Treatment for inflammatory bowel disease

Abstract

The present invention relates to the development of therapeutic compounds for the treatment of inflammatory bowel disease. More specifically, the present invention provides NLRP3 inhibitors or pharmaceutically acceptable salts thereof or suitable compositions useful in the treatment of inflammatory bowel disease. These severe and persistent diseases include Crohn's disease and ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal diseases, eosinophilic gastrointestinal diseases, and other related forms of disorders.

Description

[Technical Field]

[0001] The present invention relates to the development of therapeutic compounds for the treatment of inflammatory bowel disease (IBD). More specifically, the present invention provides NLRP3 inhibitors or pharmaceutically acceptable salts thereof or suitable compositions useful in the treatment of inflammatory bowel disease. These severe and persistent diseases include Crohn's disease and ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal diseases, eosinophilic gastrointestinal diseases, and other related forms of disorders. [Background technology]

[0002] The nucleotide-binding oligomerized domain (NOD)-like receptor family, pyrin-domain-containing inflammasome 3 (NLRP3 or NALP3), is a major source of mucosal interleukin (IL)-1β, and the inflammasome is primarily activated by multiple aspects of inflammation-associated stress. NLRP3 is a cytosolic pattern recognition receptor (PRR) that senses exogenous and endogenous danger signals. The NLRP3 protein consists of three domains: a leucine-rich repeat domain (LRR), a NOD (NACHT) containing a caspase-activating and mobilizing domain (CARD), and a pyrin domain (PYD). Upon activation, NLRP3 oligomerizes the CARD-containing adapter apoptosis-associated speck-like protein (ASC) via PYD-PYD interactions, triggering its association. The ASC fibrils associate to form a larger structure called ASC-speck, which mobilizes pro-caspase-1, leading to its autoproteolytic activity. Activated caspase-1 can generate the inflammatory cytokines IL-1β and IL-18 by cleaving pro-IL-1β and pro-IL-18 (Guo et al., 2015; Dinarello et al., 2012).

[0003] The involvement of the NLRP3 inflammasome in different types of diseases offers new avenues for designing drugs that target the NLRP3 inflammasome. To date, clinical treatments for NLRP3-related diseases have targeted IL-1β with IL-1β antibodies or recombinant IL-1β receptor antagonists, e.g., canakinumab and anakinra, respectively. In addition, a few small molecule compounds, including MCC950, β-hydroxybutyrate (BHB), Bay 11-7082, dimethyl sulfoxide (DMSO), and type I interferons, have shown anti-inflammatory effects against NLRP3 inflammasome activation in vitro. However, most of these inhibitors are relatively nonspecific and have low potency. Regarding inhibitors that target IL-1β, it should be noted that IL-1β secretion is not solely a product of NLRP3 inflammasome activation; instead, other pro-inflammatory cytokines, including high-mobility box 1 (HMGB1) and IL-18, may also be involved in the pathogenesis of these diseases. Furthermore, IL-1β can be produced via inflammasome-independent pathways or by other inflammasomes. Therefore, inhibitors targeting IL-1β may lead to unintended immunosuppressive effects beyond simply preventing NLRP3 inflammasome activation itself. Pharmacological inhibitors specific to the NLRP3 inflammasome may be the best option for treating NLRP3-related disorders (Yang et al., 2019).

[0004] IBD is a chronic gastrointestinal inflammatory disease affecting the entire gastrointestinal tract and the colon. Two of the most common types of IBD are ulcerative colitis (UC) and Crohn's disease (CD). More than 5 million people in the industrialized world suffer from IBD. In Europe, the incidence of UC and CD was 0.5% and 1%, respectively. The number of IBD patients is increasing dramatically globally, especially in China and other Asian countries. Major symptoms of IBD include abdominal pain, abdominal distension, diarrhea, and mucous purulent blood, which significantly impact the quality of life of these patients. Current treatments for IBD mainly involve steroids and immunosuppressants, particularly antibodies against inflammatory cytokines. These biological agents exert their function by neutralizing inflammatory cytokines. For example, infliximab (IFLX), the first antitumor necrosis factor (TNF)-α monoclonal antibody approved by the US Food and Drug Administration (FDA), eliminates the biological activity of the cytosolic and membrane-bound pro-inflammatory cytokine TNF-α. Subsequently, IFLX induces apoptotic cell death in pro-inflammatory cells. IFLX increases clinical remission in patients with CD and UC and heals fistulas in CD. However, long-term use of IFLX and other biological agents can lead to relapse, production of anti-drug antibodies, or malignancy. Anti-interleukin (IL)-12 / IL-23 therapies, small molecule inhibitors of sphingosine-1-phosphate, Janus kinase, purine receptor P2X, ligand-opening ion channel 7 receptor, and Bruton's tyrosine kinase (BTK), are currently in the IBD pipeline. However, the detailed virulence factors that trigger IBD are extremely complex and remain largely unknown. Combinations of drugs with different activities can increase clinical efficacy and / or safety profiles. Therefore, novel therapies with distinct mechanisms of action are urgently needed for the long-term management of IBD patients in remission and / or to improve the quality of life for affected patients. (Biomedicine & Pharmacotherapy, June 2021, 111442).

[0005] NLRP3 activation is considered a key trigger for IBD lesion formation, such as the activation of sterile inflammation in intestinal epithelial cells and the sustained activation of macrophages. [Overview of the project] [Problems that the invention aims to solve]

[0006] The present invention provides therapeutic compounds of formula (I) and pharmaceutically acceptable salts thereof for the prevention and treatment of inflammatory bowel diseases. These severe and persistent diseases include Crohn's disease and ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal diseases, eosinophilic gastrointestinal diseases, and other related forms of disorders. [Means for solving the problem]

[0007] In one embodiment, the present invention relates to formula (I) suitable for the treatment and prevention of inflammatory bowel disease.

[0008] [ka]

[0009] The present invention provides therapeutic compounds for the following severe and persistent diseases: Crohn's disease and ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal diseases, eosinophilic gastrointestinal diseases, and other related forms of disorders.

[0010] In one embodiment, the present invention provides compounds of formula (I) and pharmaceutically acceptable salts thereof suitable for the treatment of inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal diseases and eosinophilic gastrointestinal diseases, and other related forms of disorders.

[0011] In another embodiment, the present invention provides the administration of therapeutic compounds of formula (I) and pharmaceutically acceptable salts thereof, either alone or in combination with other agents suitable for the treatment and prevention of inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal diseases, eosinophilic gastrointestinal diseases, and other related forms of disorders.

[0012] In another embodiment, the present invention provides suitable compositions comprising a compound of formula (I) or suitable pharmaceutical compositions thereof for the treatment and prevention of inflammatory bowel diseases such as Crohn's disease, ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal diseases, eosinophilic gastrointestinal diseases, and other related forms of disorders. [Brief explanation of the drawing]

[0013] [Figure 1] This figure shows the effect of the compound of formula (11) in a rat model of 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced IBD. [Modes for carrying out the invention]

[0014] "Patient" includes both humans and animals. "Mammal" means humans and other mammals.

[0015] The term "prevention" refers to preventing the subject from acquiring a disability or disease in the first place.

[0016] The "subjects" are mammals, preferably humans, but may also include animals requiring veterinary treatment, such as companion animals (e.g., dogs, cats, etc.), farm animals (e.g., cows, sheep, pigs, horses, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.).

[0017] As used herein, “to treat” includes, in part or substantially, achieving one or more of the following results: reducing the degree of a disease, disorder or syndrome in part or in whole; delaying, inhibiting or preventing the progression of a disease, disorder or syndrome, including, for example, delaying, inhibiting or preventing inflammatory bowel disease. The present invention describes a method for treating a person suffering from inflammatory bowel disease.

[0018] This invention describes a method for treating subjects suffering from inflammatory bowel diseases such as Crohn's disease, ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal disease, eosinophilic gastrointestinal disease, and other related forms of disorders.

[0019] In further embodiments, the present invention provides the use of compounds of formula (I) or suitable pharmaceutical compositions thereof for the treatment or prevention of inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal diseases, eosinophilic gastrointestinal diseases, and other related forms of disorders.

[0020] In a preferred embodiment, the inflammatory bowel disease is ulcerative colitis.

[0021] In one embodiment, the present invention provides compounds of formula (I) and pharmaceutically acceptable salts thereof suitable for the treatment of IBD. These severe and persistent diseases include Crohn's disease and ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal diseases, eosinophilic gastrointestinal diseases, and other related forms of disorders.

[0022] The method is given by formula (I),

[0023] [ka]

[0024] This involves administering an effective amount of a pharmaceutical composition containing compounds, their tautomer forms, their stereoisomers, their enantiomers, their metabolites, their deuterium analogs, their pharmaceutically acceptable salts, and mixtures thereof, to the target. During the ceremony, X is O, NH, or NR 3 And here, R 3 Each occurrence is independently substituted by a group selected from hydrogen, hydroxyl, halogen, nitro, cyano, haloalkyl, amine, or any other group: (C1~C 10 ) alkyl, (C1~C 10 )alkoxy, (C3~C 10 )Cycloalkyl, (C2~C 10 ) Alkenil, (C2~C 10 ) represents alkynyl, SO2(C1~C6)alkyl, thiol, thioalkyl, thio-alkoxy, SO(C1~C6)alkyl, benzyl, aryl, heteroaryl, and heterocyclyl; Y is O, S; R 1At each occurrence, independently, is hydrogen, halogen, haloalkyl, cyano, a group optionally substituted by any one selected from the following: (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkoxy, (C3-C7) cycloalkyl, (C1-C6) alkylSO2(C1-C6) alkyl, (C1-C6) alkylN(C1-C6) alkyl, (C1-C6) alkylN(C3-C7) cycloalkyl, aryl, heteroaryl, 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, a 4- to 7-membered heterocyclic ring, a 7- to 14-membered bicyclic heterocyclic ring system, a bridged or spiro ring system optionally having one or more heteroatoms.

[0025] In certain embodiments, R 1 represents the following:

[0026]

Chemical formula

[0027] n independently represents an integer from 0 to 3; R'​​​​​​​Each of R2' and R2'' is independently substituted in each occurrence by a group of any choice selected from hydrogen, halogen, haloalkyl, cyano, etc.: (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 - Represents 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 rings, 7- to 14-membered bicyclic heterocyclic ring systems, and optionally bridged or spirocyclic ring systems having one or more heteroatoms; in some embodiments, R' and R'' optionally form 4- to 7-membered heterocyclic ring systems; R 2 It is selected from the following ring systems.

[0028] [ka]

[0029] (In the formula, X, Y, and Z each independently represent C, N, S, SO2, and O, and these may be substituted by any choice; R 4Each occurrence independently represents a group substituted by hydrogen, halogen, haloalkyl, cyano, or any choice selected from the following: (C1-C6) alkyl, (C2-C6) alkenyl, (C1-C6) alkoxy, (C3-C7) cycloalkyl, aryl, heteroaryl, heterocyclyl, benzyl, bicyclic or heterocyclic ring systems, substituted amines, thiols, mercaptoalkyl, or (C1-C6) thio-alkoxy groups; R 7 , R 8 , R 9 , R 10 、 R 11 and R 12 Each of the groups in each occurrence is substituted by an optional group selected from hydrogen, halogen, cyano, amide, sulfonamide, acyl, hydroxyl, independently selected from (C1-C6) alkyl, (C1-C6) haloalkyl, (C3-C6) cycloalkyl, (C1-C6) alkoxy, benzyl, aryl, heteroaryl, heterocyclyl; in one embodiment, R 8 and R 9 、 R 9 and R 10 , R 10 and R 11 R 11 and R 12 Each of them, whenever possible, together, is N, O, and S(O) p A group consisting of 0 to 2 additional heteroatoms can be selected to form a 4- to 7-membered saturated or partially saturated ring (p = 1 to 2). R x and R y In each occurrence, the group is substituted by hydrogen, halogen, or any choice selected from the following: (C1~C6) alkyl groups, independently selected; alternatively, R x and R y Together, they can form a heterocyclic ring system with 4 to 7 members; "M" is selected from aryl, heteroaryl, and heterocyclyl; If any of the groups defined above are substituted, the substituents therein may be selected from those listed above, or the group may be substituted by any choice selected from hydrogen, hydroxy, cyano, halo, haloalkyl, haloalkyloxy, alkylthio, and the following: (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C 10 )Cycloalkyl, C1-C6 alkoxy, aryl, heterocyclyl, 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 , -SO2R 11 You can choose from the base, where R 11 and R 12 Each of these is a hydrogen atom, substituted by any choice selected from the following: (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C7) cycloalkyl, aryl, heteroaryl, and heterocyclyl groups, independently selected from these; In a preferred embodiment, the groups and radicals described above can be selected from the following: "Alkyl," as well as other groups having the prefix "alk," such as alkoxy and alkanoyl, means a carbon chain that may be further substituted with oxygen atoms, as will be well understood by those skilled in the art, and furthermore, unless otherwise defined, the carbon chain may be linear, branched, or a combination thereof. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, and hexyl. The specified number of carbon atoms is, for example, C 3~10 Where possible, the term alkyl also includes cycloalkyl groups and combinations of linear or branched alkyl chains combined with cycloalkyl structures. If the number of carbon atoms is not specified, C 1~6This is intended. Substituted alkyls include alkyls substituted with one or more parts selected from the group consisting of halo{e.g., CI, F, Br and I); alkyl halides{e.g., CF3, 2-Br-ethyl, CH2F, CH2CI, CH2CF3, or CF2CF3); hydroxyl; amino; carboxylate; carboxyamide; alkylamino; arylamino; alkoxy; aryloxy; nitro; azide; cyano; thio; sulfonic acid; sulfate; phosphonic acid; phosphate; and phosphonate, as well as alkyls substituted with one or more parts selected from the group consisting of those listed under the definition of "optionally substituted".

[0030] "Alkenyl" means a carbon chain containing at least one carbon-carbon double bond, and unless otherwise defined, the carbon chain may be linear, branched, or a combination thereof. Examples of alkenyls include, but are not limited to, vinyl, allyl, isopropenyl, hexenyl, pentenyl, heptenyl, l-propenyl, : Examples include 2-butenyl and 2-methyl-2-butenyl. The specified number of carbon atoms is, for example, C 5~10 Where possible, the term alkenyl includes cycloalkenyl groups, as well as combinations of linear, branched, and cyclic structures. If the number of carbon atoms is not specified, C 2~6 This is intended.

[0031] "Alkynyl" refers to a carbon chain containing at least one carbon-carbon triple bond, which may be linear, branched, or a combination thereof. Examples of alkynyls include ethynyl, propargyl, and 3-methyl-l-pentynyl. The term is intended to refer to cases where the number of carbon atoms is not specified.

[0032] The "thioalkyl" group, used alone or in combination with other groups, represents an alkyl group as defined above, attached to a group of formula -SR'(sulfur and its oxidation form), where R' represents hydrogen, an alkyl group, or an aryl group, such as thiomethyl, methylthiomethyl, or phenylthiomethyl, which may be optionally substituted.

[0033] As used herein, “carbocyclic” or “carbocyclic residue” is intended to mean any stable monocyclic, bicyclic, or tricyclic ring, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocyclic rings 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 sense, the term carbocyclic ring is intended to include, whenever applicable, groups representing cycloalkyl, phenyl, and other saturated, partially saturated, or aromatic residues;

[0034] The terms "cycloalkyl" and "cycloalkenyl" refer to monocyclic, bicyclic, or tricyclic carbon groups that are optionally substituted with saturated or unsaturated carbon atoms. Where appropriate, cycloalkyl or cycloalkenyl groups may have a specified number of carbon atoms; for example, C3-C6 cycloalkyl or cycloalkenyl groups include carbocyclic groups having 3, 4, 5, or 6 carbon atoms. Examples of such substituents can be selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, and the like. Substituted cycloalkyl or cycloalkenyls include substitutions by one or more parts selected from the group consisting of halo (e.g., CI, F, Br, and I); alkyl halides (e.g., CF3, 2-Br-ethyl, CH2F, CH2CI, CH2CF3, or CF2CF3); hydroxyl; amino; carboxylate; carboxyamide; alkylamino; arylamino; alkoxy; aryloxy; nitro; azide; cyano; thio; sulfonic acid; sulfate; phosphonic acid; phosphate; and phosphonate, as well as those listed under the definition of "optionally substituted".

[0035] The term "alkoxy" refers to a linear or branched alkoxide with a specified number of carbon atoms.

[0036] "Aryl" refers to a monocyclic or polycyclic aromatic ring system containing a carbocyclic atom. Preferred aryls are monocyclic or bicyclic aromatic ring systems with 6 to 10 members. Phenyl and naphthyl are preferred aryls.

[0037] "Heterocyclyl" means 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, and optionally containing oxidation forms of sulfur, i.e., SO and SO2. A heterocyclyl system may have any number of carbon atoms or heteroatoms attached to other parts of the group and may be both saturated and unsaturated. Examples of heterocycles include tetrahydrofuran (THF), dihydrofuran, 1,4-dioxane, morpholine, 1,4-dithiane, piperazine, piperidine, 1,3-dioxolane, imidazoline, imidazolidine, pyrrolidine, pyrroline, tetrahydropyran, dihydropyran, oxathiolane, dithiolane, 1,3-dioxane, 1,3-dithiane, oxathiane, thiomorpholine, and the like. The term "heterocycloalkyl" refers to a heterocyclic group, as defined above, that is connected to an alkyl group, as defined above;

[0038] "Heteroaryl" means an aromatic or partially aromatic heterocycle containing at least one ring heteroatom selected from O, S, and N. Heteroaryls therefore include heteroaryls fused to other types of rings, such as aryl, cycloalkyl, and non-aromatic heterocycles. 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, isoindo Ryl, dihydrobenzothienyl, indolinyl, pyridadinyl, indazolyl, isoindolyl, dihydrobenzothienyl, indolidinyl, cinnolinyl, phthalazinyl, quinazolinyl, napthyridinyl, carbazolyl, benzodioxolyl, quinoxalinyl, purinyl, flazanil, isobenzylfuranil, benzimidazolyl, benzofuranil, benzothienyl, quinolyl, indolyl, isoquinolyl, dibenzofuranil, etc. Heterocyclyl and heteroaryl groups contain rings and ring systems with 3 to 15 carbon atoms, forming 1 to 3 rings.

[0039] The term "haloalkyl" refers to an alkyl structure in which at least one hydrogen atom is replaced by a halogen atom. In certain embodiments in which two or more hydrogen atoms are replaced by halogen atoms, all halogen atoms are identical to one another.

[0040] The "haloalkoxy" group is selected from a suitable haloalkyl group as defined above, more preferably from a group selected from fluoromethoxy, chloromethoxy, fluoroethoxy, chloroethoxy, etc., which is directly attached to an oxygen atom;

[0041] In certain other embodiments, where two or more hydrogen atoms are replaced by halogen atoms, the halogen atoms are not all the same as one another.

[0042] "Aryloxyalkyl" means an alkyl group substituted with an aryloxy group as defined herein.

[0043] "Aryloxyaryl" means an aryl group substituted with an aryloxy group as defined herein.

[0044] "Aryloxyheteroaryl" means a heteroaryl group substituted with an aryloxy group as defined herein.

[0045] "Halo" refers to fluorine, chlorine, bromine, and iodine. Chlorine and fluorine are generally preferred.

[0046] A suitable group and substituent on the group can be selected from those described elsewhere in this specification.

[0047] As used herein, the term "substituted" means that any one or more hydrogen atoms on the designated atom are replaced with a group selected from those indicated, provided that the substitution does not exceed the normal valence of the designated atom and results in a stable compound.

[0048] "Pharmacologically acceptable salts" refer to derivatives of disclosed compounds in which the parent compound is modified by forming an acid salt or base salt thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral salts or organic acid salts of basic residues. Such conventional non-toxic salts include, but are not limited to, 1,2-ethanedisulfonic acid, 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptanoic acid, gluconic acid, glutamic acid, glycolic acid, glycolylarsanilic acid, hexylresorcinic acid, hydrabamic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxymaleic acid. Examples include those derived from inorganic and organic acids selected from ic acid, hydroxynaphthoic acid, isethionic acid, lactic acid, lactobionic acid, lauryl sulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, napsylic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, basic acetic acid, succinic acid, sulfamic acid, sulfanilic acid, sulfuric acid, tannic acid, tartaric acid, and toluenesulfonic acid.

[0049] The terms "optional" or "by option" mean that the subsequent described event or situation may or may not occur, and the description includes examples in which such event or situation occurs and examples in which it does not occur. For example, "optionally substituted alkyl" means either "alkyl" or "substituted alkyl". A group that is further optionally substituted is an unsubstituted group.

[0050] Unless otherwise specified herein, the structures illustrated herein are to mean that they contain different compounds only in the presence of one or more isotopically enriched atoms.

[0051] Particularly useful compounds include, but are not limited to, the following: N'-Cyano-N-((1,2,3,5,6,7-Hexahydro-s-Indacen-4-yl)Carbamoyl)-5-(2-Hydroxypropan-2-yl)Thiophen-2-Sulfonimidoamide; N'-Cyano-4-fluoro-N-((1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-3-(2-hydroxypropan-2-yl)benzenesulfonimidoamide; N'-Cyano-N-((1,2,3,5,6,7-Hexahydro-s-Indacen-4-yl)Carbamoyl)-4-(2-Hydroxypropan-2-yl)Fran-2-Sulfonimidoamide; (E)-N-((1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-2-(thiazole-2-yl)ethensulfonamide; (E)-2-(1-ethyl-1H-imidazole-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)ethensulfonamide; (E)-2-(1-ethyl-4-methyl-1H-imidazole-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)ethensulfonamide; (R,E)-2-(1-ethylpyrrolidine-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-ethanesulfonamide; (R,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(pyrrolidine-2-yl)ethen-1-sulfonamide; (R,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-methylpyrrolidine-2-yl)ethen-1-sulfonamide; (S,E)-2-(1-ethylpyrrolidine-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-ethanesulfonamide; (R,E)-2-(1,2-dimethylpyrrolidine-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethen-1-sulfonamide; (S,E)-2-(1,2-dimethylpyrrolidine-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide; Sodium (S,E)-((2-(1,2-dimethylpyrrolidine-2-yl)vinyl)sulfonyl)((1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)amide; Potassium (R,E)-((2-(1,2-dimethylpyrrolidine-2-yl)vinyl)sulfonyl)((1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)amide; Sodium (R,E)-((2-(1,2-dimethylpyrrolidine-2-yl)vinyl)sulfonyl)((1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)amide; (E)-N'-Cyano-2-((S)-1,2-dimethylpyrrolidine-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonimidoamide; (E)-N'-Cyano-N-((1,2,3,5,6,7-Hexahydro-s-Indacen-4-yl)Carbamoyl)-2-((R)-1-Methylpyrrolidine-2-yl)Ethene-1-Sulfonimidoamide; (E)-N'-Cyano-N-((1,2,3,5,6,7-Hexahydro-s-Indacen-4-yl)Carbamoyl)-2-((R)-1-Methylpyrrolidine-2-yl)Ethene-1-Sulfonimidoamide; (E)-N'-Cyano-2-((R)-1,2-dimethylpyrrolidine-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonimidoamide; N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-((1S,8aR)-3,3,8a-trimethyloctahydropyrrolo[1,2-a]pyrazine-1-yl)methanesulfonamide; N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-((4S,8aS)-2,3,3,8a-tetramethyloctahydropyrrolo[1,2-a]pyrazine-4-yl)methanesulfonamide; (E)-3-(dimethylamino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)propa-1-en-1-sulfonamide; Sodium (E)-((3-(dimethylamino)-3-methylbuta-1-en-1-yl)sulfonyl)((1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)amide; (S,E)-N-((1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-2-(2-methyl-1-(methyl-d)pyrrolidine-2-yl)ethen-1-sulfonamide; (R,E)-N-((1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-2-(2-methyl-1-(methyl-d)pyrrolidine-2-yl)ethene-1-sulfonamide (R,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(methyl-d)pyrrolidine-2-yl)ethen-1-sulfonamide; (E)-3-(bis(methyl-d)amino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-methylbuta-1-en-1-sulfonamide; Sodium (R,E)-((1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)((2-(2-methyl-1-(methyl-d)pyrrolidine-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]pyrazine-1-yl)methanesulfonamide; (R,E)-2-(1,2-dimethylpyrrolidine-2-yl)-N-((1,2,3,5-tetrahydro-s-indacen-4-yl)carbamoyl)ethen-1-sulfonamide; (E)-2-((R)-1,2-dimethylpyrrolidine-2-yl)-N-((2-hydroxy-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide; (E)-2-((R)-1,2-dimethylpyrrolidine-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-dimethylpyrrolidine-2-yl)-N-((1-hydroxy-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide; Alternatively, one can choose from any pharmaceutically acceptable salt of the above compounds.

[0052] In one embodiment, the present invention provides a suitable composition comprising a compound of formula (I) or a suitable pharmaceutical composition thereof for the treatment and prevention of IBD, including Crohn's disease and ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal disease, eosinophilic gastrointestinal disease, and other related forms of disorders.

[0053] The term “pharmaceutical composition” refers to a mixture of an NLRP3 antagonist or any other compound described herein with other chemical components (collectively referred to herein as “excipients”), such as carriers, stabilizers, diluents, dispersants, suspending agents, and / or thickeners. The pharmaceutical composition facilitates the administration of the NLRP3 antagonist or any other compound to a living organism. Multiple techniques for administering the compounds exist in the prior art and include, but are not limited to, rectal, oral, and intravenous, aerosol, as well as parenteral, ophthalmic, pulmonary, and topical administration.

[0054] In one embodiment, the present invention provides an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, selected from 1 mg to 500 mg; preferably from 1 mg to 250 mg, more preferably from 1 mg to 150 mg, for the treatment and prevention of IBD such as Crohn's disease and ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal disease, eosinophilic gastrointestinal disease, and other related forms of disorders.

[0055] In certain embodiments, the compound is administered orally in an amount that provides the compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 150 mg on each day the compound is administered to the subject. For example, in certain embodiments, the compound is administered orally in an amount that provides the compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 25 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount that provides the compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 25 mg to about 50 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount that provides the compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 50 mg to about 75 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount that provides the compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 75 mg to about 100 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount that provides the compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 100 mg to about 125 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount that provides the compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 125 mg to about 150 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount that provides the compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 150 mg to about 175 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount that provides the compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 175 mg to about 200 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount that provides the compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 200 mg to about 225 mg on each day the compound is administered to the subject. In a particular embodiment, the compound is administered orally in an amount that provides the compound of formula (I) or a pharmaceutically acceptable salt thereof, ranging from about 225 mg to about 250 mg on each day the compound is administered to the subject. In certain other embodiments, the compound is administered orally in an amount that provides the compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 25 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount that provides the compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 50 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount that provides the compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 75 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount that provides the compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 100 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount that provides the compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 125 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount that provides the compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 150 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount that provides the compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 175 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount that provides the compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 200 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount that provides the compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 225 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount that provides the compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 250 mg on each day the compound is administered to the subject.

[0056] The dose amounts in the range of approximately 1 mg to approximately 500 mg in accordance with this disclosure include each integer and non-integer number within the special range.

[0057] Enumerating a numerical range by endpoints includes all numbers that fall within that range (for example, 1 to 5 includes 1, 1.25, 1.5, 1.75, 2.0, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4.0, 4.25, 4.5, 4.75, 5, etc.).

[0058] In one embodiment, the present invention provides an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof that can be administered by oral, topical, parenteral, intravenous, or intramuscular routes of administration. In a preferred embodiment, the present invention provides an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof that can be administered by an oral route of administration.

[0059] The compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered to a person in need on a daily or weekly basis, as prescribed by a physician.

[0060] In another embodiment, the present invention provides a method for treating subjects suffering from Crohn's disease and ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal disease, eosinophilic gastrointestinal disease, and other related forms of disorders, preferably Crohn's disease and ulcerative colitis, which comprises treating patients requiring such treatment using a compound of formula (I) or a pharmaceutically acceptable salt thereof or a suitable pharmaceutical composition containing them.

[0061] In one embodiment, the present invention provides a combination of compounds of formula (I) or pharmaceutically acceptable salts thereof with other suitable agents as therapeutic agents for the treatment of IBD such as Crohn's disease and ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal disease, eosinophilic gastrointestinal disease, and other related forms of disorders.

[0062] In one embodiment, additional therapeutic agents used are selected from interleukin-1β inhibitors (e.g., lilonacept, canakinumab, and anakinra); immunosuppressants (e.g., methotrexate, mercaptopurine, cyclophosphamide), metabolic disordering drugs, glucocorticoids, nonsteroidal anti-inflammatory drugs, gasdermin D inhibitors (e.g., necrosulfonamide); Cox-2 specific inhibitors, TNF-α binding proteins (e.g., infliximab, etanercept), interferon-13, interferon, interleukin-2, antihistamines, beta-agonists, BTK inhibitors, anticholinergics, anticancer agents; antiviral agents, e.g., remdesivir, lopinavir / ritonavir, favipiravir, mornupiravir, tamiflu; antimalarial agents, e.g., chloroquinone, hydroxylchloroquinone; or suitable pharmaceutically acceptable salts thereof. Further examples of use in combination include non-alcoholic steatohepatitis (NASH) and fibrosis drugs; anticancer drugs; antibiotics, e.g., azithromycin; hormones, aromatase inhibitors, colchicine, anticoagulants, antibodies, cytokines, anti-IL6 drugs; antiparasitic drugs; vaccines; interferons; drug conjugates; drugs originally developed for SARS (ACE2 protein decoy); intravenous vitamin C; mitogen-activated protein kinase signaling inhibitors (e.g., BAY 43-9006); Syk inhibitors; mTOR inhibitors; antibodies (rituxan); and BCR / ABL antagonists.

[0063] The compounds of formula (I) of the present invention or pharmaceutically acceptable salts thereof may be further used in any combination with one or more suitable pharmaceutically active agents selected from the following therapeutic agents: MAO B inhibitors, selegiline (Zelapar), rasagiline (Azilect), and safinamide (Xadago); catechol O-methyltransferase (COMT) inhibitors, entacapone (Comtan), and opicapone (Ongentys); benztropine (Cogentin), trihexyphenidyl, amantadine; cholinesterase inhibitors, donepezil (Aricept), galantamine (Razadyne), and rivastigmine (Exelon); memantine (Namenda ), aducanumab (Aduhelm); riluzole (Rilutek); edaravone (Radicava); ocrelizumab (Ocrevus), prednisone and methylprednisolone; tetrabenazine (Xenazine) and deutetrabenazine (Austedo), haloperidol (Haldol) and fluphenazine, risperidone (Risperdal), olanzapine (Zyprexa) and quetiapine (Seroquel), levetiracetam (Keppra, Elepsia) XR, Spritam) and clonazepam (Klonopin); citalopram (Celexa), escitalopram (Lexapro), fluoxetine (Prozac, Sarafem) and sertraline (Zoloft), quetiapine (Seroquel), risperidone (Risperdal) and olanzapine (Zyprexa), divalproex (Depakote), carbamazepine (Carbatrol, Epitol) and lamotrigine (Lamictal).

[0064] The compounds and compositions of the present invention are also intended to be used in conjunction with general care provided to patients with arenavirus infection, including parenteral fluids (including dextrose saline and Ringer's lactate solution) and nutrition, antibiotics (including metronidazole and cephalosporin antibiotics, e.g., ceftriaxone and cefuroxime) and / or antifungal prophylactic agents, fever and pain medications, antiemetics (e.g., metoclopramide) and / or antidiarrheal agents, vitamin and mineral supplements (including vitamin C and / or K and zinc sulfate), anti-inflammatory agents (e.g., ibuprofen), pain medications, and antimalarial agents (including artemether and artesunate-lumefantrine combination therapy), typhus (including quinolone antibiotics, e.g., ciprofloxacin, macrolide antibiotics, e.g., azithromycin, cephalosporin antibiotics, e.g., ceftriaxone, or aminopenicillin, e.g., ampicillin), or drugs for other common diseases in the patient population, such as bacterial dysentery.

[0065] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is provided in the form of a pharmaceutical composition.

[0066] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof for the treatment of Crohn's disease and ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal disease, eosinophilic gastrointestinal disease, and other related forms of disorders, preferably inflammatory bowel diseases such as ulcerative colitis, wherein the compound of formula (I) is

[0067] [ka]

[0068] That is the case.

[0069] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I) and a suitable pharmaceutically acceptable excipient for the treatment of Crohn's disease and inflammatory bowel diseases such as ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal diseases, eosinophilic gastrointestinal diseases, and other related forms of disorders, preferably inflammatory bowel diseases such as ulcerative colitis.

[0070] Pharmacochemically acceptable excipients can be selected from at least one of the following: diluents, carriers, binders, disintegrants, lubricants, surfactants, etc.

[0071] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein an effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof can be selected from 1 mg to 500 mg; preferably 1 mg to 250 mg, more preferably 1 mg to 150 mg, for the treatment of Crohn's disease and inflammatory bowel diseases such as ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal diseases, eosinophilic gastrointestinal diseases, and other related forms of disorders, preferably inflammatory bowel diseases such as ulcerative colitis.

[0072] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, which can be administered by oral, topical, parenteral, intravenous, or intramuscular routes of administration. In a preferred embodiment, the pharmaceutical composition can be administered by oral route of administration.

[0073] Another embodiment of the present invention provides a process for preparing a stable pharmaceutical composition of a compound of formula (1) or a pharmaceutically acceptable salt thereof.

[0074] Stable pharmaceutical compositions can be prepared by dry mixing, wet granulation, or dry granulation methods, according to techniques known to those skilled in the art. Therefore, for example,

[0075] In a wet granulation process, the drug is mixed with one or more pharmaceutical excipients and granulated with a suitable binding solution as described above to form wet granules, which are then dried and optionally sieved. The dried granules are mixed with one or more suitable excipients from those described elsewhere and then compressed into tablets or filled into capsules.

[0076] In the dry mixing process, the drug is mixed with all the necessary pharmaceutical excipients. The blend is then mixed with one or more suitable excipients from those described elsewhere, and the final blend is either compressed into tablets or filled into capsules.

[0077] In the dry granulation process, the drug is mixed with one or more pharmaceutical excipients, compressed into slag, and these slags are passed through the required sieves. The sieved granules are mixed with one or more suitable excipients from those described elsewhere, and then compressed into tablets or filled into capsules.

[0078] One or more solvents or vehicles used in the formulation are selected from water, acetone, chloroform, dichloromethane, ethyl alcohol, ethyl acetate, methyl alcohol, isopropyl alcohol and combinations thereof, as well as other such materials known to those skilled in the art.

[0079] The present invention further discloses the use of the compounds of formula (I) or suitable pharmaceutical compositions thereof for the treatment of Crohn's disease and ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal diseases, eosinophilic gastrointestinal diseases, and other related forms of disorders, preferably inflammatory bowel diseases such as ulcerative colitis.

[0080] In another embodiment, the present invention provides a method for treating inflammatory bowel disease using a pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In a preferred embodiment, a method for treating inflammatory bowel disease using a compound of formula (I) or a pharmaceutical composition thereof.

[0081] In a preferred embodiment, the present invention relates to formula (11) suitable for the treatment of inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal diseases, eosinophilic gastrointestinal diseases, and other related forms of disorders.

[0082] [ka]

[0083] The present invention provides a compound or a pharmaceutically acceptable salt thereof.

[0084] In a more preferred embodiment, the present invention provides the use of compounds of formula (11) or suitable pharmaceutical compositions thereof for the treatment of inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal disease, eosinophilic gastrointestinal disease, and other related forms of disorders.

[0085] In another preferred embodiment, the present invention provides an effective amount of a compound of formula (11) or a pharmaceutically acceptable salt thereof, which can be selected from 1 mg to 500 mg; preferably from 1 mg to 250 mg, more preferably from 1 mg to 150 mg, for the treatment of inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal disease, eosinophilic gastrointestinal disease, and other related forms of disorders.

[0086] In certain embodiments, the compound is administered orally in an amount that provides the compound of formula (11) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 250 mg on each day the compound is administered to the subject. For example, in certain embodiments, the compound is administered orally in an amount that provides the compound of formula (11) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 25 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount that provides the compound of formula (11) or a pharmaceutically acceptable salt thereof in the range of about 25 mg to about 50 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount that provides the compound of formula (11) or a pharmaceutically acceptable salt thereof in the range of about 50 mg to about 75 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount that provides the compound of formula (11) or a pharmaceutically acceptable salt thereof in the range of about 75 mg to about 100 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount that provides the compound of formula (11) or a pharmaceutically acceptable salt thereof in the range of about 100 mg to about 125 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount that provides the compound of formula (11) or a pharmaceutically acceptable salt thereof in the range of about 125 mg to about 150 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount that provides the compound of formula (11) or a pharmaceutically acceptable salt thereof in the range of about 150 mg to about 175 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount that provides the compound of formula (11) or a pharmaceutically acceptable salt thereof in the range of about 175 mg to about 200 mg on each day the compound is administered to the subject. In a particular embodiment, the compound is administered orally in an amount that provides the compound of formula (11) or a pharmaceutically acceptable salt thereof, ranging from about 200 mg to about 225 mg on each day the compound is administered to the subject.In a particular embodiment, the compound is administered orally in an amount that provides the compound of formula (11) or a pharmaceutically acceptable salt thereof, ranging from about 225 mg to about 250 mg on each day the compound is administered to the subject.

[0087] In certain other embodiments, the compound is administered orally in an amount that provides the compound of formula (11) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 25 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount that provides the compound of formula (11) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 50 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount that provides the compound of formula (11) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 75 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount that provides the compound of formula (11) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 100 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount that provides the compound of formula (11) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 125 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount that provides the compound of formula (11) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 150 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount that provides the compound of formula (11) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 175 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount that provides the compound of formula (11) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 200 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount that provides the compound of formula (11) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 225 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount that provides the compound of formula (11) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 250 mg on each day the compound is administered to the subject.

[0088] The dose amounts in the range of approximately 1 mg to approximately 500 mg in accordance with this disclosure include each integer and non-integer number within the special range.

[0089] Enumerating a numerical range by endpoints includes all numbers that fall within that range (for example, 1 to 5 includes 1, 1.25, 1.5, 1.75, 2.0, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4.0, 4.25, 4.5, 4.75, 5, etc.).

[0090] In another preferred embodiment, the present invention provides an effective amount of a compound of formula (11) or a pharmaceutically acceptable salt thereof that can be administered by oral, topical, parenteral, intravenous, or intramuscular routes of administration. In another preferred embodiment, the present invention provides an effective amount of formula (11) or a pharmaceutically acceptable salt thereof that is administered by an oral route of administration.

[0091] The compound of formula (11) or a pharmaceutically acceptable salt thereof may be provided to a person in need on a daily or weekly basis as prescribed by a physician.

[0092] In one preferred embodiment, the present invention provides combinations of compounds of formula (11) and pharmaceutically acceptable salts thereof with other suitable agents as therapeutic agents for the treatment of Crohn's disease and inflammatory bowel diseases such as ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal diseases, eosinophilic gastrointestinal diseases, and other related forms of disorders, preferably ulcerative colitis.

[0093] Other suitable therapeutic agents can be selected from interleukin-1β inhibitors (e.g., lilonacept, canakinumab, and anakinra); immunosuppressants (e.g., methotrexate, mercaptopurine, cyclophosphamide), metabolic disordering drugs, glucocorticoids, nonsteroidal anti-inflammatory drugs, gasdermin D inhibitors (e.g., necrosulfonamide); Cox-2 specific inhibitors, TNF-α binding proteins (e.g., infliximab, etanercept), interferon-13, interferon, interleukin-2, antihistamines, beta-agonists, BTK inhibitors, anticholinergics, anticancer agents; antiviral agents, e.g., remdesivir, lopinavir / ritonavir, favipiravir, mornupiravir, tamiflu; antimalarial agents, e.g., chloroquinone, hydroxylchloroquinone; or suitable pharmaceutically acceptable salts thereof. Drugs for non-alcoholic steatohepatitis (NASH) and fibrosis; anticancer drugs; antibiotics, e.g., azithromycin; hormones, aromatase inhibitors, colchicine, anticoagulants, antibodies, cytokines, anti-IL6 drugs; antiparasitic drugs; vaccines; interferons; drug conjugates; drugs originally developed for SARS (ACE2 protein decoy); intravenous vitamin C; mitogen-activated protein kinase signaling inhibitors (e.g., BAY 43-9006); Syk inhibitors; mTOR inhibitors; antibodies (rituxan); and further examples of use in combination with BCR / ABL antagonists include use in combination with compounds of formula (11) for the treatment of Crohn's disease and ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal diseases, eosinophilic gastrointestinal diseases, and other related forms of disorders, preferably inflammatory bowel diseases such as ulcerative colitis.

[0094] The compounds of formula (11) of the present invention or pharmaceutically acceptable salts thereof may be further used in any combination with one or more suitable pharmaceutically active agents selected from the following therapeutic agents: MAO B inhibitors, selegiline (Zelapar), rasagiline (Azilect), and safinamide (Xadago); catechol O-methyltransferase (COMT) inhibitors, entacapone (Comtan), and opicapone (Ongentys); benztropine (Cogentin), trihexyphenidyl, amantadine; cholinesterase inhibitors, donepezil (Aricept), galantamine (Razadyne), and rivastigmine (Exelon); memantine (Namenda ), aducanumab (Aduhelm); riluzole (Rilutek); edaravone (Radicava); ocrelizumab (Ocrevus), prednisone and methylprednisolone; tetrabenazine (Xenazine) and deutetrabenazine (Austedo), haloperidol (Haldol) and fluphenazine, risperidone (Risperdal), olanzapine (Zyprexa) and quetiapine (Seroquel), levetiracetam (Keppra, Elepsia) XR, Spritam) and clonazepam (Klonopin); citalopram (Celexa), escitalopram (Lexapro), fluoxetine (Prozac, Sarafem) and sertraline (Zoloft), quetiapine (Seroquel), risperidone (Risperdal) and olanzapine (Zyprexa), divalproex (Depakote), carbamazepine (Carbatrol, Epitol) and lamotrigine (Lamictal).

[0095] The compounds of formula (11) and compositions thereof of the present invention are used in parenteral fluids (including dextrose saline and Ringer's lactate solution) and nutrition, antibiotics (including metronidazole and cephalosporin antibiotics, e.g., ceftriaxone and cefuroxime) and / or antifungal prophylactic administration, fever and pain drug therapy, antiemetics (such as metoclopramide) and / or antidiarrheals, vitamin and mineral supplements (including vitamin C and / or K and zinc sulfate), anti-inflammatory agents (such as ibuprofen), pain drug therapy, and antifungal It is also intended to be used in conjunction with general care provided to patients with arenaviridae virus infections, including lariaticides (including artemether and artesunate-lumefantrine combination therapy), typhus (including quinolone antibiotics, e.g., ciprofloxacin; macrolide antibiotics, e.g., azithromycin; cephalosporin antibiotics, e.g., ceftriaxone; or aminopenicillin, e.g., ampicillin), or pharmacotherapy for other common diseases in the patient population, such as bacterial dysentery.

[0096] In a preferred embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (11) or a pharmaceutically acceptable salt thereof for the treatment of Crohn's disease and inflammatory bowel diseases such as ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal diseases, eosinophilic gastrointestinal diseases, and other related forms of disorders, preferably ulcerative colitis.

[0097] In another preferred embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (11) and a suitable pharmaceutically acceptable excipient for the treatment of Crohn's disease and inflammatory bowel diseases such as ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal diseases, eosinophilic gastrointestinal diseases, and other related forms of disorders, preferably inflammatory bowel diseases such as ulcerative colitis. The pharmaceutically acceptable excipient can be selected from at least one of diluents, carriers, binders, disintegrants, lubricants, surfactants, etc.

[0098] In another embodiment, the present invention further discloses the use of the compounds of formula (11) or suitable pharmaceutical compositions thereof for the treatment of Crohn's disease and ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal disease, eosinophilic gastrointestinal disease, and other related forms of disorders, preferably inflammatory bowel diseases such as ulcerative colitis.

[0099] In another preferred embodiment, the present invention provides a method for treating Crohn's disease and inflammatory bowel diseases, such as ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal diseases, eosinophilic gastrointestinal diseases, and other related forms of disorders, preferably ulcerative colitis, using a pharmaceutical composition of a compound of formula (11) or a pharmaceutically acceptable salt thereof.

[0100] A preferred embodiment involves using a compound of formula (11) or a pharmaceutical composition thereof to treat Crohn's disease and inflammatory bowel diseases such as ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal diseases, eosinophilic gastrointestinal diseases, and other related forms of disorders, preferably ulcerative colitis.

[0101] Another preferred embodiment of the present invention provides a process for preparing a stable pharmaceutical composition of the compound of formula (11).

[0102] Stable pharmaceutical compositions can be prepared by dry mixing, wet granulation, or dry granulation methods known to those skilled in the art. Therefore, for example,

[0103] In a wet granulation process, the drug is mixed with one or more pharmaceutical excipients and granulated with a suitable binding solution as described above to form wet granules, which are then dried and optionally sieved. The dried granules are mixed with one or more suitable excipients from those described elsewhere and then compressed into tablets or filled into capsules.

[0104] In the dry mixing process, the drug is mixed with all the necessary pharmaceutical excipients. The blend is then mixed with one or more suitable excipients from those described elsewhere, and the final blend is either compressed into tablets or filled into capsules.

[0105] In the dry granulation process, the drug is mixed with one or more pharmaceutical excipients, compressed into slag, and these slags are passed through the required sieves. The sieved granules are mixed with one or more suitable excipients from those described elsewhere, and then compressed into tablets or filled into capsules.

[0106] One or more solvents or vehicles used in the formulation are selected from water, acetone, chloroform, dichloromethane, ethyl alcohol, ethyl acetate, methyl alcohol, isopropyl alcohol and combinations thereof, as well as other such materials known to those skilled in the art.

[0107] In one embodiment, the pharmaceutically acceptable excipients described in the present invention are selected from at least one of diluents, carriers, binders, disintegrants, lubricants, surfactants, and the like.

[0108] Examples of diluents include, but are not limited to, lactose monohydrate, polymethacrylates selected from Eudragit, potassium chloride, sulfobutyl ether β-cyclodextrin, sodium chloride, and spray-dried lactose, combinations thereof, and other such materials known to those skilled in the art.

[0109] Examples of carriers include, but are not limited to, lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate and kaolin, crystalline cellulose and silicic acid, combinations thereof, and other such materials known to those skilled in the art.

[0110] Examples of binders include, but are not limited to, carbomers selected from Carbopol, gellan, gum arabic, hydrogenated vegetable oils, polymethacrylates selected from Eudragit, xanthan gum, lactose, and zein, combinations thereof, and other such materials known to those skilled in the art.

[0111] Examples of disintegrants include, but are not limited to, bicarbonates, chitin, gellan gum, potassium polariphosphate, and sodium doxate, combinations thereof, and other such materials known to those skilled in the art.

[0112] Examples of lubricants used include, but are not limited to, glycerin behenate, hydrogenated vegetable oil, sodium stearyl fumarate, and myristic acid, combinations thereof, and other such materials known to those skilled in the art.

[0113] Examples of surfactants include, but are not limited to, nonionic surfactants selected from alkyl polyglucosides, cocamide DEA, cocamide MBA, cocamide TEA, decyl maltoside, and octyl glucoside; anionic surfactants selected from arachidic acid and arachidonic acid; cationic surfactants selected from cetyltrimethylammonium bromide and cetylpyridinium chloride, combinations thereof, and other such materials known to those skilled in the art.

[0114] General process for preparation The novel compounds of the present invention can be prepared using the reactions and techniques described below, along with the prior art known to those skilled in the art of organic synthesis or modifications thereof.

[0115] The reaction can be carried out in a solvent suitable for the transformation, which is appropriate for the reagents and materials used. Preferred methods include, but are not limited to, those listed below, where all symbols are as initially defined unless otherwise defined below.

[0116] Compounds of general formula (I) can be prepared as described in the scheme below, with appropriate modifications / changes that are well within the scope of those skilled in the art.

[0117] [ka]

[0118] In the formula, R 1 , R 2 , X 、 Each of and Y is as previously defined. Compounds 1 and 2 can be prepared by various methods familiar to those skilled in the art using the reported procedures. Compound (1) in a treatment using the isocyanate derivative (2) under appropriate conditions in the presence of a base such as sodium hydride and a suitable solvent to obtain the compound of formula (I).

[0119] The specific reaction conditions, solvents, and other parameters required to carry out the process steps described above are well within the capabilities of those skilled in the art.

[0120] The present invention is further illustrated by the following non-limiting embodiments, which describe preferred ways of carrying out the invention. These are provided without limiting the scope of the invention in any way.

[0121] As shown in the examples 1 ¹H NMR spectral data (see below) were recorded using a 400 MHz spectrometer (Bruker AVANCE-400) and reported on a delta scale. Unless otherwise stated, the solvent used for NMR is CDCl3, with TMS used as the internal standard. [Examples]

[0122] (Example 1) N'-Cyano-N-((1,2,3,5,6,7-Hexahydro-s-Indacen-4-yl)Carbamoyl)-5-(2-Hydroxypropan-2-yl)Thiophen-2-Sulfonimidoamide

[0123] [ka]

[0124] 1 H NMR (400 MHz, DMSO-d6): δ = 7.95 (bs, 1H), 7.23 (d, J = 4.0 Hz, 1H), 6.82 (d, J = 4.0 Hz, 1H), 6.81 (s, 1H), 5.63 (s, 2H), 2.77 (t, J = MS (ESI): m / z (%) = 445.10 (100%) (M+H) + , 443.10 (100%) (MH).

[0125] (Example 2) N'-Cyano-4-fluoro-N-((1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-3-(2-hydroxypropan-2-yl)benzenesulfonimidoamide

[0126] [ka]

[0127] 1H NMR (400 MHz, DMSO): δ = 8.13 (dd, J=2.4Hz, J=7.6Hz, 1H), 8.00 (bs, 1H), 7.68-7.64 (m, 1H), 7.24-7.19 (m, 2H), 6.79 (s, 1H), 2.76-2.60 (m, 8H), 1.95-1.85 (m, 4H), 1.50 (s, 3H), 1.48 (s, 3H); MS (ESI): m / z (%) = 456.88 (100%) (M+H) + .

[0128] (Example 3) N'-Cyano-N-((1,2,3,5,6,7-Hexahydro-s-Indacen-4-yl)Carbamoyl)-4-(2-Hydroxypropan-2-yl)Fran-2-Sulfonimidoamide

[0129] [ka]

[0130] 1 H NMR (400 MHz, DMSO-d6): δ = 8.10 (bs, 1H), 7.55 (s, 1H), 6.82 (s, 1H), 6.79 (s, 1H), 5.03 (s, 1H), 2.77 (t, J = 7.2 Hz, 4H), 2.68 (t, J = 7.2 Hz, 4H), 1.94 (quintet, J = 7.2 Hz, 4H), 1.38 (s, 6H); MS (ESI): m / z (%) = 429.20 (100%) (M+H) + , 427.30 (100%) (MH).

[0131] (Example 4) (E)-N-((1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-2-(thiazole-2-yl)ethensulfonamide

[0132] [ka]

[0133] 1 1H NMR (400 MHz, DMSO-d 6, D2O-X): δ = 10.7 (br, s, 1H), 8.23 ​​(s, 1H), 8.05 (d, J = 2.8 Hz, 1H), 8.02 (d, J = 2.8 Hz, 1H), 7.74 (d, J = 15.2 Hz, 1H), 7.58 (d, J = MS (ESI): m / z (%) = 389.92 (100%) (M+H) + , 411.90 (20%) (M+Na + ).

[0134] (Example 5) (E)-2-(1-ethyl-1H-imidazole-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)ethensulfonamide

[0135] [ka]

[0136] 1H NMR (400 MHz, DMSO): δ = 10.55 (bs, 1H), 8.20 (s, 1H), 7.46-7.42 (m, 2H), 7.29 (d, J=14.8Hz, 1H), 7.13 (s, 1H), 6.95 (s, 1H), 4.16 (q, J=7.2Hz, 2H), 2.82-2.78 (m, 4H), 2.67-2.64 (m, 4H), 1.98-1.91 (m, 4H), 4.16 (t, J=7.2Hz, 3H); MS (ESI): m / z (%) = 401.15 (100%) (M+H) + ; 423.15 (50%) (M+Na) + .

[0137] (Example 6) (E)-2-(1-ethyl-4-methyl-1H-imidazole-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)ethensulfonamide

[0138] [ka]

[0139] 1 H NMR (400 MHz, DMSO-d6): δ = 10.55 (s, 1H), 8.16 (s, 1H), 7.36 (d, J = 14.8 Hz, 1H), 7.21 (d, J = 14.8 Hz, 1H), 7.17 (s, 1H), 6.95 (s, 1H), 4.08 (q, J = 7.2 Hz, 2H), 2.80 (t, J = 7.2 Hz, 4H), 2.66 (t, J = 7.2 Hz, 4H), 2.12 (s, 3H), 1.98 - 1.91 (m, 4H), 1.27 (d, J = 7.2 Hz, 3H); MS (ESI): m / z (%) = 415.18 (100%) (M+H) + .

[0140] (Example 7) (R,E)-2-(1-ethylpyrrolidine-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-ethanesulfonamide

[0141] [ka]

[0142] 1 H NMR (400 MHz, DMSO-d6): δ = 8.03 (s, 1H), 6.92 (s, 1H), 6.87 (d, J=14.8Hz, 1H), 6.60-6.54 (m, 1H), 3.27-3.16 (m, 3H), 2.80 (t, MS (ESI): m / z (%) = 404.20 (100%) (M+H) + .

[0143] (Example 8) (R,E)-N-((1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-2-(pyrrolidine-2-yl)ethen-1-sulfonamide

[0144] [ka]

[0145] 1H NMR (400 MHz, DMSO-d6): δ = 9.71 (brs, 1H), 7.49 (s, 1H), 6.95 (d, J = 15.2 Hz, 1H), 6.80 (s, 1H), 6.36 (dd, J = 7.2 Hz, J = 15.2 Hz, 1H), 4.08 - 4.02 (m, 1H), 3.18 - 3.03 (m, 2H), 2.77 (t, J = 7.2 Hz, 4H), 2.70 (t, J = 7.2 Hz, 4H), 2.14 - 2.07 (m, 4H), 2.03 - 1.80 (m, 6H), 1.70 - 1.60 (m, 1H); MS (ESI): m / z (%) = 376.10 (100%) (M+H) + , 374.05 (100%) (M-1).

[0146] (Example 9) (R,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-methylpyrrolidine-2-yl)ethen-1-sulfonamide

[0147] [ka]

[0148] 1H NMR (400 MHz, DMSO-d6): δ = 10.53 (brs, 1H), 7.97 (s, 1H), 6.92 (s, 1H), 6.84 (d, J = 15.2 Hz, 1H), 6.53 (dd, J = 7.6 Hz, J = 15.2 Hz, 1H), 3.13 - 3.04 (m, 1H), 3.05 - 2.92 (m, 1H), 2.80 (t, J = 7.2 Hz, 4H), 2.67 (t, J = 7.2 Hz, 4H), 2.33 - 2.28 (m, 1H), 2.26 (s, 3H), 2.05 - 1.91 (m, 5H), 1.79 - 1.72 (m, 2H), 1.59 - 1.54 (m, 1H); MS (ESI): m / z (%) = 390.17 (100%) (M+H) + , 388.07 (30%) (M-1).

[0149] (Example 10) (S,E)-2-(1-ethylpyrrolidine-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-ethanesulfonamide

[0150] [ka]

[0151] 1 H NMR (400 MHz, DMSO-d6): δ = 8.03 (s, 1H), 6.92 (s, 1H), 6.87 (d, J=14.8Hz, 1H), 6.60-6.54 (m, 1H), 3.27-3.16 (m, 3H), 2.80 (t, MS (ESI): m / z (%) = 404.20 (100%) (M+H) + .

[0152] (Example 11) (R,E)-2-(1,2-dimethylpyrrolidine-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide

[0153] [ka]

[0154] 1 H NMR (400 MHz, DMSO-d6): δ = 8.04 (s, 1H), 6.93 (s, 1H), 6.74 (d, J = 15.6 Hz, 1H), 6.65 (d, J = 15.2 Hz, 1H), 2.93 - 2.86 (m, 1H), 2.80 (t, J = 7.2 Hz, 4H), 2.67 (t, J = 7.2 Hz, 4H), 2.19 (s, 3H), 1.99 - 1.91 (m, 5H), 1.80 - 1.69 (m, 4H), 1.13 (s, 3H), MS (ESI): m / z (%) = 404.16 (100%) (M+H) + .

[0155] (Example 12) (S,E)-2-(1,2-dimethylpyrrolidine-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide

[0156] [ka]

[0157] 1H NMR (400 MHz, DMSO-d6): δ =8.04 (s, 1H), 6.93 (s, 1H), 6.73 (d, J = 15.2 Hz, 1H), 6.65 (d, J= 15.2 Hz, 1H), 2.80 (t, J = 7.2 Hz, 4H), 2.68 (t, J = 7.2 Hz, 4H), 2.20 (s, 3H), 1.96 (m, 4H), 1.72 (m, 4H), 1.13 (s, 3H); MS (ESI): m / z (%) = 404.25 (100%) (M+1).

[0158] (Example 13) Sodium (S,E)-((2-(1,2-dimethylpyrrolidine-2-yl)vinyl)sulfonyl)((1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)amide

[0159] [ka]

[0160] 1H NMR (400 MHz, DMSO-d6): δ =7.33 (s, 1H), 6.77 (s, 1H), 6.56 (d, J = 15.2 Hz, 1H), 6.16 (d, J= 16 Hz, 1H), 2.76 (t, J = 7.2 Hz, 4H), 2.69 (t, J = 7.2 Hz, 4H), 2.62 (m, 1H), 2.08 (s, 3H), 1.90 (m, 4H), 1.72 (m, 4H), 1.60 (m, 3H), 1.01 (s, 3H); MS (ESI): m / z (%) = 404.20 (100%) (M+1).

[0161] (Example 14) Potassium (R,E)-((2-(1,2-dimethylpyrrolidine-2-yl)vinyl)sulfonyl)((1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)amide

[0162] [ka]

[0163] 1 H NMR (400 MHz, DMSO-d6): δ = 7.33 (s, 1H), 6.77 (s, 1H), 6.58 (d, J = 15.6 Hz, 1H), 6.18 (d, J = 15.6 Hz, 1H), 2.77 - 2.72 (m, 5H), 2.69 (t, J = 7.2 Hz, 4H), 2.64 - 2.58 (m, 1H), 2.08 (s, 3H), 1.90 (quintet, J = 7.6 Hz, 4H), 1.75 - 1.70 (m, 3H), 1.62 - 1.60 (m, 1H), 1.01 (s, 3H); MS (ESI): m / z (%) = 404.21 (100%) (MK) + .

[0164] (Example 15) Sodium (R,E)-((2-(1,2-dimethylpyrrolidine-2-yl)vinyl)sulfonyl)((1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)amide

[0165] [ka]

[0166] 1H NMR (400 MHz, DMSO-d6): δ = 7.36 (s, 1H), 6.77 (s, 1H), 6.57 (d, J = 15.6 Hz, 1H), 6.19 (d, J = 15.6 Hz, 1H), 2.76 (t, J = 7.2 Hz, 5H), 2.69 (t, J = 7.2 Hz, 4H), 2.64 - 2.59 (m, 1H), 2.08 (s, 3H), 1.91 (quintet, J = 7.6 Hz, 4H), 1.74 - 1.68 (m, 3H), 1.62 - 1.60 (m, 1H), 1.01 (s, 3H); MS (ESI): m / z (%) = 404.17 (100%) (M-Na) + .

[0167] (Example 16) (E)-N'-Cyano-2-((S)-1,2-dimethylpyrrolidine-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)ethene-1-sulfonimidoamide

[0168] [ka]

[0169] 1 H NMR (400 MHz, DMSO-d6): δ = 9.94 (s, 1H), 8.06 (s, 1H), 6.97 (d, J = 16.0 Hz, 1H), 6.83 (s, 1H), 6.56 - 6.48 (m, 1H), 3.58 (br s, 1H), 3.24 - 3.12 (m, 1H), 2.77 (t, J = 7.2 Hz, 4H), 2.69 (t, J = 7.2 Hz, 7H), 2.10 - 1.99 (m, 3H), 1.95 - 1.88 (m, 5H), 1.53 - 1.36 (m, 3H); ESI-Q-TOF-MS: m / z [M-HCl+H] + [C22H30N5O2S] +Calculated value: 428.2120; Measured value: 428.2052

[0170] (Example 17) (E)-N'-Cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-((R)-1-methylpyrrolidin-2-yl)ethene-1-sulfonimidamide

[0171]

Chemical Structure

[0172] 1 H NMR (400 MHz, DMSO-d6): δ = 9.82 (s, 1H), 8. ; MS (TOF): m / z (%) = 414.1897 (100%) (M+H) 1 H NMR (400 MHz, DMSO-d6): δ = 9.82 (s, 1H), 8.06 (s, 1H), 7.11 - 7.02 (m, 1H), 6.83 (s, 1H), 6.43 - 6.35 (m, 1H), 4.99 (br s, 1H), 3.62 - 3.61 (m, 1H), 3.09 - 3.07 (m, 1H), 2.77 (t, J = 7.2 Hz, 7H), 2.70 (t, J = 7.2 Hz, 4H), 2.33 - 2.27 (m, 1H), 2. 1 - 1.88 (m, 7H); MS (TOF): m / z (%) = 414.1897 (100%) (M+H) + , 412.1765 (100%) (M-1) - .

[0173] (Example 18) (E)-N'-Cyano-2-((R)-1,2-dimethylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonimidamide

[0174]

Chemical Structure

[0175] [[ID=H NMR (400 MHz, DMSO-d6): δ = 9.98 (s, 1H), 8.03 (s, 1H), 6.94 - 6.90 (m, 1H), 6.83 (s, 1H), 6.54 - 6.51 (m, 1H), 2.77 (t, J = 7.2 Hz, MS (TOF): m / z (%) = 428.2097 (100%) (M+H) + , 426.1941 (60%) (M-1) - .

[0176] (Example 19) N-((1,2,3,5,6,7-hexahydro-s-indasen-4-yl)carbamoyl)-1-((1S,8aR)-3,3,8a-trimethyloctahydropyrrolo[1,2-a]pyrazine-1-yl)methanesulfonamide

[0177] [ka]

[0178] 1 H NMR (400 MHz, DMSO-d6): δ = 7.92 (s, 1H), 6.87 (s, 1H), 3.42 - 3.26 (m, 5H), 3.07 - 3.01 (m, 1H), 2.89 - 2.80 (m, 1H), 2.89 - 2.80 (m, 1H), 2.77 (t, J=7.2Hz, 4H), 2.73 - 2.67 (m, 4H), 2.58 - 2.44 (m, 1H), 2.38 - 2.33 (m, 1H), 1.98 - 1.92 (m, 4H), 1.69 - 1.61 (m, 2H), 1.31 (s, 3H), 1.18 (s, 3H), 0.78 (s, 3H); MS (TOF): m / z (%) = 461.2537 (100%) (M+H)+ .

[0179] (Example 20) N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-((4S,8aS)-2,3,3,8a-tetramethyloctahydropyrrolo[1,2-a]pyrazin-4-yl)methanesulfonamide

[0180] [Chemical Structure]

[0181] 1 H NMR (400 MHz, DMSO-d6): δ = 8.03 (s, 1H), 6.93 (s, 1H), 3.52 - 3.48 (m, 2H), 3.18 - 3.09 (m, 1H), 3.09 - 3.01 (m, 1H), 3.00 - 2.88 (m, 1H), 2.81 (t, J = 7.2 Hz, 4H), 2.70 (t, J = 7.2 Hz, 4H), 2.36 - 2.33 (m, 2H), 2.19 (s, 3H), 2.01 - 1.93 (m, 4H), 1.76 - 1.69 (m, 1H), 1.67 - 1.54 (m, 3H), 1.01 - 1.04 (m, 6H), 0.86 (s, 3H); MS (TOF): m / z (%) = 475.2709 (100%) (M+H) + , 473.2593 (20%) (M-1).

[0182] (Example 21) (E)-3-(Dimethylamino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)prop-1-ene-1-sulfonamide

[0183] [Chemical Structure]

[0184] 1 1H NMR (400 MHz, DMSO-d6): δ = 10.22 (broad singlet, 1H), 7.94 (singlet, 1H), 6.91 (singlet, 1H), 6.86 (doublet, J = 15.2 Hz, 1H), 6.62 - 6.55 (multiplet, 1H), 3.27 (triplet, J = 6.0 Hz, 2H), 2.79 (triplet, J = 7.2 Hz, 4H), 2.67 (triplet, J = 7.2 Hz, 4H), 2.30 (singlet, 6H), 1.99 - 1.91 (multiplet, 4H); MS (ESI): m / z (%) = 364.1513 (100%) (M+H) + .

[0185] (Example 22) Sodium (E)-((3-(dimethylamino)-3-methylbut-1-en-1-yl)sulfonyl)((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)amide

[0186] [Chemical formula]

[0187] 1 1H NMR (do 400 MHz, DMSO-d6): δ = 7.36 (singlet, 1H), 6.77 (singlet, 1H), 6.51 (doublet, J = 15.6 Hz, 1H), 6.23 (doublet, J = 15.6 Hz, 1H), 2.76 (triplet, J = 7.2 Hz, 4H), 2.69 (triplet, J = 7.2 Hz, 4H), 2.11 (singlet, 1H), 1.94 - 1.87 (multiplet, 4H), 1.06 (singlet, 6H); MS (TOF): m / z (%) = 392.1987 (100%) (M+H) + , 390.1841 (20%) (M-1).

[0188] <00,00902>(Example 23) (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

[0189]

Chem.

[0190] 1 H NMR (400 MHz, DMSO-d6): δ = 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 (quintet, 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] - .

[0191] (Example 24) (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

[0192]

Chem.

[0193] 1H NMR (400 MHz, DMSO-d6): δ = 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 (quintet, 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%) [MH] - .

[0194] (Example 25) (R,E)-N-((1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-2-(1-(methyl-d)pyrrolidine-2-yl)ethen-1-sulfonamide

[0195] [ka]

[0196] 1 H NMR (400 MHz, DMSO-d6): δ = 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, J 2 =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 (quintet, 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%) [MH] - .

[0197] (Example 26) (E)-3-(bis(methyl-d)amino)-N-((1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-3-methylbuta-1-en-1-sulfonamide

[0198] [ka]

[0199] 1 H NMR (400 MHz, DMSO-d6): δ = 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%) [MH] - .

[0200] (Example 27) 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

[0201]

Chemical Structure

[0202] 1 H NMR (400 MHz, DMSO-d6): δ = 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).

[0203] (Example 28) 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

[0204]

Chemical Structure

[0205] 1H NMR (400 MHz, DMSO-d6): δ = 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) - .

[0206] (Example 29) (R,E)-2-(1,2-dimethylpyrrolidine-2-yl)-N-((1,2,3,5-tetrahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide

[0207] [ka]

[0208] 1 H NMR (400 MHz, DMSO-d6): δ = 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 MS (TOF): m / z (%) = 402.25 (100%) (M+H) + .

[0209] (Example 30) (E)-2-((R)-1,2-dimethylpyrrolidine-2-yl)-N-((2-hydroxy-1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)ethene-1-sulfonamide

[0210] [ka]

[0211] 1 H NMR (400 MHz, DMSO-d6): δ = 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, MS (TOF): m / z (%) = 420.19 (100%) (M+H) + .

[0212] (Example 31) (E)-2-((R)-1,2-dimethylpyrrolidine-2-yl)-N-((3-hydroxy-1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)ethene-1-sulfonamide

[0213] [ka]

[0214] 1H NMR (400 MHz, DMSO-d6): δ = 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).

[0215] (Example 32) (E)-2-((R)-1,2-dimethylpyrrolidine-2-yl)-N-((1-hydroxy-1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)ethene-1-sulfonamide

[0216] [ka]

[0217] 1H NMR (400 MHz, DMSO-d6): δ = 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).

[0218] While the present invention has been described in relation to specific embodiments thereof, certain modifications and equivalents will be obvious to those skilled in the art and are intended to be included within the scope of the present invention.

[0219] Biological activity: In vitro assay: THP1 monocytes were differentiated with PMA (100 ng / ml) and incubated at 37°C for 20 hours in the presence of 5% CO2. 2 × 10 5 Differentiated cells were cultured in each well of a 96-well tissue culture plate. Cells were primed with 500 ng / mL lipopolysaccharide and incubated under the same conditions for 4 hours. Cells were then treated with various concentrations of the compound for 30 minutes, followed by treatment with 5 mM ATP for 1 hour. The supernatant was collected and analyzed using an IL-1β (Mabtech Cat No. 3415-1H-20) or TNF-α (Mabtech Cat No. 3510-1H-20) detection kit. Data were analyzed using a GraphPad Prism V7.0. Percentage cell viability data were fitted to the GraphPad Prism using nonlinear regression analysis to obtain IC. 50To determine the values, dose-response curves (DRCs) were constructed. In vitro IL-1β inhibitory activity (IC) was measured for representative compounds. 50 These are listed in Table 1.

[0220] [Table 1]

[0221] In vivo efficacy studies: The effects of the compound of formula (11) were investigated in a mouse model of dextran sulfate sodium (DSS)-induced inflammation. Female C57BL / 6 mice were housed at the inventors' facility for one week, after which the DSS experiment was performed. Colitis was induced by administration of DSS (molecular weight [MW] = 36,000-50,000 Da; MP Biomedicals). Three groups of animals were treated twice daily for eight days with varying doses (1 mg / kg, 5 mg / kg, and 10 mg / kg, po) of the compound of formula (11). The control group received only the vehicle. Mice were treated for five days with 2% DSS dissolved in drinking water, after which normal access to water was maintained until the end of the study. Weight loss and mortality were monitored daily until the end of the study. A scoring system was applied to determine the presence of diarrhea and occult or overt blood in the stool on the final day of the study. Changes in body weight were expressed as a percentage decrease in baseline body weight. The Disease Activity Index (DAI) was determined based on a scoring system. The scoring criteria included: (a) weight, where 0 corresponds to no weight loss and 4 corresponds to >20% weight loss; (b) stool viscosity, where 0 is normal and 3 is diarrhea; and criteria for rectal bleeding, where 0 is normal and 4 is severe.

[0222] result Dextran sulfate sodium (DSS) (affected control) caused increased DAI score associated with colonic length contraction compared to the normal control group. Treatment with the compound of formula (11) was found to improve colonic length and reduce disease activity index (DAI) associated with it.

[0223] [Table 2]

[0224] Compounds of formula (I) or pharmaceutical compositions containing them are useful as pharmaceuticals for inhibiting NLRP3 activity and are suitable for humans and other warm-blooded animals, and can be administered orally, topically, or parenterally.

[0225] Evaluation of the effect of the compound of formula (11) in a rat 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced IBD model. TNBS-IBD is a chemically induced IBD model with an overall pathogenesis, including some immunological and histological changes in the GI tubules, similar to that of human disease. The inventors aimed to evaluate the effect of formula (11) in a TNBS-induced IBD model in rats. Male Sprague Dawley rats were randomized to various treatment groups and subjected to colitis induction by rectal administration of TNBS in 50% ethanol. Animals from different groups were treated with various doses of formula (11) (1, 5, 25, and 50 mg / kg, po) twice daily for 6 days. Control group animals received vehicle only. On day 7, body weight was recorded, animals were sacrificed, the colon was removed, washed, and its length and weight were recorded.

[0226] result Treatment using the compound of formula (11) showed dose-related improvement in weight loss induced by TNBS loading (Figure 1) and shortening of colon length (as shown in the table below).

[0227] [Table 3]

[0228] Research protocols and methodologies used in research Protocol Title: A randomized, double-blind, parallel Phase II-a proof-of-concept trial to evaluate the efficacy and safety of Compound 11 for the treatment of patients with mild to moderately active ulcerative colitis (UC) resistant to high-dose mesalamine treatment.

[0229] Purpose and endpoint: The purpose of this study is to evaluate the efficacy and safety of compound 11 oral capsules twice daily for 12 weeks for the treatment of mild to moderately active ulcerative colitis resistant to high-dose mesalamine.

[0230] [Table 4A]

[0231] [Table 4B]

[0232] Safety standards: Physical examination A complete physical examination includes assessment of at least the cardiovascular, respiratory, gastrointestinal, musculoskeletal, and nervous systems. Height and weight are also measured and recorded.

[0233] A basic physical examination includes evaluation of the head, neck, eyes, ears, nose, pharynx, chest, heart, lungs, abdomen, and skin.

[0234] Vital signs Vital signs should be measured in a resting state, including seated blood pressure (systolic and diastolic), pulse rate, respiratory rate, and body temperature.

[0235] electro-cardiogram A 12-lead ECG will be performed.

[0236] Clinical safety laboratory testing Clinical laboratory judgments include: Hematology: Hematocrit, hemoglobin, mean corpuscular hemoglobin, mean corpuscular volume, MCHC, platelet count, red blood cell count, white blood cell count, differential WBC count, red blood cell distribution width. Liver function tests: aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, gamma-glutamyltransferase, serum protein, albumin, and total bilirubin (using direct and indirect bilirubin). Renal function tests: serum urea nitrogen, serum creatinine / creatinine clearance, and uric acid. Urine microscopy: epithelial cells, red blood cells, suppurative cells, casts, and crystals; physical examination of urine including: appearance and color. Urine chemistry: pH, specific gravity, protein, glucose, bilirubin, albumin, urobilinogen, ketones, and nightlight.

[0237] Pregnancy testing: Serum pregnancy tests / urine pregnancy tests are performed on female participants who are capable of giving birth.

[0238] Adverse events The frequency and severity of adverse events (AEs) for all registered participants are recorded. All AEs are Causality severity Severity It is classified using

[0239] Note: All safety assessments are performed at specific points in time as described in the protocol.

[0240] Methodology: This is a Phase IIa, randomized, two-arm, double-blind, double-dummy, parallel, multicenter study to evaluate the efficacy and safety of Compound 11 oral capsules for the treatment of mild to moderately active ulcerative colitis resistant to high-dose mesalamine.

[0241] The study consists of: a screening period of up to 4 weeks, a treatment period of 12 weeks (the first 6 weeks: induction period and the remaining 6 weeks: maintenance period), and the end of the study at 13 weeks. Eligible participants will be randomly assigned to one of the following two study arms:

[0242] Eligible participants will be screened within four weeks prior to enrollment. Informed consent will be obtained from all eligible participants before any research-related activities in accordance with regulatory requirements. Eligibility will be verified during visits 1 and 2.

[0243] Eligible participants will be randomly assigned in a 1:1 ratio to one of the following on day 0: Arm 1: Oral compound 11 capsules 25 mg + 50 mg placebo twice daily for 6 weeks Arm 2: Oral compound 11 capsules 50 mg + 25 mg placebo twice daily for 6 weeks

[0244] This trial will be conducted over a period of 12 weeks. The treatment period will consist of two phases: a 6-week blinded induction phase, followed by a 6-week open-label maintenance phase.

[0245] Participants will receive treatment for six weeks as described above. At the end of the six weeks, participants will be assessed for achieving clinical remission.

[0246] Participants in either arm demonstrating clinical remission will continue receiving the same dose for an additional six weeks during the maintenance period.

[0247] Participants who do not achieve clinical remission (non-responders) within 6 weeks in the 25 mg compound 11 arm will be moved to a follow-up period to receive 6 weeks of capsule compound 11 50 mg.

[0248] Participants in the compound 11 50 mg arm who do not achieve clinical remission will be offered rescue / standard treatment (steroids or biological agents) and will be withdrawn from the study.

[0249] The effectiveness is determined using a tool called the Modified Mayo Score (mMS). The mMS is a composite instrument consisting of three subscores determined by a central reviewer: 1. bowel movement frequency, 2. rectal bleeding, and 3. endoscopic findings. Detailed evaluation procedures are described in Section 8.

[0250] Dosage adjustments will be made during the treatment period.

[0251] All participants will be evaluated for adverse events at every visit during the treatment period. In the event of any adverse event (AE) requiring further investigation, the investigator will be advised to determine the AE and take necessary measures. Participants will be advised to contact the investigator about any discomfort.

[0252] Number of subjects per treatment arm: A total of 24 participants (12 participants per arm) were scheduled to be enrolled in the study. Duration of treatment: 12 weeks (Induction period: 6 weeks and maintenance period: 6 weeks) Study duration: 119 days, including a 28-day screening period.

Claims

1. Equation (I) 【Chemistry 1】 A method for treating inflammatory bowel disease comprising the step of administering a compound or a pharmaceutically acceptable salt thereof. [In the formula, X is O, NH, or N-R 2 , 3 , 10 , 1 , 1 , 10 , 6 , 1 , 6 , 10 , 2 , 10 , 2 where R 3 is, in each occurrence, hydrogen, hydroxyl, halogen, nitro, cyano, haloalkyl, a group optionally substituted with any of the following: (C 1 to C 10 )alkyl, (C 1 to C 10 )alkoxy, (C 3 to C 10 )cycloalkyl, (C[[ID=X]] 2 to C 10 )alkenyl, (C 2 to C 10 )alkynyl, SO 2 (C 1 to C 6 )alkyl, thiol, thioalkyl, thio-alkoxy, SO(C 1 to C 6 )alkyl, benzyl, aryl, heteroaryl, heterocyclyl, independently selected; It should be noted that there seems to be a typo in the original text where the 'X' in the formula should probably be a number or a specific symbol. I've translated it as it is while keeping the tags intact. If this is a critical error, it might affect the overall understanding of the patent text. Y is O, S; R 1 In each occurrence, the group is substituted by hydrogen, halogen, haloalkyl, cyano, or any other group selected from the following: (C 1 ~C 6 ) alkyl, (C 1 ~C 6 ) Haloalkyl, (C 2 ~C 6 ) Alkenil, (C 2 ~C 6 ) Alkinyl, (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 ) Alkyl N(C 1 ~C 6 ) alkyl, (C 1 ~C 6 ) Alkyl N(C 3 ~C 7 )Cycloalkyl, aryl, heteroaryl, heterocyclyl, benzyl, tert-butyloxycarbonyl, NH(C 1 ~C 6 )alkyl, N((C 1 ~C 6 )alkyl) 2 , NH(C 2 ~C 6 ) Alkenil, N((C 2 ~C 6 )Alkenil) 2 , -N-heterocyclyl, N(C 1 ~C 6 ) Alkyl-heterocyclyl, NR'R", thiol, mercaptoalkyl, SO 2 (C 1 ~C 6 ) alkyl, SO 2 (C 3 ~C 7 ) Cycloalkyl, SO 2 -Ayl, SO 2 -heterocyclyl, (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 ) Independently selected from haloalkyls, -CO-aryls, -CO-heteroaryls, -CO-heterocyclines, 4- to 7-membered heterocyclic rings, 7- to 14-membered bicyclic heterocyclic ring systems, and bridges or spirocyclic systems having one or more heteroatoms by optional choice; As an alternative, R 1 teeth, 【Chemistry 2】 Selected from, n is independently chosen from integers 0 to 3; R', R", R 1 ' 、 R 1 ", R 2 ' and R 2 " each, in each occurrence, is hydrogen, halogen, haloalkyl, cyano, a group optionally substituted by any one selected from the following: (C 1 ~C 6 )alkyl, (C 1 ~C 6 )haloalkyl, (C 2 ~C 6 )alkenyl, (C 2 ​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​) alkyl, -CO(C 1 ~C 6 ) independently selected from haloalkyls, -CO-aryls, -CO-heteroaryls, -CO-heterocyclines, 4- to 7-membered heterocyclic rings, 7- to 14-membered bicyclic heterocyclic ring systems, and bridges or spirocyclic systems having one or more heteroatoms by optional choice; in some embodiments, R' and R'' optionally form 4- to 7-membered heterocyclic ring systems; R 2 It is selected from the following ring systems. 【Transformation 3】 (In the formula, X, Y, and Z are independently C, N, S, and SO in each occurrence.) 2 , and O represent and may be substituted by choice; R 7 , R 8 , R 9 , R 10 、 R 11 and R 12 Each of these is a group that, in each occurrence, is substituted by any choice selected from hydrogen, halogen, cyano, amide, sulfonamide, acyl, hydroxyl, and the following: (C 1 ~C 6 ) alkyl, (C 1 ~C 6 ) Haloalkyl, (C 3 ~C 6 )Cycloalkyl, (C 1 ~C 6 ) independently selected from alkoxy, benzyl, aryl, heteroaryl, and heterocyclyl; in one embodiment, R 8 and R 9 、 R 9 and R 10 , R 10 and R 11 R 11 and R 12 Each of them, whenever possible, together, N, O, and S(O) p It can form a 4- to 7-membered saturated or partially saturated ring containing 0 to 2 additional heteroatoms selected from the group consisting of; p = 1 to 2; R x and R y In each occurrence, the group is substituted by hydrogen, halogen, or any choice selected from the following: (C 1 ~C 6 ) independently selected from alkyl; alternatively, R x and R y Together, they can form a heterocyclic ring system with 4 to 7 members; "M" is selected from aryl, heteroaryl, and heterocyclyl groups; where, if any of the groups defined above are substituted, the substitutions are selected from those listed above, or are groups substituted by any choice selected from hydrogen, hydroxy, cyano, halo, haloalkyl, haloalkyloxy, alkylthio, and the following: (C 1 ~C 6 ) alkyl, (C 2 ~C 6 ) Alkenil, (C 2 ~C 6 ) Alkinyl, (C 3 ~C 10 ) Cycloalkyl, C 1 ~C 6 Alkoxy, aryl, heterocyclyl, 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 You can choose from the base, where R 11 and R 12 Each of these is a hydrogen atom, or a group substituted by any choice selected from the following: (C 1 ~C 6 ) alkyl, (C 2 ~C 6 ) Alkenil, (C 2 ~C 6 ) Alkinyl, (C 3 ~C 7 (Independently selected from cycloalkyl, aryl, heteroaryl, and heterocyclyl groups).

2. The method according to claim 1, wherein the inflammatory bowel disease is selected from Crohn's disease and ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal disease, eosinophilic gastrointestinal disease, and other related forms of disorder.

3. The method according to claims 1 and 2, wherein the inflammatory bowel disease is ulcerative colitis.

4. The compounds of formula (I) belong to the following group: N'-Cyano-N-((1,2,3,5,6,7-Hexahydro-s-Indacen-4-yl)Carbamoyl)-5-(2-Hydroxypropane-2-N'-Cyano-4-Fluoro-N-((1,2,3,5,6,7-Hexahydro-s-Indacen-4-yl)Carbamoyl)-3-(2-Hydroxypropane-2-yl)Benzenesulfonimidoamide; N'-Cyano-N-((1,2,3,5,6,7-Hexahydro-s-Indacen-4-yl)Carbamoyl)-4-(2-Hydroxypropan-2-yl)Fran-2-Sulfonimidoamide; (E)-N-((1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-2-(thiazole-2-yl)ethensulfonamide; (E)-2-(1-ethyl-1H-imidazole-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)ethensulfonamide; (E)-2-(1-ethyl-4-methyl-1H-imidazole-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)ethensulfonamide; (R,E)-2-(1-ethylpyrrolidine-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-ethanesulfonamide; (R,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(pyrrolidine-2-yl)ethen-1-sulfonamide; (R,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-methylpyrrolidine-2-yl)ethen-1-sulfonamide; (S,E)-2-(1-ethylpyrrolidine-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-ethanesulfonamide; (R,E)-2-(1,2-dimethylpyrrolidine-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethen-1-sulfonamide; (S,E)-2-(1,2-dimethylpyrrolidine-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide; Sodium (S,E)-((2-(1,2-dimethylpyrrolidine-2-yl)vinyl)sulfonyl)((1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)amide; Potassium (R,E)-((2-(1,2-dimethylpyrrolidine-2-yl)vinyl)sulfonyl)((1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)amide; Sodium (R,E)-((2-(1,2-dimethylpyrrolidine-2-yl)vinyl)sulfonyl)((1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)amide; (E)-N'-Cyano-2-((S)-1,2-dimethylpyrrolidine-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonimidoamide; (E)-N'-Cyano-N-((1,2,3,5,6,7-Hexahydro-s-Indacen-4-yl)Carbamoyl)-2-((R)-1-Methylpyrrolidine-2-yl)Ethene-1-Sulfonimidoamide; (E)-N'-Cyano-2-((R)-1,2-dimethylpyrrolidine-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonimidoamide; N-((1,2,3,5,6,7-hexahydro-s-indasen-4-yl)carbamoyl)-1-((1S,8aR)-3,3,8a-trimethyloctahydropyrrolo[1,2-a]pyrazine-1-yl)methanesulfonamide N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-((4S,8aS)-2,3,3,8a-tetramethyloctahydropyrrolo[1,2-a]pyrazine-4-yl)methanesulfonamide; (E)-3-(dimethylamino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)propa-1-en-1-sulfonamide; Sodium (E)-((3-(dimethylamino)-3-methylbuta-1-en-1-yl)sulfonyl)((1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)amide; (S,E)-N-((1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-2-(2-methyl-1-(methyl-d)pyrrolidine-2-yl)ethen-1-sulfonamide; (R,E)-N-((1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-2-(2-methyl-1-(methyl-d)pyrrolidine-2-yl)ethen-1-sulfonamide; (R,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(methyl-d)pyrrolidine-2-yl)ethen-1-sulfonamide; The method according to claim 1, or selected from any pharmaceutically acceptable salt of any of the above compounds.

5. The method according to claim 1, wherein the therapeutically effective dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from 1 mg to 500 mg, preferably from 1 mg to 250 mg, and more preferably from 1 mg to 150 mg.

6. The method according to claim 1, wherein a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered by an oral, topical, or parenteral route, preferably by an oral route.

7. The method according to claim 1, wherein a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with another suitable therapeutic agent.

8. The method according to claim 1, wherein a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in the form of a pharmaceutical composition.

9. Use of the compound of formula (I) as defined in claims 1 and 4 for the preparation of a medicament for the treatment of inflammatory bowel disease.

10. The use of the compound of formula (I) as defined in claims 1 and 4, wherein the compound is administered in a daily dose range selected from 1 mg to 500 mg, preferably selected from 1 mg to 250 mg, and more preferably selected from 1 mg to 150 mg.

11. The compound of formula (I) 【Chemistry 4】 A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, for the treatment of inflammatory bowel disease.

12. The pharmaceutical composition according to claim 11, wherein the inflammatory bowel disease is selected from Crohn's disease and ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal disease, eosinophilic gastrointestinal disease, and other related forms of disorder.

13. The pharmaceutical composition according to claims 11 and 12, wherein the inflammatory bowel disease is ulcerative colitis.

14. The pharmaceutical composition according to claim 11, wherein the therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from 1 mg to 500 mg, preferably from 1 mg to 250 mg, and more preferably from 1 mg to 150 mg.

15. The pharmaceutical composition according to claim 11, comprising a compound of formula (I) and other pharmaceutically acceptable excipients for the treatment of inflammatory bowel disease.

16. The pharmaceutical composition according to claim 11, wherein a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with another suitable therapeutic agent.

17. Use of the pharmaceutical composition according to claim 11 for the preparation of a pharmaceutical for the treatment of inflammatory bowel disease.

18. A method for treating inflammatory bowel disease, Formula (11) 【Transformation 5】 A method comprising the step of administering a compound or a pharmaceutically acceptable salt thereof.

19. The method according to claim 18, wherein the inflammatory bowel disease is selected from Crohn's disease and ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal disease, eosinophilic gastrointestinal disease, and other related forms of disorder.

20. The method according to claims 18 and 19, wherein the inflammatory bowel disease is ulcerative colitis.

21. The method according to claim 18, wherein the therapeutically effective dose of the compound of formula (11) or a pharmaceutically acceptable salt thereof is selected from 1 mg to 500 mg, preferably from 1 mg to 250 mg, and more preferably from 1 mg to 150 mg.

22. The method according to claim 18, wherein a compound of formula (11) or a pharmaceutically acceptable salt thereof is administered by an oral, topical, or parenteral route, preferably by an oral route.

23. The method according to claim 18, wherein a compound of formula (11) or a pharmaceutically acceptable salt thereof is administered in combination with another suitable therapeutic agent.

24. The method according to claim 13, wherein a compound of formula (11) or a pharmaceutically acceptable salt thereof is administered in the form of a pharmaceutical composition.

25. Use of a compound of formula (11) as defined in any one of claims 1 to 24 for the preparation of a medicament for the treatment of inflammatory bowel disease.

26. Use of a compound of formula (11) as defined in any one of claims 1 to 25, wherein the compound is administered in a daily dose range selected from 1 mg to 500 mg, preferably selected from 1 mg to 250 mg, and more preferably selected from 1 mg to 150 mg.

27. A pharmaceutical composition for the treatment of inflammatory bowel disease comprising a compound of formula (11) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (11) is 【Transformation 6】 A pharmaceutical composition.

28. The pharmaceutical composition according to claim 27, wherein the inflammatory bowel disease is selected from Crohn's disease and ulcerative colitis, lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune enteropathy, allergic gastrointestinal disease, eosinophilic gastrointestinal disease, and other related forms of disorder.

29. The pharmaceutical compositions according to claims 27 and 28, wherein the inflammatory bowel disease is ulcerative colitis.

30. The pharmaceutical composition according to claim 27, wherein the therapeutically effective dose of the compound of formula (11) or a pharmaceutically acceptable salt thereof is selected from 1 mg to 500 mg, preferably from 1 mg to 250 mg, and more preferably from 1 mg to 150 mg.

31. A pharmaceutical composition according to claim 27, comprising a compound of formula (11) and other pharmaceutically acceptable excipients, for the treatment of inflammatory bowel disease.

32. The pharmaceutical composition according to claim 27, wherein a compound of formula (11) or a pharmaceutically acceptable salt thereof is administered in combination with another suitable therapeutic agent.

33. Use of the pharmaceutical composition according to claim 27 for the preparation of a pharmaceutical for the treatment of inflammatory bowel disease.

34. The pharmaceutical composition according to claim 31, wherein other pharmaceutically acceptable excipients are selected from diluents, carriers, binders, disintegrants, lubricants and surfactants.

35. A pharmaceutical composition according to any one of claims 1 to 34, wherein the diluent is selected from lactose monohydrate, polymethacrylate selected from Eudragit, potassium chloride, sulfobutyl ether β-cyclodextrin, sodium chloride, spray-dried lactose, and suitable combinations thereof.

36. A pharmaceutical composition according to any one of claims 1 to 35, wherein the carrier is selected from lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate and kaolin, crystalline cellulose, silicic acid and suitable combinations thereof.

37. A pharmaceutical composition according to any one of claims 1 to 36, wherein the binder is a carbomer selected from Carbopol, gellan, gum arabic, hydrogenated vegetable oil, polymethacrylate selected from Eudragit, xanthan, lactose, and zein, and suitable combinations thereof.

38. A pharmaceutical composition according to any one of claims 1 to 37, wherein the disintegrant is selected from bicarbonate, chitin, gellan gum, potassium polacrylin, sodium doxate, and suitable combinations thereof.

39. A pharmaceutical composition according to any one of claims 1 to 38, wherein the lubricant is selected from glycerin behenate, hydrogenated vegetable oil, sodium stearyl fumarate, myristic acid, and suitable combinations thereof.

40. A pharmaceutical composition according to any one of claims 1 to 39, wherein the surfactant is a nonionic surfactant selected from alkyl polyglucoside, cocamide DEA, cocamide MBA, cocamide TEA, decyl maltoside and octyl glucoside; an anionic surfactant selected from arachidic acid and arachidonic acid; a cationic surfactant selected from cetyltrimethylammonium bromide and cetylpyridinium chloride, and a suitable combination thereof.

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