DESC:
FIELD OF THE INVENTION
The present invention relates to novel compounds of the general formula (I) their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, deuterated analogs, metabolites, diastereomers and polymorphs. The invention also relates to processes for the preparation of the compounds of invention, pharmaceutical compositions containing the compounds and their use as the compounds of the invention belong to the family of NOD-like receptor family (NLR) protein NLRP3 modulators. The present invention thus relates to novel NLRP3 modulators as well as to the use of the novel inhibitor compounds in the treatment of diseases or conditions in which interleukin 1ß activity is implicated.
BACKGROUND OF THE INVENTION
The NOD-like receptor family (NLR) protein NLRP3 is an intracellular signaling molecule that senses many pathogens, environmental and host-derived factors. (Wen., et. al., Immunity. 2013; 39:432–441). Activation of NLRP3 leads to binding with apoptosis associated speck-like protein containing a CARD (ASC). ASC in turn interacts with the cysteine protease caspase-1, forming a complex termed the inflammasome. This results in the activation of caspase-1, which cleaves the pro-inflammatory cytokines IL-1ß and IL-18 to their active forms and mediates a type of inflammatory cell death known as pyroptosis. Other intracellular pattern recognition receptors (PRRs) are also capable of forming inflammasomes. These include other NLR family members such as NLRP1 and NLRC4 and non-NLR PRRs such as the double-stranded DNA (dsDNA) sensors absent in melanoma 2 (AIM2) and interferon, gamma inducible protein 16 (IFI16) (Latz, et. al., Nat Rev Immunol. 2013; 13:397–411). NLRP3-dependent IL-1ß processing can also be activated by an indirect, non-canonical pathway downstream of caspase-1 (Lamkanfi, et. al., Cell. 2014; 157:1013–1022).
Inflammasome components such as NLRP3, ASC and caspase-1 are expressed in immune cells in the liver including Kupffer cells, infiltrating macrophages, hepatocytes, and hepatic stellate cells. Inflammasome activation is dependent on two successive signals. Signal 1 is driven by TLR and IL-1R signaling, includes expression of component proteins including NLRP3, ASC, pro-caspase-1, pro-IL-1ß, and pro-IL-18. Signal 2 is provided by danger signals (DAMPS) that during NASH development are mainly released by stressed or dying hepatocytes or via a ”leaky” gut (PAMPs). This process leads to oligomerization of the inflammasome components and cleavage of pro-caspase-1, leading to the release of active pro-inflammatory cytokines.
The NLRP3 inflammasome acts as a key mediator of inflammatory responses through the activation of caspase-1 leading to processing and release of the pro-inflammatory cytokines interleukin-1ß (IL-1ß) and interleukin-18 (IL-18). The NLRP3 inflammasome is a component of the inflammatory process and its aberrant activation is pathogenic in inherited disorders such as the rare periodic fever syndrome, cryopyrin associated periodic syndromes (CAPS), Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) and complex diseases such as multiple sclerosis, type 2 diabetes, atherosclerosis, asthma, gouty arthritis, and inflammatory central nervous system (CNS) diseases including Alzheimer’s and other brain diseases. (Masters, et. al., Annu Rev Immunol. 2009; 27:621–668; Strowig, et. al., Nature 2012, 481, 278-286; Guo, et. al., Nat. Med. 2015, 21, 677; Ising, et.al., Nature 2019, 575, 669–673).
Inflammation is an essential host response to infection and injury. The regulation of the pro-inflammatory cytokine interleukin-1ß (IL-1ß), which is central to host responses to infection, also causes tissue injury when activated inappropriately. (Dinarello, et. al., Nat. Rev. Drug Discovery 2012, 11, 633-652.) NLRP3 inflammasome activation plays a key role in each of the components including induction of pro-inflammatory signaling, hepatocellular injury and cell death, and activation of the hepatic stellate cells (HSC) that are responsible for collagen deposition and liver fibrosis. In particular, the transition from NAFLD to NASH associates with NLRP3-inflammasome activation and an increased expression of inflammasome-related components, including apoptosis-associated speck-like protein containing a carboxy-terminal CARD (ASC), caspase-1 (CASP-1) and pannexin. (Mridha, et. al., Journal of Hepatology, 2017, 66 (5), 1037-1046).
We herein disclose novel compounds of general formula (I) which are NLRP3 modulators for the prevention and treatment of disease states mediated by NLRP3 or conditions in which interleukin 1ß activity is implicated, including inflammation, gouty arthritis, type 2 diabetes, atherosclerosis, and liver fibrosis. More particularly, embodiments of the present invention are useful as therapeutics in the treatment of a variety of pathological conditions including (but not limited to) lymphoma, auto-immune diseases, heteroimmune diseases, inflammatory diseases, cancer, and neurodegenerative diseases or conditions.
SUMMARY OF THE INVENTION
The present invention discloses novel compounds as defined by the general formula (I) that are NLRP3 modulators for the prevention and treatment of disease states mediated by NLRP3 as well as treatment of diseases or conditions in which interleukin 1ß activity is implicated. The compounds of the present invention are useful in the treatment of human or animal body, by inhibition of NLRP3. The compounds of this invention are therefore suitable for the prevention and treatment of disease states mediated by NLRP3.
EMBODIMENT(S) OF THE INVENTION
An embodiment of the present invention provides novel compounds represented by the general formula (I), their tautomeric forms, their enantiomers, their deuterated analogs, their metabolites, their diastereoisomers, their stereoisomers, their pharmaceutically acceptable salts and pharmaceutical compositions containing them or their mixtures thereof.
In an another embodiment of the present invention is provided pharmaceutical compositions containing compounds of the general formula (I), their tautomeric forms, their enantiomers, their deuterated analogs, their metabolites, their diastereoisomers, their stereoisomers, their pharmaceutically acceptable salts, or their mixtures in combination with suitable carriers, solvents, diluents and other media normally employed in preparing such compositions.
In a further embodiment is provided the use of compounds of the present invention as NLRP3 modulators, by administering a therapeutically effective and non-toxic amount of compounds of general formula (I) or their pharmaceutically acceptable compositions to the mammals.
In a still further embodiment compound of formula (I) of the present invention may be used in combination with one or more suitable pharmaceutically active agents.
In another further embodiment is provided a process for preparing the novel compounds of the present invention.
DESCRIPTION OF THE INVENTION
Accordingly, the present invention relates to compound of the general formula (I)

Formula (I)

their tautomeric forms, their stereoisomers; their enantiomers; their metabolites; their deuterated analogs; their pharmaceutically acceptable salts; and pharmaceutical compositions containing them or their mixtures thereof,
wherein
X is O, NH, or N-R3 wherein R3 at each occurrence independently represents hydrogen, hydroxyl, halogen, nitro, cyano, haloalkyl, optionally substituted groups selected from (C1-C10)alkyl, (C1-C10)alkoxy, (C3-C10)cycloalkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, SO2(C1-C6)alkyl, thiol, thioalkyl, thio-alkoxy, SO(C1-C6)alkyl, benzyl, aryl, heteroaryl, heterocyclyl;
Y is O, S;
R1 at each occurrence independently represents hydrogen, halogen, haloalkyl, cyano, optionally substituted groups selected from (C1-C6)alkyl (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C3-C7)cycloalkyl,(C1-C6)alkylSO2(C1-C6)alkyl,(C1-C6)alkylN(C1-C6)alkyl, (C1-C6)alkylN(C3-C7)cycloalkyl, aryl, heteroaryl, heterocyclyl, benzyl, tert-butyloxycarbonyl, NH(C1-C6)alkyl, N((C1-C6)alkyl)2, NH(C2-C6)alkenyl, N((C2-C6)alkenyl)2, -N-heterocyclyl, N(C1-C6)alkyl-heterocyclyl, NR’R’’, thiol, mercaptoalkyl, SO2(C1-C6)alkyl, SO2(C3-C7)cycloalkyl, SO2-aryl, SO2-heterocyclyl, (C1-C6)thioalkyl, (C1-C6)thioalkoxy, (C1-C6)alkylSO2NH2, -CONH2, -CO(C1-C6)alkyl, -CO(C1-C6)haloalkyl, -CO-aryl, -CO-heteroaryl, -CO-heterocyclyl, 4- to 7-membered heterocyclic ring, 7- to 14-membered bicyclic heterocyclic ring system, bridged or spiro ring system having optionally one or more than one heteroatoms;
Alternatively R1 represents:
, , ,
n, is independently selected from integer 0-3;
Each of R’, R”, R1’, R1’’, R2’ and R2” at each occurrence independently represents hydrogen, halogen, haloalkyl, cyano, optionally substituted groups selected from (C1-C6)alkyl, , deuterated (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C3-C7)cycloalkyl, (C1-C6)alkylSO2(C1-C6)alkyl, (C1-C6)alkylN(C1-C6)alkyl, (C1-C6)alkylN(C3-C7)cycloalkyl, aryl, heteroaryl, heterocyclyl, benzyl, tert-butyloxycarbonyl, thiol, mercaptoalkyl, SO2(C1-C6)alkyl, SO2(C3-C7)cycloalkyl, SO2-aryl, SO2-heterocyclyl, (C1-C6)thioalkyl, (C1-C6)thioalkoxy, (C1-C6)alkylSO2NH2, -CONH2, -CO(C1-C6)alkyl, -CO(C1-C6)haloalkyl, -CO-aryl, -CO-heteroaryl, -CO-heterocyclyl, 4- to 7-membered heterocyclic ring, 7- to 14-membered bicyclic heterocyclic ring system, bridged or spiro ring system having optionally one or more than one heteroatoms; In an embodiment R’ and R” optionally forms 4- to 7-membered heterocyclic ring system.
R2 is selected from the following ring system

wherein X, Y, Z at each occurrence independently represents C, N, S, SO2, and O, which may be optionally substituted;
Each of R7, R8, R9, R10, R11 and R12 at each occurrence are independently selected from hydrogen, halogen, cyano, amide, sulphonamide, acyl, hydroxyl, optionally substituted groups selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, benzyl, aryl, heteroaryl, heterocyclyl; Alternatively each of R8 and R9, R9 and R10, R10 and R11 and R11 and R12 wherever possible, together may form a 4 to 7 membered saturated or partially saturated ring containing from 0-2 additional heteroatoms selected from the group consisting of N, O, and S(O)p; p = 1-2.
Rx and Ry at each occurrence are independently selected from hydrogen, halogen, optionally substituted groups selected from (C1-C6)alkyl; Alternatively Rx and Ry together may form a 4- to 7-membered heterocyclic ring system;
‘M’ is selected from aryl, heteroaryl, heterocyclyl,
When any of above defined group is substituted the substitutions on them may be selected from those described above or may be selected from hydrogen, hydroxy, cyano, halo, haloalkyl, haloalkyloxy, alkylthio, optionally substituted group selected from (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C10)cycloalkyl, C1-C6 alkoxy, aryl, heterocyclyl, heteroaryl, -COR11, -CSR11, C(O)OR11, C(O)-R11, -C(O)-NR11R12, -C(S)-NR11R12, -SO2R11 group, wherein each of, R11 and R12 is independently selected from hydrogen, optionally substituted group selected from (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C7)cycloalkyl, aryl, heteroaryl, heterocyclyl groups;
In a preferred embodiment, the groups, radicals described above may be selected from:
"Alkyl", as well as other groups having the prefix "alk", such as alkoxy and alkanoyl, means a carbon chain which may further be substituted with an oxygen atom as is well understood by a skilled artisan, which may further be either linear or branched, and combinations thereof, unless the carbon chain is defined otherwise. Examples of alkyl group include but not limited to methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert. -butyl, pentyl, hexyl etc. Where the specified number of carbon atoms permits e.g. from C3-10, the term alkyl also includes cycloalkyl groups, and combinations of linear or branched alkyl chains combined with cycloalkyl structures. When no number of carbon atoms is specified, C1-6 is intended. Substituted alkyl includes alkyl substituted with one or more moieties selected from the group consisting of halo {e.g., CI, F, Br, and I); halogenated alkyl {e.g., CF3, 2-Br-ethyl, CH2F, CH2CI, CH2CF3, or CF2CF3); hydroxyl; amino; carboxylate; carboxamido; alkylamino; arylamino; alkoxy; aryloxy; nitro; azido; cyano; thio; sulfonic acid; sulfate; phosphonic acid; phosphate; and phosphonate as well as those described under the definition of ‘Optionally substituted’.
‘Deuterated alkyl’ means a carbon chain wherein one or more hydrogen atom of the alkyl chain may be substituted by deuterium atom. For example deuterated groups may be selected from –CD3, CHD2, CH2D and the like.
"Alkenyl" means carbon chains which contain at least one carbon-carbon double bond, and which may be linear or branched or combinations thereof, unless the carbon chain is defined otherwise. Examples of alkenyl include but not limited to vinyl, allyl, isopropenyl, hexenyl, pentenyl, heptenyl, l -propenyl, 2-butenyl, 2-methyl -2-butenyl etc. Where the specified number of carbon atoms permits, e.g., from C5-10, the term alkenyl also includes cycloalkenyl groups and combinations of linear, branched and cyclic structures. When no number of carbon atoms is specified, C2-6) is intended.
"Alkynyl" means carbon chains which contain at least one carbon-carbon triple bond, and which may be linear or branched or combinations thereof. Examples of alkynyl include ethynyl, propargyl, 3-methyl- l -pentynyl etc. When no number of carbon atoms is specified, is intended.
the “thioalkyl” group used either alone or in combination with other radicals, denotes an alkyl group, as defined above, attached to a group of formula –SR’, (sulfur and its oxidized forms) where R’ represents hydrogen, alkyl or aryl group, e.g. thiomethyl, methylthiomethyl, phenylthiomethyl and the like, which may be optionally substituted.
As used herein, "carbocycle" or "carbocyclic residue" is intended to mean any stable monocyclic or bicyclic or tricyclic ring, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin). In a broader perspective, the term carbocycle is intended to include, wherever applicable, the groups representing cycloalkyl, phenyl and other saturated, partially saturated or aromatic residues;
The terms "cycloalkyl" and "cycloalkenyl" refers to optionally substituted, saturated and unsaturated mono-cyclic, bicyclic or tricyclic carbon groups. Where appropriate, the cycloalkyl or cycloalkenyl group may have a specified number of carbon atoms, for example, C3-C6 cycloalkyl or cycloalkenyl includes within its scope a carbocyclic group having 3, 4, 5 or 6 carbon atoms. Examples of such substituents may be selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl and the like. Substituted cycloalkyl or cycloalkenyl includes substitutions with one or more moieties selected from the group consisting of halo (e.g. , CI, F, Br, and I); halogenated alkyl (e.g. , CF3, 2-Br-ethyl, CH2F, CH2CI, CH2CF3, or CF2CF3); hydroxyl; amino; carboxylate; carboxamido; alkylamino; arylamino; alkoxy; aryloxy; nitro; azido; cyano; thio; sulfonic acid; sulfate; phosphonic acid; phosphate; and phosphonate as well as those described under the definition of ‘Optionally substituted’.
The "alkoxy" refers to the straight or branched chain alkoxides of the number of carbon atoms specified.
"Aryl" means a mono- or polycyclic aromatic ring system containing carbon ring atoms. The preferred aryls are monocyclic or bicyclic 6-10 membered aromatic ring systems. Phenyl and naphthyl are preferred aryls.
“Heterocyclyl” means a saturated, partially saturated or unsaturated aromatic or non-aromatic mono, bi or tricyclic radicals, containing one or more heteroatoms selected from nitrogen, sulfur and oxygen, further optionally including the oxidized forms of sulfur, namely SO & SO2 Heterocyclyl systems may be attached to another moiety via any number of carbon atoms or heteroatoms of the radical and may be both saturated and unsaturated. Examples of heterocycles include tetrahydrofuran (THF), dihydrofuran, 1,4-dioxane, morpholine, 1 ,4-dithiane, piperazine, piperidine, 1 ,3-dioxolane, imidazoline, imidazolidine, pyrrolidine, pyrroline, tetrahydropyran, dihydropyran, oxathiolane, dithiolane, 1 ,3-dioxane, 1 ,3-dithiane, oxathiane, thiomorpholine, etc. The term "heterocycloalkyl" refers to a heterocyclic group as defined above connected to an alkyl group as defined above;
"Heteroaryl" means an aromatic or partially aromatic heterocycle that contains at least one ring heteroatom selected from O, S and N. Heteroaryls thus include heteroaryls fused to other kinds of rings, such as aryls, cycloalkyls, and heterocycles that are not aromatic. Examples of heteroaryl groups include; pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, triazinyl, thienyl, pyrimidyl, benzisoxazolyl, benzoxazolyl, benzthiazolyl, benzothiadiazolyl, dihydrobenzofuranyl, indolinyl, pyridazinyl, indazolyl, isoindolyl, dihydrobenzothienyl, indolinyl, pyridazinyl, indazolyl, isoindolyl, dihydrobenzothienyl, indolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, napthyridinyl, carbazolyl, benzodioxolyl, quinoxalinyl, purinyl, furazanyl, isobenzylfuranyl, benzimidazolyl, benzofuranyt, benzothienyl, quinolyl, indolyl, isoquinolyl, dibenzofuranyl etc. For heterocyclyl; and heteroaryl groups, rings and ring systems containing from 3-15 carbon atoms are included, forming 1-3 rings.
The term "haloalkyl "means an alkyl structure in which at least one hydrogen is replaced with a halogen atom. In certain embodiments in which two or more hydrogen atoms are replaced with halogen atoms, the halogen atoms are all the same as one another.
the “haloalkoxy” group is selected from suitable haloalkyl, as defined above, directly attached to an oxygen atom, more preferably groups selected from fluoromethoxy, chloromethoxy, fluoroethoxy, chloroethoxy and the like;
In certain other embodiment in which two or more hydrogen atoms are replaced with halogen atoms, the halogen atoms are not all the same as one another.
"Aryloxyalkyl" means an alkyl radical substituted with aryloxy group as defined herein.
"Aryloxyaryl" means an aryl radical substituted with aryloxy group as defined herein.
"Aryloxyheteroaryl" means a heteroaryl radical substituted with aryloxy group as defined herein.
"Halo/ Halogen" refers to fluorine, chlorine, bromine, iodine. Chlorine and fluorine are generally preferred.
Suitable groups and substituents on the groups may be selected from those described anywhere in the specification.
The term "substituted," as used herein, means that any one or more hydrogen on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. The term "substituted," as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound.
"Pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of the basic residues. Such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 1 , 2-ethanedisulfonic, 2-acetoxybenzoic, 2-hydroxyethanesulfonic, acetic, ascorbic, benzenesulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic, ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromie, hydrochloric, hydroiodide, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, -lauryl sulfonic, maleic, malic, mandelic, methanesulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic, salicyclic, stearic, subacetic, succinic, sulfamic, sulfanilic, sulfuric, tannic, tartaric, and toluenesulfonic.
The term 'optional' or ‘optionally' means that the subsequent described event or circumstance may or may not occur, and the description includes instances where the event or circumstance occur and instances in which it does not. For example, optionally substituted alkyl' means either 'alkyl' or 'substituted alkyl'. Further an optionally substituted group includes an unsubstituted group.
Unless otherwise stated in the specification, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms.
Particularly useful compounds may be selected from but not limited to the following:
(S,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-methyl-1-(methyl-d)pyrrolidin-2-yl)ethene-1-sulfonamide;
(R,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-methyl-1-(methyl-d)pyrrolidin-2-yl)ethene-1-sulfonamide;
(S,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(methyl-d)pyrrolidin-2-yl)ethene-1-sulfonamide;
(R,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(methyl-d)pyrrolidin-2-yl)ethene-1-sulfonamide;
(R,E)-N-((2,6-diisopropylphenyl)carbamoyl)-2-(2-methyl-1-(methyl-d)pyrrolidin-2-yl)ethene-1-sulfonamide;
(S,E)-N-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)-2-(1-(methyl-d)pyrrolidin-2-yl)ethene-1-sulfonamide;
(E)-2-((R)-1,2-dimethylpyrrolidin-2-yl)-N-((2-hydroxy-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide;
(R,E)-2-(1,2-dimethylpyrrolidin-2-yl)-N-((1,2,3,7-tetrahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide;
(R,E)-2-(1,2-dimethylpyrrolidin-2-yl)-N-((1,2,3,5-tetrahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide;
(E)-2-((R)-1,2-dimethylpyrrolidin-2-yl)-N-((3-hydroxy-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide;
(E)-2-((R)-1,2-dimethylpyrrolidin-2-yl)-N-((1-hydroxy-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide;
(R,E)-2-(1,2-dimethylpyrrolidin-2-yl)-N-((1-oxo-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide;
(R,E)-N-((2,6-diisopropylphenyl)carbamoyl)-2-(2-methyl-1-(methyl-d)pyrrolidin-2-yl)ethene-1-sulfonamide;
(E)-3-(bis(methyl-d)amino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-methylbut-1-ene-1-sulfonamide;
Sodium (S,E)-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)((2-(2-methyl-1-(methyl-d)pyrrolidin-2-yl)vinyl)sulfonyl)amide;
Sodium (R,E)-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)((2-(2-methyl-1-(methyl-d)pyrrolidin-2-yl)vinyl)sulfonyl)amide;
N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-((1S,8aR)-3,3,8a-trimethyl-2-(methyl-d)octahydropyrrolo[1,2-a]pyrazin-1-yl)methanesulfonamide;
(S,E)-2-(1,2-dimethylpyrrolidin-2-yl)-N-((2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-yl)carbamoyl)ethene-1-sulfonamide;
S,E)-2-(pyrrolidin-2-yl)-N-((2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-yl)carbamoyl)ethene-1-sulfonamide;
(S,E)-2-(2-methylpyrrolidin-2-yl)-N-((2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-yl)carbamoyl)ethene-1-sulfonamide;
(S,E)-2-(1,2-dimethylpyrrolidin-2-yl)-N-(tricyclo[6.2.0.03,6]deca-1,3(6),7-trien-2-ylcarbamoyl)ethene-1-sulfonamide;
(S,E)-2-(pyrrolidin-2-yl)-N-(tricyclo[6.2.0.03,6]deca-1,3(6),7-trien-2-ylcarbamoyl)ethene-1-sulfonamide;
(S,E)-2-(2-methylpyrrolidin-2-yl)-N-(tricyclo[6.2.0.03,6]deca-1,3(6),7-trien-2-ylcarbamoyl)ethene-1-sulfonamide;
(S,E)-2-(1,2-dimethylpyrrolidin-2-yl)-N-((1-oxo-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide;
(S,E)-N-((1-oxo-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(pyrrolidin-2-yl)ethene-1-sulfonamide;
(S,E)-2-(2-methylpyrrolidin-2-yl)-N-((1-oxo-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide;
(S,E)-2-(1,2-dimethylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)ethene-1-sulfonamide;
(S,E)-N-((1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)-2-(pyrrolidin-2-yl)ethene-1-sulfonamide;
(S,E)-N-((1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)-2-(2-methylpyrrolidin-2-yl)ethene-1-sulfonamide;
(S,E)-N-((4-cyano-2,6-diisopropylphenyl)carbamoyl)-2-(1,2-dimethylpyrrolidin-2-yl)ethene-1-sulfonamide;
(S,E)-N-((4-cyano-2,6-diisopropylphenyl)carbamoyl)-2-(pyrrolidin-2-yl)ethene-1-sulfonamide;
(S,E)-N-((4-cyano-2,6-diisopropylphenyl)carbamoyl)-2-(2-methylpyrrolidin-2-yl)ethene-1-sulfonamide;
(S,E)-N-((9H-carbazol-9-yl)carbamoyl)-2-(1,2-dimethylpyrrolidin-2-yl)ethene-1-sulfonamide;
(R,E)-N-((1,2,3,4,5,6,7,8-octahydroanthracen-9-yl)carbamoyl)-3-(pyrrolidin-2-yl)prop-1-ene-1-sulfonamide;
(R,E)-2-(1,2-dimethylpyrrolidin-2-yl)-N-((1,2,3,4,5,6,7,8-octahydroanthracen-9-yl)carbamoyl)ethene-1-sulfonamide;
(R,E)-2-(1,2-dimethylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)ethene-1-sulfonamide;
(R,E)-N-((1,2,3,4,6,7,8,9-octahydropyrido[1,2-a]indol-10-yl)carbamoyl)-3-(pyrrolidin-2-yl)prop-1-ene-1-sulfonamide;
(R,E)-2-(1,2-dimethylpyrrolidin-2-yl)-N-((1,2,3,4,6,7,8,9-octahydropyrido[1,2-a]indol-10-yl)carbamoyl)ethene-1-sulfonamide;
(R,E)-2-(1,2-dimethylpyrrolidin-2-yl)-N-((1,2,3,4,7,8,9,10-octahydropyrido[2,1-a]isoindol-6-yl)carbamoyl)ethene-1-sulfonamide;
(R,E)-N-((1,2,3,4,5,6,7,8-octahydro-9H-carbazol-9-yl)carbamoyl)-3-(pyrrolidin-2-yl)prop-1-ene-1-sulfonamide;
(R,E)-2-(1,2-dimethylpyrrolidin-2-yl)-N-((1,2,3,4,5,6,7,8-octahydro-9H-carbazol-9-yl)carbamoyl)ethene-1-sulfonamide;
(R,E)-N-((1,2,3,5,6,7-hexahydro-4H-dicyclopenta[b,d]pyrrol-4-yl)carbamoyl)-3-(2-methylpyrrolidin-2-yl)prop-1-ene-1-sulfonamide;
(R,E)-2-(1,2-dimethylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-4H-dicyclopenta[b,d]pyrrol-4-yl)carbamoyl)ethene-1-sulfonamide;
(R,E)-2-(1,2-dimethylpyrrolidin-2-yl)-N-((3,5,6,7-tetrahydro-2H-indeno[5,6-b]furan-4-yl)carbamoyl)ethene-1-sulfonamide;
(R,E)-2-(1,2-dimethylpyrrolidin-2-yl)-N-((5-(3-methoxyphenyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)ethene-1-sulfonamide;
(R,E)-2-(1,2-dimethylpyrrolidin-2-yl)-N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)ethene-1-sulfonamide;
(S,E)-N-((9H-fluoren-9-yl)carbamoyl)-2-(1,2-dimethylpyrrolidin-2-yl)ethene-1-sulfonamide;
(R,E)-2-(1,2-dimethylpyrrolidin-2-yl)-N-((2-isopropyl-6-(pyridin-4-yl)phenyl)carbamoyl)ethene-1-sulfonamide;
(R,E)-N-((2-isopropyl-6-(pyridin-4-yl)phenyl)carbamoyl)-3-(pyrrolidin-2-yl)prop-1-ene-1-sulfonamide;
(R,E)-2-(1,2-dimethylpyrrolidin-2-yl)-N-((2-isopropyl-6-(pyridin-3-yl)phenyl)carbamoyl)ethene-1-sulfonamide;
(R,E)-N-((2-isopropyl-6-(pyridin-3-yl)phenyl)carbamoyl)-3-(2-methylpyrrolidin-2-yl)prop-1-ene-1-sulfonamide;
(R,E)-2-(1,2-dimethylpyrrolidin-2-yl)-N-((4-fluoro-2-isopropyl-6-(pyridin-3-yl)phenyl)carbamoyl)ethene-1-sulfonamide;
(R,E)-N-((4-fluoro-2-isopropyl-6-(pyridin-3-yl)phenyl)carbamoyl)-3-(pyrrolidin-2-yl)prop-1-ene-1-sulfonamide;
(R,E)-N-((4-chloro-2,6-diisopropylphenyl)carbamoyl)-2-(1,2-dimethylpyrrolidin-2-yl)ethene-1-sulfonamide;
(R,E)-2-(1,2-dimethylpyrrolidin-2-yl)-N-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)ethene-1-sulfonamide;
(R,E)-N-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)-3-(pyrrolidin-2-yl)prop-1-ene-1-sulfonamide;
(R,E)-2-(1,2-dimethylpyrrolidin-2-yl)-N-((7-fluoro-5-(pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)ethene-1-sulfonamide;
(R,E)-N-((7-fluoro-5-(pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-3-(2-methylpyrrolidin-2-yl)prop-1-ene-1-sulfonamide;
tert-butyl (2R)-2-((E)-2-(N-((2-hydroxy-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)-2-methylpyrrolidine-1-carboxylate;
(E)-N-((2-hydroxy-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-((R)-2-methylpyrrolidin-2-yl)ethene-1-sulfonamide;
(R,E)-2-(2-methylpyrrolidin-2-yl)-N-((1,2,3,7-tetrahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide;
(R,E)-2-(2-methylpyrrolidin-2-yl)-N-((1,2,3,5-tetrahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide;
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(5-methylhexahydro-1H-furo[3,4-c]pyrrol-4-yl)ethene-1-sulfonamide;
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-methyloctahydrocyclopenta[c]pyrrol-5-yl)ethene-1-sulfonamide;
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-methylisoindolin-1-yl)ethene-1-sulfonamide;
(R,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-methyl-1-(methyl-d3)pyrrolidin-2-yl)ethene-1-sulfonamide;
(R,E)-2-(1,2-dimethyl-2,5-dihydro-1H-pyrrol-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide;
(R,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-isobutoxy-2-methylpyrrolidin-2-yl)ethene-1-sulfonamide;
(R,E)-2-(1,2-dimethylpyrrolidin-2-yl)-N-((6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)carbamoyl)ethene-1-sulfonamide;
(R,E)-N-((7,8-dihydro-6H-cyclopenta[d]imidazo[1,2-a]pyrimidin-5-yl)carbamoyl)-2-(1,2-dimethylpyrrolidin-2-yl)ethene-1-sulfonamide;
(R,E)-2-(1,2-dimethylpyrrolidin-2-yl)-N-((3-(2-hydroxypropan-2-yl)-5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl)carbamoyl)ethene-1-sulfonamide;
(R,E)-N-((6,7-dihydro-5H-cyclopenta[d]pyrazolo[1,5-a]pyrimidin-8-yl)carbamoyl)-2-(1,2-dimethylpyrrolidin-2-yl)ethene-1-sulfonamide;
ethyl(R,E)-3-(3-((2-(1,2-dimethylpyrrolidin-2-yl)vinyl)sulfonyl)ureido)-5,6-dihydro-4H-cyclopenta[b]thiophene-2-carboxylate;
(E)-2-((R)-1,2-dimethylpyrrolidin-2-yl)-N-((1,2,3,4-tetrahydro-1,4-methanonaphthalen-5-yl)carbamoyl)ethene-1-sulfonamide;
or pharmaceutically acceptable salts of any of the compounds above.
Following is a list of abbreviations used in the description of the preparation of the compounds of the present invention:
µg: microgram
1H NMR : Proton nuclear magnetic resonance
bs: broad singlet
CDC13: Deuterated chloroform
CHC13: Chloroform
D: Deuterium
d: doublet
DAMP: damage-associated molecular pattern;
DBU: 1,8-Diazabicyclo(5.4.0)undec-7-ene
DCM: Dichloromethane
dd: doublet of doublet
DMAC: N,N-(Dimethylacetamide)
DMAP: 4-(Dimethylamino) pyridine
DMF: N,N-Dimethyl formamide
DMSO: Dimethyl sulfoxide
DMSO-d6: Deuterated Dimethyl sulfoxide
dt: doublet of triplet
EDTA: Ethylenediaminetertraacetic acid
EtOAc: Ethyl acetate
EtOH: Ethanol
HCl(g): Hydrogen chloride (gas)
IL1ß: Interleukin 1 beta
K2CO3: Potassium carbonate
m: multiplet
MeOH: Methanol
mmol: millimoles
MS: Mass spectrum
N2: Nitrogen
Na2CO3: Sodium carbonate
ng: nanogram
NIS: N-iodosuccinimide
PAMP: pathogen-associated molecular pattern;
PMA = Phorbol 12-myristate 13-acetate
POCI3: Phosphorylchloride
RM: reaction mixture
r.t., RT: room temperature
s: singlet
t: Triplet
td: triplet of doublet
THF: Tetrahydrofuran
TLC: Thin layer chromatography
TLR: Toll-like receptor.
TNF a: Tumor necrosis factor alpha
General Process for Preparation
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 thereon as appreciated by those skilled in the art.
The reactions can be performed in solvents appropriate to the reagents and materials employed and suitable for the transformations being affected. Preferred methods include, but not limited to those described below, where all symbols are as defined earlier unless and otherwise defined below.
The compounds of the general formula (I) can be prepared as described in schemes below along with suitable modifications/variations which are well within the scope of a person skilled in the art.

Scheme 1

Formula (I)
Wherein each of R1, R2, X, and Y, are as defined earlier. Compound 1 and Compound 2 can be prepared by variety of methods familiar to those skilled in art using reported procedures. Compound (1) on treatment with isocyanato derivative (2) under suitable conditions in presence of base like sodium hydride and appropriate solvent to afford compound of formula (I).
Specific reaction conditions, solvents and other parameters necessary for carrying out the process steps as described above are well within the capabilities of a person skilled in the art.
The invention is further illustrated by the following non-limiting examples, which describe the preferred way of carrying out the present invention. These are provided without limiting the scope of the present invention in any way.
1H NMR spectral data given in the examples (vide infra) are recorded using a 400 MHz spectrometer (Bruker AVANCE-400) and reported in d scale. Until and otherwise mentioned the solvent used for NMR is CDCl3 using TMS as the internal standard.
Example-1
(S,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-methyl-1-(methyl-d)pyrrolidin-2-yl)ethene-1-sulfonamide

Procedure: - To a solution of (S,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-methylpyrrolidin-2-yl)ethene-1-sulfonamide 2,2,2-trifluoroacetate (0.5 g, 0.993 mmol) in MeOH (10 mL) under nitrogen atmosphere. Triethyamine (0.166 mL, 1.192 mmol) was added and the reaction mixture was stirred for 10 min. at room temperature. Then paraformaldehyde (0.060 g, 1.986 mmol) was added and reaction mixture was stirred for 10 min. at room temperature. Then the reaction mixture was cooled to 0 °C and added sodium cyanoborodeuteride (0.078 g, 1.192 mmol) in one portion. After the addition reaction mixture was warmed to room temperature and stirred for 17 h. Completion of reaction checked by TLC. The reaction was concentrated in vacuo. Crude product was purified by preparative HPLC to yield, (S,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-methyl-1-(methyl-d)pyrrolidin-2-yl)ethene-1-sulfonamide (61 mg, 0.151 mmol).
1H NMR (400 MHz, DMSO-d6): d = 7.93 (s, 1H), 6.91 (s, 1H), 6.71 (d, J = 15.2 Hz, 1H), 6.60 (d, J = 15.6 Hz, 1H), 2.85 – 2.83 (m, 1H), 2.80 (t, J = 7.2 Hz, 4H), 2.73 – 2.71 (m, 1H), 2.67 (t, J = 7.2 Hz, 4H), 2.15 (s, 2H), 1.95 (quin, J = 7.2 Hz, 4H), 1.81 – 1.69 (m, 4H), 1.10 (s, 3H). ESI-Q-TOF-MS: m/z 405.2268 (100%) [M+H]+, 403.1901 (100%) [M-H]-.
Example-2
(R,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-methyl-1-(methyl-d)pyrrolidin-2-yl)ethene-1-sulfonamide

1H NMR (400 MHz, DMSO-d6): d = 7.94 (s, 1H), 6.91 (s, 1H), 6.72 (d, J = 15.2 Hz, 1H), 6.61 (d, J = 15.2 Hz, 1H), 2.88 – 2.83 (m, 1H), 2.80 (t, J = 7.2 Hz, 4H), 2.75 – 2.71 (m, 1H), 2.67 (t, J = 7.2 Hz, 4H), 2.15 (s, 2H), 1.95 (quin, J = 7.2 Hz, 4H), 1.82 – 1.69 (m, 4H), 1.11 (s, 3H), ESI-Q-TOF-MS: m/z 405.2104 (100%) [M+H]+, 403.1915 (100%) [M-H]-.
Example-3
(S,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(methyl-d)pyrrolidin-2-yl)ethene-1-sulfonamide

1H NMR (400 MHz, DMSO-d6): d = 7.97 (s, 1H), 6.92 (s, 1H), 6.85 (d, J = 15.2 Hz, 1H), 6.54 (dd, J1 = 7.6 Hz, J2 = 15.2 Hz, 1H), 3.11 – 3.06 (m, 2H), 2.80 (t, J = 7.2 Hz, 4H), 2.67 (t, J = 7.2 Hz, 4H), 2.36 – 2.30 (m, 1H), 2.24 (s, 2H), 2.08 – 2.04 (m, 1H), 1.95 (quin, J = 7.2 Hz, 4H), 1.89 – 1.72 (m, 2H), 1.62 – 1.53 (m, 1H), ESI-Q-TOF-MS: m/z 391.1943 (100%) [M+H]+, 389.1764 (100%) [M-H]-.
Example-4
(R,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(methyl-d)pyrrolidin-2-yl)ethene-1-sulfonamide

1H NMR (400 MHz, DMSO-d6): d = 10.5 (br s, 1H), 7.99 (s, 1H), 6.92 (s, 1H), 6.86 (d, J = 15.2 Hz, 1H), 6.56 (dd, J1 = 7.6 Hz, J2 = 15.2 Hz, 1H), 3.12 – 3.06 (m, 2H), 2.80 (t, J = 7.2 Hz, 4H), 2.67 (t, J = 7.2 Hz, 4H), 2.38 – 2.32 (m, 1H), 2.25 (s, 2H), 2.08 – 2.01 (m, 1H), 1.95 (quin, J = 7.2 Hz, 4H), 1.80 – 1.73 (m, 2H), 1.63 – 1.54 (m, 1H), ESI-Q-TOF-MS: m/z 391.1956 (100%) [M+H]+, 389.1756 (100%) [M-H]-.

Example-5
(R,E)-N-((2,6-diisopropylphenyl)carbamoyl)-2-(2-methyl-1-(methyl-d)pyrrolidin-2-yl)ethene-1-sulfonamide

1H NMR (400 MHz, DMSO-d6): d = 7.55 (s, 1H), 7.16 (t, J = 7.6 Hz, 1H), 7.08 (d, J = 7.6 Hz, 2H), 6.64 (d, J = 15.6 Hz, 1H), 6.39 (d, J = 15.6 Hz, 1H), 3.16 – 3.13 (m, 2H), 2.77 – 2.75 (m, 1H), 2.67 – 2.64 (m, 1H), 2.08 (s, 2H), 1.76 – 1.69 (m, 3H), 1.64 – 1.62 (m,1H), 1.11 (d, J = 6.8 Hz, 12H), 1.03 (s, 3H), MS (TOF): ESI-Q-TOF-MS: m/z 409.2422 (100%) [M+H]+, 407.2229 (100%) [M-H]-.
Example-6
(S,E)-N-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)-2-(1-(methyl-d)pyrrolidin-2-yl)ethene-1-sulfonamide

1H NMR (400 MHz, DMSO-d6): d = 7.69 (s, 1H), 6.91 - 6.63 (m, 3H), 6.45 - 6.40 (m, 1H), 3.19 - 3.05 (m, 3H), 2.85 - 2.76 (m, 2H), 2.25 - 2.23 (m, 1H), 2.17 (s, 2H), 2.02 - 1.94 (m, 1H), 1.76 - 1.69 (m, 2H), 1.57 - 1.45 (m, 1H), 1.10 (d, J=6.4Hz, 12H); MS (TOF): m/z (%) = 413.2120 (100%) (M+H)+, 411.1925 (100%) (M-1)-;
Example-7
(R,E)-2-(1,2-dimethylpyrrolidin-2-yl)-N-((1,2,3,7-tetrahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide

Intermediate 1: (R,E)-2-(2-methylpyrrolidin-2-yl)ethene-1-sulfonamide

To a solution of tert-butyl (R,E)-2-methyl-2-(2-sulfamoylvinyl)pyrrolidine-1-carboxylate (CAS No. 2455521-71-6) (0.65 g, 2.238 mmol) in DCM (10 mL) was added TFA (1.725 mL, 22.38 mmol) at r.t. The reaction mixture was stirred at r.t. for 2 h. The reaction mixture was evaporated to afford (R,E)-2-(2-methylpyrrolidin-2-yl)ethene-1-sulfonamide 2,2,2-trifluoroacetate. MS (ESI): m/z (%) = 191.1023 (100%) (M+H)+;
Intermediate 2: (R,E)-2-(1,2-dimethylpyrrolidin-2-yl)ethene-1-sulfonamide

To a solution of (R,E)-2-(2-methylpyrrolidin-2-yl)ethene-1-sulfonamide 2,2,2-trifluoroacetate (0.566 g, 1.860 mmol) in MeOH (12 mL) was added Et3N (0.311 mL, 2.232 mmol), paraformaldehyde (0.084 g, 2.79 mmol) and sodium cyanoborohydride (0.140 g, 2.232 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was evaporated to get crude product which was purified by preparative HPLC to afford (R,E)-2-(1,2-dimethylpyrrolidin-2-yl)ethene-1-sulfonamide. 1H NMR (400 MHz, DMSO-d6): d = 10.24 (bs, 1H), 7.27 - 7.24 (m, 2H), 6.92 - 6.88 (m, 1H), 6.6 -6.59 (m, 1H), 3.70 - 3.60 (m, 1H), 3.39 - 3.17 (m, 1H), 2.67 - 2.65 (m, 3H), 2.09 - 2.02 (m, 3H), 1.55 - 1.39 (m, 3H); MS (ESI): m/z (%) = 205.09 (100%) (M+H)+;

To a solution of 8-isocyanato-1,2,3,5-tetrahydro-s-indacene (0.478 g, 2.423 mmol) (CAS No.: 2260973-09-7) and (R,E)-2-(1,2-dimethylpyrrolidin-2-yl)ethene-1-sulfonamide (0.45 g, 2.203 mmol) in THF (9 mL) was added DBU (0.664 mL, 4.41 mmol) at r.t. Reaction mixture was stirred for 16h at rt. The reaction mixture was evaporated. The crude product was purified by preparative HPLC to afford Example 7 and Example 8.
1H NMR (400 MHz, DMSO-d6): d = 8.16 (bs, 1H), 7.13 (s, 1H), 6.84 - 6.83 (m, 1H), 6.75 (d, J=15.6Hz, 1H), 6.63 (d, J=15.2Hz, 1H), 6.51 - 6.50 (m, 1H), 3.34 - 3.26 (m, 2H), 2.90 - 2.86 (m, 3H), 2.79 - 2.74 (m, 3H), 2.23 (s, 3H), 2.08 - 1.96 (m, 2H), 1.88 - 1.71 (m, 4H), 1.15 (s, 3H); MS (TOF): m/z (%) = 402.24 (100%) (M+H)+;
Example-8
(R,E)-2-(1,2-dimethylpyrrolidin-2-yl)-N-((1,2,3,5-tetrahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide

1H NMR (400 MHz, DMSO-d6): d = 8.27 (bs, 1H), 7.18 (s, 1H), 6.79 - 6.73 (m, 2H), 6.66 - 6.62 (m, 1H), 6.46 - 6.45 (m, 1H), 3.34 - 3.22 (m, 2H), 2.90 - 2.86 (m, 3H), 2.78 - 2.72 (m, 3H), 2.22 (s, 3H), 2.03 - 1.96 (m, 2H), 1.88 - 1.73 (m, 4H), 1.15 (s, 3H);
MS (TOF): m/z (%) = 402.25 (100%) (M+H)+;
Example-9
(E)-2-((R)-1,2-dimethylpyrrolidin-2-yl)-N-((2-hydroxy-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide

1H NMR (400 MHz, DMSO-d6): d = 10.5 (bs, 1H), 8.10 (s, 1H), 6.91 (s, 1H), 6.77 - 6.65 (m, 2H), 4.79 (d, J=3.6Hz, 1H), 4.43 (d, J=2.8Hz, 1H), 3.03 - 2.97 (m, 3H), 2.81 - 2.78 (m, 7H), 2.33 (s, 3H), 1.99 - 1.76 (m, 6H), 1.16 (s, 3H); MS (TOF): m/z (%) = 420.19 (100%) (M+H)+;
Example-10
(E)-2-((R)-1,2-dimethylpyrrolidin-2-yl)-N-((3-hydroxy-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide (III)

1H NMR (400 MHz, DMSO-d6): d = 8.05 (s, 1H), 6.90 (s, 1H), 6.75 (t, J = 15.2 Hz, 1H), 6.60 (t, J = 15.6 Hz, 1H), 5.01 (t, J = 3.2 Hz, 1H), 3.18 – 2.89 (m, 2H), 2.87 – 2.67 (m, 3H), 2.68 – 2.60 (m, 2H), 2.32 – 2.19 (m, 4H), 2.07 – 1.93 (m, 2H), 1.90 – 1.79 (m, 6H), 1.17 (s, 3H);
MS (TOF): m/z (%) = 420.1937 (50%) (M+H)+, 418.1843 (5%) (M-1);
Example-11
(E)-2-((R)-1,2-dimethylpyrrolidin-2-yl)-N-((1-hydroxy-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide

1H NMR (400 MHz, DMSO-d6): d = 10.4 (br s, 1H), 8.02 (s, 1H), 7.02 (s, 1H), 6.75 (t, J = 15.2 Hz, 1H), 6.65 (t, J = 15.6 Hz, 1H), 5.13 (d, J = 4.4 Hz, 1H), 4.98 (d, J = 3.6 Hz, 1H), 2.88 – 2.79 (m, 3H), 2.77 – 2.60 (m, 4H), 2.56 – 2.54 (m, 1H), 2.30 – 2.24 (m, 1H), 2.20 (s, 3H), 2.00 – 1.91 (m, 2H), 1.84 – 1.67 (m, 5H), 1.13 (s, 3H);
MS (TOF): m/z (%) = 420.1947 (100%) (M+H)+, 418.1800 (20%) (M-1)-;
Example-12
(R,E)-2-(1,2-dimethylpyrrolidin-2-yl)-N-((1-oxo-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide

1H NMR (400 MHz, DMSO-d6): d = 8.07 (s, 1H), 7.25 (s, 1H), 6.76 (t, J = 15.2 Hz, 1H), 6.48 (t, J = 15.6 Hz, 1H), 2.94 – 2.85 (m, 5H), 2.81 (t, J = 7.2 Hz, 3H), 2.60 – 2.57 (m, 2H), 2.26 (s, 3H), 2.0 (quin, J = 7.2 Hz, 2H), 1.80 – 1.72 (m, 4H), 1.13 (s, 3H); MS (TOF): m/z (%) = 418.2041 (100%) (M+H)+, 416.1698 (100%) (M-1)-.
Example-13
(S,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-methyl-1-(methyl-d3)pyrrolidin-2-yl)ethene-1-sulfonamide

To a solution of (S,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-methylpyrrolidin-2-yl)ethene-1-sulfonamide 2,2,2-trifluoroacetate (0.5 g, 0.993 mmol) in MeOH (10 mL) under N2 atm. TEA (0.166 mL, 1.192 mmol) was added and reaction mixture was stirred for 10 min. at rt. then formaldehyde-d2 (0.064 g, 1.986 mmol) was added and reaction mixture was stirred for 10 min. at rt. Then the reaction mixture was cooled to 0 °C and Sodium cyanoborodeuteride (0.078 g, 1.192 mmol) was added portion wise. After the addition reaction mixture was warmed to rt and stirred for 17 h. TLC was checked no starting material was observed. Crude product was purified by preparative HPLC, to afford (S,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-methyl-1-(methyl-d3)pyrrolidin-2-yl)ethene-1-sulfonamide (85 mg, 0.207 mmol, 21 % yield).
1H NMR (400 MHz, DMSO-d6): d = 7.92 (br s, 1H), 6.91 (s, 1H), 6.72 (d, J = 15.2 Hz, 1H), 6.60 (d, J = 15.6 Hz, 1H), 2.81 – 2.78 (m, 5H), 2.71 – 2.65 (m, 5H), 1.95 (quin, J = 7.2 Hz, 4H), 1.80 – 1.71 (m, 4H), 1.11 (s, 3H); MS (ESI): m/z (%) = 407.10 (100%) (M+H)+, 405.10 (100%) (M-H)-; IR (KBr): ? = 3319, 2945, 2841, 1708, 1593, 1504, 1427, 1504, 1265, 1136, 1093, 906 cm-1.
Example-14
(S,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-methyl-1-(methyl-d2)pyrrolidin-2-yl)ethene-1-sulfonamide

To a solution of (S,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-methylpyrrolidin-2-yl)ethene-1-sulfonamide 2,2,2-trifluoroacetate (0.5 g, 0.993 mmol) in MeOH (10 mL) under nitrogen atmosphere TEA (0.166 mL, 1.192 mmol) was added and reaction mixture was stirred for 10 min. at room temperature, then formaldehyde-d2 (0.064 g, 1.986 mmol) was added and the reaction mixture was stirred for 10 min. at rt. The reaction mixture was cooled to 0 °C and sodium cyanoborohydride was added portion wise (0.075 g, 1.192 mmol). After the addition reaction mixture was warmed to rt and stirred for 17 h. TLC was checked no starting material was observed. Crude product was purified by preparative HPLC to yield, (S,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-methyl-1-(methyl-d2)pyrrolidin-2-yl)ethene-1-sulfonamide (137 mg, 0.336 mmol, 33.8 % yield).
1H NMR (400 MHz, DMSO-d6): d = 8.00 (s, 1H), 6.92 (s, 1H), 6.74 (d, J = 15.2 Hz, 1H), 6.65 (d, J = 15.2 Hz, 1H), 2.87 (br s, 1H), 2.82 (d, J = 7.2 Hz, 5H), 2.67 (d, J = 7.2 Hz, 4H), 2.16 (br s, 1H), 1.95 (quin, J = 7.2 Hz, 4H), 1.85 – 1.71 (m, 4H), 1.13 (s, 3H); MS (TOF): m/z (%) = 406.2169 (100%) (M+H)+, 404.1986 (100%) (M-H)-; IR (KBr): ? = 3327, 2951, 2841, 1693, 1593, 1504, 1265, 1136, 1093, 906 cm-1.
Example-15
Sodium (S,E)-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)((2-(2-methyl-1-(methyl-d)pyrrolidin-2-yl)vinyl)sulfonyl)amide

1H NMR (400 MHz, DMSO-d6): d = 7.35 (s, 1H), 6.77 (s, 1H), 6.55 (d, J = 15.6 Hz, 1H), 6.18 (d, J = 15.6 Hz, 1H), 2.78 – 2.68 (m, 9H), 2.64 – 2.61 (m, 1H), 2.06 (s, 2H), 1.94 – 1.87 (m, 4H), 1.74 – 1.68 (m, 3H), 1.62 – 1.60 (m, 1H), 1.01 (s, 3H); MS (ESI): m/z (%) = 405.2096 (100%) (M+H)+, 403.1928 (100%) (M-1);
Example-16
Sodium (R,E)-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)((2-(2-methyl-1-(methyl-d)pyrrolidin-2-yl)vinyl)sulfonyl)amide

1H NMR (400 MHz, DMSO-d6): d = 7.35 (s, 1H), 6.77 (s, 1H), 6.55 (d, J = 15.6 Hz, 1H), 6.18 (d, J = 15.6 Hz, 1H), 2.78 – 2.68 (m, 9H), 2.64 – 2.59 (m, 1H), 2.06 (s, 2H), 1.94 – 1.87 (m, 4H), 1.74 – 1.70 (m, 3H), 1.60 – 1.57 (m, 1H), 1.01 (s, 3H); MS (ESI): m/z (%) = 405.2101 (100%) (M+H)+, 403.1921 (100%) (M-1);
Example-17
N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-((1S,8aR)-3,3,8a-trimethyl-2-(methyl-d)octahydropyrrolo[1,2-a]pyrazin-1-yl)methanesulfonamide

1H NMR (400 MHz, DMSO-d6): d = 8.01 (bs, 1H), 6.94 (s, 1H), 3.54 (s, 2H), 2.98 - 2.50 (m, 10H), 2.45 - 2.09 (m, 5H), 1.99 - 1.91 (m, 4H), 1.81 - 1.65 (m, 4H), 1.10 (s, 6H), 0.8 (s, 3H); MS (TOF): m/z (%) = 476.2797 (100%) (M+H)+; 474.2623 (100%) (M-1)-;
Example-18
Sodium (R,E)-((2,6-diisopropylphenyl)carbamoyl)((2-(2-methyl-1-(methyl-d)pyrrolidin-2-yl)vinyl)sulfonyl)amide

1H NMR (400 MHz, DMSO-d6): d = 7.23 (s, 1H), 7.12 – 7.10 (m, 1H), 7.03 (d, J = 7.6 Hz, 2H), 6.54 (d, J = 15.6 Hz, 1H), 6.18 (d, J = 16.0 Hz, 1H), 3.24 – 3.20 (m, 2H), 2.76 – 2.70 (m, 1H), 2.65 – 2.59 (m, 1H), 2.08 (s, 2H), 1.72 – 1.67 (m, 3H), 1.63 – 1.56 (m, 1H), 1.09 (d, J = 6.4 Hz, 12H), 1.00 (s, 3H); MS (ESI): m/z (%) = 409.2391 (100%) (M+H)+, 407.2236 (100%) (M-1).
Example-19
(S,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-methyl-1-(methyl-d)pyrrolidin-2-yl)ethene-1-sulfonamide

1H NMR (400 MHz, DMSO-d6): d = 7.93 (s, 1H), 6.91 (s, 1H), 6.71 (d, J = 15.2 Hz, 1H), 6.60 (d, J = 15.6 Hz, 1H), 2.85 – 2.83 (m, 1H), 2.80 (t, J = 7.2 Hz, 4H), 2.73 – 2.71 (m, 1H), 2.67 (t, J = 7.2 Hz, 4H), 2.15 (s, 2H), 1.95 (quin, J = 7.2 Hz, 4H), 1.81 – 1.69 (m, 4H), 1.10 (s, 3H); MS (TOF): m/z (%) = 405.2268 (100%) (M+H)+, 403.1901 (100%) (M-H)-; IR (KBr): ? = 2949, 2843, 1710, 1593, 1504, 1456, 1427, 1265, 1138, 1093, 906 cm-1.
Example-20
(R,E)-2-(2-methylpyrrolidin-2-yl)-N-((1,2,3,7-tetrahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide

1H NMR (400 MHz, DMSO-d6): d = 8.72 (bs, 1H), 7.74 (s, 1H), 7.02 (s, 1H), 6.94 (d, J=15.6Hz, 1H), 6.80 (d, J=5.2Hz, 1H), 6.52 (d, J=15.6Hz, 1H), 6.47 (d, J=5.6Hz, 1H), 3.29 - 3.12 (m, 5H), 2.85 (t, J=7.2Hz, 2H), 2.79 (t, J=7.2Hz, 2H), 1.98 - 1.78 (m, 6H), 1.39 (s, 3H); MS (TOF): m/z (%) = 388.1740 (100%) (M+H)+, 388.1460 (100%) (M-1)-.
Example-21
(E)-N-((2-hydroxy-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-((R)-2-methylpyrrolidin-2-yl)ethene-1-sulfonamide

1H NMR (400 MHz, DMSO-d6): d = 8.65 (bs, 1H), 7.55 (s, 1H), 6.88 (d, J=15.2Hz, 1H), 6.78 (s, 1H), 6.44 (d, J=15.2Hz, 1H), 4.70 (bs, 1H), 4.41 - 4.38 (m, 1H), 3.43 - 3.10 (m, 2H), 2.99 - 2.90 (m, 2H), 2.79 - 2.54 (m, 6H), 1.95 - 1.85 (m, 6H), 1.36 (s, 3H); MS (TOF): m/z (%) = 406.1802 (100%) (M+H)+, 404.1651 (100%) (M-1)-.
Example-22
(E)-N-((2-hydroxy-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-((R)-2-methyl-1-(methyl-d)pyrrolidin-2-yl)ethene-1-sulfonamide

1H NMR (400 MHz, DMSO-d6): d = 7.98 (s, 1H), 6.90 (s, 1H), 6.74 - 6.60 (m, 2H), 4.78 (s, 1H), 4.43 (s, 1H), 3.02 - 2.97 (m, 2H), 2.91 - 2.85 (m, 2H), 2.82 - 2.78 (m, 2H), 2.75 - 2.67 (m, 4H), 2.17 (s, 2H); 1.95 (t, J=7.2Hz, 2H), 1.82 - 1.62 (m, 4H), 1.13 (s, 3H); MS (TOF): m/z (%) = 421.2567 (100%) (M+H)+, 419.2240 (100%) (M-1)-.
Example-23
N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-((1S,8aR)-3,3,8a-trimethyl-2-(methyl-d)octahydropyrrolo[1,2-a]pyrazin-1-yl)methanesulfonamide

1H NMR (400 MHz, DMSO-d6): d = 8.01 (bs, 1H), 6.94 (s, 1H), 3.54 (s, 2H), 2.98 - 2.50 (m, 10H), 2.45 - 2.09 (m, 5H), 1.99 - 1.91 (m, 4H), 1.81 - 1.65 (m, 4H), 1.10 (s, 6H), 0.8 (s, 3H); MS (TOF): m/z (%) = 476.2797 (100%) (M+H)+; 474.2623 (100%) (M-1)-.
Example-24
(E)-3-(bis(methyl-d)amino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)prop-1-ene-1-sulfonamide

1H NMR (400 MHz, DMSO-d6): d = 7.97 (s, 1H), 6.92 (s, 1H), 6.89 (d, J = 15.2 Hz, 1H), 6.63 – 6.56 (m, 1H), 3.31 (d, J = 5.6 Hz, 2H), 2.80 (t, J = 7.2 Hz, 4H), 2.67 (t, J = 7.2 Hz, 4H), 2.30 (s, 4H), 1.95 – 1.93 (quin, J = 7.2 Hz, 4H); MS (TOF): m/z (%) = 366.1852 (100%) (M+H)+, 364.1676 (100%) (M-H)-; IR (KBr): ? = 3552, 3379, 2958, 2843, 1595, 1500, 1456, 1425, 1271, 1095, 925, 908 cm-1.
Example-25
(R,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-methyl-1-(methyl-d2)pyrrolidin-2-yl)ethene-1-sulfonamide

1H NMR (400 MHz, DMSO-d6): d = 7.93 (s, 1H), 6.11 (s, 1H), 6.71 (d, J = 15.2 Hz, 1H), 6.59 (d, J = 15.2 Hz, 1H), 2.87 – 2.78 (m, 5H), 2.75 – 2.65 (m, 5H), 2.13 (s, 1H), 1.95 (quin, J = 7.2 Hz, 4H), 1.80 – 1.67 (m, 4H), 1.10 (s, 3H); MS (TOF): m/z (%) = 406.2798 (100%) (M+H)+, 404.2802 (100%) (M-H)-; IR (KBr): ? = 3311, 2945, 2843, 1716, 1593, 1506, 1456, 1427, 1276, 1136, 1093 cm-1.
Example-26
sodium (R,E)-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)((2-(2-methyl-1-(methyl-d2)pyrrolidin-2-yl)vinyl)sulfonyl)amide

1H NMR (400 MHz, DMSO-d6): d = 7.35 (s, 1H), 6.77 (s, 1H), 6.59 (d, J = 15.6 Hz, 1H), 6.20 (d, J = 15.6 Hz, 1H), 2.76 (t, J = 7.2 Hz, 5H), 2.70 (t, J = 7.2 Hz, 4H), 2.64 – 2.61 (m, 1H), 2.04 (s, 1H), 1.91 (quin, J = 7.2 Hz, 4H), 1.74 – 1.71 (m, 3H), 1.65 – 1.60 (m, 1H), 1.01 (s, 3H); MS (TOF): m/z (%) = 406.2711 (100%) (M-Na+H)+, 404.2441 (100%) (M-H)-; IR (KBr): ? = 3346, 2956, 2839, 1602, 1508, 1427, 1271, 1230, 1132, 1083, 931 cm-1.
Example-27
(R,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-methyl-1-(methyl-d3)pyrrolidin-2-yl)ethene-1-sulfonamide

1H NMR (400 MHz, DMSO-d6): d = 10.77 (br s, 1H), 8.33 (s, 1H), 6.94 (s, 1H), 6.92 (d, J = 15.6 Hz, 1H), 6.79 (d, J = 15.2 Hz, 1H), 3.07 – 3.01 (m, 2H), 2.80 (t, J = 7.2 Hz, 4H), 2.67 (t, J = 7.2 Hz, 4H), 2.07 – 1.92 (m, 6H), 1.87 – 1.80 (m, 2H), 1.27 (s, 3H); MS (TOF): m/z (%) = 407.3355 (100%) (M+H)+, 405.2491 (100%) (M-H)-; IR (KBr): ? = 3140, 3053, 2945, 2843, 1710, 1506, 1591, 1543, 1257, 1141, 908 cm-1.
Example-28
sodium (R,E)-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)((2-(2-methyl-1-(methyl-d3)pyrrolidin-2-yl)vinyl)sulfonyl)amide

1H NMR (400 MHz, DMSO-d6): d = 7.53 (s, 1H), 6.80 (s, 1H), 6.59 (d, J = 15.6 Hz, 1H), 6.27 (d, J = 15.2 Hz, 1H), 2.76 (t, J = 7.2 Hz, 5H), 2.69 (t, J = 7.2 Hz, 4H), 2.65 – 2.63 (m, 1H), 1.95 – 1.88 (m, 4H), 1.74 – 1.70 (m, 3H), 1.64 – 1.60 (m, 1H), 1.03 (s, 3H); MS (ESI): m/z (%) = 406.80 (100%) (M-Na+H)+, 404.70 (100%) (M-Na-H)-; IR (KBr): ? = 3350, 2958, 2837, 1600, 1508, 1419, 1271, 1136, 1085 cm-1.
Example-29
(E)-N'-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-((R)-2-methyl-1-(methyl-d)pyrrolidin-2-yl)ethene-1-sulfonimidamide

1H NMR (400 MHz, DMSO-d6): d = 9.91 (br s, 1H), 8.04 (s, 1H), 6.99 – 6.97 (s, 1H), 6.83 (s, 1H), 6.57 – 6.48 (s, 1H), 3.58 (br s, 1H), 3.26 (br s, 1H), 2.77 (t, J = 7.2 Hz, 4H), 2.71 - 2.68 (m, 6H), 2.10 – 2.08 (m, 1H), 2.04 – 2.00 (m, 2H), 1.91 – 1.88 (m, 5H), 1.36 (s, 3H); MS (ESI): m/z (%) = 429.19 (100%) (M+H)+, 427.15 (100%) (M-H)-; IR (KBr): ? = 3226, 2956, 2843, 2185, 1589, 1514, 1427, 1280, 1247, 1114, 1012, 844 cm-1.
Example-30
(E)-3-(bis(methyl-d2)amino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)prop-1-ene-1-sulfonamide

1H NMR (400 MHz, DMSO-d6): d = 7.91 (s, 1H), 6.90 (s, 1H), 6.88 (d, J = 15.2 Hz, 1H), 6.60 – 6.55 (m, 1H), 3.29 (d, J = 5.6 Hz, 2H), 2.79 (t, J = 7.2 Hz, 4H), 2.67 (t, J = 7.2 Hz, 4H), 2.27 (s, 2H), 1.95 (quin, J = 7.2 Hz, 4H); MS (TOF): m/z (%) = 368.1995 (100%) (M+H)+, 366.1792 (100%) (M-H)-; IR (KBr): ? = 3552, 3379, 2960, 2935, 2843, 1595, 1498, 1446, 1425, 1392, 1271, 1136 cm-1.
Example-31
(E)-3-(bis(methyl-d3)amino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)prop-1-ene-1-sulfonamide

1H NMR (400 MHz, DMSO-d6): d = 7.90 (s, 1H), 6.90 (s, 1H), 6.88 (d, J = 15.2 Hz, 1H), 6.60 – 6.53 (m, 1H), 3.30 (d, J = 6.0 Hz, 2H), 2.79 (t, J = 7.6 Hz, 4H), 2.67 (t, J = 7.6 Hz, 4H), 1.95 (quin, J = 7.2 Hz, 4H); MS (TOF): m/z (%) = 370.2079 (100%) (M+H)+, 368.1919 (100%) (M-H)-; IR (KBr): ? = 3552, 3375, 2958, 2841, 1595, 1498, 1458, 1425, 1273, 1251, 1136, 1097 cm-1.
Example-32
(E)-N'-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-((R)-2-methyl-1-(methyl-d2)pyrrolidin-2-yl)ethene-1-sulfonimidamide

1H NMR (400 MHz, DMSO-d6): d = 9.91 (br s, 1H), 8.05 (s, 1H), 7.03 – 6.93 (s, 1H), 6.83 (s, 1H), 6.58 – 6.44 (m, 1H), 3.59 (br s, 1H), 3.28 – 3.25 (m, 1H), 2.77 (t, J = 7.2 Hz, 4H), 2.71 - 2.65 (m, 4H), 2.61 (br s, 1H), 2.10 – 2.03 (m, 4H), 1.95 – 1.88 (m, 4H), 1.36 (s, 3H); MS (TOF): m/z (%) = 430.2246 (100%) (M+H)+, 428.2097 (100%) (M-H)-; IR (KBr): ? = 3219, 2953, 2841, 2185, 1589, 1568, 1512, 1446, 1427, 1280, 1247, 1114 cm-1.
Example-33
(E)-N'-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-((R)-2-methyl-1-(methyl-d3)pyrrolidin-2-yl)ethene-1-sulfonimidamide

1H NMR (400 MHz, DMSO-d6): d = 9.91 (br s, 1H), 8.05 (s, 1H), 6.99 – 6.93 (s, 1H), 6.83 (s, 1H), 6.58 – 6.47 (m, 1H), 3.59 (br s, 1H), 3.24 – 3.11 (m, 1H), 2.77 (t, J = 7.2 Hz, 4H), 2.70 (t, J = 7.2 Hz, 4H), 2.07 - 2.00 (m, 4H), 1.95 – 1.88 (m, 4H), 1.36 (s, 3H); MS (TOF): m/z (%) = 431.2691 (100%) (M+H)+, 429.2724 (100%) (M-H)-; IR (KBr): ? = 3221, 2956, 2841, 2185, 1589, 1514, 1446, 1427, 1280, 1247, 1213 cm-1.
Example-34
(E)-N'-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-((S)-2-methyl-1-(methyl-d)pyrrolidin-2-yl)ethene-1-sulfonimidamide

1H NMR (400 MHz, DMSO-d6): d = 9.90 (br s, 1H), 8.04 (s, 1H), 7.07 – 6.96 (s, 1H), 6.83 (s, 1H), 6.51 (br s, 1H), 3.56 (br s, 1H), 3.30 (br s, 1H), 2.77 (t, J = 7.2 Hz, 4H), 2.71 - 2.65 (m, 6H), 2.02 (br s, 3H), 1.95 – 1.88 (m, 5H), 1.37 (s, 3H); MS (ESI): m/z (%) = 429.15 (100%) (M+H)+, 427.15 (100%) (M-H)-; IR (KBr): ? = 3224, 2954, 2841, 2183, 1591, 1510, 1446, 1427, 1278, 1246, 1207, 1114 cm-1.
Example-35
(E)-N'-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-((S)-2-methyl-1-(methyl-d2)pyrrolidin-2-yl)ethene-1-sulfonimidamide

1H NMR (400 MHz, DMSO-d6): d = 9.81 (br s, 1H), 8.04 (s, 1H), 6.95 – 6.92 (s, 1H), 6.83 (s, 1H), 6.51 (br s, 1H), 3.57 (br s, 1H), 3.28 – 3.25 (m, 1H), 2.77 (t, J = 7.2 Hz, 4H), 2.71 - 2.68 (m, 4H), 2.61 (br s, 1H), 2.10 – 2.01 (m, 3H), 1.95 – 1.88 (m, 5H), 1.36 (s, 3H); MS (ESI): m/z (%) = 430.10 (100%) (M+H)+, 428.15 (100%) (M-H)-; IR (KBr): ? = 3224, 2953, 2841, 2179, 1591, 1510, 1427, 1280, 1247, 1207, 1114, 1012 cm-1.
Example-36
(E)-N'-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-((S)-2-methyl-1-(methyl-d3)pyrrolidin-2-yl)ethene-1-sulfonimidamide

1H NMR (400 MHz, DMSO-d6): d = 9.89 (br s, 1H), 8.05 (s, 1H), 6.97 (d, J = 14.8 Hz, 1H), 6.83 (s, 1H), 6.57 – 6.43 (m, 1H), 3.59 (br s, 1H), 3.25 – 3.11 (m, 1H), 2.77 (t, J = 7.2 Hz, 4H), 2.70 (t, J = 7.2 Hz, 4H), 2.10 – 2.06 (m, 3H), 1.95 – 1.88 (m, 5H), 1.36 (s, 3H); MS (ESI): m/z (%) = 431.10 (100%) (M+H)+, 429.20 (100%) (M-H)-; IR (KBr): ? = 3223, 2953, 2841, 2185, 1589, 1512, 1524, 1280, 1247, 1213, 1114, 844 cm-1.
Example-37
N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-((1R,8aS)-8a-methyl-2-(methyl-d)octahydropyrrolo[1,2-a]pyrazin-1-yl)methanesulfonamide

1H NMR (400 MHz, DMSO-d6): d = 7.86 (s, 1H), 6.90 (s, 1H), 3.41 – 3.31 (m, 4H), 2.99 (br s, 1H), 2.80 (t, J = 7.2 Hz, 4H), 2.71 – 2.58 (m, 6H), 2.39 – 2.33 (m, 2H), 2.27 (br s, 2H), 1.98 (quin, J = 7.2 Hz, 4H), 1.76 – 1.66 (m, 3H), 1.50 – 1.48 (m, 1H), 0.90 (s, 3H); MS (TOF): m/z (%) = 448.2539 (100%) (M+H)+, 446.2333 (100%) (M-H)-; IR (KBr): ? = 2947, 2843, 1708, 1568, 1460, 1325, 1261, 1138, 1089, 906 cm-1.
Example-38
N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-((1R,8aS)-8a-methyl-2-(methyl-d2)octahydropyrrolo[1,2-a]pyrazin-1-yl)methanesulfonamide

1H NMR (400 MHz, DMSO-d6): d = 7.96 (s, 1H), 6.93 (s, 1H), 3.49 – 3.32 (m, 4H), 3.04 (br s, 1H), 2.80 (t, J = 7.2 Hz, 4H), 2.71 – 2.67 (m, 6H), 2.44 (br s, 1H), 2.36 – 2.31 (m, 1H), 2.20 (br s, 1H), 2.00 – 1.91 (m, 4H), 1.76 – 1.73 (m, 3H), 1.53 – 1.49 (m, 1H), 0.93 (s, 3H); MS (TOF): m/z (%) = 449.3015 (100%) (M+H)+, 447.2892 (100%) (M-H)-; IR (KBr): ? = 2943, 2843, 1708, 1672, 1589, 1504, 1460, 1265, 1138, 906 cm-1.
Example-39
N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-((1R,8aS)-8a-methyl-2-(methyl-d3)octahydropyrrolo[1,2-a]pyrazin-1-yl)methanesulfonamide

1H NMR (400 MHz, DMSO-d6): d = 7.87 (s, 1H), 6.90 (s, 1H), 3.41 – 3.31 (m, 4H), 3.00 (br s, 1H), 2.80 (t, J = 7.2 Hz, 4H), 2.71 – 2.63 (m, 6H), 2.40 (br s, 1H), 2.33 – 2.29 (m, 1H), 1.96 (quin, J = 7.2 Hz, 4H), 1.76 – 1.66 (m, 3H), 1.50 – 1.48 (m, 1H), 0.90 (s, 3H); MS (TOF): m/z (%) = 450.2667 (100%) (M+H)+, 448.2457 (100%) (M-H)-; IR (KBr): ? = 3248, 2949, 2843, 1701, 1570, 1498, 1458, 1263, 1141, 906 cm-1.
Example-40
lithium (S,E)-((2-(1,2-dimethylpyrrolidin-2-yl)vinyl)sulfonyl)((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)amide

1H NMR (400 MHz, DMSO-d6): d = 7.55 (s, 1H), 6.79 (s, 1H), 6.52 (d, J = 15.6 Hz, 1H), 6.23 (d, J = 15.6 Hz, 1H), 2.76 (d, J = 7.6 Hz, 5H), 2.70 (d, J = 7.2 Hz, 4H), 2.65 – 2.59 (m, 1H), 2.09 (s, 3H), 1.95 (quin, J = 7.2 Hz, 4H), 1.75 – 1.70 (m, 3H), 1.63 – 1.61 (m, 1H), 1.13 (s, 3H); MS (TOF): m/z (%) = 404.2061 (100%) (M-Li+H)+, 402.1875 (100%) (M-Li-H)-; IR (KBr): ? = 3317, 2943, 2841, 1573, 1514, 1429, 1138, 1093, 931 cm-1.
Example-41
(E)-3-(bis(methyl-d2)amino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-methylbut-1-ene-1-sulfonamide

1H NMR (400 MHz, DMSO-d6): d = 7.87 (s, 1H), 6.89 (s, 1H), 6.74 (d, J = 15.2 Hz, 1H), 6.60 (d, J = 15.2 Hz, 1H), 2.89 (t, J = 7.6 Hz, 4H), 2.67 (t, J = 7.6 Hz, 4H), 2.31 (s, 2H), 1.96 (quin, J = 7.6 Hz, 4H), 1.22 (s, 6H); MS (TOF): m/z (%) = 396.2283 (100%) (M+H)+, 394.2107 (100%) (M-H)-; IR (KBr): ? = 3302, 2949, 2843, 2628, 1716, 1589, 1280, 1255 1138, 1093 cm-1.
Example-42
(E)-3-(bis(methyl-d)amino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-methylbut-1-ene-1-sulfonamide

1H NMR (400 MHz, DMSO-d6): d = 7.87 (s, 1H), 6.89 (s, 1H), 6.73 (d, J = 15.2 Hz, 1H), 6.61 (d, J = 15.2 Hz, 1H), 2.79 (t, J = 7.6 Hz, 4H), 2.67 (t, J = 7.2 Hz, 4H), 2.30 (s, 4H), 1.97 – 1.93 (m, 4H), 1.21 (s, 6H), ESI-Q-TOF-MS: m/z 394.2150 (100%) [M+H]+, 392.1980 (100%) [M-H]-;
Biological Activity:
In-vitro assays:
THP1 monocytes were differentiated with PMA (100ng/mL) and incubated at 37 °C for 20 hrs in presence of 5% CO2. 2 x105 differentiated cells were plated per well of 96 well tissue culture plates. The cells were primed using 500ng/mL Lipopolysaccharide and incubating for 4h under the same condition. The cells were then treated with various concentrations of the compounds for 30 min followed by treatment with 5mM ATP for 1hr. The supernatants were collected and analyzed by IL-1b (Mabtech Cat # 3415-1H-20) or TNF-a (Mabtech; Cat # 3510-1H-20) detection kit. The data were analyzed using GraphPad Prism V7.0. Dose Response Curve (DRC) was constructed to determine the IC50 value by fitting percentage cell survival data to the GraphPad Prism using nonlinear regression analysis. The in vitro IL-1ß inhibitory activity (IC50) for representative compounds are listed in Table 1.
Table 1
Compound IL-1ß (IC50) (nM)
Example 1 1.4 nM
Example 2 4.7 nM
Example-4 3.1 nM
Example-7 15 nM
Example-8 35 nM
Example-13 2.3 nM
Example-14 2.1 nM
Example-30 9.3 nM
Example-31 5.6 nM
Example-32 10 nM
Example-33 10.6 nM
Example-34 10.8 nM
Example-35 11.4 nM
Example-36 9.5 nM
Example-41 3.2 nM
Example-42 4.5 nM

In-vivo efficacy studies:
Demonstration of in vivo efficacy of test compounds in rats mice, oral routes of administration.
Animals
All the animal experiments were carried out in female rats and mice, bred in-house. Animals were housed in groups of 6 animals per cage, for a week, in order to habituate them to vivarium conditions (25 ± 4 °C, 60-65 % relative humidity, 12: 12 h light: dark cycle, with lights on at 7.30 am). All the animal experiments were carried out according to the internationally valid guidelines following approval by the 'Zydus Research Center animal ethical committee'.
In-vivo LPS and ATP induced IL-1ß assay:
Female C57 mice (6-8 weeks) received intraperitoneal injection of 50 µg/mouse of lipopolysaccharide (LPS) in PBS. Animals were treated immediately with the test compounds or the vehicle. After 2h of LPS injection, animals were administered with ATP at 12.5 mg/mouse dissolved in PBS via intraperitoneal route. After 30 minutes of ATP injection, serum was collected for IL-1ß estimation by ELISA.
The novel compounds of the present invention can be formulated into suitable pharmaceutically acceptable compositions by combining with suitable excipients by techniques and processes and concentrations as are well known.
The compounds of formula (I) or pharmaceutical compositions containing them are useful as a medicament for the inhibition of NLRP3 activity and suitable for humans and other warm blooded animals, and may be administered either by oral, topical or parenteral administration.
Thus, a pharmaceutical composition comprising the compounds of the present invention may comprise a suitable binder, suitable bulking agent &/or diluent and any other suitable agents as may be necessary. Optionally, the pharmaceutical composition may be suitably coated with suitable coating agents.
The compounds of the present invention, Formula (I) are NLRP3 inhibitors and are useful in the treatment of disease states mediated by NLRP3, preferably diseases or conditions in which interleukin 1ß activity is implicated and related disorders, including inflammation, gouty arthritis, Inflammatory bowel disease (IBD), Cryopyrin Associated Periodic Syndromes (CAPS), TNF receptor-associated periodic syndrome (TRAPS), Juvenile Idiopathic Arthritis (JIA), type 2 diabetes, atherosclerosis, and liver fibrosis. More particularly, embodiments of the present invention are useful as therapeutics in the treatment of a variety of pathological conditions including (but not limited to) lymphoma, auto-immune diseases, heteroimmune diseases, inflammatory diseases, type 1 diabetes, chronic inflammation, cancer, and neurodegenerative diseases or conditions.
The quantity of active component, that is, the compounds of Formula (I) according to this invention, in the pharmaceutical composition and unit dosage form thereof may be varied or adjusted widely depending upon the particular application method, the potency of the particular compound and the desired concentration. Generally, the quantity of active component will range between 0.5% to 90% by weight of the composition.
The compounds of the present invention, formula (I), may be used alone or in any combination with one or more other therapeutic agents which a skilled medical practitioner can easily identify. Such other therapeutic agent may be selected depending on the type of disease being treated, the severity, other medications being taken by the patients etc. Thus for example, for treatment of rheumatoid arthritis, one or more DMARDs may be used in combination with the compounds of the present invention.
In one of the embodiments compound of formula (I) of the present invention may be used in combination with one or more suitable pharmaceutically active agents selected from following therapeutic agents in any combination such as inhibitors of interleukin-1ß (e.g. rilonacept, canakinumab, and anakinra); immune-suppressants (e.g., Methotrexate, mercaptopurine, cyclophosphamide), Mesalamine, Cyclosporine, metabolic disorders drugs, glucocorticoids, non-steroidal anti-inflammatory drugs, Cox-2 specific inhibitors, TNF-a binding proteins (eg.,Infliximab, etanercept), interferon- 13, interferon, interleukin-2, antihistamines, beta-agonist, BTK inhibitors, anticolinergics, anti-cancer agents or their suitable pharmaceutically acceptable salts. Further examples for use in combination with Non-Alcoholic Steato- Hepatitis (NASH) and fibrosis drugs, anticancer antibiotics, hormones, Aromatase inhibitors, antibodies, cytokines, vaccines, drug conjugates, inhibitors of mitogen-activated protein kinase signaling (ex: BAY 43-9006), Syk inhibitors, mTOR inhibitors, antibodies (Rituxan), and BCR/ABL antagonist.
Compositions of the invention are also used in combination with other active ingredients. For the treatment of Arenaviridae virus infections, preferably, the other active therapeutic agent is active against Arenaviridae virus infections, particularly Lassa virus and Junin virus infections. 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. The compounds and compositions of the present invention are also intended for use with general care provided patients with Arenaviridae viral infections, including parenteral fluids (including dextrose saline and Ringer's lactate) and nutrition, antibiotic (including Metronidazole and Cephalosporin antibiotics, such as Ceftriaxone and Cefuroxime) and/or antifungal prophylaxis, fever and pain medication, antiemetic (such as Metoclopramide) and/or antidiarrheal agents, vitamin and mineral supplements (including Vitamin C or/and K and zinc sulfate), anti-inflammatory agents (such as Ibuprofen), pain medications, and medications for other common diseases in the patient population, such anti-malarial agents (including Artemether and Artesunate-lumefantrine combination therapy), typhoid (including quinolone antibiotics, such as Ciprofloxacin, macrolide antibiotics, such as Azithromycin, cephalosporin antibiotics, such as Ceftriaxone, or aminopenicillins, such as Ampicillin), or shigellosis.
Pharmaceutical Formulation
The compounds of the present invention are formulated with conventional carriers and excipients, which will be selected in accord with ordinary practice. Tablets will contain excipients, glidants, fillers, binders and the like. Aqueous formulations are prepared in sterile form and when intended for delivery by other than oral administration generally will be isotonic. All formulations will optionally contain excipients such as those set forth in the “Handbook of Pharmaceutical Excipients” (1986).
While it is possible for the active ingredients to be administered alone it may be preferable to present them as pharmaceutical formulations. The formulations, both for veterinary and for human use, of the invention comprise at least one active ingredient, as above defined, together with one or more acceptable carriers therefore and optionally other therapeutic ingredients, particularly those additional therapeutic ingredients as discussed herein. The carrier(s) must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and physiologically innocuous to the recipient thereof.
Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient: as a powder or granules: as a solution or a suspension in an aqueous or non-aqueous liquid: or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be administered as a bolus, electuary or paste.
Pharmaceutical formulation according to the present invention comprise a combination according to the invention together with one or more pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents. Pharmaceutical formulations containing the active ingredient may be in any form suitable for the intended method of administration. When used for oral use for example tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs may be prepared.
One or more compounds of the invention (herein referred to as the active ingredients) are administered by any route appropriate to the condition to be treated. Suitable routes include oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural), and the like. It will be appreciated that the preferred route may vary with for example the condition of the recipient. An advantage of the compounds of this invention is that they are orally bioavailable and can be dosed orally.
The quantity of active component, that is, the compounds of Formula (I) according to this invention, in the pharmaceutical composition and unit dosage form thereof may be varied or adjusted widely depending upon the particular application method, the potency of the particular compound and the desired concentration. Generally, the quantity of active component will range between 0.5% to 90% by weight of the composition.
The compounds of the present invention, formula (I) may be used alone or in any combination with one or more other therapeutic agents which a skilled medical practitioner can easily identify. Such other therapeutic agent may be selected depending on the type of disease being treated, the severity, other medications being taken by the patients etc. Thus for example, for treatment of rheumatoid arthritis, one or more DMARDs may be used in combination with the compounds of the present invention.
In one of the embodiments compound of formula (I) of the present invention may be used in combination with one or more suitable pharmaceutically active agents selected from following therapeutic agents in any combination. Inhibitors of interleukin-1ß (e.g. Rilonacept, Canakinumab, and Anakinra); immune-suppressants (e.g., Methotrexate, Mercaptopurine, Cyclophosphamide), metabolic disorders drugs, glucocorticoids, non-steroidal anti-inflammatory drugs, Gasdermin D inhibitors (e.g., Necrosulfonamide); Cox-2 specific inhibitors, TNF-a binding proteins (e.g.,Infliximab, Etanercept), Interferon-13, Interferon, Interleukin-2, antihistamines, beta-agonist, BTK inhibitors, anticolinergics, anti-cancer agents; anti-viral drugs, for example: Remdesivir, Lopinavir/Ritonavir, Favipiravir, Molnupiravir, Tamiflu; anti-malarial agents, for example: Choloroquinone, Hydroxyl Chloroquinone; or their suitable pharmaceutically acceptable salts. Further examples for use in combination with Non-Alcoholic Steato- Hepatitis (NASH) and fibrosis drugs; anticancer; antibiotics, for example Azithromycin; hormones, Aromatase inhibitors, Colchicine, Anticoagulants, antibodies, cytokines, anti-IL6 drugs; Antiparasitics; vaccines; Interferons; drug conjugates; Drugs originally developed for SARS (ACE2 protein decoy); Intravenous vitamin C; inhibitors of mitogen-activated protein kinase signaling (ex: BAY 43-9006); Syk inhibitors; mTOR inhibitors; antibodies (Rituxan); and BCR/ABL antagonist.
Compositions of the invention are also used in combination with other active ingredients. For the treatment of Arenaviridae virus infections, preferably, the other active therapeutic agent is active against Arenaviridae virus infections, particularly Lassa virus and Junin virus infections. 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. The compounds and compositions of the present invention are also intended for use with general care provided patients with Arenaviridae viral infections, including parenteral fluids (including dextrose saline and Ringer's lactate) and nutrition, antibiotic (including Metronidazole and Cephalosporin antibiotics, such as Ceftriaxone and Cefuroxime) and/or antifungal prophylaxis, fever and pain medication, antiemetic (such as Metoclopramide) and/or antidiarrheal agents, vitamin and mineral supplements (including Vitamin C or/and K and zinc sulfate), anti-inflammatory agents (such as Ibuprofen), pain medications, and medications for other common diseases in the patient population, such anti-malarial agents (including Artemether and Artesunate-lumefantrine combination therapy), typhoid (including quinolone antibiotics, such as Ciprofloxacin, macrolide antibiotics, such as Azithromycin, cephalosporin antibiotics, such as Ceftriaxone, or aminopenicillins, such as Ampicillin), or shigellosis.
While the present invention has been described in terms of its specific embodiments, 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:We Claim:
1. Compound having a structure of general formula (I)

Formula (I)
their tautomeric forms, their stereoisomers; their enantiomers; their metabolites; their deuterated analogs; their pharmaceutically acceptable salts; and pharmaceutical compositions containing them wherein
X is O, NH, or N-R3 wherein R3 at each occurrence independently represents hydrogen, hydroxyl, halogen, nitro, cyano, haloalkyl, optionally substituted groups selected from (C1-C10)alkyl, (C1-C10)alkoxy, (C3-C10)cycloalkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, SO2(C1-C6)alkyl, thiol, thioalkyl, thio-alkoxy, SO(C1-C6)alkyl, benzyl, aryl, heteroaryl, heterocyclyl;
Y is O, S;
R1 at each occurrence is independently selected from hydrogen, halogen, haloalkyl, cyano, optionally substituted groups selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C3-C7)cycloalkyl,(C1-C6)alkylSO2(C1-C6)alkyl,(C1-C6)alkylN(C1-C6)alkyl, (C1-C6)alkylN(C3-C7)cycloalkyl, aryl, heteroaryl, heterocyclyl, benzyl, tert-butyloxycarbonyl, NH(C1-C6)alkyl, N((C1-C6)alkyl)2, NH(C2-C6)alkenyl, N((C2-C6)alkenyl)2, -N-heterocyclyl, N(C1-C6)alkyl-heterocyclyl, NR’R’’, thiol, mercaptoalkyl, SO2(C1-C6)alkyl, SO2(C3-C7)cycloalkyl, SO2-aryl, SO2-heterocyclyl, (C1-C6)thioalkyl, (C1-C6)thioalkoxy, (C1-C6)alkylSO2NH2, -CONH2, -CO(C1-C6)alkyl, -CO(C1-C6)haloalkyl, -CO-aryl, -CO-heteroaryl, -CO-heterocyclyl, 4- to 7-membered heterocyclic ring, 7- to 14-membered bicyclic heterocyclic ring system, bridged or spiro ring system having optionally one or more than one heteroatoms;
Alternatively R1 represents:
, , ,

n, is independently selected from integer 0-3;
Each of R’, R”, R1’, R1’’, R2’ and R2” at each occurrence is independently selected from hydrogen, halogen, haloalkyl, cyano, optionally substituted groups selected from (C1-C6)alkyl, deuterated (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C3-C7)cycloalkyl, (C1-C6)alkylSO2(C1-C6)alkyl, (C1-C6)alkylN(C1-C6)alkyl, (C1-C6)alkylN(C3-C7)cycloalkyl, aryl, heteroaryl, heterocyclyl, benzyl, tert-butyloxycarbonyl, thiol, mercaptoalkyl, SO2(C1-C6)alkyl, SO2(C3-C7)cycloalkyl, SO2-aryl, SO2-heterocyclyl, (C1-C6)thioalkyl, (C1-C6)thioalkoxy, (C1-C6)alkylSO2NH2, -CONH2, -CO(C1-C6)alkyl, -CO(C1-C6)haloalkyl, -CO-aryl, -CO-heteroaryl, -CO-heterocyclyl, 4- to 7-membered heterocyclic ring, 7- to 14-membered bicyclic heterocyclic ring system, bridged or spiro ring system having optionally one or more than one heteroatoms; In an embodiment R’ and R” optionally forms 4- to 7-membered heterocyclic ring system.
R2 is selected from the following ring system

wherein X, Y, Z at each occurrence independently represents C, N, S, SO2, and O, which may be optionally substituted;
Each of R7, R8, R9, R10, R11 and R12 at each occurrence is independently selected from hydrogen, halogen, cyano, amide, sulphonamide, acyl, hydroxyl, optionally substituted groups selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, benzyl, aryl, heteroaryl, heterocyclyl; Alternatively each of R8 and R9, R9 and R10, R10 and R11 and R11 and R12 wherever possible, together may form a 4 to 7 membered saturated or partially saturated ring containing from 0-2 additional heteroatoms selected from the group consisting of N, O, and S(O)p; p = 1-2.
Rx and Ry at each occurrence is independently selected from hydrogen, halogen, optionally substituted groups selected from (C1-C6)alkyl; Alternatively Rx and Ry together may form a 4- to 7-membered heterocyclic ring system;
‘M’ is selected from aryl, heteroaryl, heterocyclyl.
2. The compound as claimed in claim 1, wherein Y is -O-.
3. The compound as claimed in claim 1, wherein X is selected from -O- and N-CN.
4. The compound of formula (I) as claimed in claim 1 is selected from:
(S,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-methyl-1-(methyl-d)pyrrolidin-2-yl)ethene-1-sulfonamide;
(R,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-methyl-1-(methyl-d)pyrrolidin-2-yl)ethene-1-sulfonamide;
(S,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(methyl-d)pyrrolidin-2-yl)ethene-1-sulfonamide;
(R,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(methyl-d)pyrrolidin-2-yl)ethene-1-sulfonamide;
(R,E)-N-((2,6-diisopropylphenyl)carbamoyl)-2-(2-methyl-1-(methyl-d)pyrrolidin-2-yl)ethene-1-sulfonamide;
(S,E)-N-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)-2-(1-(methyl-d)pyrrolidin-2-yl)ethene-1-sulfonamide;
(E)-2-((R)-1,2-dimethylpyrrolidin-2-yl)-N-((2-hydroxy-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide;
(R,E)-2-(1,2-dimethylpyrrolidin-2-yl)-N-((1,2,3,7-tetrahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide;
(R,E)-2-(1,2-dimethylpyrrolidin-2-yl)-N-((1,2,3,5-tetrahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide;
(E)-2-((R)-1,2-dimethylpyrrolidin-2-yl)-N-((3-hydroxy-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide;
(E)-2-((R)-1,2-dimethylpyrrolidin-2-yl)-N-((1-hydroxy-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide;
(R,E)-2-(1,2-dimethylpyrrolidin-2-yl)-N-((1-oxo-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide;
(R,E)-N-((2,6-diisopropylphenyl)carbamoyl)-2-(2-methyl-1-(methyl-d)pyrrolidin-2-yl)ethene-1-sulfonamide;
(E)-3-(bis(methyl-d)amino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-methylbut-1-ene-1-sulfonamide;
Sodium (S,E)-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)((2-(2-methyl-1-(methyl-d)pyrrolidin-2-yl)vinyl)sulfonyl)amide;
Sodium (R,E)-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)((2-(2-methyl-1-(methyl-d)pyrrolidin-2-yl)vinyl)sulfonyl)amide;
N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-((1S,8aR)-3,3,8a-trimethyl-2-(methyl-d)octahydropyrrolo[1,2-a]pyrazin-1-yl)methanesulfonamide;
(S,E)-2-(1,2-dimethylpyrrolidin-2-yl)-N-((2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-yl)carbamoyl)ethene-1-sulfonamide;
S,E)-2-(pyrrolidin-2-yl)-N-((2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-yl)carbamoyl)ethene-1-sulfonamide;
(S,E)-2-(2-methylpyrrolidin-2-yl)-N-((2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-yl)carbamoyl)ethene-1-sulfonamide;
(S,E)-2-(1,2-dimethylpyrrolidin-2-yl)-N-(tricyclo[6.2.0.03,6]deca-1,3(6),7-trien-2-ylcarbamoyl)ethene-1-sulfonamide;
(S,E)-2-(pyrrolidin-2-yl)-N-(tricyclo[6.2.0.03,6]deca-1,3(6),7-trien-2-ylcarbamoyl)ethene-1-sulfonamide;
(S,E)-2-(2-methylpyrrolidin-2-yl)-N-(tricyclo[6.2.0.03,6]deca-1,3(6),7-trien-2-ylcarbamoyl)ethene-1-sulfonamide;
(S,E)-2-(1,2-dimethylpyrrolidin-2-yl)-N-((1-oxo-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide;
(S,E)-N-((1-oxo-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(pyrrolidin-2-yl)ethene-1-sulfonamide;
(S,E)-2-(2-methylpyrrolidin-2-yl)-N-((1-oxo-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide;
(S,E)-2-(1,2-dimethylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)ethene-1-sulfonamide;
(S,E)-N-((1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)-2-(pyrrolidin-2-yl)ethene-1-sulfonamide;
(S,E)-N-((1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)-2-(2-methylpyrrolidin-2-yl)ethene-1-sulfonamide;
(S,E)-N-((4-cyano-2,6-diisopropylphenyl)carbamoyl)-2-(1,2-dimethylpyrrolidin-2-yl)ethene-1-sulfonamide;
(S,E)-N-((4-cyano-2,6-diisopropylphenyl)carbamoyl)-2-(pyrrolidin-2-yl)ethene-1-sulfonamide;
(S,E)-N-((4-cyano-2,6-diisopropylphenyl)carbamoyl)-2-(2-methylpyrrolidin-2-yl)ethene-1-sulfonamide;
(S,E)-N-((9H-carbazol-9-yl)carbamoyl)-2-(1,2-dimethylpyrrolidin-2-yl)ethene-1-sulfonamide;
(R,E)-N-((1,2,3,4,5,6,7,8-octahydroanthracen-9-yl)carbamoyl)-3-(pyrrolidin-2-yl)prop-1-ene-1-sulfonamide;
(R,E)-2-(1,2-dimethylpyrrolidin-2-yl)-N-((1,2,3,4,5,6,7,8-octahydroanthracen-9-yl)carbamoyl)ethene-1-sulfonamide;
(R,E)-2-(1,2-dimethylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)ethene-1-sulfonamide;
(R,E)-N-((1,2,3,4,6,7,8,9-octahydropyrido[1,2-a]indol-10-yl)carbamoyl)-3-(pyrrolidin-2-yl)prop-1-ene-1-sulfonamide;
(R,E)-2-(1,2-dimethylpyrrolidin-2-yl)-N-((1,2,3,4,6,7,8,9-octahydropyrido[1,2-a]indol-10-yl)carbamoyl)ethene-1-sulfonamide;
(R,E)-2-(1,2-dimethylpyrrolidin-2-yl)-N-((1,2,3,4,7,8,9,10-octahydropyrido[2,1-a]isoindol-6-yl)carbamoyl)ethene-1-sulfonamide;
(R,E)-N-((1,2,3,4,5,6,7,8-octahydro-9H-carbazol-9-yl)carbamoyl)-3-(pyrrolidin-2-yl)prop-1-ene-1-sulfonamide;
(R,E)-2-(1,2-dimethylpyrrolidin-2-yl)-N-((1,2,3,4,5,6,7,8-octahydro-9H-carbazol-9-yl)carbamoyl)ethene-1-sulfonamide;
(R,E)-N-((1,2,3,5,6,7-hexahydro-4H-dicyclopenta[b,d]pyrrol-4-yl)carbamoyl)-3-(2-methylpyrrolidin-2-yl)prop-1-ene-1-sulfonamide;
(R,E)-2-(1,2-dimethylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-4H-dicyclopenta[b,d]pyrrol-4-yl)carbamoyl)ethene-1-sulfonamide;
(R,E)-2-(1,2-dimethylpyrrolidin-2-yl)-N-((3,5,6,7-tetrahydro-2H-indeno[5,6-b]furan-4-yl)carbamoyl)ethene-1-sulfonamide;
(R,E)-2-(1,2-dimethylpyrrolidin-2-yl)-N-((5-(3-methoxyphenyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)ethene-1-sulfonamide;
(R,E)-2-(1,2-dimethylpyrrolidin-2-yl)-N-((5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)ethene-1-sulfonamide;
(S,E)-N-((9H-fluoren-9-yl)carbamoyl)-2-(1,2-dimethylpyrrolidin-2-yl)ethene-1-sulfonamide;
(R,E)-2-(1,2-dimethylpyrrolidin-2-yl)-N-((2-isopropyl-6-(pyridin-4-yl)phenyl)carbamoyl)ethene-1-sulfonamide;
(R,E)-N-((2-isopropyl-6-(pyridin-4-yl)phenyl)carbamoyl)-3-(pyrrolidin-2-yl)prop-1-ene-1-sulfonamide;
(R,E)-2-(1,2-dimethylpyrrolidin-2-yl)-N-((2-isopropyl-6-(pyridin-3-yl)phenyl)carbamoyl)ethene-1-sulfonamide;
(R,E)-N-((2-isopropyl-6-(pyridin-3-yl)phenyl)carbamoyl)-3-(2-methylpyrrolidin-2-yl)prop-1-ene-1-sulfonamide;
(R,E)-2-(1,2-dimethylpyrrolidin-2-yl)-N-((4-fluoro-2-isopropyl-6-(pyridin-3-yl)phenyl)carbamoyl)ethene-1-sulfonamide;
(R,E)-N-((4-fluoro-2-isopropyl-6-(pyridin-3-yl)phenyl)carbamoyl)-3-(pyrrolidin-2-yl)prop-1-ene-1-sulfonamide;
(R,E)-N-((4-chloro-2,6-diisopropylphenyl)carbamoyl)-2-(1,2-dimethylpyrrolidin-2-yl)ethene-1-sulfonamide;
(R,E)-2-(1,2-dimethylpyrrolidin-2-yl)-N-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)ethene-1-sulfonamide;
(R,E)-N-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)-3-(pyrrolidin-2-yl)prop-1-ene-1-sulfonamide;
(R,E)-2-(1,2-dimethylpyrrolidin-2-yl)-N-((7-fluoro-5-(pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)ethene-1-sulfonamide;
(R,E)-N-((7-fluoro-5-(pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-3-(2-methylpyrrolidin-2-yl)prop-1-ene-1-sulfonamide;
tert-butyl (2R)-2-((E)-2-(N-((2-hydroxy-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)vinyl)-2-methylpyrrolidine-1-carboxylate;
(E)-N-((2-hydroxy-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-((R)-2-methylpyrrolidin-2-yl)ethene-1-sulfonamide;
(R,E)-2-(2-methylpyrrolidin-2-yl)-N-((1,2,3,7-tetrahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide;
(R,E)-2-(2-methylpyrrolidin-2-yl)-N-((1,2,3,5-tetrahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide;
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(5-methylhexahydro-1H-furo[3,4-c]pyrrol-4-yl)ethene-1-sulfonamide;
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-methyloctahydrocyclopenta[c]pyrrol-5-yl)ethene-1-sulfonamide;
(E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-methylisoindolin-1-yl)ethene-1-sulfonamide;
(R,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-methyl-1-(methyl-d3)pyrrolidin-2-yl)ethene-1-sulfonamide;
(R,E)-2-(1,2-dimethyl-2,5-dihydro-1H-pyrrol-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide;
(R,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-isobutoxy-2-methylpyrrolidin-2-yl)ethene-1-sulfonamide;
(R,E)-2-(1,2-dimethylpyrrolidin-2-yl)-N-((6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)carbamoyl)ethene-1-sulfonamide;
(R,E)-N-((7,8-dihydro-6H-cyclopenta[d]imidazo[1,2-a]pyrimidin-5-yl)carbamoyl)-2-(1,2-dimethylpyrrolidin-2-yl)ethene-1-sulfonamide;
(R,E)-2-(1,2-dimethylpyrrolidin-2-yl)-N-((3-(2-hydroxypropan-2-yl)-5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl)carbamoyl)ethene-1-sulfonamide;
(R,E)-N-((6,7-dihydro-5H-cyclopenta[d]pyrazolo[1,5-a]pyrimidin-8-yl)carbamoyl)-2-(1,2-dimethylpyrrolidin-2-yl)ethene-1-sulfonamide;
ethyl(R,E)-3-(3-((2-(1,2-dimethylpyrrolidin-2-yl)vinyl)sulfonyl)ureido)-5,6-dihydro-4H-cyclopenta[b]thiophene-2-carboxylate;
(E)-2-((R)-1,2-dimethylpyrrolidin-2-yl)-N-((1,2,3,4-tetrahydro-1,4-methanonaphthalen-5-yl)carbamoyl)ethene-1-sulfonamide.
5. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) as claimed in any of the preceding claims and optionally one or more pharmaceutically acceptable excipients.
6. The pharmaceutical composition as claimed in claims 8 in combination with one or more suitable pharmaceutically active agents selected from Inhibitors of interleukin-1ß; immune-suppressants; metabolic disorders drugs, glucocorticoids, non-steroidal anti-inflammatory drugs, COX-2 specific inhibitors, anti-inflammatory drugs, TNF-a binding proteins, interferon-13, interferon, interleukin-2, antihistamines, beta-agonist, BTK inhibitors, anticolinergics, anti-cancer agents or their suitable pharmaceutically acceptable salts, Non-Alcoholic Steato- Hepatitis (NASH) and fibrosis drugs, anticancer drugs, antibiotics, hormones, aromatase inhibitors, inhibitors of mitogen-activated protein kinase signaling, Syk inhibitors, mTOR inhibitors, BCR/ABL antagonists, Arenaviridae virus infections, particularly Lassa virus and Junin virus infections, antibiotic and/or antifungal prophylaxis, fever and pain medication, antiemetic and/or antidiarrheal agents, vitamin and mineral supplements, anti-inflammatory agents, anti-inflammatory and immunosuppressant agents, pain medications, and medications for other common diseases in the patient population, anti-malarial agents and cephalosporin antibiotics.
7. A method of treating diseases medicated by the NLRP3 modulators as well as treatment of diseases or conditions in which interleukin 1ß activity and interleukin-18 (IL-18) are implicated which comprising administering to a patient in need thereof an effective amount of a compound of Formula (I) as claimed in any of the preceding claims or its suitable pharmaceutical composition.
8. The use of compounds of formula (I) or its pharmaceutical compositions as claimed in any of the preceding claim suitable for treatment of diseases wherein the NLRP3 modulator has a pathophysiological function.

Dated this 17th day of June 2022.

(HARIHARAN SUBRAMANIAM)
(IN/PA-93)
Of SUBRAMANIAM & ASSOCIATES
ATTORNEYS FOR THE APPLICANTS