASC) containing carboxyl-terminal CARD, caspase-1 (CASP-1) and pan-linked proteins. (Mridha et al., Journal of Hepatology, 2017, 66 (5), 1037-1046)

[0006] Current treatments for NLRP3-related diseases include biologic agents that target 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] Inhibition of IL-1β and IL-18 using NLRP3 inflammasome inhibitors would be an effective treatment during cytokine storms and may be a reasonable treatment option for diseases such as severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), Spanish flu, COVID19 (coronavirus disease 2019), hepatitis C virus, Kikenyi virus, influenza A virus, herpes simplex virus type 1, and Japanese encephalitis virus, in which high levels of interleukin (IL)-1β and / or IL-18 are associated with inflammation and pathogenesis (Lancet 2020, 395, (10223), 497-506; The FASEB Journal 2020, 33, 8865-6677).

[0008] Wipo patent applications Nos. WO98 / 32733, WO2001 / 019390, WO2014 / 190015, WO2016 / 123229, and WO2016 / 131098 disclose sulfonylurea derivatives and related compounds as NLRP3 inflammasome inhibitors. WO2017 / 017469 discloses certain cyclic diarylboron derivatives as NLRP3 inflammasome inhibitors for the treatment of diseases or conditions 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 / 068772, WO2020 / 035466, WO2020 / 208249, WO2020 / 035465, WO2020 / 254697, also disclose certain classes of compounds as NLRP3 inhibitors.

[0009] We disclose herein novel compounds of general formula (I) that are NLRP3 modulators for the prevention and treatment of disease states mediated by NLRP3 or conditions in which interleukin 1β activity is involved, including inflammation, gouty arthritis, type 2 diabetes, atherosclerosis, and liver fibrosis. More particularly, embodiments of the present invention may be used as therapeutic agents for the treatment of a variety of pathological conditions, including, but not limited to, lymphomas, autoimmune diseases, heteroimmune diseases, inflammatory diseases, cancers, and neurodegenerative diseases or conditions. Summary of the invention

[0010] The present invention discloses novel compounds as defined by general formula (I), which are NLRP3 modulators for preventing and treating disease states mediated by NLRP3 and treating diseases or conditions in which interleukin 1β activity is involved. The compounds of the present invention can be used to treat the human or animal body by inhibiting NLRP3. Therefore, the compounds of the present invention are suitable for preventing and treating disease states mediated by NLRP3.

[0011] Embodiments of the present invention

[0012] The embodiments of the present invention provide novel compounds represented by the 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, a pharmaceutical composition is provided, which comprises a compound of the general formula (I), its tautomeric form, its enantiomer, its diastereomer, its stereoisomer, its pharmaceutically acceptable salt or a mixture thereof in combination with a suitable carrier, solvent, diluent and other solvents commonly used for the preparation of such compositions.

[0014] In another embodiment, there is provided a use of the compound of the present invention as a NLRP3 modulator by administering to a mammal a therapeutically effective and non-toxic amount of a compound of formula (I) or a pharmaceutically acceptable composition thereof.

[0015] In yet another embodiment, the compounds of formula (I) of the present invention may be used in combination with one or more suitable pharmaceutically active agents.

[0016] In another embodiment, processes for preparing the novel compounds of the invention are provided. DETAILED DESCRIPTION

[0017] Therefore, the present invention relates to compounds of general formula (I)

[0018]

[0019] Its tautomeric form, its stereoisomer, its enantiomer, its pharmaceutically acceptable salt and pharmaceutical composition containing them, wherein

[0020] R 1 and R 2 Each of the above independently represents hydrogen, halogen, haloalkyl, cyano, an optionally substituted group selected from the following: 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 )Alkyl SO 2 (C 1 -C 6 ) alkyl, (C 1 -C 6 )alkylN(C 1 -C 6 ) alkyl, (C 1 -C 6 )alkylN(C3 -C 7 )cycloalkyl, aryl, heteroaryl, heterocyclic, 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 )Alkyl SO 2 NH 2 、-CONH 2 、-CO(C 1 -C 6 )alkyl, -CO(C 1 -C 6 ) halogenated alkyl, CO(O)(C 1 -C 6 ) alkyl, -CO-aryl, -CO-heteroaryl, -CO-heterocyclyl, a 4- to 7-membered heterocycle, a 7- to 14-membered bicyclic heterocyclic ring system, a bridged ring or a spiro ring system optionally having one or more heteroatoms; or R 1 , R 2 Together with N, it can form a saturated or partially saturated 3- to 8-membered heterocyclic ring system, a 7- to 14-membered bicyclic heterocyclic ring system, a bridged ring or a spiro ring system optionally having one or more heteroatoms;

[0021] R 3 and R 4 Each of the above, at each occurrence, represents hydrogen, halogen, haloalkyl, cyano, nitro, amide, sulfonamide, acyl, hydroxyl, an optionally substituted group 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, mercaptoalkylbenzyl, aryl, heteroaryl, heterocyclic; or R 3 and R 4 can form bonds;

[0022] X is O, NR 6 ; R 6 represents independently at each occurrence hydrogen, hydroxy, halogen, nitro, cyano, haloalkyl, an optionally substituted group selected from the group consisting of: (C 1 -C 10 ) alkyl, (C 1 -C 10 ) alkoxy, (C 3 -C 10 )cycloalkyl, (C 2 -C 10 ) alkenyl, (C 2 -C 10 )Alkynyl, SO 2 (C 1 -C 6 ) alkyl, thiol, thioalkyl, thioalkoxy, SO 2 (C 1 -C 6 )alkyl, SO(C 1 -C 6 ) alkyl, benzyl, aryl, heteroaryl, heterocyclyl;

[0023] n is independently selected from integers 0 to 3;

[0024] R 5 represents independently at each occurrence hydrogen, halogen, haloalkyl, cyano, an optionally substituted group selected from the group consisting of: (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 2 -C 6 ) alkenyl, (C 3 -C 7 )cycloalkyl, benzyl, aryl, heteroaryl, heterocyclic, thiol, thioalkyl, thioalkoxy, SO 2 (C 1 -C 6 )alkyl, SO(C 1 -C 6 ) alkyl, a bridged ring or a spiro ring system optionally having one or more heteroatoms;

[0025] "A" is selected from the following ring systems

[0026]

[0027] Where X, Y, and Z represent C, N, S, and SO independently at each occurrence. 2 and O, which may be optionally substituted;

[0028] R 7, R 8 , R 9 , R 10 , R 11 and R 12 is independently selected at each occurrence from hydrogen, halogen, cyano, amide, sulfonamide, acyl, hydroxyl, an optionally substituted group 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 R 8 and R 9 , R 9 and R 10 , R 10 and R 11 and R 11 and R 12 Each of which, if possible, may together form a p a 4- to 7-membered saturated or partially saturated ring having an additional heteroatom; p=1 to 2.

[0029] When any of the above defined groups is substituted, the substitutions therefor 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 10 ) cycloalkyl, C 1 -(C 1 -C 6 ) alkoxy, aryl, heterocyclic, heteroaryl, -COR 11 、-CSR 11 、C(O)OR 11 、C(O)-R 11 、-C(O)-NR 11 R 12 、-C(S)-NR 11 R 12 、-SO 2 R 11 Group, where R 11 and R 12 Each of which is independently selected from hydrogen, an optionally substituted group selected from the following: (C1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 3 -C 7 ) cycloalkyl, aryl, heteroaryl, heterocyclyl groups;

[0030] In a preferred embodiment, R 3 and R 4 Each of the following is independently selected at each occurrence from hydrogen, halogen, an optionally substituted group selected from the following: (C 1 -C 6 )alkyl;

[0031] In a preferred embodiment, R 5 Each occurrence independently represents hydrogen, halogen, an optionally substituted group selected from the following: (C 1 -C 6 )alkyl;

[0032] In a preferred embodiment, R 6 Each occurrence independently represents hydrogen, cyano;

[0033] In a preferred embodiment, R 7 , R 8 , R 9 , R 10 , R 11 and R 12 Each of the following is independently selected at each occurrence from hydrogen, halogen, hydroxy, an optionally substituted group selected from the following: (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl;

[0034] In a preferred embodiment, the groups described above may be selected from:

[0035] "Alkyl" and other groups with the prefix "alk", such as alkoxy and alkanoyl, mean a carbon chain which may be further substituted with oxygen atoms, which may be straight or branched, and combinations thereof, as is well known to those skilled in the art, 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, and the like, where the number of carbon atoms specified allows, such as C 3-10 The term alkyl also includes cycloalkyl, and combinations of straight or branched alkyl chains combined with cycloalkyl structures. When the number of carbon atoms is not specified, it means C 1-6Substituted alkyl groups include alkyl groups substituted with one or more moieties selected from the group consisting of 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 ), hydroxyl, amino, carboxylate, carboxamido, alkylamino, arylamino, alkoxy, aryloxy, nitro, azido, cyano, thio, sulfonic acid, sulfate, phosphonic acid, phosphate and phosphonate, and those described under the definition of "optionally substituted".

[0036] "Alkenyl" means a carbon chain containing at least one carbon-carbon double bond, and it may be linear or branched, or a combination thereof, unless otherwise defined for carbon chain. Examples of alkenyl include, but are not limited to, vinyl, allyl, isopropenyl, hexenyl, pentenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl, and the like, where the number of carbon atoms specified permits, e.g., C 5-10 The term alkenyl also includes cycloalkenyl and combinations of straight chain, branched chain and cyclic structures. When the number of carbon atoms is not specified, it means C 2-6 .

[0037] "Alkynyl" means a carbon chain containing at least one carbon-carbon triple bond, and it may be linear or branched or a combination thereof. Examples of alkynyl include ethynyl, propargyl, 3-methyl-1-pentynyl, etc. When no carbon number is specified, it means

[0038] A "thioalkyl" group, used alone or in combination with other groups, refers to an alkyl group as defined above attached to a group of the formula -SR' (sulfur and its oxidized forms) (wherein R' represents hydrogen, an alkyl or aryl group), for example, thiomethyl, methylthiomethyl, phenylthiomethyl, etc., which may be optionally substituted.

[0039] As used herein, "carbocycle" or "carbocyclic residue" is intended to mean any stable monocyclic or bicyclic or tricyclic ring, any of which may be saturated, partially unsaturated or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl or tetrahydronaphthyl (tetrahydronaphthalene). In a broader view, the term carbocycle is intended to include, where applicable, groups representing cycloalkyl, phenyl and other saturated, partially saturated or aromatic residues;

[0040] 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 6 Cycloalkyl or cycloalkenyl include within their scope carbocyclic groups having 3, 4, 5 or 6 carbon atoms. Examples of such substituents may be selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, etc. Substituted cycloalkyl or cycloalkenyl include substituted with one or more moieties selected from the group consisting of 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 ), hydroxyl, amino, carboxylate, carboxamido, alkylamino, arylamino, alkoxy, aryloxy, nitro, azido, cyano, thio, sulfonic acid, sulfate, phosphonic acid, phosphate and phosphonate, and those described under the definition of "optionally substituted".

[0041] "Alkoxy" refers to a straight or branched chain alkoxide having a specified number of carbon atoms.

[0042] "Aryl" means a monocyclic or polycyclic aromatic ring system containing carbon ring atoms. Preferred aryl groups are monocyclic or bicyclic 6 to 10 membered aromatic ring systems. Phenyl and naphthyl are preferred aryl groups.

[0043] "Heterocyclyl" refers to a saturated, partially saturated or unsaturated aromatic or non-aromatic monocyclic, bicyclic 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 system may be attached to the other moieties via any number of carbon atoms or heteroatoms and may be 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, dihydropyran, oxathiolane, dithiolane, 1,3-dioxane, 1,3-dithiane, oxathiolane, thiomorpholine, and the like. The term "heterocycloalkyl" refers to a heterocyclic group as defined above attached to an alkyl group as defined above;

[0044] "Heteroaryl" means an aromatic or partially aromatic heterocycle containing at least one ring heteroatom selected from O, S and N. Thus, heteroaryl includes heteroaryl fused to other types of rings, such as aryl, cycloalkyl and non-aromatic heterocycles. Examples of heteroaryl groups include: pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridinyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, pyrimidinyl, benzisoxazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, dihydrobenzofuranyl, indolyl, pyridazinyl, indazolyl, isoindole ... In some embodiments, the present invention includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 51, 52, 53, 54, 55, 56, 57, 58, 59, 61, 62, 63, 64, 65, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 101, 102, 113, 124, 135, 147, 159, 119, 129, 130, 131, 132, 148, 15

[0045] 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 all identical to each other.

[0046] A "haloalkoxy" group is selected from a suitable haloalkyl group as defined above directly attached to an oxygen atom, more preferably selected from fluoromethoxy, chloromethoxy, fluoroethoxy, chloroethoxy and the like;

[0047] In certain other embodiments where two or more hydrogen atoms are replaced with halogen atoms, the halogen atoms are not all identical to one another.

[0048] "Aryloxyalkyl" means an alkyl group substituted with an aryloxy group as defined herein.

[0049] "Aryloxyaryl" means an aryl group substituted with an aryloxy group as defined herein.

[0050] "Aryloxyheteroaryl" means a heteroaryl group substituted with an aryloxy group as defined herein.

[0051] "Halo / halogen" refers to fluorine, chlorine, bromine, iodine. Chlorine and fluorine are generally preferred.

[0052] Suitable groups and substituents on these groups may be selected from those described anywhere in the specification.

[0053] As used herein, the term "substituted" means that any one or more hydrogens on a designated atom are replaced by a selected designated group, provided that the normal valence of the designated 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 designated atom are replaced by a selected designated group, provided that the normal valence of the designated atom is not exceeded, and the substitution results in a stable compound.

[0054] "Pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds in which the parent compound is modified by preparing acid or base salts thereof. 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 1,2-ethanedisulfonic acid, 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonic acid, carbonic acid, citric acid, ethylenediaminetetraacetic acid, ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, glycolylaminophenylarsonic acid (glycollyars nilic), hexylresorcinic acid, hepatoic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxymaleic acid, hydroxynaphthoic acid, isethionic acid, lactic acid, lactobionic acid, laurylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, naphthalenesulfonic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, acetic acid, succinic acid, sulfamic acid, sulfanilic acid, sulfuric acid, tannic acid, tartaric acid and toluenesulfonic acid.

[0055] The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where the event or circumstance does not occur. For example, an optionally substituted alkyl group refers to "alkyl" or "substituted alkyl". In addition, optionally substituted groups include unsubstituted groups.

[0056] Unless stated otherwise in the specification, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.

[0057] Particularly useful compounds may be selected from, but are not limited to, the following:

[0058] (E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-(isopropylamino)prop-1-ene-1-sulfonamide;

[0059] (E)-3-(Dimethylamino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)prop-1-ene-1-sulfonamide;

[0060] (E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-(methyl(propyl)amino)prop-1-ene-1-sulfonamide;

[0061] (E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-(propylamino)prop-1-ene-1-sulfonamide;

[0062] (E)-3-((Cyclopropylmethyl)amino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)prop-1-ene-1-sulfonamide;

[0063] (E)-3-((Cyclopropylmethyl)(methyl)amino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)prop-1-ene-1-sulfonamide;

[0064] (E)-3-(Ethyl(methyl)amino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)prop-1-ene-1-sulfonamide;

[0065] (E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-(N-methylmethylsulfonamido)prop-1-ene-1-sulfonamide;

[0066] (E)-N-(3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)allyl)-N-methylcyclopropanesulfonamide;

[0067] (E)-N-(3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)allyl)-N-methylcyclohexanesulfonamide;

[0068] (E)-N-(3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)allyl)cyclohexanesulfonamide;

[0069] (E)-3-((cyclohexylmethyl)amino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)prop-1-ene-1-sulfonamide;

[0070] (E)-3-((cyclohexylmethyl)(methyl)amino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)prop-1-ene-1-sulfonamide;

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

[0072] (E)-N-(3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)allyl)-N-methylacetamide;

[0073] (E)-N-(3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)allyl)-N-methylcyclopropanecarboxamide;

[0074] (E)-N-((2,6-diisopropylphenyl)carbamoyl)-3-(dimethylamino)prop-1-ene-1-sulfonamide;

[0075] (E)-N-((2,6-diisopropyl-4-methylphenyl)carbamoyl)-3-(dimethylamino)prop-1-ene-1-sulfonamide;

[0076] (E)-3-(Dimethylamino)-N-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)prop-1-ene-1-sulfonamide;

[0077] (E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-(methyl(phenyl)amino)prop-1-ene-1-sulfonamide;

[0078] (E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-(phenylamino)prop-1-ene-1-sulfonamide;

[0079] (E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-(thiazol-2-ylamino)prop-1-ene-1-sulfonamide;

[0080] (E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-(methyl(thiazol-2-yl)amino)prop-1-ene-1-sulfonamide;

[0081] (E)-N'-cyano-3-(dimethylamino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)prop-1-ene-1-sulfonylimideamide;

[0082] (E)-N'-cyano-3-(ethyl(methyl)amino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)prop-1-ene-1-sulfonylimideamide;

[0083] (E)-N'-cyano-3-((cyclopropylmethyl)(methyl)amino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)prop-1-ene-1-sulfonylimideamide;

[0084] (E)-N'-cyano-3-((cyclopropylmethyl)amino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)prop-1-ene-1-sulfonylimideamide;

[0085] (E)-N'-cyano-3-(dimethylamino)-N-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)prop-1-ene-1-sulfonylimideamide;

[0086] (E)-3-((cyclopropylmethyl)amino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)prop-1-ene-1-sulfonylimideamide;

[0087] (E)-3-((cyclopropylmethyl)(methyl)amino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)prop-1-ene-1-sulfonylimideamide;

[0088] (E)-3-(dimethylamino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)prop-1-ene-1-sulfonylimideamide;

[0089] (E)-3-(Dimethylamino)-N-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)prop-1-ene-1-sulfonylimideamide;

[0090] (E)-3-(dimethylamino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-N'-methylprop-1-ene-1-sulfonylimideamide;

[0091] (E)-N'-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-(methyl(oxetan-3-yl)amino)prop-1-ene-1-sulfonylimideamide;

[0092] (E)-N'-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-(oxetan-3-ylamino)prop-1-ene-1-sulfonylimideamide;

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

[0094] (E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-(oxetan-3-ylamino)prop-1-ene-1-sulfonamide;

[0095] (E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)prop-1-ene-1-sulfonamide;

[0096] (E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)prop-1-ene-1-sulfonamide;

[0097] (E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-(5-(methylsulfonyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)prop-1-ene-1-sulfonamide;

[0098] (E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)prop-1-ene-1-sulfonamide;

[0099] (E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)prop-1-ene-1-sulfonamide;

[0100] (E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-(3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)prop-1-ene-1-sulfonamide;

[0101] (E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-3-(5-(methylsulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)prop-1-ene-1-sulfonamide.

[0102] or a pharmaceutically acceptable salt of any of the above compounds.

[0103] The following is a list of abbreviations used in the description of the preparation of the compounds of the present invention:

[0104] μg: microgram

[0105] 1 H NMR: proton nuclear magnetic resonance

[0106] bs: wide single peak

[0107] CDC1 3 : Deuterated chloroform

[0108] CHC1 3 :Chloroform

[0109] d: Twin Peaks

[0110] DAMP: damage-associated molecular pattern;

[0111] DBU: 1,8-diazabicyclo(5.4.0)undec-7-ene

[0112] DCM: dichloromethane

[0113] dd: double double peaks

[0114] DMAC: N,N-(dimethylacetamide)

[0115] DMAP: 4-(dimethylamino)pyridine

[0116] DMF: N,N-dimethylformamide

[0117] DMSO: dimethyl sulfoxide

[0118] dt: double triple peak

[0119] EDTA: Ethylenediaminetetraacetic acid

[0120] EtOAc: Ethyl acetate

[0121] EtOH: ethanol

[0122] HCl(g): Hydrogen chloride (gas)

[0123] IL1β: interleukin 1β

[0124] K2 CO 3 :Potassium carbonate

[0125] m: multiple peaks

[0126] MeOH: Methanol

[0127] mmol: millimole

[0128] MS: Mass spectrometry

[0129] N 2 :Nitrogen

[0130] Na 2 CO 3 :Sodium carbonate

[0131] ng: nanogram

[0132] NIS: N-iodosuccinimide

[0133] PAMP: pathogen-associated molecular pattern;

[0134] PMA = phorbol 12-myristate 13-acetate

[0135] POCI 3 :Phosphorus oxychloride

[0136] RM: reaction mixture

[0137] rt,RT: room temperature

[0138] s: Single peak

[0139] t: Three Peaks

[0140] td: triple double peaks

[0141] THF: Tetrahydrofuran

[0142] TLC: Thin layer chromatography

[0143] TLR: Toll-like receptor.

[0144] TNFα: tumor necrosis factor alpha

[0145] General method for preparation

[0146] The novel compounds of the present invention can be prepared using the reactions and techniques described below, together with conventional techniques known to those skilled in the art of organic synthesis or variations thereof as appreciated by those skilled in the art.

[0147] The reactions may be performed in solvents appropriate to the reagents and materials employed and suitable for the transformations being effected. Preferred methods include, but are not limited to, those described below, in which all symbols are as defined above unless otherwise defined below.

[0148] Compounds of general formula (I) can be prepared as described in the following schemes with appropriate modifications / variations within the purview of those skilled in the art.

[0149] Solution 1

[0150]

[0151] Among them, 'A', R 1 , R 2 , R 3 , R 4 and R 5 As defined above. Compound (2) can be prepared by commercially available methanesulfonamide (1) using reagents such as Boc anhydride by a variety of methods familiar to those skilled in the art. Compound (2) is treated with diphenylphosphinyl chloride under suitable conditions and suitable solvents to obtain compound (3) (reference Synthesis 2003, 15, 2321-24). Under suitable conditions, in the presence of a base (such as sodium hydride) and a suitable solvent, compound (3) is treated with an aldehyde or ketone derivative (4) to obtain compound (5), which can be deprotected under suitable conditions to obtain compound (6). Under suitable conditions, in the presence of a base (such as sodium hydride) and a suitable solvent, compound (6) is treated with an isocyanate derivative (7) to obtain compound (8). The protecting group of compound (8) is deprotected, and then the compound of formula (I) is obtained by treating with an appropriate substituted aldehyde or ketone or by treating with an alkyl halide.

[0152] The specific reaction conditions, solvents and other parameters required to carry out the process steps as described above are within the capabilities of those skilled in the art.

[0153] The present invention is further illustrated by the following non-limiting examples which describe preferred modes of carrying out the invention. These are not intended to limit the scope of the invention in any way.

[0154] The examples given in the 1 H NMR spectral data (see below) were recorded using a 400 MHz spectrometer (Bruker AVANCE-400) and are reported on the delta scale. Unless otherwise stated, the solvent used for NMR was CDCl 3 , using TMS as the internal standard.

[0155] Example-1

[0156] Preparation of (E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-(isopropylamino)prop-1-ene-1-sulfonamide

[0157] Intermediate-1a: Preparation of tert-butyl (E)-((3-((tert-butoxycarbonyl)amino)prop-1-en-1-yl)sulfonyl)carbamate

[0158]

[0159] 250mL, three-necked, round-bottomed flask is equipped with magnetic stirrer, N2 air bag, insulation bag, dry ice bath.Under nitrogen atmosphere, ((diphenylphosphoryl) methyl) sulfonyl carbamic acid tert-butyl ester (Synthesis 2003,15,2321-24) (1 equivalent) is dissolved in DMF (100ml).It is cooled to -20 ℃ and NaH (2.2 equivalents) is added.It is gradually warmed to 25 ℃ and stirred for 30 minutes.It is cooled to -20 ℃ again, and the DMF solution of (2-oxoethyl) carbamic acid tert-butyl ester (CASNo.:89711-08-0) (1.2 equivalents) is added dropwise at -20 ℃, lasting 1 hour.After addition, the reaction mixture is warmed to room temperature, and stirred for another 17 hours.The reaction mixture is cooled to 0 ℃, and acidified with saturated citric acid solution (30mL) and water (200mL). The reaction mixture was extracted with ethyl acetate and the organic layers were collected and dried to give tert-butyl (E)-((3-((tert-butoxycarbonyl)amino)prop-1-en-1-yl)sulfonyl)carbamate (25% yield).

[0160] 1 H NMR (400 MHz, DMSO-d 6 ): δ=11.28(s,1H),7.29(t,J=5.6Hz,1H),6.76–6.70(m,1H),6.58(d,J=15.2Hz,1H), 3.88–3.70(m,2H),1.41(s,9H),1.39(s,9H); MS(TOF): m / z(%)=359.1603(80%)(M+Na) + ,335.1516(100%)(M-1)

[0161] Intermediate-1b: Preparation of tert-butyl (E)-((3-((tert-butoxycarbonyl)amino)-3-methylbut-1-en-1-yl)sulfonyl)carbamate

[0162]

[0163] Intermediate-1b was also prepared according to the procedure described for the synthesis of Intermediate-1a using tert-butyl (2-methyl-1-oxopropan-2-yl)carbamate (CAS No.: 109608-77-7).

[0164] 1 H NMR (400 MHz, DMSO-d 6 ): δ=11.25(s,1H),7.07(s,1H),6.84(d,J=15.6Hz,1H),6.45(d,J=15.2Hz,1H), 1.41 (s, 9H), 1.37 (s, 9H), 1.31 (s, 6H); MS (TOF): m / z (%) = 363.1556 (80%) (M+Na) + .

[0165] Intermediate-2a: Preparation of tert-butyl (E)-(3-sulfamoylallyl)carbamate

[0166]

[0167] Intermediate 1 (equivalent) was dissolved in DMSO (30 ml) and heated to 80 ° C for 2 hours (disappearance of starting material was monitored by TLC). The reaction was cooled, poured into water (100 ml) and extracted with EtOAc (3 x 100 ml). The solvent was concentrated in vacuo and purified by silica gel column chromatography (50% EtOAc: n-hexane) to give the product (E)-tert-butyl (3-sulfamoylallyl) carbamate (89% yield).

[0168] 1 H NMR (400 MHz, DMSO-d 6 ): δ = 7.24 (t, J = 5.6Hz, 1H), 6.99 (s, 2H), 6.49–6.38 (m, 2H), 3.74–3.71 (m, 2H), 1.39 (s, 9H); MS (TOF): m / z (%) = 259.0998 (100%) (M+Na) + ,2.350928(40%)(M-1).

[0169] Intermediate-2b: Preparation of tert-butyl (E)-(2-methyl-4-sulfamoylbut-3-en-2-yl)carbamate

[0170]

[0171] Intermediate-2b was also prepared according to the procedure described for the synthesis of Intermediate-2a using tert-butyl (E)-((3-((tert-butoxycarbonyl)amino)-3-methylbut-1-en-1-yl)sulfonyl)carbamate.

[0172] 1 H NMR (400 MHz, DMSO-d 6): δ = 6.96 (s, 3H), 6.60 (d, J = 15.2Hz, 1H), 6.27 (d, J = 15.2Hz, 1H), 1.39 (s, 9H), 1.30 (s, 6H); MS (TOF): m / z (%) = 287.1022 (50%) (M+Na) + .

[0173] Intermediate-3: Preparation of tert-butyl (E)-(3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)allyl)carbamate.

[0174]

[0175] To a solution of sulfonamide [Intermediate 2] (1 eq.) in DMF (220 ml) was added DBU (2.2 eq.) at 0°C. The reaction was allowed to warm to room temperature and stirred for 30 minutes. 4-Isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (1.2 eq.) was added in portions at 0°C, the reaction was allowed to warm to room temperature and stirred overnight. The reaction was acidified to pH = 2.0 using 50% aqueous citric acid, diluted with water (1500 ml), the precipitate was filtered through a Buchner funnel and dried to give the product (76% yield).

[0176] 1H NMR (400MHz, DMSO-d6): δ = 10.49 (brs, 1H), 8.09 (s, 1H), 7.28 (t, J = 5.6Hz, 1H), 6.96 (s, 1H), 6.78–6.72 (m, 1H), 6.67 (d, J = 15.6Hz, 1H), 3 .96–3.85(m,2H),2.81(t,J=7.2Hz,4H),2.01(t,J=7.2Hz,4H),2.01–1.94(m,4H),1.42(s,9H); MS(ESI):m / z(%)=434.1724(100%)(M-1).

[0177] Intermediate-4 :Preparation of (E)-3-amino-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)prop-1-ene-1-sulfonamide 2,2,2-trifluoroacetate

[0178]

[0179] To a solution of intermediate 3 (1 eq) in DCM (2.5 ml) was added TFA (10 eq) at 0°C. The reaction was allowed to warm to room temperature and stirred for an additional 3 hours. The reaction mixture was concentrated in vacuo and purified to give the product.

[0180] 1 H NMR (400 MHz, DMSO-d 6 ): δ=10.87(brs,1H),8.14(s,1H),8.02(s,3H),7.05(d,J=15.2Hz,1H),6.97(s,1H),6.80–6.74(m,1H),3.89–3.6 9(m,2H),2.81(t,J=7.2Hz,4H),2.01(t,J=7.2Hz,4H),2.01–1.94(m,4H); MS(ESI):m / z(%)=336.1316(100%)(M+H) + ,334.1172(100%)(M-1).

[0181] Example-1

[0182] (E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-3-(isopropylamino)prop-1-ene-1-sulfonamide

[0183]

[0184] To a solution of intermediate 4 (1 eq.) in MeOH (7.0 mL) was added triethylamine (2.5 eq.) at room temperature and stirred for 5 min. Acetone (3.5 eq.) was added at room temperature and stirred for 2 h. Thereafter, NaCNBH 3 The reaction mixture was treated with 2-(4-(2-hydroxy-1-piperidin-2-yl)-2-nitropropene (1.5 equiv.) and then allowed to warm to room temperature and stirred overnight. The reaction mixture was purified by preparative HPLC to give the pure product.

[0185] 1 H NMR (400 MHz, DMSO-d 6 ):δ=8.28(br s,1H),7.51(s,1H),6.97(d,J=15.6Hz,1H),6.80(s,1H),6.36–6.29(m,1H),3.64(d,J=6.4Hz,2H),3.20–3.14(m,1H),2.77 (t,J=7.6Hz,4H),2.70(t,J=7.2Hz,4H),1.96–1.88(m,4H),1.16(d,J=6.4Hz,6H); MS(ESI):m / z(%)=378.1787(100%)(M+H) + ,376.1640(100%)(M-1).

[0186] The following compounds were prepared in a similar manner using appropriate starting materials and appropriate modification of the method described in Example 1, including appropriate addition and / or deletion of steps as may be necessary (which is within the scope of those skilled in the art).

[0187] Example-2

[0188] (E)-3-(Dimethylamino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)prop-1-ene-1-sulfonamide

[0189] To a solution of intermediate 4 (1 eq.) in MeOH (7.0 mL) was added triethylamine (2.5 eq.) at room temperature and stirred for 5 min. Paraformaldehyde (5 eq.) was added at room temperature and stirred for 2 h. Thereafter, NaCNBH 3 The reaction mixture was treated with 2-(4-(2-hydroxy-1-piperidin-2-yl)-2-nitropropene (2.5 equiv.) and then allowed to warm to room temperature and stirred overnight. The reaction mixture was purified by preparative HPLC to give the pure product.

[0190]

[0191] 1 H NMR (400 MHz, DMSO-d 6 ): δ=10.22(brs,1H),7.94(s,1H),6.91(s,1H),6.86(d,J=15.2Hz,1H),6.62–6.55(m,1H),3.27(t,J=6.0Hz,2H),2. 79(t,J=7.2Hz,4H),2.67(t,J=7.2Hz,4H),2.30(s,6H),1.99–1.91(m,4H); MS(ESI):m / z(%)=364.1513(100%)(M+H) + .

[0192] Example-3

[0193] (E)-3-Amino-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)prop-1-ene-1-sulfonamide 2,2,2-trifluoroacetate

[0194]

[0195] 1 H NMR (400 MHz, DMSO-d 6): δ=10.87(brs,1H),8.14(s,1H),8.02(s,3H),7.05(d,J=15.2Hz,1H),6.97(s,1H),6.80–6.74(m,1H),3.89–3.6 9(m,2H),2.81(t,J=7.2Hz,4H),2.01(t,J=7.2Hz,4H),2.01–1.94(m,4H); MS(TOF):m / z(%)=336.1316(100%)(M+H) + ,334.1172(100%)(M-1).

[0196] Example-4

[0197] (E)-3-(Dipropylamino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)prop-1-ene-1-sulfonamide

[0198]

[0199] 1 H NMR (400 MHz, DMSO-d 6 ): δ=10.27(brs,1H),8.02(s,1H),6.94(s,1H),6.88(d,J=15.2Hz,1H),6.67–6.37(m,1H),3.45–3.28(m,2H),2.80(t,J=7.2Hz,4H),2.67(t ,J=7.2Hz,4H),2.41(t,J=6.8Hz,4H),2.00–1.92(m,4H),1.45–1.36(m,4H),0.82(t,J=7.2Hz,6H); MS(TOF):m / z(%)=420.2633(100%)(M+H) + ,418.2245(100%)(M-1).

[0200] Example-5

[0201] (E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-(isopropyl(methyl)amino)prop-1-ene-1-sulfonamide

[0202]

[0203] 1 H NMR (400 MHz, DMSO-d 6): δ=7.89(s,1H),6.90–6.86(m,2H),6.61–6.54(m,1H),3.60–3.37(m,2H),3.02–2.99(m,1H),2.79(t,J=7.2Hz,4H), 2.67(t,J=7.2Hz,4H),2.27(s,3H),1.99–1.91(m,4H),1.01(d,J=6.8Hz,6H); MS(TOF):m / z(%)=392.1983(100%)(M+H) + ,390.1817(100%)(M-1).

[0204] Example-6

[0205] (E)-3-(Dimethylamino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-methylbut-1-ene-1-sulfonamide

[0206]

[0207] 1 H NMR (400 MHz, DMSO-d 6 ): δ=7.88(s,1H),6.90(s,1H),6.71(d,J=15.6Hz,1H),6.60(d,J=15.2Hz,1H),2.77(t,J=7.2Hz,4H),2.6 7(t,J=7.2Hz,4H),2.32(s,6H),1.98–1.91(m,4H),1.21(s,6H); MS(TOF):m / z(%)=392.1992(100%)(M+H) + ,390.1819(100%)(M-1).

[0208] Example-7

[0209] (E)-tert-Butyl (4-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-2-methylbut-3-en-2-yl)carbamate

[0210]

[0211] 1 H NMR (400 MHz, DMSO-d 6): δ=9.05(s,1H),7.81(s,1H),6.95(s,1H),6.89(s,1H),6.72(d,J=16.0Hz,1H),6.56(d,J=15.2Hz,1H),2.79(t,J=7.2Hz,4H),2. 79(t,J=7.2Hz,4H),2.68(t,J=7.2Hz,4H),1.98–1.91(m,4H),1.36(s,9H),1.21(s,6H); MS(TOF):m / z(%)=462.2029(100%)(M-1).

[0212] Example-8

[0213] (E)-3-Amino-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-methylbut-1-ene-1-sulfonamide 2,2,2-trifluoroacetate

[0214]

[0215] 1 H NMR (400 MHz, DMSO-d 6 ): δ=10.90(brs,1H),8.42(s,1H),8.32(s,1H),7.81(s,1H),6.97–6.86(m,3H),2.81(t,J=7.2Hz,4 H), 2.69 (t, J=7.2Hz, 4H), 2.01–1.90 (m, 4H), 1.41 (s, 6H); MS (TOF): m / z (%) = 364.1659 (100%) (M+H) + ,364.1659(10%)(M-1).

[0216] Example-9

[0217] (E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-3-((tetrahydro-2H-pyran-4-yl)amino)prop-1-ene-1-sulfonamide

[0218]

[0219] 1 H NMR (400 MHz, DMSO-d 6): δ=7.68(s,1H),6.93(d,J=15.2Hz,1H),6.85(s,1H),6.52–6.46(m,1H), 3.85–3.82(m,2H),3.60(d,J=5.6Hz,2H),3.26–3.20(m,2H),3.04–2.90(m ,1H),2.78(t,J=7.2Hz,4H),2.70(t,J=7.2Hz,4H),1.97–1.90(m,4H),1.8 4–1.81(m,2H),1.42–1.34(m,2H); MS(TOF):m / z(%)=420.1931(100%)(M+H) + .

[0220] Example-10

[0221] (E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-3-((1-methylpiperidin-4-yl)amino)prop-1-ene-1-sulfonamide

[0222]

[0223] 1 H NMR (400 MHz, DMSO-d 6 ): δ=7.61(s,1H),6.88(d,J=15.6Hz,1H),6.85(s,1H),6.42(dt,J=15.2Hz,J =6.0Hz,1H),3.51(d,J=5.6Hz,2H),2.92–2.89(m,2H),2.80(t,J=7.2Hz,4H) ,2.72(t,J=7.2Hz,4H),2.29(s,3H),2.21–2.08(m,2H),2.01–1.94(m,4H),1 .93–1.87(m,3H),1.48–1.40(m,2H); MS(TOF):m / z(%)=433.2725(100%)(M+H) + ,431.2362(20%)(M-1).

[0224] Example-11

[0225] (E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-((tetrahydro-2H-thiopyran-4-yl)amino)prop-1-ene-1-sulfonamide

[0226]

[0227] 1 H NMR (400 MHz, DMSO-d 6 ): δ=7.74(s,1H),6.92(d,J=15.2Hz,1H),6.87(s,1H),6.54–6.51(m,1H),3.57(d,J=5.2Hz,2H),2.79(t,J=7.2Hz,4H),2.71(t,J=7.2Hz,4 H),2.67–2.63(m,2H),2.57–2.51(m,3H),2.18–2.16(m,2H),1.99–1.92(m,4H),1.52–1.42(m,2H); MS(TOF):m / z(%)=436.2359(100%)(M+H) + ,434.1904(50%)(M-1).

[0228] Example-12

[0229] ((E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-3-(isopropylamino)-3-methylbut-1-ene-1-sulfonamide

[0230]

[0231] 1 H NMR (400 MHz, DMSO-d 6 ): δ=7.55(s,1H),6.83–6.80(m,2H),6.47(d,J=16.0Hz,1H),3.23–3.14(m,1H),2.77(t,J=7.2Hz,4H),2.69(t ,J=7.2Hz,4H),1.96–1.89(m,4H),1.37(s,6H),1.13(d,J=6.4Hz,6H); MS(TOF):m / z(%)=406.2135(100%)(M+H) + ,404.1985(30%)(M-1).

[0232] Example-13

[0233] (E)-3-(Cyclohexylamino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-methylbut-1-ene-1-sulfonamide

[0234]

[0235] 1 H NMR (400 MHz, DMSO-d6 ): δ=7.58(s,1H),6.81–6.77(m,2H),6.48(d,J=15.2Hz,1H),2.82–2.80(m,1H), 2.75(t,J=7.2Hz,4H),2.67(t,J=7.2Hz,4H),1.94–1.87(m,4H),1.82–1.73(m,2 H),1.67–1.52(m,2H),1.49–1.41(m,1H),1.32(s,6H),1.21–1.11(m,4H),1.03– 1.01 (m, 1H); MS (TOF): m / z (%) = 446.2445 (100%) (M + H) +, 444.2301 (300%) (M-1).

[0236] Example-14

[0237] ((E)-3-Amino-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-methylbut-1-ene-1-sulfonamide

[0238]

[0239] 1H NMR (400MHz, DMSO-d6): δ = 7.93 (brs, 2H), 7.39 (s, 1H), 6.85 (d, J = 15.6Hz, 1H), 6.76 (s, 1H), 6.36 (d, J = 15.6Hz, 1H), 2 .74(t,J=7.2Hz,4H),2.68(t,J=7.2Hz,4H),1.93–1.85(m,4H),1.31(m,6H); MS(TOF):m / z(%)=364.1665(100%)(M+H) + ,362.1531(10%)(M-1).

[0240] Example-15

[0241] (E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-(methyl(1-methylpiperidin-4-yl)amino)prop-1-ene-1-sulfonamide

[0242]

[0243] 1 H NMR (400 MHz, DMSO-d 6): δ=7.65(s,1H),6.83(s,1H),6.71(d,J=15.6Hz,1H),6.39–6.32(m,1H) ,3.18(d,J=5.2Hz,2H),2.93–2.90(m,2H),2.78(t,J=7.2Hz,4H),2.69(t ,J=7.2Hz,4H),2.24(s,3H),2.17–2.12(m,4H),1.97–1.91(m,6H),1.71– 1.68(m,2H),1.54–1.46(m,2H); MS(TOF):m / z(%)=447.2401(100%)(M+H) + ,445.2269(20%)(M-1).

[0244] Example-16

[0245] (E)-3-(Diethylamino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-methylbut-1-ene-1-sulfonamide

[0246]

[0247] 1 H NMR (400 MHz, DMSO-d 6 ): δ=7.68(s,1H),6.90(s,1H),6.67(d,J=15.6Hz,1H),6.60(d,J=15.6Hz,1H),2.80(t,J=7.2Hz,4H),2.72(t,J=7.2Hz, 4H), 2.64–2.54 (m, 4H), 1.99–1.92 (m, 4H), 1.19 (s, 6H), 1.00 (t, J = 6.4Hz, 6H); MS (TOF): m / z (%) = 420.2287 (100%) (M+H) + ,418.2140(20%)(M-1).

[0248] Example-17

[0249] (E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-3-(piperidin-1-yl)prop-1-ene-1-sulfonamide

[0250]

[0251] 1 H NMR (400 MHz, DMSO-d 6): δ=7.85(s,1H),6.88(s,1H),6.79(d,J=15.6Hz,1H),6.52(d,J=3.6Hz,1H),2.79(t,J=7.2Hz,4H),2.67( t, J=7.2Hz, 4H), 1.93 (d, J=13.6Hz, 7H), 1.51 (m, 4H), 1.39 (m, 4H); MS (ESI): m / z (%) = 404.19 (100%) (M+1).

[0252] Example-18

[0253] (E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-3-(pyrrolidin-1-yl)prop-1-ene-1-sulfonamide

[0254]

[0255] 1 H NMR (400 MHz, DMSO-d 6 ): δ=10.22(s,1H),7.82(s,1H),7.00(s,1H),6.91(d,J=15.6Hz,1H),6.57(d,J=8.4Hz,1H),3.47(m,3H),2. 79 (t, J=7.2Hz, 4H), 2.68 (t, J=7.2Hz, 4H), 1.95 (m, 4H), 1.76 (s, 4H); MS (ESI): m / z (%) = 390.18 (100%) (M+1).

[0256] Example-19

[0257] (E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-(methyl(tetrahydro-2H-pyran-4-yl)amino)prop-1-ene-1-sulfonamide

[0258]

[0259] 1 H NMR (400 MHz, DMSO-d 6): δ=10.28(brs,1H),8.02(s,1H),6.92(s,1H),6.84(d,J=15.2Hz,1H),6.71–6. 58(m,1H),3.85–3.82(m,2H),3.48–3.29(m,2H),3.23–3.17(m,2H),2.78(t,J=7. 2Hz,4H),2.65(t,J=7.2Hz,4H),2.59–2.54(m,1H),2.19(s,3H),1.98–1.90(m,4H ),1.64–1.61(m,2H),1.45–1.34(m,2H); MS(TOF):m / z(%)=434.2078(100%)(M+H) + ,432.1949(30%)(M-1).

[0260] Example-20

[0261] (E)-3-(Ethyl(methyl)amino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-methylbut-1-ene-1-sulfonamide

[0262]

[0263] 1 H NMR (400 MHz, DMSO-d 6 ): δ=7.87(s,1H),6.70(d,J=15.6Hz,1H),6.89(s,1H),6.59(d,J=15.2Hz,1H),2.78(t,J=7.2Hz,4H),2.67(t,J=7.2Hz,4H),2 .49–2.50(m,2H),2.28(s,3H),1.98–1.90(m,4H),1.19(s,6H),1.01(t,J=6.8Hz,3H);MS(TOF):m / z(%)=406.2131(100%)(M+H) + ,404.1986(100%)(M-1).

[0264] Example-21

[0265] (E)-3-(Cyclobutyl(methyl)amino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-methylbut-1-ene-1-sulfonamide

[0266]

[0267] 1 H NMR (400 MHz, DMSO-d 6 ): δ=10.33(brs,1H),7.97(s,1H),6.97(s,1H),6.77–6.58(m,2H),3.52–3.37(m,1H),2.79(t,J=7.2Hz,4H),2.67(t,J =7.2Hz, 4H), 2.81 (s, 3H), 1.99–1.87 (m, 8H), 1.59–1.40 (m, 2H), 1.15 (s, 6H); MS (TOF): m / z (%) = 432.2295 (100%) (M+H) + ,430.2140(100%)(M-1).

[0268] Example-22

[0269] (E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-(methyl(tetrahydro-2H-thiopyran-4-yl)amino)prop-1-ene-1-sulfonamide

[0270]

[0271] 1 H NMR (400 MHz, DMSO-d 6 ): δ=8.05(s,1H),6.94(s,1H),6.84(d,J=15.2Hz,1H),6.68(dt,J=14.8Hz,J=5.6Hz,1H),3.33–3.31(m,2H),2.80(t,J=7.2Hz,4H),2 .67(t,J=7.2Hz,4H),2.61–2.52(m,5H),2.20(s,1H),2.00–1.91(m,6H),1.61–1.50(m,2H); MS(TOF):m / z(%)=450.1869(100%)(M+H) + ,448.1711(50%)(M-1).

[0272] Example-23

[0273] (E)-3-(Cyclobutyl(methyl)amino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-methylbut-1-ene-1-sulfonamide

[0274]

[0275] 1H NMR (400 MHz, DMSO-d 6 ): δ=8.21(s,1H),6.93(s,1H),6.71–6.86(m,2H),3.64–3.61(m,1H),2.80(t,J=7.2Hz,4H),2.68(t,J=7.2Hz,4H),2.33(s ,3H),1.99–1.91(m,4H),1.72–1.60(m,2H),1.59–1.45(m,4H),1.41–1.10(m,8H); MS(TOF):m / z(%)=446.2457(100%)(M+H) + ,444.2307(40%)(M-1).

[0276] Example-24

[0277] (E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-(isopropyl(methyl)amino)-3-methylbut-1-ene-1-sulfonamide

[0278]

[0279] 1 H NMR (400 MHz, DMSO-d 6 ): δ=7.94(s,1H),6.92(s,1H),6.75–6.59(m,2H),3.34–3.21(m,1H),2.80(t,J=7.2Hz,4H),2.67(t,J=7.2Hz,4 H), 2.20 (s, 3H), 1.99–1.92 (m, 8H), 1.22 (s, 6H), 0.98 (d, J = 6.4Hz, 6H); MS (TOF): m / z (%) = 420.2871 (100%) (M+H) + ,418.2452(100%)(M-1).

[0280] Example-25

[0281] (E)-3-((Cyclopropylmethyl)amino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-methylbut-1-ene-1-sulfonamide

[0282]

[0283] 1 H NMR (400 MHz, DMSO-d 6): δ=7.49(s,1H),6.81(s,1H),6.77(d,J=15.6Hz,1H),6.38(d,J=15.6Hz,1H),2.77(t,J=7.2Hz,4H),2.70(t,J=7.2Hz,4H),2.65(d,J=7.2 Hz,2H),1.96–1.89(m,4H),1.34(s,6H),0.97–0.89(m,1H),0.54–0.48(m,2H),0.30–0.22(m,2H); MS(TOF):m / z(%)=418.2132(100%)(M+H) + ,416.1982(30%)(M-1).

[0284] Example-26

[0285] (E)-3-(Cyclobutyl(methyl)amino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)prop-1-ene-1-sulfonamide

[0286]

[0287] 1 H NMR (400 MHz, DMSO-d 6 ): δ=10.49(brs,1H),8.02(s,1H),6.93(s,1H),6.85(d,J=15.2Hz,1H), 6.69–6.63(m,1H),3.14(d,J=5.6Hz,2H),2.99–2.91(m,1H),2.80(t,J=7 .2Hz,4H),2.67(t,J=7.2Hz,4H),2.09(s,3H),2.01–1.90(m,8H),1.85– 1.75(m,2H),1.65–1.51(m,2H);MS(TOF):m / z(%)=404.1974(100%)(M+H) + ,402.1866(10%)(M-1).

[0288] Example-27

[0289] (E)-3-(Dicyclobutylamino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)prop-1-ene-1-sulfonamide

[0290]

[0291] 1H NMR (400 MHz, DMSO-d 6 ): δ=10.31(brs,1H),8.07(s,1H),6.95(s,1H),6.86(d,J=15.2Hz,1H),6.78–6.72(m,1H),3.29–3.21(m,2H),3.20–3.05(m,2H ),2.81(t,J=7.2Hz,4H),2.68(t,J=7.2Hz,4H),2.00–1.76(m,12H),1.60–1.44(m,4H); MS(TOF):m / z(%)=444.2285(100%)(M+H) + ,442.2158(30%)(M-1).

[0292] Example-28

[0293] tert-Butyl (Z)-(3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)allyl)carbamate

[0294]

[0295] 1 H NMR (400 MHz, DMSO-d 6 ): δ=10.52(brs,1H),8.12(s,1H),7.19–7.16(m,1H),6.96(s,1H),6.51(dt,J=11.2Hz,J=2.4Hz,1H),6.30–6.23(m,1H),4.10–4 .09(m,2H),2.81(t,J=7.2Hz,4H),2.71(t,J=7.2Hz,4H),2.01–1.91(m,4H),1.38(s,9H);MS(TOF):m / z(%)=436.1961(5%)(M+H) + ,458.1747(40%)(M+Na),434.1802(5%)(M-1).

[0296] Example-29

[0297] (Z)-3-Amino-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)prop-1-ene-1-sulfonamide 2,2,2-trifluoroacetate

[0298]

[0299] 1H NMR (400 MHz, DMSO-d 6 ): δ=10.96(brs,1H),8.52(s,1H),8.00(s,3H),6.97(s,1H),6.74(d,J=11.2Hz,1H),6.40–6.34(m,1H),4.19–4.0 5(m,2H),2.81(t,J=7.2Hz,4H),2.68(t,J=7.2Hz,4H),2.07–1.94(m,4H); MS(TOF):m / z(%)=336.1851(100%)(M+H) + ,334.1538(30%)(M-1).

[0300] Example-30

[0301] (Z)-3-(Dimethylamino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)prop-1-ene-1-sulfonamide

[0302]

[0303] 1 H NMR (400 MHz, DMSO-d 6 ): δ=11.21(brs,1H),8.08(s,1H),6.84(s,1H),6.57(d,J=11.2Hz,1H),6.24–6.17(m,1H),3.95(d,J=7.6Hz ,2H),2.77(t,J=7.2Hz,4H),2.70–2.68(m,10H),1.99–1.86(m,4H); MS(TOF):m / z(%)=364.2137(100%)(M+H) + ,362.1824(10%)(M-1).

[0304] Example-31

[0305] Sodium (E)-((3-(dimethylamino)-3-methylbut-1-en-1-yl)sulfonyl)((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)amide

[0306]

[0307] 1 H NMR (400 MHz, DMSO-d 6): δ=7.36(s,1H),6.77(s,1H),6.51(d,J=15.6Hz,1H),6.23(d,J=15.6Hz,1H),2.76(t,J=7.2Hz,4H),2.6 9(t,J=7.2Hz,4H),2.11(s,1H),1.94–1.87(m,4H),1.06(s,6H); MS(TOF):m / z(%)=392.1987(100%)(M+H) + ,390.1841(20%)(M-1).

[0308] Example-32

[0309] Sodium (E)-((3-(dimethylamino)prop-1-en-1-yl)sulfonyl)((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)amide

[0310]

[0311] 1 H NMR (400 MHz, DMSO-d 6 ): δ=7.36(s,1H),6.77(s,1H),6.62(d,J=15.2Hz,1H),6.18(dt,J=15.2Hz,J=6.4Hz,1H),2.91(dd,J=6.4Hz,J=1.2Hz,2H ),2.76(t,J=7.2Hz,4H),2.69(t,J=7.2Hz,4H),2.13(s,6H),1.96–1.70(m,4H); MS(TOF):m / z(%)=364.1676(100%)(M+H) + ,362.1552(5%)(M-1).

[0312] Example-33

[0313] (E)-3-((3-aminopropyl)(methyl)amino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)prop-1-ene-1-sulfonamide.

[0314]

[0315] 1 H NMR (400 MHz, DMSO-d 6): δ=7.47(s,1H),6.79(s,1H),6.64(d,J=15.2Hz,1H),6.27–6.20(m,1H),3.03(d,J=6.0Hz,2H),2.80–2.75(m,6H),2.68(t,J= 7.2Hz, 4H), 2.38 (t, J=6.4Hz, 2H), 2.10 (s, 3H), 1.95–1.88 (m, 4H), 1.68–1.63 (m, 2H); MS (TOF): m / z (%) = 407.2104 (100%) (M+H) + ,405.2004(10%)(M-1) - .

[0316] Example-34

[0317] (E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-3-(piperidin-1-yl)prop-1-ene-1-sulfonamide

[0318]

[0319] 1 H NMR (400 MHz, DMSO-d 6 ): δ=8.02(s,1H),7.15(m,3H),6.95(d,J=11.2Hz,2H),6.65(m,6H),6.47(t,J=3.6Hz,1H),4.18(d,J=3.2Hz,2H),2.9 1 (t, J=2.4Hz, 4H), 2.79 (t, J=7.2Hz, 4H), 2.65 (t, J=7.2Hz, 4H), 1.983 (m, 4H); MS (ESI): m / z (%) = 426.18 (100%) (M+1).

[0320] Example-35

[0321] (E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-(isobutyl(methyl)amino)-3-methylbut-1-ene-1-sulfonamide

[0322]

[0323] 1 H NMR (400 MHz, DMSO-d 6): δ=10.34(brs,1H),8.04(s,1H),6.94(s,1H),6.72(d,J=15.6Hz,1H),6.66(d,J=15.2Hz,1H),2.80(t,J=7.2Hz,4H),2.67(t,J=7.2Hz,4H),2. 14(s,3H),2.10–2.08(m,2H),2.00–1.92(m,4H),1.68–1.61(m,1H),1.1 3(s,6H),0.82(d,J=6.8Hz,3H);MS(TOF):m / z(%)=434.3021(100%)(M+H) + ,432.2628(20%)(M-1).

[0324] Example-36

[0325] (E)-3-(Dimethylamino)-N-((1,2,3,7-tetrahydro-s-indacen-4-yl)carbamoyl)prop-1-ene-1-sulfonamide

[0326]

[0327] 1 H NMR (400 MHz, DMSO-d 6 ): δ=8.21(bs,1H),7.16(s,1H),6.87(d,J=15.2Hz,1H),6.80(d,J=5.6Hz,1H),6.69-6.51(m,1H),6.40(d,J=5.6Hz,1H),3.30-3 .28 (m, 4H), 2.87 (t, J = 7.2Hz, 2H), 2.74 (t, J = 7.2Hz, 2H), 2.32 (s, 6H), 2.02-1.95 (m, 2H); MS (TOF): m / z (%) = 362.15 (100%) (M+H) + .

[0328] Example-37

[0329] (E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-methyl-3-(methylsulfonamido)but-1-ene-1-sulfonamide

[0330]

[0331] 1 H NMR (400 MHz, DMSO-d 6): δ=10.47(brs,1H),8.10(s,1H),7.42(s,1H),6.96(s,1H),6.89(d,J=15.2Hz,1H),6.75(d,J=15.2Hz,1H),2.99(s,3H ), 2.81 (t, J=7.2Hz, 4H), 2.68 (t, J=7.2Hz, 4H), 2.01–1.93 (m, 4H), 1.40 (s, 6H); MS (TOF): m / z (%) = 442.1452 (100%) (M+H) + ,440.1309(20%)(M-1).

[0332] Example-38

[0333] (E)-3-(Dimethylamino)-N-((1,2,3,5-tetrahydro-s-indacen-4-yl)carbamoyl)prop-1-ene-1-sulfonamide

[0334]

[0335] 1 H NMR (400 MHz, DMSO-d 6 ): δ=8.11(bs,1H),7.10(s,1H),6.88(d,J=15.2Hz,1H),6.83(d,J=5.6Hz,1H),6.61-6.52(m,1H),6.50(d,J=5.2Hz,1H),3.32-3 .26 (m, 4H), 2.87 (t, J = 7.2Hz, 2H), 2.76 (t, J = 7.2Hz, 2H), 2.34 (s, 6H), 2.03-1.95 (m, 2H); MS (TOF): m / z (%) = 362.15 (100%) (M+H) + .

[0336] Example-39

[0337] (E)-3-(Dipropylamino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)prop-1-ene-1-sulfonamide

[0338]

[0339] 1 H NMR (400 MHz, DMSO-d 6): δ=7.96(s,1H),6.92(s,1H),3.32(t,J=7.2Hz,4H),2.80(t,J=7.2Hz,4H),2.70(t,J=7.2Hz,4H),2.63(t,J=7.2Hz,2H),2.50–2. 45(m,2H),2.00–1.91(m,4H),1.86–1.82(m,2H),1.46–1.40(m,4H),0.84(d,J=7.2Hz,6H); MS(TOF):m / z(%)=422.2451(100%)(M+H) + ,420.2326(20%)(M-1).

[0340] Example-40

[0341] (E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-3-((2-methyl-2-(pyrrolidin-1-yl)propyl)amino)prop-1-ene-1-sulfonamide.

[0342]

[0343] 1 H NMR (400 MHz, DMSO-d 6 ): δ=7.48(s,1H),6.77(s,1H),6.69(d,J=15.2Hz,1H),6.27–6.22(m,1H),3.25–3.24(m,2H),2.76(t,J=7.2Hz,4H),2.70(t,J=7.2H z,4H),2.64–2.60(m,4H),2.45(s,2H),1.95–1.89(m,4H),1.67–1.65(m,4H),1.01(s,6H); MS(TOF): m / z(%)=461.2562(100%)(M+H) + ,459.2421(30%)(M-1) - .

[0344] Example-41

[0345] (E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-3-(methyl(2-methyl-2-(pyrrolidin-1-yl)propyl)amino)prop-1-ene-1-sulfonamide.

[0346]

[0347] 1H NMR (400 MHz, DMSO-d 6 ): δ=7.48(s,1H),6.77(s,1H),6.69(d,J=15.2Hz,1H),6.27–6.22(m,1H),3.25–3.24(m,2H),2.76(t,J=7.2Hz,4H),2.70(t,J=7.2Hz,4H) ,2.64–2.60(m,4H),2.45(s,2H),2.19(s,3H),1.95–1.89(m,4H),1.67–1.65(m,4H),1.01(s,6H);MS(TOF):m / z(%)=475.2717(100%)(M+H) + ,473.2633(30%)(M-1) - .

[0348] Example-42

[0349] (E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-3-methyl-3-(pyrrolidin-1-yl)but-1-ene-1-sulfonamide.

[0350]

[0351] 1 H NMR (400 MHz, DMSO-d 6 ): δ=7.79(s,1H),6.87(s,1H),6.76(d,J=15.6Hz,1H),6.61(d,J=15.6Hz,1H) ,2.78(t,J=7.2Hz,8H),2.68(t,J=7.2Hz,4H),1.96(t,J=7.2Hz,4H),1.71(br s, 4H), 1.28 (s, 6H); MS (TOF): m / z (%) = 418.2295 (100%) (M+H) + .

[0352] Example-43

[0353] (E)-4-(Dimethylamino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)but-1-ene-1-sulfonamide

[0354]

[0355] 1 H NMR (400 MHz, DMSO-d 6): δ=7.85(s,1H),6.90(s,1H),6.74(d,J=15.2Hz,1H),6.58–6.51(m,1H),2.79(t,J=7.2Hz,2H),2.72–2 .65(m,6H),2.46–2.43(m,2H),2.30(s,6H),1.97–1.91(m,4H);MS(TOF):m / z(%)=378.1834(100%)(M+H) + ,376.1680(100%)(M-1) - ;

[0356] Example-44

[0357] (E)-4-Amino-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)but-1-ene-1-sulfonamide

[0358]

[0359] 1 H NMR (400 MHz, DMSO-d 6 ): δ=7.46(s,1H),6.79(s,1H),6.58(d,J=15.2Hz,1H),6.26–6.19(m,1H),2.88(t,J=7.2Hz,2H),2.76(t,J=7. 2Hz, 4H), 2.69 (t, J=7.2Hz, 4H), 2.40–2.33 (m, 2H), 1.96–1.89 (m, 4H); MS (TOF): m / z (%) = 350.1945 (100%) (M+H) + ,348.1652(10%)(M-1) - .

[0360] Embodiment 45

[0361] tert-Butyl (E)-(3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)allyl)carbamate

[0362]

[0363] 1H NMR (400MHz, DMSO-d6): δ = 10.49 (br s,1H),8.09(s,1H),7.28(t,J=5.6Hz,1H),6.96(s,1H),6.78–6.72(m,1H),6.67(d,J=15.6Hz,1H) ,3.96–3.85(m,2H),2.81(t,J=7.2Hz,4H),2.01(t,J=7.2Hz,4H),2.01–1.94(m,4H),1.42(s,9H).

[0364] Scenario 2:

[0365]

[0366] Among them, "A", R 1 , R 2 , R 3 , R 4 and R 5 As defined above. The synthesis of compound 6 is as described above. The amine group of 6 is protected with a suitable protecting group such as a substituted silyl chloride to obtain 9. Compound 9 is treated with triphenylphosphine and hexachloroethane under suitable conditions and a suitable solvent, followed by treatment with ammonia to obtain compound 10. Compound 10 is treated with an isocyanate derivative (7) under suitable conditions (base (such as butyl lithium or sodium hydride) and a suitable solvent) to obtain 11. Compound 11 is deprotected with a suitable reagent under suitable conditions and then reacted with an alkyl bromide to obtain 12. Deprotection of compound 12 is followed by treatment with an alkyl bromide or an aldehyde or ketone derivative under suitable conditions in the presence of a base (such as sodium hydride) and a suitable solvent to obtain a compound of formula (I").

[0367] The specific reaction conditions, solvents and other parameters required to carry out the process steps as described above are within the capabilities of those skilled in the art.

[0368] The present invention is further illustrated by the following non-limiting examples which describe preferred modes of carrying out the invention. These are not intended to limit the scope of the invention in any way.

[0369] The examples given in the 1 H NMR spectral data (see below) were recorded using a 400 MHz spectrometer (Bruker AVANCE-400) and are reported on the delta scale. Unless otherwise stated, the solvent used for NMR was CDCl 3 , using TMS as the internal standard.

[0370] Example-49

[0371] Preparation of (E)-N'-cyano-3-(dimethylamino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-methylbut-1-ene-1-sulfonylimideamide

[0372] Intermediate-5: Preparation of tert-butyl (E)-(4-(N-(tert-butyldiphenylsilyl)sulfamoyl)-2-methylbut-3-en-2-yl)carbamate

[0373]

[0374] Triethylamine (6.59 ml, 47.3 mmol) was added to a solution of (E)-(2-methyl-4-sulfamoylbut-3-ene-2-yl)carbamic acid tert-butyl ester (5 g, 18.92 mmol) in THF (50 ml) at room temperature. The reaction mixture was stirred at 50°C for 0.5 hours. TBDPS-Cl (6.07 ml, 23.64 mmol) was added dropwise at 50°C. The reaction mixture was stirred at 50°C for 16 hours. Additional triethylamine (6.59 ml, 47.3 mmol) and TBDPS-Cl (6.07 ml, 23.64 mmol) were added at 50°C. The reaction mixture was stirred at 50°C for 16 hours. The reaction mixture was evaporated to give a crude product. The crude product was purified by column chromatography using EtOAc:hexanes as eluent to afford tert-butyl (E)-(4-(N-(tert-butyldiphenylsilyl)sulfamoyl)-2-methylbut-3-en-2-yl)carbamate (4 g, 7.96 mmol, 42.1% yield).

[0375] 1 H NMR (400 MHz, DMSO-d 6 ): δ=7.77-7.70(m,5H),7.48-7.40(m,6H),6.97(bs,1H),6.97(d,J=14.8Hz,1H),6.14(d,J= 15.2Hz, 1H), 1.38 (s, 9H), 1.24 (s, 6H), 0.95 (s, 9H); MS (TOF): m / z (%) = 525.22 (20%) (M+Na)+

[0376] Intermediate-6: Preparation of tert-butyl (E)-(4-(N-(tert-butyldiphenylsilyl)sulfonyl imide amido)-2-methylbut-3-en-2-yl)carbamate

[0377]

[0378] Under nitrogen atmosphere, a solution of triphenylphosphine (0.678 g, 2.59 mmol) and perfluoroethane (0.612 g, 2.59 mmol) in dry chloroform (10 mL) was heated to 70 ° C for 6 hours. The solid ppt was cooled to room temperature and triethylamine (0.491 ml, 3.52 mmol) was added and stirred for 10 minutes. Cooled to 0 ° C and a solution of (E)-tert-butyl (4-(N-(tert-butyldiphenylsilyl)sulfamoyl)-2-methylbut-3-en-2-yl)carbamate (1 g, 1.989 mmol) in CHCl3 (10 mL) was added, which was stirred at 0 ° C for 30 minutes and purged with ammonia at 0 ° C for 1 hour. The solvent was evaporated to give a crude product. The crude product was purified by column chromatography using EtOAc:hexanes as eluent to afford tert-butyl (E)-(4-(N-(tert-butyldiphenylsilyl)sulfonylimideamido)-2-methylbut-3-en-2-yl)carbamate (0.9 g, 1.794 mmol, 90% yield).

[0379] 1 H NMR (400 MHz, DMSO-d 6 ): δ=7.76-7.73(m,4H),7.38-7.31(m,6H),6.86(bs,1H),6.51(s,2H),6.62(d,J=14.8Hz,1H),6.34(d , J=15.2Hz, 1H), 1.40 (s, 9H), 1.26-1.18 (m, 6H), 1.04 (s, 9H); MS (TOF): m / z (%) = 502.24 (100%) (M+H)+.

[0380] Intermediate-7: tert-Butyl (E)-(4-(N'-(tert-butyldiphenylsilyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfonyl imide amido)-2-methylbut-3-en-2-yl)carbamate

[0381]

[0382] To a solution of tert-butyl (E)-(4-(N-(tert-butyldiphenylsilyl)sulfonylimideamido)-2-methylbut-3-en-2-yl)carbamate (0.4 g, 0.797 mmol) in THF (4 ml) was added NaH (0.070 g, 1.754 mmol) at 0°C under a nitrogen atmosphere. The reaction mixture was stirred for an additional 30 minutes and then for an additional 30 minutes at room temperature. A solution of 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (0.191 g, 0.957 mmol) in THF was added in one portion. The resulting suspension was stirred at room temperature for an additional 2 hours. The reaction mixture was acidified with 30% citric acid solution and water was added. The aqueous layer was extracted with ethyl acetate. The combined organic layers were purified by Na 2 SO 4 Drying, evaporation of the solvent and purification of the residue by column chromatography using EtOAc: hexanes gave tert-butyl (E)-(4-(N′-(tert-butyldiphenylsilyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfonylimideamido)-2-methylbut-3-en-2-yl)carbamate (0.335 g, 0.478 mmol, 60% yield).

[0383] 1H NMR (400MHz, DMSO-d6): δ = 9.78 (s, 1H), 8.00 (s, 1H), 7.75-7.74 (m, 4H), 7.3 9-7.34(m,6H),6.96-6.93(m,2H),6.84(d,J=14.8Hz,1H),6.64(d,J=15.2H z,1H)2.79(t,J=7.2Hz,4H),2.62(t,J=7.2Hz,4H),1.99-1.91(m,4H),1.41 (s, 9H), 1.26 (s, 6H), 1.04 (s, 9H); MS (ESI): m / z (%) = 701.35 (100%) (M+H)+.

[0384] Intermediate-8 :Preparation of tert-butyl (E)-(4-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfonyl imide amido)-2-methylbut-3-en-2-yl)carbamate

[0385]

[0386] To a solution of tert-butyl (E)-(4-(N'-(tert-butyldiphenylsilyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfonylimideamido)-2-methylbut-3-en-2-yl)carbamate (3.4 g, 4.85 mmol) in isopropyl acetate (34 ml) was added citric acid (19.40 ml, 48.5 mmol). The reaction mixture was stirred at room temperature for 48 hours. The reaction mixture was concentrated under reduced pressure, and the solid product was filtered to obtain a crude product. The crude product was purified by column chromatography using EtOAc:hexanes to give tert-butyl (E)-(4-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfonylimideamido)-2-methylbut-3-en-2-yl)carbamate (1.2 g, 2.59 mmol, 53.5% yield).

[0387] 1 H NMR (400 MHz, DMSO-d 6 ): δ=8.29(bs,1H),7.19(s,1H),7.00(bs,1H),6.87(s,1H),6.73(d,J=16.0Hz,1H),6.60(d,J=15.2Hz,1H),2.78(t,J=7 .2Hz, 4H), 2.71 (t, J = 7.2Hz, 4H), 1.99-1.90 (m, 4H), 1.38 (s, 9H), 1.32 (s, 6H); MS (TOF): m / z (%) = 463.29 (100%) (M + H) +.

[0388] Intermediate-9: Preparation of tert-butyl (E)-(4-(N'-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfonyl imide amido)-2-methylbut-3-en-2-yl)carbamate

[0389]

[0390] To a solution of tert-butyl (E)-(4-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfonylimideamido)-2-methylbut-3-en-2-yl)carbamate (0.180 g, 0.389 mmol) in DMF (4 ml) were added triethylamine (0.217 ml, 1.556 mmol) and cyanogen bromide (0.082 g, 0.778 mmol) at room temperature, and the reaction mixture was stirred at room temperature for 17 hours. The reaction mixture was purified by preparative HPLC to give tert-butyl (E)-(4-(N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfonylimideamido)-2-methylbut-3-en-2-yl)carbamate (0.080 g, 0.164 mmol, 42.2% yield).

[0391] 1 H NMR (400 MHz, DMSO-d 6 ): δ=7.86(bs,1H),6.90(bs,1H),6.83(s,1H),6.65(d,J=15.6Hz,1H),6.47(d,J=15.2Hz,1H),2.77(t,J=7.2Hz, 4H), 2.71 (t, J=7.2Hz, 4H), 1.96-1.88 (m, 4H), 1.37 (s, 9H), 1.30 (s, 6H); MS (TOF): m / z (%) = 488.23 (100%) (M+H)+.

[0392] Intermediate-10: Preparation of (E)-3-amino-N'-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-methylbut-1-ene-1-sulfonylimideamide

[0393]

[0394] A mixture of (E)-tert-butyl (4-(N'-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfonylimideamido)-2-methylbut-3-en-2-yl)carbamate (0.55 g, 1.128 mmol) and HCl in dioxane (3.76 ml, 11.28 mmol, 4 M) was stirred at room temperature for 1 hour. The solvent was evaporated to give a crude product. The crude product was purified by preparative HPLC to give (E)-3-amino-N'-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-methylbut-1-ene-1-sulfonylimideamide (0.095 g, 0.245 mmol, 21.74% yield).

[0395] 1 H NMR (400 MHz, DMSO-d 6 ): δ=7.93(bs,1H),6.84-6.80(m,2H),6.56(d,J=15.2Hz,1H),2.77(t,J=7.2Hz,4H),2.71 (t, J=7.2Hz, 4H), 1.95-1.88 (m, 4H), 1.34 (s, 6H); MS (TOF): m / z (%) = 388.17 (100%) (M+H)+.

[0396] Example-49

[0397] (E)-N'-cyano-3-(dimethylamino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-methylbut-1-ene-1-sulfonylimideamide

[0398]

[0399] To a solution of (E)-3-amino-N'-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-methylbut-1-ene-1-sulfonylimideamide (0.085 g, 0.219 mmol) in MeOH (2 ml) was added triethylamine (0.037 ml, 0.263 mmol), paraformaldehyde (0.023 g, 0.768 mmol) and sodium cyanoborotrihydrogenate (0.034 g, 0.548 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 hours. The solvent was evaporated and the crude product was purified by preparative HPLC to give (E)-N'-cyano-3-(dimethylamino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-methylbut-1-ene-1-sulfonylimideamide (0.042 g, 0.101 mmol, 46.1% yield).

[0400] 1 H NMR (400 MHz, DMSO-d 6 ): δ=9.70(bs,1H),8.07(bs,1H),6.90(d,J=15.2Hz,1H),6.83(s,1H),6.52(d,J=15.6Hz,1H),2.78-2.75 (m, 10H), 2.69 (t, J=7.2Hz, 4H), 1.98-1.88 (m, 4H), 1.45 (s, 6H); MS (TOF): m / z (%) = 416.21 (100%) (M+H)+.

[0401] The following compounds were prepared in a similar manner using appropriate starting materials and appropriate modification of the method described in Example 1, including appropriate addition and / or deletion of steps as may be necessary (which is within the scope of those skilled in the art).

[0402] Example-46

[0403] (E)-tert-Butyl (4-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfonylimideamido)-2-methylbut-3-en-2-yl)carbamate

[0404]

[0405] 1 H NMR (400 MHz, DMSO-d 6): δ=8.29(bs,1H),7.19(s,1H),7.00(bs,1H),6.87(s,1H),6.73(d,J=16.0Hz,1H),6.60(d,J=15.2Hz,1H),2.78(t,J= 7.2Hz, 4H), 2.71 (t, J = 7.2Hz, 4H), 1.99-1.90 (m, 4H), 1.38 (s, 9H), 1.32 (s, 6H); MS (TOF): m / z (%) = 463.29 (100%) (M+H) + .

[0406] Example-47

[0407] (E)-tert-Butyl (4-(N'-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfonyl imide amido)-2-methylbut-3-en-2-yl)carbamate

[0408]

[0409] 1 H NMR (400 MHz, DMSO-d 6 ): δ=7.86(bs,1H),6.90(bs,1H),6.83(s,1H),6.65(d,J=15.6Hz,1H),6.47(d,J=15.2Hz,1H),2.77(t,J=7.2Hz ,4H),2.71(t,J=7.2Hz,4H),1.96-1.88(m,4H),1.37(s,9H),1.30(s,6H); MS(TOF):m / z(%)=488.23(100%)(M+H) + .

[0410] Example-48

[0411] (E)-3-Amino-N'-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-methylbut-1-ene-1-sulfonylimideamide

[0412]

[0413] 1 H NMR (400 MHz, DMSO-d 6): δ=7.93(bs,1H),6.84-6.80(m,2H),6.56(d,J=15.2Hz,1H),2.77(t,J=7.2Hz,4H),2.7 1(t,J=7.2Hz,4H),1.95-1.88(m,4H),1.34(s,6H); MS(TOF):m / z(%)=388.17(100%)(M+H) + .

[0414] Example-49

[0415] (E)-N'-cyano-3-(dimethylamino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-methylbut-1-ene-1-sulfonylimideamide

[0416]

[0417] 1 H NMR (400 MHz, DMSO-d 6 ): δ=9.70(bs,1H),8.07(bs,1H),6.90(d,J=15.2Hz,1H),6.83(s,1H),6.52(d,J=15.6Hz,1H),2.78-2.7 5(m,10H),2.69(t,J=7.2Hz,4H),1.98-1.88(m,4H),1.45(s,6H);MS(TOF):m / z(%)=416.21(100%)(M+H) + .

[0418] Example-50

[0419] (E)-3-Amino-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-methylbut-1-ene-1-sulfonylimideamide

[0420]

[0421] 1 H NMR (400 MHz, DMSO-d 6 ): δ=8.28(bs,1H),6.87(s,1H),6.72-6.64(m,2H),2.78(t,J=7.2Hz,4H),2.71(t,J =7.2Hz, 4H), 1.97-1.90 (m, 4H), 1.30 (s, 6H); MS (TOF): m / z (%) = 363.18 (100%) (M+H) + .

[0422] Biological Activity:

[0423] In vitro assays:

[0424] THP1 monocytes were differentiated with PMA (100 ng / ml) and incubated at 37°C in the presence of 5% CO2 for 20 h. 2 × 10 5 Differentiated cells. Cells were primed with 500 ng / ml lipopolysaccharide and incubated for 4 hours under the same conditions. Cells were then treated with various concentrations of compounds for 30 minutes, followed by 5 mM ATP for 1 hour. Supernatants were collected and analyzed by IL-1b (Mabtech Cat#3415-1H-20) or TNF-a (Mabtech; Cat#3510-1H-20) detection kits. Data were analyzed using GraphPad Prism V7.0. Dose response curves (DRCs) were constructed to determine IC by fitting the cell survival percentage data to GraphPad Prism using nonlinear regression analysis. 50 In vitro IL-1β inhibitory activity (IC 50 ) are listed in Table 1.

[0425] Table 1

[0426] Compound <![CDATA[IC 50 (nM)]]> Example 1 43 Example 2 3.2 Example 5 20

[0427] Example 6 5.6 Embodiment 18 6.6 Embodiment 20 9.9 Embodiment 21 6.0 Embodiment 24 7.5 Embodiment 35 11 Embodiment 36 9.6 Embodiment 38 3.6 Embodiment 42 12.6 Embodiment 47 3.8 Embodiment 48 12 Embodiment 49 6.5

[0428] In vivo efficacy studies:

[0429] Demonstration of in vivo efficacy of test compounds in rats and mice, oral administration route.

[0430] animal

[0431] All animal experiments were performed on female rats and mice, housed in-house. The animals were housed in groups of 6 animals per cage for one week in order to acclimate them to the house conditions (25±4°C, 60-65% relative humidity, 12:12h light:dark cycle, lights on at 7.30am). All animal experiments were performed according to internationally valid guidelines approved by the "Zydus Research Center animal ethical committee".

[0432] In vivo LPS and ATP-induced IL-1β assay:

[0433] Female C57 mice (6-8 weeks) received an intraperitoneal injection of 50 μg / mouse of lipopolysaccharide (LPS) in PBS. Animals were immediately treated with test compounds or vehicle. Two hours after LPS injection, 12.5 mg / mouse of ATP dissolved in PBS was administered to the animals via the intraperitoneal route. 30 minutes after ATP injection, serum was collected for evaluation of IL-1β by ELISA.

[0434] The novel compounds of the present invention can be formulated into suitable pharmaceutically acceptable compositions by combining with suitable excipients and concentrations using well-known techniques and methods.

[0435] 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 orally, topically or parenterally.

[0436] Therefore, the pharmaceutical composition containing the compound of the present invention may contain a suitable binder, a suitable filler and / or diluent and any other suitable agents as may be required. Optionally, the pharmaceutical composition may be suitably coated with a suitable coating agent.

[0437] Compounds (I) of the present invention are NLRP3 inhibitors and are useful for treating disease states mediated by NLRP3, preferably diseases or disorders in which interleukin 1β activity is involved, and related conditions.

[0438] 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 be widely changed or adjusted according to the specific application method, the efficacy of the specific compound and the required concentration. Typically, the amount of the active ingredient will be 0.5% to 90% by weight of the composition.

[0439] The compounds of formula (I) of the present invention can be used alone or in combination with other therapeutic agents that can be easily identified by one or more skilled medical practitioners. Such other therapeutic agents can be selected according to the type of the disease being treated, the severity, other drugs taken by the patient, etc. Therefore, for example, for the treatment of rheumatoid arthritis, one or more DMARDs can be used in combination with the compounds of the present invention.

[0440] In one embodiment, the compound of formula (I) of the present invention can be used in combination with one or more suitable pharmaceutically active agents selected from the following therapeutic agents in any combination. Interleukin-1β inhibitors (e.g., rilonacept, canakinumab, and anakinra); immunosuppressants (e.g., methotrexate, mercaptopurine, cyclophosphamide), metabolic disorder drugs, glucocorticoids, nonsteroidal anti-inflammatory drugs, Cox-2 specific inhibitors, TNF-α binding proteins (e.g., infliximab, etanercept), interferon-13, interferon, interleukin-2, antihistamines, β-agonists, BTK inhibitors, anticholinergics, anticancer agents, or suitable pharmaceutically acceptable salts thereof. Other examples of use in combination with non-alcoholic steatohepatitis (NASH) and fibrosis drugs, anti-cancer antibiotics, hormones, aromatase inhibitors, antibodies, cytokines, vaccines, drug conjugates, mitogen-activated protein kinase signaling inhibitors (e.g., Bay43-9006), Syk inhibitors, mTOR inhibitors, antibodies (Rituxan), and BCR / ABL antagonists.

[0441] The composition of the present invention is also used in combination with other active ingredients. In order to treat Arenaviridae virus infection, preferably, other active therapeutic agents are active against Arenaviridae virus infection, particularly Lassa virus and Junin virus infection. Non-limiting examples of these other active therapeutic agents are Ribavirin, Favipiravir (also known as T-705 or Avigan), T-705 monophosphate, T-705 diphosphate, T-705 triphosphate, ST-193 and mixtures thereof. RNA-dependent RNA polymerase (RDRP) regulators, such as Remdesivir. The compounds and compositions of the invention are also intended for use with general care provided to patients with Arenaviridae viral infections, including parenteral fluids (including dextrose saline and Ringer's lactate) and nutrition, antibiotics (including metronidazole and cephalosporin antibiotics, such as ceftriaxone and cefuroxime) and / or antifungal prophylaxis, antipyretic and analgesic medications, antiemetics (such as metoclopramide) and / or antidiarrheal medications, vitamin and mineral supplements (including vitamin C or / and K and zinc sulfate), anti-inflammatory agents (such as ibuprofen), anti-inflammatory and immunosuppressive agents (such as dexamethasone); analgesics, and medications for other common diseases in the patient population, such as antimalarials (including artemether and artesunate-lumefantrine combination therapy), typhoid medications (including quinolone antibiotics, such as ciprofloxacin, macrolide antibiotics, such as azithromycin, cephalosporin antibiotics, such as ceftriaxone, or aminopenicillins, such as ampicillin), or shigellosis.

[0442] While the invention has been described with respect to 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 this invention.

Claims

1. A compound having a structure of general formula (I): Its pharmaceutically acceptable salts and pharmaceutical compositions containing them, wherein R 1 and R 2 Each of the R independently represents hydrogen, (C1-C6)alkyl, (C3-C7)cycloalkyl at each occurrence; or R 1 and R 2 Together they form a saturated 3- to 8-membered heterocyclic ring system; the (C1-C6)alkyl, (C3-C7)cycloalkyl are optionally substituted by hydroxy, cyano, halo, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, (C1-C6)alkyl; R 3 and R 4 Each of these represents hydrogen at each occurrence; n is independently selected from the integer 1 or 2; R 5 represents hydrogen independently at each occurrence; "A" is selected from the following ring systems Where X, Y, and Z represent C independently at each occurrence; R 7 It's hydrogen.

2. The compound according to claim 1, which is selected from: (E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-(isopropylamino)prop-1-ene-1-sulfonamide; (E)-3-(Dimethylamino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)prop-1-ene-1-sulfonamide; (E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-(isopropyl(methyl)amino)prop-1-ene-1-sulfonamide; (E)-3-(dimethylamino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-methylbut-1-ene-1-sulfonamide; (E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-(pyrrolidin-1-yl)prop-1-ene-1-sulfonamide; (E)-3-(ethyl(methyl)amino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-methylbut-1-ene-1-sulfonamide; (E)-3-(cyclobutyl(methyl)amino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-methylbut-1-ene-1-sulfonamide; (E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-(isopropyl(methyl)amino)-3-methylbut-1-ene-1-sulfonamide; (E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-(isobutyl(methyl)amino)-3-methylbut-1-ene-1-sulfonamide; (E)-3-(Dimethylamino)-N-((1,2,3,7-tetrahydro-s-indacen-4-yl)carbamoyl)prop-1-ene-1-sulfonamide; (E)-3-(Dimethylamino)-N-((1,2,3,5-tetrahydro-s-indacen-4-yl)carbamoyl)prop-1-ene-1-sulfonamide; (E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-methyl-3-(pyrrolidin-1-yl)but-1-ene-1-sulfonamide; (E)-tert-butyl (4-(N'-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfonylimidoamido)-2-methylbut-3-en-2-yl)carbamate; (E)-3-amino-N'-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-methylbut-1-ene-1-sulfonylimideamide; (E)-N'-cyano-3-(dimethylamino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-methylbut-1-ene-1-sulfonylimideamide; or a pharmaceutically acceptable salt of any of the above compounds.

3. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) as claimed in claim 1 or 2 and optionally one or more pharmaceutically acceptable carriers, diluents or excipients.

4. The pharmaceutical composition of claim 3, which is used in combination with one or more suitable pharmaceutically active agents selected from the group consisting of interleukin-1β inhibitors; immunosuppressants; metabolic disorder drugs, COX-2 specific inhibitors, anti-inflammatory drugs, TNF-α binding proteins, interferons, interleukin-2, antihistamines, β-agonists, BTK inhibitors, anticholinergics, anticancer agents or their suitable pharmaceutically acceptable salts, non-alcoholic steatohepatitis (NASH) and fibrosis drugs, antibiotics, hormones, aromatase inhibitors, inhibitors of mitogen-activated protein kinase signaling, Syk inhibitors, mTOR inhibitors, BCR / ABL antagonists, therapeutic agents for Arenaviridae viral infections, antimalarials, antipyretic and analgesic drugs, antiemetic and / or antidiarrheal agents, vitamin and mineral supplements, analgesics.

5. The pharmaceutical composition according to claim 4, wherein The hormones include glucocorticoids; The anti-inflammatory drugs include non-steroidal anti-inflammatory drugs; The interferon includes interferon-13; The Arenaviridae virus infection therapeutic agent includes a Lassa virus infection therapeutic agent and a Junin virus infection therapeutic agent; The antibiotics include cephalosporins and antifungal prophylactics.

6. Use of a compound of formula (I) according to claim 1 or 2 or a pharmaceutical composition according to claim 3 in the preparation of a medicament for treating a disease or condition in which interleukin 1β activity and interleukin-18 (IL-18) are involved.

7. Use of the compound of formula (I) according to claim 1 or 2 or the pharmaceutical composition according to claim 3 in the preparation of a medicament for treating a disease mediated by an NLRP3 modulator, wherein the NLRP3 modulator has a pathophysiological function.

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