Treatment for cryopyrin-associated periodic syndromes (CAPS)

Abstract

The present invention relates to the development of a compound of formula (I) for the treatment of cryopyrin-associated periodic syndrome (CAPS). In particular, the present invention provides an NLRP3 inhibitor or a pharma- ceutically acceptable salt thereof for the treatment of cryopyrin-associated periodic syndrome (CAPS). The invention also relates to a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof for the treatment of cryopyrin-associated periodic syndrome (CAPS).

Description

[Technical field]

[0001] The present invention relates to the development of a compound of formula (I) for the treatment of cryopyrin-associated periodic syndrome (CAPS). In particular, the present invention provides an NLRP3 inhibitor or a pharma- ceutically acceptable salt thereof for the treatment of cryopyrin-associated periodic syndrome (CAPS). The invention further relates to a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof for the treatment of cryopyrin-associated periodic syndrome (CAPS). [Background technology]

[0002] The nucleotide-binding oligomerization domain (NOD)-like receptor family, pyrin domain-containing 3 (NLRP3 or NALP3) inflammasome is the major source of mucosal interleukin (IL)-1β, and inflammasomes are 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 is composed of three domains: a leucine-rich repeat domain (LRR), a NOD (NACHT) containing caspase activation and recruitment domain (CARD), and a pyrin domain (PYD). Upon activation, NLRP3 oligomerizes and triggers the assembly of the CARD-containing adaptor apoptosis-associated speck-like protein (ASC) through PYD-PYD interactions. ASC fibrils assemble into large structures called ASC specks, which recruit pro-caspase-1, leading to its autoproteolytic activity. Activated caspase-1 can generate the proinflammatory cytokines IL-1β and IL-18 by cleaving proIL-1β and proIL-18 ( Guo et al., 2015 ; Dinarello et al., 2012 ).

[0003] The involvement of NLRP3 inflammasome in different kinds of diseases provides a new avenue for designing drugs that target NLRP3 inflammasome. To date, clinical treatment of NLRP3-related diseases targets IL-1β with IL-1β antibodies or recombinant IL-1β receptor antagonists, such as canakinumab and anakinra, respectively. In addition, a few small molecule compounds have shown anti-inflammatory effects on NLRP3 inflammasome activation in vitro, including MCC950, β-hydroxybutyrate (BHB), Bay 11-7082, dimethyl sulfoxide (DMSO), and type I interferon. However, most of these inhibitors are relatively nonspecific and have low efficacy. For inhibitors that target IL-1β, it should be noted that IL-1β secretion is not only a product of NLRP3 inflammasome activation; instead, other pro-inflammatory cytokines, including high mobility group box 1 (HMGB1) and IL-18, may be involved in the pathogenesis of these diseases. Furthermore, IL-1β can be produced by inflammasome-independent pathways or other inflammasomes. Therefore, inhibitors targeting IL-1β may lead to unintended immunosuppressive effects other than preventing NLRP3 inflammasome activation itself. Pharmacological inhibitors specific for NLRP3 inflammasome may be the best choice for the treatment of NLRP3-related diseases. (Yang et al., 2019).

[0004] Cryopyrin-associated periodic syndromes (CAPs) are a rare family of heterogeneous autoinflammatory diseases characterized by IL-1β-mediated systemic inflammation and clinical symptoms involving the skin, joints, central nervous system, and eyes. CAPS are associated with activating mutations in NLRP3, of which approximately 200 mutations have been defined. While some mutations are classified as benign and do not display adverse clinical phenotypes, approximately 100 of the reported mutations result in chronic proinflammatory symptoms. CAPS are categorized into three clinical subgroups in order of increasing severity: familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease (NOMID), (also called chronic infantile neurological cutaneous articular syndrome or CINCA) (Booshehri et al., 2019). Mice with mutant forms of NLRP3 that emerge in CAPS die during the neonatal period and have increased concentrations of circulating IL-1β and IL-18 (Coll et al., 2015). It has previously been demonstrated that MCC950 inhibited NLRP3 activation in a mouse model of MWS. Peripheral blood mononuclear cells (PBMCs) from patients with low-penetrance NLRP3 variants (Q703K and V198M) were shown to exhibit enhanced IL-1β levels following inflammasome activation compared to healthy controls. Furthermore, IL-1β release was shown to be NLRP3-dependent, as it was blocked by MCC950 (Schuh et al., 2019). The IL-1 receptor antagonist anakinra is traditionally used to control symptoms of the syndrome, but patients relapse when treatment is discontinued.

[0005] There are various drugs in various stages of phase 1 and phase II development targeting the NLRP3 inflammasome (Freeman et al., 2020). Drugs such as MCC950, CY-09, OLT1177, tranilast, oridonin, and NT-0167 exhibited good therapeutic properties because they directly targeted NLRP3 itself but did not target other components upstream / downstream of NLRP3 inflammasome activation (NEK7, ASC, caspase-1, or IL-1β). Moreover, these inhibitors have been used in clinical practice and investigated in phase II clinical trials, showing a relatively high safety profile (Yang et al., 2019).

[0006] NLRP3 in innate immune cells is activated by pathogen-associated molecular patterns and death-associated molecular patterns. The resulting NLRP3 inflammasome activates caspase-1, which then cleaves and releases IL-1b and IL-18. NLRP3 inflammasome inhibitors have the potential to abolish IL-1-mediated disease pathologies, including CAPS. Summary of the Invention [Problem to be solved by the invention]

[0007] All current treatments are limited to injectable biologics that often have limited central nervous system (CNS) penetration, which is particularly important in NOMID patients with severe CNS disease. Therefore, there remains an unmet clinical need for more targeted, and preferably small molecule, compounds as alternatives to IL-1-targeted biologics. [Means for solving the problem]

[0008] The present invention provides a therapeutic compound of formula (I) or a pharma- ceutically acceptable salt thereof for the prevention and treatment of cryopyrin-associated periodic syndromes (CAPS) and related disorders. The present invention further relates to a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable excipient, useful for the treatment of cryopyrin-associated periodic syndromes (CAPS).

[0009] EMBODIMENTS OF THE PRESENT DISCLOSURE In certain embodiments, the present invention provides therapeutic compounds of formula (I) or pharma- ceutically acceptable salts thereof suitable for the treatment and prevention of cryopyrin-associated periodic syndromes (CAPS).

[0010] [ka]

[0011] In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable excipient for the treatment and prevention of cryopyrin-associated periodic syndromes (CAPS).

[0012] In yet another embodiment, the present invention provides for the administration of therapeutic compounds of formula (I) and their pharma- ceutically acceptable salts, alone or in combination with other agents suitable for the treatment and prevention of cryopyrin-associated periodic syndromes (CAPS).

[0013] In a further embodiment, the present invention provides the use of a compound of formula (I) or a pharma- ceutically acceptable salt thereof for the treatment of cryopyrin-associated periodic syndromes (CAPS).

[0014] In another embodiment, the present invention provides a method of treating cryopyrin-associated periodic syndromes (CAPS) using a pharmaceutical composition of a compound of formula (I) or a pharma- ceutically acceptable salt thereof.

[0015] These and other embodiments of the present invention are further disclosed hereinafter. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0016] Definition: The term "treatment" or "treating" refers to slowing, halting, or retarding the progression of a disease or clinical symptoms in a patient, as evidenced by the reduction or elimination of clinical or diagnostic symptoms of the disease, disorder, or condition.

[0017] The term "subject" refers to a mammal.

[0018] The term "effective amount" in the context of administration is that amount of a drug substance sufficient to have a desired effect.

[0019] "Patient" includes both humans and animals. "Mammal" means humans and other mammals.

[0020] The term "preventing" refers to barring a subject from acquiring a disorder or disease in the first place.

[0021] A "subject" is a mammal, preferably a human, but may also be an animal 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.).

[0022] As used herein, "treating" includes partially or substantially achieving one or more of the following results: partially or wholly reducing the severity of a disease, disorder or syndrome. Slowing, inhibiting or preventing the progression of a disease, disorder or syndrome includes, for example, slowing, inhibiting or preventing the progression of cryopyrin-associated periodic syndromes (CAPS).

[0023] The present invention describes a method of treating a subject suffering from cryopyrin-associated periodic syndromes (CAPS).

[0024] In one embodiment, the present invention provides compounds of formula (I) or pharma- ceutically acceptable salts thereof suitable for the treatment of cryopyrin-associated periodic syndromes (CAPS).

[0025] In a further embodiment, the present invention provides the use of compounds of formula (I) or suitable pharmaceutical compositions thereof for the treatment of cryopyrin-associated periodic syndromes (CAPS).

[0026] The method comprises the steps of:

[0027] [ka]

[0028] or a tautomeric form thereof, a stereoisomer thereof; an enantiomer thereof; a metabolite thereof; a deuterium analog thereof; a pharma- ceutically acceptable salt thereof; or a pharmaceutical composition comprising the same or a mixture thereof, During the ceremony, X is O, NH, or NR 3 where R 3 is independently selected at each occurrence from hydrogen, hydroxyl, halogen, nitro, cyano, haloalkyl, a group optionally substituted with: (C 10 ) Alkyl, (C1-C 10 )Alkoxy, (C3-C 10 )Cycloalkyl, (C2-C 10 ) alkenyl, (C2-C 10 )alkynyl, SO2(C1-C6)alkyl, thiol, thioalkyl, thio-alkoxy, SO(C1-C6)alkyl, benzyl, aryl, heteroaryl, heterocyclyl; Y is O, S; R 1is independently, at each occurrence, hydrogen, halogen, haloalkyl, cyano, a group optionally substituted with a group 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)alkyl), C6)alkenyl), -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)alkylSONH2, -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, bridged or spiro ring systems optionally having one or more heteroatoms.

[0029] In some embodiments, R 1 means:

[0030] [ka]

[0031] n, is independently selected from an integer 0 to 3; Each of R', R", R1', R1", R2' and R2" independently represents, at each occurrence, hydrogen, halogen, haloalkyl, cyano, a group optionally substituted 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, thiol, mercaptoa, alkyl, SO2(C1-C6)alkyl, SO2(C3-C7)cycloalkyl, SO2-aryl, SO2-heterocyclyl, (C1-C6)thioalkyl, (C1-C6)thioalkoxy, (C1-C6)alkylSON2NH2, -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; in certain embodiments R' and R" optionally form a 4- to 7-membered heterocyclic ring system. R 2 is selected from the following ring systems:

[0032] [ka]

[0033] wherein X, Y, and Z, at each occurrence, independently represent C, N, S, SO2, and O, which may be optionally substituted; R 7 , R 8 , R 9 , R 10 、 R 11 and R 12is independently selected at each occurrence from hydrogen, halogen, cyano, amido, sulfonamido, acyl, hydroxyl, an optionally substituted group 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 , and R 11 and R 12 Each of the following, taken together whenever possible, is N, O, and S(O) p and wherein p=1-2). R x and R y is independently selected at each occurrence from hydrogen, halogen, an optionally substituted group selected from: (C1-C6) alkyl; alternatively, R x and R y can together form a 4- to 7-membered heterocyclic ring system; "M" is selected from aryl, heteroaryl, heterocyclyl; If any of the groups defined above are substituted, the substitutions therein may be selected from those described above or may be selected from hydrogen, hydroxy, cyano, halo, haloalkyl, haloalkyloxy, alkylthio, optionally substituted groups selected from: (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C6) alkoxy ... 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 11R 12、 -SO2R 11 can be selected from the group, where R 11 and R 12 each is independently selected from hydrogen, an optionally substituted group selected from: (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C7) cycloalkyl, aryl, heteroaryl, heterocyclyl; In preferred embodiments, the groups, radicals described above can be selected from the following: "Alkyl", as well as other groups having the prefix "alk", such as alkoxy and alkanoyl, refer to carbon chains which may be further substituted with oxygen atoms, as is well understood by those of ordinary skill in the art, and further, unless the carbon chain is defined otherwise, may be either linear or branched and combinations thereof. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, hexyl, and the like. The number of carbon atoms specified may vary, e.g., C 3~10 Where permitted, the term alkyl also includes cycloalkyl groups, and combinations of straight or branched alkyl chains combined with cycloalkyl structures. 1~6 Substituted alkyl includes alkyl substituted with one or more moieties 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; carboxamido; alkylamino; arylamino; alkoxy; aryloxy; nitro; azido; cyano; thio; sulfonic acid; sulfate; phosphonic acid; phosphate; and phosphonate, as well as those listed under the definition of "optionally substituted."

[0034] "Alkenyl" means a carbon chain containing at least one carbon-carbon double bond, and unless the carbon chain is otherwise defined, may be linear or branched or a combination thereof. Examples of alkenyl include, but are not limited to, vinyl, allyl, isopropenyl, hexenyl, pentenyl, heptenyl, l-propenyl, : 2-butenyl, 2-methyl-2-butenyl, etc. The number of carbon atoms specified may be, for example, C 5~10 Where permitted, the term alkenyl also includes cycloalkenyl groups, and combinations of linear, branched and cyclic structures. If the number of carbon atoms is not specified, C 2~6 is intended.

[0035] "Alkynyl" means carbon chains which contain at least one carbon-carbon triple bond, and which may be linear or branched or combinations thereof. Examples of alkynyl include ethynyl, propargyl, 3-methyl-l-pentynyl, and the like. When no number of carbon atoms is specified, is intended.

[0036] A "thioalkyl" group, used either alone or in combination with other groups, refers to an alkyl group, as defined above, attached to a group of the formula -SR' (sulfur and its oxidized forms), where R' represents hydrogen, an alkyl group, or an aryl group, such as thiomethyl, methylthiomethyl, phenylthiomethyl, and the like, which may be optionally substituted.

[0037] As used herein, "carbocycle" 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 carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin). In a broader sense, the term carbocycle is intended to include, wherever applicable, cycloalkyl, phenyl, and other groups representing saturated, partially saturated or aromatic residues;

[0038] The terms "cycloalkyl" and "cycloalkenyl" refer to optionally substituted saturated and unsaturated monocyclic, bicyclic, or tricyclic carbon groups. Where appropriate, the cycloalkyl or cycloalkenyl group can have the number of carbon atoms specified, for example, C3-C6 cycloalkyl or cycloalkenyl includes within its scope 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 cycloalkenyl includes substitution with one or more moieties selected from the group consisting of halo (e.g., CI, F, Br, and I); alkyl halides (e.g., CF, 2-Br-ethyl, CHF, CHCI, CHCF, or CFCF); hydroxyl; amino; carboxylate; carboxamido; alkylamino; arylamino; alkoxy; aryloxy; nitro; azido; cyano; thio; sulfonic acid; sulfate; phosphonic acid; phosphate; and phosphonate, as well as those listed under the definition of "optionally substituted."

[0039] The term "alkoxy" refers to straight or branched chain alkoxides of the specified number of carbon atoms.

[0040] "Aryl" means a monocyclic or polycyclic aromatic ring system containing carbon ring atoms. Preferred aryls are monocyclic or bicyclic 6-10 membered aromatic ring systems. Phenyl and naphthyl are preferred aryls.

[0041] "Heterocyclyl" refers to a saturated, partially saturated or unsaturated aromatic or non-aromatic monocyclic, bicyclic or tricyclic group containing one or more heteroatoms selected from nitrogen, sulfur and oxygen, and optionally including oxidized forms of sulfur, i.e., SO and SO2. A heterocyclyl system may be attached to another moiety through any number of the carbon atoms or heteroatoms of the group, and may be both saturated and unsaturated. Examples of heterocycles include tetrahydrofuran (THF), dihydrofuran, 1,4-dioxane, morpholine, 1,4-dithiane, piperazine, piperidine, 1,3-dioxolane, imidazoline, imidazolidine, pyrrolidine, pyrroline, tetrahydropyran, 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, attached to an alkyl group, as defined above;

[0042] "Heteroaryl" refers to an aromatic or partially aromatic heterocycle containing at least one ring heteroatom selected from O, S, and N. Heteroaryl thus includes heteroaryls fused to other types of rings, such as aryls, cycloalkyls, 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, isoindoline, cycloalkyl ... allyl, dihydrobenzothienyl, indolinyl, pyridazinyl, indazolyl, isoindolyl, dihydrobenzothienyl, indolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, napthyridinyl, carbazolyl, benzodioxolyl, quinoxalinyl, purinyl, furazanyl, isobenzylfuranyl, benzimidazolyl, benzofuranyl, benzothienyl, quinolyl, indolyl, isoquinolyl, dibenzofuranyl, etc. For heterocyclyl and heteroaryl groups, rings and ring systems containing 3 to 15 carbon atoms are included, forming 1 to 3 rings.

[0043] The term "haloalkyl" refers to an alkyl structure in which at least one hydrogen has been replaced with a halogen atom. In certain embodiments in which two or more hydrogen atoms have been replaced with halogen atoms, the halogen atoms are all the same as one another.

[0044] "Haloalkoxy" groups are selected from the appropriate haloalkyl as defined above directly attached to an oxygen atom, more preferably groups selected from fluoromethoxy, chloromethoxy, fluoroethoxy, chloroethoxy, and the like;

[0045] In certain other embodiments in which two or more hydrogen atoms are replaced with halogen atoms, the halogen atoms are not all the same as one another.

[0046] "Aryloxyalkyl" means an alkyl group substituted with an aryloxy group, as defined herein.

[0047] "Aryloxyaryl" means an aryl group substituted with an aryloxy group, as defined herein.

[0048] "Aryloxyheteroaryl" means a heteroaryl group substituted with an aryloxy group, as defined herein.

[0049] "Halo / halogen" refers to fluorine, chlorine, bromine and iodine, with chlorine and fluorine being generally preferred.

[0050] Suitable groups and substituents thereon can be selected from those described elsewhere herein.

[0051] The term "substituted," as used herein, means that any one or more hydrogens on the designated atom are replaced with one selected from the indicated group, provided that the normal valences of the designated atom are not exceeded, and the substitution results in a stable compound. The term "substituted," as used herein, means that any one or more hydrogens on the designated atom are replaced with one selected from the indicated group, provided that the normal valences of the designated atom are not exceeded, and the substitution results in a stable compound.

[0052] "Pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds, where the parent compound has been modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of 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, hexylresorcylic acid, hydrabamic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxymaleic acid, benzo ... and those derived from inorganic and organic acids selected from: acetic acid, hydroxynaphthoic acid, isethionic acid, lactic acid, lactobionic acid, laurylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, napsylic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, basic acetic acid, succinic acid, sulfamic acid, sulfanilic acid, sulfuric acid, tannic acid, tartaric acid, and toluenesulfonic acid.

[0053] The term "optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes instances in which the event or circumstance occurs as well as instances in which it does not occur. For example, "optionally substituted alkyl" means either "alkyl" or "substituted alkyl." Further optionally substituted groups include groups that are not substituted.

[0054] Unless otherwise stated herein, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.

[0055] 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)thiophene-2-sulfonimidamide; N'-cyano-4-fluoro-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-(2-hydroxypropan-2-yl)benzenesulfonimidamide; N'-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide; (E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(thiazol-2-yl)ethenesulfonamide; (E)-2-(1-ethyl-1H-imidazol-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethenesulfonamide; (E)-2-(1-ethyl-4-methyl-1H-imidazol-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethenesulfonamide; (R,E)-2-(1-ethylpyrrolidin-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-(pyrrolidin-2-yl)ethene-1-sulfonamide; (R,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-methylpyrrolidin-2-yl)ethene-1-sulfonamide; (S,E)-2-(1-ethylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-ethanesulfonamide; (R,E)-2-(1,2-dimethylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide; (S,E)-2-(1,2-dimethylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide; Sodium (S,E)-((2-(1,2-dimethylpyrrolidin-2-yl)vinyl)sulfonyl)((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)amide; Potassium (R,E)-((2-(1,2-dimethylpyrrolidin-2-yl)vinyl)sulfonyl)((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)amide; Sodium (R,E)-((2-(1,2-dimethylpyrrolidin-2-yl)vinyl)sulfonyl)((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)amide; (E)-N'-cyano-2-((S)-1,2-dimethylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonimidamide; (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; (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; N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-((1S,8aR)-3,3,8a-trimethyloctahydropyrrolo[1,2-a]pyrazin-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]pyrazin-4-yl)methanesulfonamide; (E)-3-(dimethylamino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)prop-1-ene-1-sulfonamide; Sodium (E)-((3-(dimethylamino)-3-methylbut-1-en-1-yl)sulfonyl)((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)amide; (S,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-methyl-1-(methyl-d)pyrrolidin-2-yl)ethene-1-sulfonamide; (R,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-methyl-1-(methyl-d)pyrrolidin-2-yl)ethene-1-sulfonamide; (R,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(methyl-d)pyrrolidin-2-yl)ethene-1-sulfonamide; or a pharma- ceutically acceptable salt of any of the above compounds.

[0056] The following is a list of abbreviations used in describing the preparation of the compounds of the invention:

[0057] μg: microgram 1 H NMR: Proton nuclear magnetic resonance bs: broad singlet CDC13: Deuterated chloroform CHC13: Chloroform d: doublet DAMPs: Damage-associated molecular patterns DBU: 1,8-diazabicyclo(5.4.0)undec-7-ene DCM: dichloromethane dd: Doublet of doublets DMAC: N,N-(dimethylacetamide) DMAP: 4-(dimethylamino)pyridine DMF: N,N-dimethylformamide DMSO: Dimethyl sulfoxide dt: triplet of doublet EDTA: Ethylenediaminetetraacetic acid EtOAc: ethyl acetate EtOH: Ethanol HCl(g): Hydrogen chloride (gas) IL1β: Interleukin 1 beta K2CO3: Potassium carbonate m:Multiplet MeOH: Methanol mmol: millimolar MS: Mass spectrum N2: Nitrogen Na2CO3: Sodium carbonate ng: nanogram NIS: N-iodosuccinimide PAMP: pathogen-associated molecular pattern; PMA: phorbol 12-myristate 13-acetate POCI3: Phosphoryl chloride RM: reaction mixture rt, RT: room temperature s: singlet t: triplet td: Triplet of doublets THF: tetrahydrofuran TLC: Thin Layer Chromatography TLR: Toll-like receptor TNFα: tumor necrosis factor alpha. WT: wild type A441V: Alanine at position 441 to Valine E692K: 692 glutamic acid to lysine A439V: Alanine at position 439 to Valine A441V: Alanine at position 441 to Valine A439V: Alanine at position 439 to Valine

[0058] The term "pharmaceutical composition" refers to a mixture of an NLRP3 antagonist or other compound described herein with other chemical components (collectively referred to herein as "excipients"), such as carriers, stabilizers, diluents, dispersants, suspending agents, and / or thickening agents. A pharmaceutical composition facilitates administration of an NLRP3 antagonist or other compound to an organism. Multiple techniques for administering a compound exist in the art, including, but not limited to, rectal, oral, and intravenous, aerosol, and parenteral, ophthalmic, pulmonary, and topical administration.

[0059] In one embodiment, the present invention provides an effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt thereof, which may be selected from 1 mg to 500 mg; preferably 1 mg to 250 mg, and more preferably 1 mg to 150 mg, for the treatment and prevention of cryopyrin-associated periodic syndromes (CAPS).

[0060] In certain other embodiments, the compound is orally administered in an amount that provides a compound of formula (I) or a pharma- ceutically acceptable salt thereof in the range of about 1 mg to about 50 mg each day the compound is administered to the subject. In certain embodiments, the compound is orally administered in an amount that provides a compound of formula (I) or a pharma- ceutically acceptable salt thereof in the range of about 1 mg to about 100 mg each day the compound is administered to the subject. In certain embodiments, the compound is orally administered in an amount that provides a compound of formula (I) or a pharma- ceutically acceptable salt thereof in the range of about 1 mg to about 150 mg each day the compound is administered to the subject. In certain embodiments, the compound is orally administered in an amount that provides a compound of formula (I) or a pharma- ceutically acceptable salt thereof in the range of about 1 mg to about 200 mg each day the compound is administered to the subject. In certain embodiments, the compound is orally administered in an amount that provides a compound of formula (I) or a pharma- ceutically acceptable salt thereof in the range of about 1 mg to about 250 mg each day the compound is administered to the subject. In certain embodiments, the compound is orally administered in an amount that provides a compound of formula (I) or a pharma- ceutically acceptable salt thereof in the range of about 1 mg to about 300 mg each day the compound is administered to the subject. In certain embodiments, the compound is orally administered in an amount that provides a compound of formula (I) or a pharma- ceutically acceptable salt thereof in the range of about 1 mg to about 350 mg each day the compound is administered to the subject. In certain embodiments, the compound is orally administered in an amount that provides a compound of formula (I) or a pharma- ceutically acceptable salt thereof in the range of about 1 mg to about 400 mg each day the compound is administered to the subject. In certain embodiments, the compound is orally administered in an amount that provides a compound of formula (I) or a pharma- ceutically acceptable salt thereof in the range of about 1 mg to about 450 mg each day the compound is administered to the subject. In certain embodiments, the compound is orally administered in an amount that provides a compound of formula (I) or a pharma- ceutically acceptable salt thereof in the range of about 1 mg to about 500 mg each day the compound is administered to the subject.

[0061] In certain embodiments, the present invention provides an effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt thereof, which may 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 pharma- ceutically acceptable salt thereof, which is administered by oral route of administration.

[0062] The compound of formula (I) or a pharma- ceutically acceptable salt thereof may be provided to a subject on a daily or weekly basis as prescribed by a physician to a person in need thereof.

[0063] In another embodiment, the present invention provides a method of treating a subject suffering from cryopyrin-associated periodic syndromes (CAPS), comprising treatment of a patient in need of such treatment with a compound of formula (I) or a pharma- ceutically acceptable salt thereof or a suitable pharmaceutical composition containing same.

[0064] In certain embodiments, the present invention provides a combination of a compound of formula (I) and its pharma- ceutically acceptable salts together with other suitable agents as therapeutic agents for the treatment of cryopyrin-associated periodic syndromes (CAPS).

[0065] In certain embodiments, the additional therapeutic agent used is selected from inhibitors of interleukin-1β (e.g., rilonacept, canakinumab, and anakinra); immunosuppressants (e.g., methotrexate, mercaptopurine, cyclophosphamide), metabolic disorder drugs, glucocorticoids, nonsteroidal anti-inflammatory drugs, gastrointestinal D inhibitors (e.g., necrosulfonamide); Cox-2 specific inhibitors, TNF-α binding proteins (e.g., infliximab, etanercept), interferon-13, interferons, interleukin-2, antihistamines, beta-agonists, BTK inhibitors, anticholinergics, anticancer drugs; antiviral drugs, such as: remdesivir, lopinavir / ritonavir, favipiravir, molnupiravir, Tamiflu; antimalarials, such as: chloroquinone, hydroxychloroquinone; or a suitable pharmaceutically acceptable salt thereof. Further examples for use in combination are non-alcoholic steatohepatitis (NASH) and fibrosis drugs; anti-cancer drugs; antibiotics such as azithromycin; hormones, aromatase inhibitors, colchicine, anticoagulants, antibodies, cytokines, anti-IL6 drugs; anti-parasitic drugs; vaccines; interferons; drug conjugates; drugs originally developed for SARS (ACE2 protein decoy); intravenous vitamin C; inhibitors of mitogen-activated protein kinase signaling (e.g., BAY 43-9006); Syk inhibitors; mTOR inhibitors; antibodies (Rituxan); and BCR / ABL antagonists.

[0066] In yet another embodiment, the compound of formula (I) is provided in the form of a pharmaceutical composition.

[0067] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof for the treatment of cryopyrin-associated periodic syndromes (CAPS), wherein the compound of formula (I) is

[0068] [ka]

[0069] It is.

[0070] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I) and a suitable pharma- ceutically acceptable excipient for the treatment of cryopyrin-associated periodic syndromes (CAPS).

[0071] The pharma- ceutically acceptable excipient may be selected from at least one of a diluent, a carrier, a binder, a disintegrant, a lubricant, a surface active agent, and the like.

[0072] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof, wherein an effective amount of the compound of formula (I) or a pharma- ceutically acceptable salt thereof can be selected from 1 mg to 500 mg; preferably 1 mg to 250 mg and more preferably 1 mg to 150 mg for the treatment of cryopyrin-associated periodic syndromes (CAPS).

[0073] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically 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.

[0074] In another embodiment of the present invention, there is provided a process for the preparation of a stable pharmaceutical composition of a compound of formula (1).

[0075] Stable pharmaceutical compositions can be prepared by dry blending, wet granulation or dry granulation methods by techniques known to those skilled in the art. Thus, for example,

[0076] In the 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 dried and optionally sieved. The dry granules are mixed with one or more suitable excipients from those described elsewhere and then compressed into tablets or filled into capsules.

[0077] In the dry blend process, the drug is mixed with all the required pharmaceutical excipients. The blend is mixed with one or more suitable excipients from those described elsewhere, and the final blend is then either compressed into tablets or filled into capsules.

[0078] In the dry granulation process, the drug is mixed with one or more pharmaceutical excipients, compressed into slugs, and these slugs are passed through the required sieve. The sieved granules are mixed with one or more suitable excipients, as described elsewhere, and then compressed into tablets or filled into capsules.

[0079] The 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 of skill in the art.

[0080] In yet another embodiment, the present invention provides for the administration of compounds of formula (I) and their pharma- ceutically acceptable salts, alone or in combination with other suitable agents, as therapeutic agents for the treatment of cryopyrin-associated periodic syndromes (CAPS).

[0081] In certain embodiments, the additional therapeutic agent used is selected from inhibitors of interleukin-1β (e.g., rilonacept, canakinumab, and anakinra); immunosuppressants (e.g., methotrexate, mercaptopurine, cyclophosphamide), metabolic disorder drugs, glucocorticoids, nonsteroidal anti-inflammatory drugs, gastrointestinal D inhibitors (e.g., necrosulfonamide); Cox-2 specific inhibitors, TNF-α binding proteins (e.g., infliximab, etanercept), interferon-13, interferons, interleukin-2, antihistamines, beta-agonists, BTK inhibitors, anticholinergic drugs, anticancer drugs; antiviral drugs, such as: remdesivir, lopinavir / ritonavir, favipiravir, molnupiravir, Tamiflu; antimalarials, such as: chloroquinone, hydroxychloroquinone; or a suitable pharmaceutically acceptable salt thereof. Further examples for use in combination are non-alcoholic steatohepatitis (NASH) and fibrosis drugs; anti-cancer drugs; antibiotics such as azithromycin; hormones, aromatase inhibitors, colchicine, anticoagulants, antibodies, cytokines, anti-IL6 drugs; anti-parasitic drugs; vaccines; interferons; drug conjugates; drugs originally developed for SARS (ACE2 protein decoy); intravenous vitamin C; inhibitors of mitogen-activated protein kinase signaling (e.g., BAY 43-9006); Syk inhibitors; mTOR inhibitors; antibodies (Rituxan); and BCR / ABL antagonists.

[0082] The compositions of the present invention may also be used in combination with other active ingredients. For the treatment of Arenaviridae virus infections, preferably the other active therapeutic agent is active against Arenaviridae virus infections, particularly Lassa virus and Junin virus infections. Non-limiting examples of these other active therapeutic agents are ribavirin, favipiravir (also known as T-705 or Avigan), T-705 monophosphate, T-705 diphosphate, T-705 triphosphate, ST-193, and mixtures thereof.

[0083] The compounds and compositions of the invention are also intended to be used in conjunction with the general care provided to patients with arenavirus infections, including parenteral fluids (including dextrose saline and lactated Ringer's solution) and nutrition, antibiotics (including metronidazole and cephalosporin antibiotics, e.g., ceftriaxone and cefuroxime) and / or antifungal prophylaxis, fever and pain medications, antiemetics (such as metoclopramide) and / or antidiarrheal medications, vitamin and mineral supplements (including vitamins C and / or K and zinc sulfate), anti-inflammatories (such as ibuprofen), pain medications, and antimalarials (including artemether and artesunate-lumefantrine combination therapy), typhoid (including quinolone antibiotics, e.g., ciprofloxacin, macrolide antibiotics, e.g., azithromycin, cephalosporin antibiotics, e.g., ceftriaxone, or aminopenicillins, e.g., ampicillin), or medications for other common illnesses in the patient population, such as shigellosis.

[0084] The present invention further discloses the use of said compounds of formula (I) or suitable pharmaceutical compositions thereof for the treatment of cryopyrin-associated periodic syndromes (CAPS).

[0085] In another embodiment, the present invention provides a method for treating cryopyrin-associated periodic syndromes (CAPS) using a pharmaceutical composition of a compound of formula (I) or a pharma- ceutically acceptable salt thereof. In a preferred embodiment, a method for treating cryopyrin-associated periodic syndromes (CAPS) using a compound of formula (I) or a pharmaceutical composition thereof.

[0086] In a preferred embodiment, the present invention provides a compound of formula (11) or a pharma- ceutically acceptable salt thereof suitable for the treatment of cryopyrin-associated periodic syndromes (CAPS).

[0087] [ka]

[0088] In a further preferred embodiment, the present invention provides the use of compounds of formula (11) or suitable pharmaceutical compositions thereof for the treatment of cryopyrin-associated periodic syndromes (CAPS).

[0089] The method includes the step of administering to the subject an effective amount of a compound according to formula (11).

[0090] In another preferred embodiment, the present invention provides an effective amount of the compound of formula (11) or a pharma- ceutically acceptable salt thereof, which may be selected from 1 mg to 500 mg; preferably 1 mg to 250 mg and more preferably 1 mg to 150 mg, for the treatment of cryopyrin-associated periodic syndromes (CAPS).

[0091] In certain other embodiments, the compound is orally administered in an amount that provides a compound of formula (11) or a pharma- ceutically acceptable salt thereof in the range of about 1 mg to about 50 mg each day the compound is administered to the subject. In certain embodiments, the compound is orally administered in an amount that provides a compound of formula (11) or a pharma- ceutically acceptable salt thereof in the range of about 1 mg to about 100 mg each day the compound is administered to the subject. In certain embodiments, the compound is orally administered in an amount that provides a compound of formula (11) or a pharma- ceutically acceptable salt thereof in the range of about 1 mg to about 150 mg each day the compound is administered to the subject. In certain embodiments, the compound is orally administered in an amount that provides a compound of formula (11) or a pharma- ceutically acceptable salt thereof in the range of about 1 mg to about 200 mg each day the compound is administered to the subject. In certain embodiments, the compound is orally administered in an amount that provides a compound of formula (11) or a pharma- ceutically acceptable salt thereof in the range of about 1 mg to about 250 mg each day the compound is administered to the subject. In certain embodiments, the compound is orally administered in an amount that provides a compound of formula (11) or a pharma- ceutically acceptable salt thereof in the range of about 1 mg to about 300 mg each day the compound is administered to the subject. In certain embodiments, the compound is orally administered in an amount that provides a compound of formula (11) or a pharma- ceutically acceptable salt thereof in the range of about 1 mg to about 350 mg each day the compound is administered to the subject. In certain embodiments, the compound is orally administered in an amount that provides a compound of formula (11) or a pharma- ceutically acceptable salt thereof in the range of about 1 mg to about 400 mg each day the compound is administered to the subject. In certain embodiments, the compound is orally administered in an amount that provides a compound of formula (11) or a pharma- ceutically acceptable salt thereof in the range of about 1 mg to about 450 mg each day the compound is administered to the subject. In certain embodiments, the compound is orally administered in an amount that provides a compound of formula (11) or a pharma- ceutically acceptable salt thereof in the range of about 1 mg to about 500 mg each day the compound is administered to the subject.

[0092] In another preferred embodiment, the present invention provides an effective amount of a compound of formula (11) or a pharma- ceutically acceptable salt thereof, which may 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 (11) or a pharma- ceutically acceptable salt thereof, which is administered by oral route of administration.

[0093] The compound of formula (11) or a pharma- ceutically acceptable salt thereof can be provided to a subject daily or weekly as prescribed by a physician to a person in need thereof.

[0094] In one preferred embodiment, the present invention provides a combination of a compound of formula (11) and its pharma- ceutically acceptable salts together with other suitable agents as therapeutic agents for the treatment of cryopyrin-associated periodic syndromes (CAPS).

[0095] Other suitable therapeutic agents may be selected from inhibitors of interleukin-1β (e.g., rilonacept, canakinumab, and anakinra); immunosuppressants (e.g., methotrexate, mercaptopurine, cyclophosphamide), metabolic disorder drugs, glucocorticoids, nonsteroidal anti-inflammatory drugs, gastrointestinal D inhibitors (e.g., necrosulfonamide); Cox-2 specific inhibitors, TNF-α binding proteins (e.g., infliximab, etanercept), interferon-13, interferons, interleukin-2, antihistamines, beta-agonists, BTK inhibitors, anticholinergic drugs, anticancer drugs; antiviral drugs, such as: remdesivir, lopinavir / ritonavir, favipiravir, molnupiravir, Tamiflu; antimalarials, such as: chloroquinone, hydroxychloroquinone; or suitable pharmaceutically acceptable salts thereof. Further examples for use in combination are non-alcoholic steatohepatitis (NASH) and fibrosis drugs; anti-cancer drugs; antibiotics such as azithromycin; hormones, aromatase inhibitors, colchicine, anticoagulants, antibodies, cytokines, anti-IL6 drugs; anti-parasitic drugs; vaccines; interferons; drug conjugates; drugs originally developed for SARS (ACE2 protein decoy); intravenous vitamin C; inhibitors of mitogen-activated protein kinase signaling (e.g. BAY 43-9006); Syk inhibitors; mTOR inhibitors; antibodies (Rituxan); and BCR / ABL antagonists can also be used in combination with the compounds of formula (11) for the treatment of cryopyrin-associated periodic syndromes (CAPS).

[0096] In a preferred embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (11) or a pharma- ceutically acceptable salt thereof for the treatment of cryopyrin-associated periodic syndromes (CAPS).

[0097] In another preferred embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (11) and suitable pharma- ceutically acceptable excipients for the treatment of cryopyrin-associated periodic syndromes (CAPS).

[0098] The pharma- ceutically acceptable excipient may be selected from at least one of a diluent, a carrier, a binder, a disintegrant, a lubricant, a surface active agent, and the like.

[0099] In another preferred embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (11), a pharma- ceutically acceptable salt thereof and optionally other suitable therapeutic agents, for the treatment of cryopyrin-associated periodic syndromes (CAPS).

[0100] Other suitable therapeutic agents may be selected from inhibitors of interleukin-1β (e.g., rilonacept, canakinumab, and anakinra); immunosuppressants (e.g., methotrexate, mercaptopurine, cyclophosphamide), metabolic disorder drugs, glucocorticoids, nonsteroidal anti-inflammatory drugs, gastrointestinal D inhibitors (e.g., necrosulfonamide); Cox-2 specific inhibitors, TNF-α binding proteins (e.g., infliximab, etanercept), interferon-13, interferons, interleukin-2, antihistamines, beta-agonists, BTK inhibitors, anticholinergic drugs, anticancer drugs; antiviral drugs, such as: remdesivir, lopinavir / ritonavir, favipiravir, molnupiravir, Tamiflu; antimalarials, such as: chloroquinone, hydroxychloroquinone; or suitable pharmaceutically acceptable salts thereof. Further examples for use in combination are non-alcoholic steatohepatitis (NASH) and fibrosis drugs; anti-cancer drugs; antibiotics such as azithromycin; hormones, aromatase inhibitors, colchicine, anticoagulants, antibodies, cytokines, anti-IL6 drugs; anti-parasitic drugs; vaccines; interferons; drug conjugates; drugs originally developed for SARS (ACE2 protein decoy); intravenous vitamin C; inhibitors of mitogen-activated protein kinase signaling (e.g. BAY 43-9006); Syk inhibitors; mTOR inhibitors; antibodies (Rituxan); and BCR / ABL antagonists can also be used in combination with the compounds of formula (11) for the treatment of cryopyrin-associated periodic syndromes (CAPS).

[0101] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (11) or a pharma- ceutically acceptable salt thereof, wherein an effective amount of the compound of formula (11) or a pharma- ceutically 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 cryopyrin-associated periodic syndromes (CAPS).

[0102] In another embodiment, the invention further discloses the use of said compounds of formula (11) or suitable pharmaceutical compositions thereof for the treatment of cryopyrin-associated periodic syndromes (CAPS).

[0103] In another embodiment, the present invention provides the use of a compound of formula (11), wherein the compound is administered in a daily dosage range selected from 1 mg to 500 mg, preferably selected from 1 mg to 250 mg, more preferably selected from 1 mg to 150 mg.

[0104] In another preferred embodiment, the present invention provides a method for treating cryopyrin-associated periodic syndromes (CAPS) using a pharmaceutical composition of a compound of formula (11) or a pharma- ceutically acceptable salt thereof. In a preferred embodiment, a method for treating cryopyrin-associated periodic syndromes (CAPS) using a compound of formula (11) or a pharmaceutical composition thereof.

[0105] In another preferred embodiment of the present invention, there is provided a process for the preparation of a stable pharmaceutical composition of a compound of formula (11).

[0106] Stable pharmaceutical compositions can be prepared by dry blending, wet granulation or dry granulation methods by techniques known to those skilled in the art. Thus, for example,

[0107] In the 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 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.

[0108] In the dry blend process, the drug is mixed with all the required pharmaceutical excipients. The blend is mixed with one or more suitable excipients from those described elsewhere, and the final blend is then either compressed into tablets or filled into capsules.

[0109] In the dry granulation process, the drug is mixed with one or more pharmaceutical excipients, compressed into slugs, and these slugs are passed through the required sieve. The sieved granules are mixed with one or more suitable excipients, as described elsewhere, and then compressed into tablets or filled into capsules.

[0110] The 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 of skill in the art.

[0111] In certain embodiments, the pharma- ceutically acceptable excipient described in the present invention is selected from at least one of a diluent, a carrier, a binder, a disintegrant, a lubricant, a surface active agent, and the like.

[0112] Diluents include, but are not limited to, lactose monohydrate, polymethacrylates selected from Eudragit, potassium chloride, sulfobutyl ether b-cyclodextrin, sodium chloride and spray dried lactose, combinations thereof and other such materials known to those of skill in the art.

[0113] Carriers include, but are not limited to, lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate and kaolin, microcrystalline cellulose and silicic acid, combinations thereof and other such materials known to those skilled in the art.

[0114] Binders include, but are not limited to, carbomers selected from Carbopol, gellan, gum arabic, hydrogenated vegetable oils, polymethacrylates selected from Eudragit, xanthan, lactose and zein, combinations thereof and other such materials known to those skilled in the art.

[0115] Disintegrants include, but are not limited to, bicarbonate, chitin, gellan gum, polacrilin potassium and docusate sodium, combinations thereof and other such materials known to those of skill in the art.

[0116] Lubricants that may be used include, but are not limited to, glyceryl behenate, hydrogenated vegetable oils, sodium stearyl fumarate and myristic acid, combinations thereof and other such materials known to those skilled in the art.

[0117] 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 cetyl trimethyl ammonium bromide and cetyl pyridinium chloride, combinations thereof, and other such materials known to those skilled in the art.

[0118] General process for preparation The novel compounds of the present invention can be prepared using the reactions and techniques described below, together with conventional techniques known to those skilled in the art of organic synthesis, or modifications thereto as appreciated by those of skill in the art.

[0119] The reactions can be carried out in a solvent appropriate to the reagents and materials employed and suitable for the transformations being effected. Preferred methods include, but are not limited to, those described below, where all variables are as originally defined unless otherwise defined below.

[0120] Compounds of general formula (I) can be prepared as depicted in the schemes below, together with appropriate modifications / alterations that are well within the skill of one in the art.

[0121] [ka]

[0122] In the formula, R 1 , R 2 , X 、 and Y are each as defined above. Compounds 1 and 2 can be prepared by a variety of methods familiar to those skilled in the art, including using reported procedures. Compound (1) upon treatment with an isocyanate derivative (2) under suitable conditions in the presence of a base such as sodium hydride and a suitable solvent to obtain a compound of formula (I).

[0123] The particular reaction conditions, solvents and other parameters required to carry out the process steps as described above are well within the capabilities of those skilled in the art.

[0124] The present invention is further illustrated by the following non-limiting examples which describe preferred modes of practicing the invention and are provided without in any way limiting the scope of the invention.

[0125] As shown in the examples 1 H NMR spectral data (see below) were recorded using a 400 MHz spectrometer (Bruker AVANCE-400) and are reported on the δ scale. Unless otherwise stated, the solvent used for NMR was CDCl3 with TMS as the internal standard. EXAMPLES

[0126] Example 1 N'-Cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-5-(2-hydroxypropan-2-yl)thiophene-2-sulfonimidamide

[0127] [ka]

[0128] 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).

[0129] Example 2 N'-Cyano-4-fluoro-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-(2-hydroxypropan-2-yl)benzenesulfonimidamide

[0130] [ka]

[0131] 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) + .

[0132] Example 3 N'-Cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide

[0133] [ka]

[0134] 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).

[0135] Example 4 (E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(thiazol-2-yl)ethenesulfonamide

[0136] [ka]

[0137] 1 H 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 + ).

[0138] Example 5 (E)-2-(1-ethyl-1H-imidazol-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethenesulfonamide

[0139] [ka]

[0140] 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) + .

[0141] Example 6 (E)-2-(1-ethyl-4-methyl-1H-imidazol-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethenesulfonamide

[0142] [ka]

[0143] 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) + .

[0144] Example 7 (R,E)-2-(1-Ethylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-ethanesulfonamide

[0145] [ka]

[0146] 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) + .

[0147] Example 8 (R,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(pyrrolidin-2-yl)ethene-1-sulfonamide

[0148] [ka]

[0149] 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).

[0150] Example 9 (R,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-methylpyrrolidin-2-yl)ethene-1-sulfonamide

[0151] [ka]

[0152] 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).

[0153] Example 10 (S,E)-2-(1-Ethylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-ethanesulfonamide

[0154] [ka]

[0155] 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) + .

[0156] Example 11 (R,E)-2-(1,2-dimethylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide

[0157] [ka]

[0158] 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) + .

[0159] Example 12 (S,E)-2-(1,2-dimethylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide

[0160] [ka]

[0161] 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).

[0162] Example 13 Sodium (S,E)-((2-(1,2-dimethylpyrrolidin-2-yl)vinyl)sulfonyl)((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)amide

[0163] [ka]

[0164] 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).

[0165] Example 14 Potassium (R,E)-((2-(1,2-dimethylpyrrolidin-2-yl)vinyl)sulfonyl)((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)amide

[0166] [ka]

[0167] 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) + .

[0168] Example 15 Sodium (R,E)-((2-(1,2-dimethylpyrrolidin-2-yl)vinyl)sulfonyl)((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)amide

[0169] [ka]

[0170] 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) + .

[0171] (Example 16) (E)-N'-Cyano-2-((S)-1,2-dimethylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonimidamide

[0172] [ka]

[0173] 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

[0174] (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

[0175] [ka]

[0176] 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) - .

[0177] (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

[0178] [ka]

[0179] 1H 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) - .

[0180] (Example 19) N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-((1S,8aR)-3,3,8a-trimethyloctahydropyrrolo[1,2-a]pyrazin-1-yl)methanesulfonamide

[0181] [ka]

[0182] 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)+ .

[0183] (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

[0184] [ka]

[0185] 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).

[0186] Example 21 (E)-3-(Dimethylamino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)prop-1-ene-1-sulfonamide

[0187] [ka]

[0188] 1 H NMR (400 MHz, DMSO-d6): δ = 10.22 (brs, 1H), 7.94 (s, 1H), 6.91 (s, 1H), 6.86 (d, J = 15.2 Hz, 1H), 6.62 - 6.55 (m, 1H), 3.27 (t, J = MS (ESI): m / z (%) = 364.1513 (100%) (M+H) + .

[0189] 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

[0190] [ka]

[0191] 1 H NMR (400 MHz, DMSO-d6): δ = 7.36 (s, 1H), 6.77 (s, 1H), 6.51 (d, J = 15.6 Hz, 1H), 6.23 (d, J = 15.6 Hz, 1H), 2.76 (t, J = 7.2 Hz, 4H), 2.69 (t, J = 7.2 Hz, 4H), 2.11 (s, 1H), 1.94 - 1.87 (m, 4H), 1.06 (s, 6H); MS (TOF): m / z (%) = 392.1987 (100%) (M+H) + , 390.1841 (20%) (M-1).

[0192] (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

[0193] [ka]

[0194] 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%) [MH] - .

[0195] (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

[0196] [ka]

[0197] 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] - .

[0198] (Example 25) (R,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(methyl-d)pyrrolidin-2-yl)ethene-1-sulfonamide

[0199] [ka]

[0200] 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] - .

[0201] In vitro studies to evaluate efficacy in healthy volunteers and against CAPS mutations: Compound 11, a potent NLRP3 inflammasome inhibitor, blocks IL-1β and IL-18 secretion from activated THP-1 cells, hPBMCs (human peripheral blood mononuclear cells), and whole blood treated with LPS (lipopolysaccharide) and ATP (adenosine triphosphate). For the whole blood assay, human peripheral venous blood was collected from healthy volunteers according to a protocol approved by the ethical committee. Whole blood was distributed in 96-well plates and primed with LPS (500 ng / mL) for 4 hours. Different concentrations of compound 11 were added in the presence of serum-free medium. NLRP3 inflammasome was induced with ATP (5 mM) for 1 hour. Supernatants were collected at the end of 1 hour and assayed for released IL-1β using an ELISA method. Inhibition in cytokine levels was plotted and induced half-maximal inhibitory concentrations.

[0202] [Table 1]

[0203] Ex vivo pharmacodynamic evaluation In the ex vivo pharmacodynamic evaluation, blood was drawn at specific intervals after dosing and NLRP3 was induced using LPS and ATP. Inhibition of IL-1β secretion was observed by >90% at all doses tested in the SAD and MAD studies. ED 90 was achieved.

[0204] To examine the efficacy of compound 11 in CAPS conditions, we first tested the efficacy of compound 11 against different CAPS mutations. Human PBMCs, which contain monocytes, express NLRP3 when induced with LPS and ATP in normal volunteers or with LPS alone in CAPS patient volunteers. Using a gradient method, human peripheral blood mononuclear cells (hPBMCs) were isolated from volunteers. hPBMCs were suspended in complete growth medium, plated overnight, and then activated with LPS and / or ATP. Half-maximal inhibitory concentrations were induced for compound 11 against normal volunteer and CAPS patient PBMCs activated with the respective stimuli and subsequent treatment with compound 11. Compound 11 showed IC values ​​of 3.0-6.0 nM in PBMCs isolated from healthy volunteers. 50 When tested in five different CAPS patient volunteer PBMCs, compound 11 showed potencies between 2.2 nM and 31.3 nM. Interestingly, the potency of compound 11 outperforms published reports of a competing molecule, MCC950, whose potency was lower in a similar family of mutations. In a direct comparison in the A439V mutation, compound 11 had IC 50 ≧100nM. (Wellcome Open Research 2020, 5:247)

[0205] [Table 2]

[0206] In a Phase 1 single ascending dose clinical study, compound 11 showed a good pharmacokinetic profile with dose-dependent modulation in plasma levels in healthy volunteers. In a multiple ascending dose BID study, compound 11 also achieved steady-state levels in a dose-dependent manner.

[0207] In conclusion, compound 11 has demonstrated nM potency in NLRP3-mediated IL-1β inhibition preclinical studies and in studies involving human healthy patients with wild-type NLRP3, as well as complete translation to the clinic. Interestingly, it was found to be equally potent in NLRP3-mediated IL-1β inhibition in proven CAPS patients with defined gain-of-function mutations in NLRP3.

[0208] Efficacy of Compound 11 in healthy adult human subjects: Protocol Title: Phase 1, Prospective Study of Compound 11 Administered via Oral Route to Investigate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics in Healthy Adult Human Subjects.

[0209] the purpose: Primary purpose: To evaluate the safety and tolerability of compound 11 administered to healthy subjects. Secondary purpose: To characterize the pharmacokinetics of compound 11 when administered as a single oral dose to healthy subjects. To evaluate the pharmacodynamic properties of compound 11 in healthy subjects. search: To profile and identify / quantify unique metabolites of compound 11 in plasma and urine. To evaluate any other pharmacodynamic properties of compound 11 in healthy subjects.

[0210] Safety standards: Record vital signs such as temperature, blood pressure, respiration rate, SpO2 and radial pulse. · Clinical examination including general and systemic examination (cardiovascular system (CVS), respiratory system (RS), gastrointestinal system (GI), central nervous system (CNS)) ECG evaluation Clinical laboratory tests (i.e. hematology, serum chemistry, urinalysis, and serology) The frequency and severity of adverse events (AEs) will be recorded for all enrolled subjects. All AEs will be Causality severity Severity are classified using

[0211] Methodology: It is an open-label study designed to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of compound 11 following administration of a single oral dose to healthy subjects.

[0212] In this study, each cohort containing 6 subjects will receive a single oral dose of compound 11 in an ascending manner. Initially, up to three cohorts of 18 subjects (including 25 mg, 50 mg and 100 mg doses) will be enrolled and dosed. Interim analysis will be conducted after the completion of the three cohorts and submitted to the Central Licensing Authority. Duration of treatment: Single dose Subjects were eligible for inclusion in the study if they were healthy, between 18 and 55 years of age (inclusive), weighed between 50 kg and 100 kg (inclusive) with a body mass index between 18.5 kg and 30.0 kg / m2 (inclusive), had a normal QTc interval [QTcF ≤ 450 ms] at screening and check-in, agreed to comply with the trial procedures, and were willing to practice highly effective contraception. Subjects were excluded from the study if they had a history or presence of a systemic disorder / disease within the past 3 months; a history of clinically significant hypersensitivity, intolerance, or allergy; a history of COVID-19 infection within 14 days or contact with a confirmed active COVID-19 positive case within 14 days; or a positive COVID-19 test within 5 days of check-in; a systolic blood pressure greater than 140 mmHg or less than 100 mmHg or a diastolic blood pressure greater than 90 mmHg or less than 60 mmHg; a pulse rate less than 55 beats per minute or greater than 100 beats per minute and other exclusion criteria as defined in the protocol. These subjects will be invited to participate in the study. Safety and efficacy evaluations will be performed according to activity charts.

[0213] Number of subjects in treatment arms: A total of 18 subjects were enrolled, i.e., 06 subjects in each of cohorts S1 (25 mg), S2 (50 mg), and S3 (100 mg). A total of 18 subjects were enrolled and dosed with compound capsules. A total of 17 subjects completed the study.

[0214] Duration of Treatment: Subjects were enrolled within a 28-day screening period, received a single dose of Compound 11 capsules orally, and were followed for up to 48 hours post-dosing.

[0215] result- Of the 18 enrolled subjects, 17 subjects completed the study. All 18 subjects were Asian, male subjects. Overall, for this study, the mean (range) age was 37 years (23 to 47 years) and the BMI was 23.51 kg / m2 (19.71 kg to 28.01 kg / m2). The compound administered via the oral route was found to be safe and well tolerated in healthy subjects up to a single dose of 100 mg. No subjects discontinued the study due to adverse events.

[0216] Pharmacokinetic and pharmacodynamic results Pharmacokinetic Results Plasma and urine samples were analyzed for compound prediction using an independently validated LC-MS / MS assay. Concentration-time data were subjected to evaluation of pharmacokinetic parameters.

[0217] Cohort S1 (25 mg dose) A total of 06 healthy male subjects received a 25 mg dose of Compound 11.

[0218] Note: 01 subject in cohort S1 withdrew his consent and discontinued the study. Therefore, this subject was not used for pharmacokinetic evaluation.

[0219] Pharmacokinetic evaluation showed that the drug was well absorbed following oral administration; the median time to reach maximum plasma concentration, T, was 1.500 h, ranging from 0.500 to 2.000 h. The mean elimination half-life was 6.526 ± 0.67 h. The mean C and AUC were 3.393 ± 0.72 μg / mL and 26.967 ± 0.39 h*μg / mL, respectively. The mean plasma clearance was 0.922 ± 0.01 L / h, and the mean volume of distribution was 8681.147 ± 929.14 mL. The mean cumulative percentage urinary recovery of unchanged compound was 93.26%.

[0220] Cohort S2 (50 mg dose) A total of 06 healthy male subjects received a 50 mg dose of Compound 11.

[0221] Pharmacokinetic evaluation showed that the drug was well absorbed following oral administration, with the median time to reach maximum plasma concentration, T, being 1.000 h and ranging from 0.500 to 2.000 h. The mean elimination half-life was 5.818 ± 0.47 h. The mean C and AUC were 5.724 ± 0.52 μg / mL and 40.838 ± 7.20 h*μg / mL, respectively. The mean plasma clearance was 1.238 ± 0.22 L / h and the mean volume of distribution was 10285.52 ± 1174.32 mL. The mean cumulative percentage urinary recovery of unchanged compound was 69.09%.

[0222] Cohort S3 (100 mg dose) A total of 06 healthy male subjects received a 100 mg dose of Compound 11.

[0223] Pharmacokinetic evaluation showed that the drug was well absorbed following oral administration, with the median time to reach maximum plasma concentration, T, being 1.000 hours, ranging from 0.500 to 1.500 hours. The mean elimination half-life was 6.275 ± 0.65 hours. The mean C and AUC were 11.489 ± 1.01 μg / mL and 92.302 ± 14.90 h*μg / mL, respectively. The mean plasma clearance was 1.099 ± 0.15 L / hour, and the mean volume of distribution was 9847.576 ± 825.72 mL. The mean cumulative percentage urinary recovery of unchanged compound was 76.63%.

[0224] Overall, compound 11 exhibited rapid oral absorption from the gastrointestinal tract with maximum concentrations achieved at 1.0 to 1.5 hours. A dose-related increase in compound 11 exposure (Cmax & AUC) was observed from the 25 mg to 100 mg doses. The mean elimination half-life was approximately 6.0 to 6.5 hours across all three doses. The majority of unchanged compound 11 was recovered in the urine, suggesting that the kidney is the primary route of compound excretion.

[0225] Pharmacodynamic results Blood isolated before dosing, 3 h, 6 h, 12 h, and 24 h was activated ex vivo with LPS and ATP, and secreted IL-1β and IL18 were measured in LPS / ATP treated and untreated whole blood.

[0226] Descriptive statistics (n, mean, standard deviation) of corrected IL-1β whole blood concentrations were summarized by treatment and time point. Levels of BLQ were set to 0. Corrected IL-1β whole blood concentrations were derived as follows: (IL-1β concentration in treated samples - IL-1β concentration in untreated samples).

[0227] The percentage of IL-1β inhibition is calculated as follows: [(treated concentration pre-dose−untreated concentration pre-dose)−(treated concentration at Rx time point−untreated concentration at Rx time point)] / (treated concentration pre-dose−untreated concentration pre-dose)*100%.

[0228] All 17 subjects showed greater than 90% inhibition of IL-1β following administration of Compound 11. Single doses of 25 mg, 50 mg, and 100 mg of Compound 11 showed greater than 90% ex vivo IL-1β inhibition by 6 hours, 12 hours, and 24 hours after dosing, respectively.

Claims

A pharmaceutical composition for the treatment of cryopyrin - associated periodic syndromes (CAPS), comprising a compound of formula (11) or a pharmaceutically acceptable salt thereof. [Chemical Formula 6]

2. The pharmaceutical composition according to claim 1, wherein the content of the compound of formula (11) or a pharmaceutically acceptable salt thereof is selected from 1 mg to 500 mg.

3. The pharmaceutical composition according to claim 1, wherein the compound of formula (11) or a pharmaceutically acceptable salt thereof is administered by an oral, topical or parenteral route of administration.

4. The pharmaceutical composition according to claim 1, wherein the compound of formula (11) or a pharmaceutically acceptable salt thereof is administered in combination with other suitable therapeutic agents.

5. Use of a compound of formula (11) as defined in claim 1 for the preparation of a medicament for the treatment of cryopyrin - associated periodic syndromes (CAPS).

6. A pharmaceutical composition for the treatment of cryopyrin - associated periodic syndromes (CAPS), comprising a compound of formula (11) and other pharmaceutically acceptable excipients, according to claim 1.

7. Use of the pharmaceutical composition according to claim 1 for the preparation of a medicament for the treatment of cryopyrin - associated periodic syndromes (CAPS).

8. The pharmaceutical composition according to claim 6, wherein the other pharmaceutically acceptable excipients are selected from diluents, carriers, binders, disintegrants, lubricants and surfactants.

9. The pharmaceutical composition according to claim 8, wherein the diluent is selected from lactose monohydrate, polymethacrylate selected from Eudragit, potassium chloride, sulfobutyl ether b - cyclodextrin, sodium chloride, spray - dried lactose and suitable combinations thereof.

10. The pharmaceutical composition according to claim 8, wherein the carrier is selected from lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate and kaolin, crystalline cellulose, silicic acid and suitable combinations thereof.

11. The pharmaceutical composition according to claim 8, 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.

12. The pharmaceutical composition according to claim 8, wherein the disintegrant is selected from bicarbonates, chitin, gellan gum, potassium polyacrylate, sodium docusate and suitable combinations thereof.

13. The pharmaceutical composition according to claim 8, wherein the lubricant is selected from glycerin behenate, hydrogenated vegetable oil, sodium stearyl fumarate, myristic acid, and suitable combinations thereof.

14. The pharmaceutical composition according to claim 8, wherein the surfactant is a nonionic surfactant selected from alkyl polyglucosides, 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 cetyl trimethyl ammonium bromide and cetyl pyridinium chloride, and suitable combinations thereof.

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