Triazinone derivatives as NLRP3 inhibitors

Abstract

The present invention relates to novel compounds having the general formula (I): # imgabs0 # wherein R1, R2, R3, R4a, R4b and R5 are as described herein; comprising the compound; and methods of using the compounds.

Description

Technical Field

[0001] The present invention relates to organic compounds useful for the treatment and / or prophylaxis in mammals, and particularly to compounds that modulate NLRP3 inhibition.

[0002] The present invention provides novel compounds of formula I,

[0003]

[0004] wherein

[0005] R 1 is H, acetyl, SF 5 , halo, alkyl, alkoxy, haloalkyl, haloalkoxy or cyano;

[0006] R 5 is H;

[0007] or R 1 and R 5 and the atoms to which they are attached form a 4- to 6-membered heterocycle containing a single O heteroatom, which heterocycle is optionally substituted with one or two substituents independently selected from halo and alkyl, or R 1 and R 5 and the atoms to which they are attached form a 4- to 6-membered cycloalkyl ring optionally substituted with 1 to 2 substituents independently selected from halo and alkyl;

[0008] R 2 is H, halo, alkyl, alkoxy, alkoxyalkyl, haloalkyl or cycloalkyl, wherein the cycloalkyl is optionally substituted with halo;

[0009] R 3 is H or alkyl;

[0010] R 4a is a heterocycle optionally substituted with 1 to 3 substituents independently selected from the following: halo, alkyl, haloalkyl, hydroxyalkyl, -OH, oxo, -CO 2 H, cycloalkylalkyl or cycloalkyl optionally substituted with halo, and R 4b is H, or

[0011] R 4a and R 4b and the N to which they are attached form a 9-membered heterocycle containing 1 or 2 N heteroatoms, which heterocycle is optionally substituted with 1 or 2 substituents independently selected from alkyl, -OH or halo;

[0012] and their pharmaceutically acceptable salts.

[0013] In addition, the present invention includes all racemic mixtures, all their corresponding enantiomers and / or optical isomers. Background Art

[0014] The NOD-like receptor (NLR) family (the NLRP3 inflammasome containing the pyrin domain) is a component of the inflammatory process, and its abnormal activity is pathogenic in genetic disorders such as cryopyrin-associated periodic syndromes (CAPS) and complex diseases such as multiple sclerosis, type 2 diabetes, Alzheimer's disease, and atherosclerosis.

[0015] NLRP3 is an intracellular signaling molecule that senses many pathogen-derived, environmental, and host-derived factors. Upon activation, NLRP3 binds to apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC). ASC then polymerizes to form large aggregates called ASC specks. The polymeric ASC then interacts with the cysteine protease caspase-1 to form a complex called the inflammasome. This leads to the activation of caspase-1, which cleaves the precursor forms of the pro-inflammatory cytokines IL-1β and IL-18 (called pro-IL-1β and pro-IL-18, respectively), thereby activating these cytokines. Caspase-1 also mediates a type of inflammatory cell death called pyroptosis. ASC specks can also recruit and activate caspase-8, which can process pro-IL-1β and pro-IL-18 and trigger apoptotic cell death.

[0016] Caspase-1 cleaves pro-IL-1β and pro-IL-18 into their active forms, which are secreted by the cell. Active caspase-1 also cleaves gasdermin-D to trigger pyroptosis. Caspase-1 can also mediate the release of alarm protein molecules such as IL-33 and high-mobility group protein 1 (HMGB1) by controlling the pyroptotic cell death pathway. Caspase-1 also cleaves intracellular IL-1R2, leading to its degradation and the release of IL-1α. In human cells, caspase-1 can also control the processing and secretion of IL-37. Many other substrates of caspase-1, such as components of the cytoskeleton and glycolytic pathways, may contribute to caspase-1-dependent inflammation.

[0017] The NLRP3-dependent release of ASC specks into the extracellular environment, where the specks can activate caspase-1, induce the processing of caspase-1 substrates, and spread inflammation.

[0018] Active cytokines derived from NLRP3 inflammasome activation are important drivers of inflammation and interact with other cytokine pathways to form immune responses to infection and injury. For example, IL-1β signaling induces the secretion of pro-inflammatory cytokines IL-6 and TNF. IL-1β and IL-18 cooperate with IL-23 to induce memory CD4 Th17 cells and γδ T cells to produce IL-17 in the absence of T cell receptor engagement. IL-18 and IL-12 also cooperate to induce IFN-γ production from memory T cells and NK cells, driving Th1 responses.

[0019] The hereditary CAPS diseases Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), and neonatal-onset multisystem inflammatory disease (NOMID) are caused by gain-of-function mutations in NLRP3, thus defining NLRP3 as a key component of the inflammatory process. NLRP3 is also associated with the pathogenesis of many complex diseases, which particularly include metabolic disorders such as type 2 diabetes, atherosclerosis, obesity, and gout.

[0020] The role of NLRP3 in central nervous system diseases is emerging, and lung diseases have also been shown to be affected by NLRP3. NLRP3 is also thought to play a role in many central nervous system disorders, including Parkinson's disease (PD), Alzheimer's disease (AD), dementia, Huntington's disease, cerebral malaria, brain injury caused by pneumococcal meningitis (Walsh et al., Nature Reviews, 15:84-97, 2014, and Dempsey et al. Brain. Behav. Immun. 2017 61:306-316). NLRP3 has also been shown to play a role in many lung diseases, including chronic obstructive pulmonary disease (COPD), asthma (including steroid-resistant asthma), asbestosis, and silicosis (De Nardo et al., Am. J. Pathol., 184:42-54, 2014 and Kim et al. Am J Respir Crit Care Med. 2017 196(3):283-97). In addition, NLRP3 has a role in the development of liver disease, kidney disease, and aging. Many of these associations were defined using Nlrp3 - / - mice, but there are also insights into NLRP3-specific activation in these diseases. In type 2 diabetes (T2D), the deposition of islet amyloid polypeptide in the pancreas activates NLRP3 and IL-1β signaling, leading to cell death and inflammation.

[0021] Several small molecules have been shown to inhibit the NLRP3 inflammasome. Glyburide inhibits IL-1β production at micromolar concentrations in response to activation of NLRP3 but not NLRC4 or NLRP1. Other previously characterized weak NLRP3 inhibitors include parthenolide, 3,4-methylenedioxy-β-nitrostyrene, and dimethyl sulfoxide (DMSO), although these agents have limited potency and are non-specific.

[0022] Current treatments for NLRP3-related diseases include biologic agents that target IL-1. These are the recombinant IL-1 receptor antagonist anakinra, the neutralizing IL-1β antibody canakinumab, and the soluble decoy IL-1 receptor rilonacept. These approaches have been shown to successfully treat CAPS, and these biologic agents have been used in clinical trials for other IL-1β-related diseases.

[0023] There is a need to provide compounds having improved pharmacological and / or physiological and / or physicochemical properties, and / or compounds that provide useful alternatives to known compounds. SUMMARY OF THE INVENTION

[0024] The present invention provides novel compounds of formula I,

[0025]

[0026] wherein

[0027] R 1 is H, acetyl, SF 5 , halo, alkyl, alkoxy, haloalkyl, haloalkoxy, or cyano;

[0028] R 5 is H;

[0029] or R 1 and R 5 and the atoms to which they are attached form a 4- to 6-membered heterocyclic ring containing a single O heteroatom, which heterocyclic ring is optionally substituted with one or two substituents independently selected from halo and alkyl, or R 1 and R 5 and the atoms to which they are attached form a 4- to 6-membered cycloalkyl ring optionally substituted with 1 to 2 substituents independently selected from halo and alkyl;

[0030] R 2 is H, halo, alkyl, alkoxy, alkoxyalkyl, haloalkyl, cycloalkyl, where the cycloalkyl is optionally substituted with halo;

[0031] R 3 is H or alkyl;

[0032] R 4a is a heterocycle optionally substituted with 1 to 3 substituents independently selected from the following: halo, alkyl, haloalkyl, hydroxyalkyl, -OH, oxo, -CO 2 H, cycloalkylalkyl or cycloalkyl optionally substituted with halo, and R 4b is H, or

[0033] R 4a and R 4b together with the N to which they are attached form a 9-membered heterocycle containing 1 or 2 N heteroatoms, the heterocycle optionally being substituted with 1 or 2 substituents independently selected from alkyl, -OH or halo;

[0034] and its pharmaceutically acceptable salts.

[0035] The term "acetyl" means -C(=O)CH 3 group.

[0036] The term "alkyl" means a monovalent straight-chain or branched-chain saturated hydrocarbon group having 1 to 6 carbon atoms. In some embodiments, unless otherwise specified, alkyl contains 1 to 6 carbon atoms (C 1-6 -alkyl) or 1 to 4 carbon atoms (C 1-4 -alkyl). Examples of C 1-6 -alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and pentyl. Particular alkyls include methyl and ethyl.

[0037] The term "alkoxy" means a group of the formula -O-R', where R' is a C 1-6 -alkyl group. Examples of C 1-6 -alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and tert-butoxy.

[0038] The term "cycloalkyl" means a monocyclic or polycyclic saturated or partially unsaturated non-aromatic hydrocarbon. In some embodiments, unless otherwise described, cycloalkyl contains 3 to 8 carbon atoms, 3 to 6 carbon atoms or 3 to 5 carbon atoms. In some embodiments, cycloalkyl is a saturated monocyclic or polycyclic hydrocarbon. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, etc.

[0039] The term "cycloalkylalkyl" means an alkyl group in which at least one hydrogen atom of the alkyl group has been replaced by a cycloalkyl group. Examples of cycloalkylalkyl include cyclopropylmethyl, cyclopropylethyl, cyclopropylbutyl, cyclobutylpropyl, 2-cyclopropylbutyl, cyclopentylbutyl, cyclohexylmethyl and cyclohexylethyl.

[0040] The terms "halogen", "halide", and "halo" are used interchangeably herein and mean fluorine, chlorine, bromine, or iodine. A particular halogen is fluorine.

[0041] The term "haloalkyl" means a C 1-6 -alkyl group in which at least one hydrogen atom of the C 1-6 -alkyl group has been replaced by the same or different halogen atoms. Examples of haloalkyls include fluoromethyl, difluoromethyl, and trifluoromethyl. A particular example is trifluoromethyl.

[0042] The term "haloalkoxy" means a C 1-6 -alkoxy group in which at least one hydrogen atom of the C 1-6 -alkoxy group has been replaced by the same or different halogen atoms. Examples of haloalkoxys are difluoromethoxy, trifluoromethoxy, difluoroethoxy, and trifluoroethoxy.

[0043] The term "heterocycle" means a monocyclic or bicyclic system of 4 to 9 ring atoms that is monovalent, saturated or partially unsaturated, and contains 1, 2, or 3 ring heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon. Examples of monocyclic saturated heterocycles are azetidinyl, diazepanyl, pyrrolidinyl, tetrahydrofuranyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, and piperazinyl. Examples of polycyclic saturated heterocycles are azaspiroheptyl, diazaspiroheptyl, azaspirooctyl, diazaspirooctyl, diazaspirononyl, oxazaspirooctyl, and oxadiazaspirononyl. A specific example of a polycyclic heterocycle includes hexahydropyrrolopyridyl. Another particular example of a heterocycle is piperidinyl.

[0044] The term "hydroxy" means an -OH group.

[0045] The term "hydroxyalkyl" means an alkyl group in which at least one hydrogen atom of the alkyl group has been replaced by a hydroxy group. Examples of hydroxyalkyls include hydroxymethyl, hydroxyethyl, hydroxypropyl, 2-hydroxy-1-propyl, 2-hydroxy-2-methyl-1-propyl, 3-hydroxy-1-propyl, etc. A particular example of a hydroxyalkyl is hydroxyethyl.

[0046] The term "nitrile" means a -C≡N group.

[0047] The term "pharmaceutically acceptable salts" refers to those salts which retain the biological effectiveness and properties of the free bases or free acids and which are not biologically or otherwise undesirable. These salts are formed with inorganic acids such as trifluoroacetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid (especially hydrochloric acid) and organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcysteine. Additionally, these salts can be prepared by adding an inorganic or organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, including substituted amines of naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyamine resins. The compounds of formula I can also exist in zwitterionic form. Particularly preferred pharmaceutically acceptable salts of the compounds of formula I are the salts formed with formic acid and with hydrochloric acid, yielding hydrochloride, dihydrochloride or trihydrochloride.

[0048] The abbreviation uM means micromole and is equivalent to the symbol μM.

[0049] The abbreviation uL means microliter and is equivalent to the symbol μL.

[0050] The abbreviation ug means microgram and is equivalent to the symbol μg.

[0051] The compounds of formula I can contain several asymmetric centers and can exist as optically pure enantiomers, mixtures of enantiomers (e.g., racemates), optically pure diastereomers, mixtures of diastereomers, diastereomeric racemates or mixtures of diastereomeric racemates.

[0052] According to the Cahn-Ingold-Prelog convention, an asymmetric carbon atom can be of the "R" or "S" configuration.

[0053] Another embodiment of the present invention provides a compound according to formula I as described herein and its pharmaceutically acceptable salts or esters, particularly a compound according to formula I as described herein and its pharmaceutically acceptable salts, more particularly a compound according to formula I as described herein.

[0054] An embodiment of the present invention provides a compound according to formula I as described herein, wherein R 1 is halo, haloalkyl or haloalkoxy and R 5 is H; or R 1 and R 5and the atoms to which they are attached form a 4- to 6-membered heterocycle containing a single O heteroatom, which heterocycle is optionally substituted with one or two substituents independently selected from halo and alkyl, or R 1 and R 5 and the atoms to which they are attached form a 4- to 6-membered cycloalkyl ring optionally substituted with 1 to 2 substituents independently selected from halo and alkyl.

[0055] Embodiments of the invention provide a compound according to formula I as described herein, wherein R 1 is halo, haloalkyl or haloalkoxy and R 5 is H; or R 1 and R 5 and the atoms to which they are attached form a 5-membered heterocycle containing a single O heteroatom, or R 1 and R 5 and the atoms to which they are attached form a 5-membered cycloalkyl ring.

[0056] Embodiments of the invention provide a compound according to formula I as described herein, wherein R 1 is halo, haloalkyl or haloalkoxy.

[0057] Embodiments of the invention provide a compound according to formula I as described herein, wherein R 1 is haloalkyl.

[0058] Embodiments of the invention provide a compound according to formula I as described herein, wherein R 5 is H, or R 1 and R 5 and the atoms to which they are attached form a 5-membered heterocycle containing a single O heteroatom, or R 1 and R 5 and the atoms to which they are attached form a 5-membered cycloalkyl ring.

[0059] Embodiments of the invention provide a compound according to formula I as described herein, wherein R 5 is H.

[0060] Embodiments of the invention provide a compound according to formula I as described herein, wherein R 2 is H or alkyl.

[0061] One embodiment of the invention provides a compound according to formula I as described herein, wherein R 2 is alkyl.

[0062] One embodiment of the invention provides a compound according to formula I as described herein, wherein R 3 is alkyl.

[0063] Embodiments of the present invention provide compounds according to formula I as described herein, wherein R 4a is a 6-membered heterocycle substituted with alkyl, hydroxyalkyl, cycloalkylalkyl, or cycloalkyl optionally substituted with halogen, and R 4b is H, or R 4a and R 4b together with the N to which they are attached form a 9-membered heterocycle containing 1 or 2 N heteroatoms optionally substituted with alkyl or halogen.

[0064] Embodiments of the present invention provide compounds according to formula I as described herein, wherein R 4a is a 6-membered heterocycle substituted with alkyl, cycloalkylalkyl, or cycloalkyl optionally substituted with halogen, and R 4b is H, or R 4a and R 4b together with the N to which they are attached form a 9-membered heterocycle containing 1 or 2 N heteroatoms optionally substituted with alkyl or halogen.

[0065] Embodiments of the present invention provide compounds according to formula I as described herein, wherein R 4a is a 6-membered heterocycle containing a single N heteroatom substituted with alkyl or hydroxyalkyl, and R 4b is H, or R 4a and R 4b together with the N to which they are attached form a 9-membered heterocycle containing 1 or 2 N heteroatoms optionally substituted with alkyl.

[0066] Embodiments of the present invention provide compounds according to formula I as described herein, wherein R 4a is a 6-membered heterocycle containing a single N heteroatom substituted with alkyl, and R 4b is H, or R 4a and R 4b together with the N to which they are attached form a 9-membered heterocycle containing 1 or 2 N heteroatoms optionally substituted with alkyl.

[0067] Embodiments of the present invention provide compounds according to formula I as described herein, wherein R 4a is a 6-membered heterocycle containing a single N heteroatom substituted with alkyl, and R 4b is H, or R 4a and R 4b together with the N to which they are attached form a 9-membered heterocycle containing 2 N heteroatoms, wherein the 9-membered heterocycle containing 2 N heteroatoms is substituted with alkyl.

[0068] Embodiments of the present invention provide compounds according to formula I as described herein, wherein R 4a is ethylpiperidinyl and R 4b is H.

[0069] One embodiment of the present invention provides a compound according to formula I as described herein, wherein

[0070] R 1 is halogen, haloalkyl or haloalkoxy;

[0071] R 5 is H;

[0072] or R 1 and R 5 and the atoms to which they are attached form a 5-membered heterocycle containing a single O heteroatom, or R 1 and R 5 and the atoms to which they are attached form a 5-membered cycloalkyl ring;

[0073] R 2 is H, halogen, alkyl, haloalkyl, cycloalkyl, wherein the cycloalkyl is optionally substituted with halogen;

[0074] R 3 is alkyl;

[0075] R 4a is a 6-membered heterocycle substituted with: alkyl, hydroxyalkyl, cycloalkylalkyl or cycloalkyl optionally substituted with halogen, and R 4b is H, or

[0076] R 4a and R 4b and the N to which they are attached form a 9-membered heterocycle containing 1 or 2 N heteroatoms optionally substituted with alkyl or halogen;

[0077] and pharmaceutically acceptable salts thereof.

[0078] One embodiment of the present invention provides a compound according to formula I as described herein, wherein

[0079] R 1 is halogen, haloalkyl or haloalkoxy;

[0080] R 5 is H;

[0081] or R 1 and R 5 and the atoms to which they are attached form a 5-membered heterocycle containing a single O heteroatom, or R 1 and R 5 and the atoms to which they are attached form a 5-membered cycloalkyl ring;

[0082] R 2 is H, halogen, alkyl, haloalkyl, cycloalkyl, wherein the cycloalkyl is optionally substituted with halogen;

[0083] R 3is an alkyl group;

[0084] R 4a is a 6 - membered heterocycle substituted by alkyl, cycloalkylalkyl or cycloalkyl optionally substituted by halogen, and R 4b is H, or

[0085] R 4a and R 4b and the N to which they are attached form a 9 - membered heterocycle containing 1 or 2 N heteroatoms optionally substituted by alkyl or halogen;

[0086] and its pharmaceutically acceptable salts.

[0087] One embodiment of the present invention provides a compound according to formula I as described herein, wherein

[0088] R 1 is halogen, haloalkyl or haloalkoxy;

[0089] R 5 is H;

[0090] or R 1 and R 5 and the atoms to which they are attached form a 5 - membered heterocycle containing a single O heteroatom, or R 1 and R 5 and the atoms to which they are attached form a 5 - membered cycloalkyl ring;

[0091] R 2 is H or alkyl;

[0092] R 3 is alkyl;

[0093] R 4a is a 6 - membered heterocycle containing a single N heteroatom substituted by alkyl or hydroxyalkyl, and R 4b is H, or

[0094] R 4a and R 4b and the N to which they are attached form a 9 - membered heterocycle containing 1 or 2 N heteroatoms optionally substituted by alkyl;

[0095] and its pharmaceutically acceptable salts.

[0096] One embodiment of the present invention provides a compound according to formula I as described herein, wherein

[0097] R 1 is halogen, haloalkyl or haloalkoxy;

[0098] R 5 is H;

[0099] or R 1and R 5 and the atoms to which they are bonded form a 5-membered hetero ring containing a single O heteroatom, or R 1 and R 5 and the atoms to which they are bonded form a 5-membered cycloalkyl ring;

[0100] R 2 is H or alkyl;

[0101] R 3 is alkyl;

[0102] R 4a is a 6-membered hetero ring containing a single N heteroatom substituted by alkyl or hydroxyalkyl, and R 4b is H, or

[0103] R 4a and R 4b and the N to which they are bonded form a 9-membered hetero ring containing 1 or 2 N heteroatoms optionally substituted by alkyl;

[0104] and its pharmaceutically acceptable salts.

[0105] One embodiment of the present invention provides a compound according to formula I as described herein, wherein

[0106] R 1 is halogen, haloalkyl or haloalkoxy;

[0107] R 5 is H;

[0108] or R 1 and R 5 and the atoms to which they are bonded form a 5-membered hetero ring containing a single O heteroatom, or R 1 and R 5 and the atoms to which they are bonded form a 5-membered cycloalkyl ring;

[0109] R 2 is alkyl;

[0110] R 3 is alkyl;

[0111] R 4a is a 6-membered hetero ring containing a single N heteroatom substituted by alkyl or hydroxyalkyl, and R 4b is H, or

[0112] R 4a and R 4b and the N to which they are bonded form a 9-membered hetero ring containing 1 or 2 N heteroatoms optionally substituted by alkyl;

[0113] and its pharmaceutically acceptable salts.

[0114] An embodiment of the present invention provides a compound according to formula I as described herein, wherein

[0115] R 1 is halogen, haloalkyl or haloalkoxy;

[0116] R 5 is H;

[0117] Or R 1 and R 5 and the atoms to which they are attached form a 5-membered heterocycle containing a single O heteroatom, or R 1 and R 5 and the atoms to which they are attached form a 5-membered cycloalkyl ring;

[0118] R 2 is H or alkyl;

[0119] R 3 is alkyl;

[0120] R 4a is a 6-membered heterocycle containing a single N heteroatom substituted with alkyl, and R 4b is H, or

[0121] R 4a and R 4b and the N to which they are attached form a 9-membered heterocycle containing 1 or 2 N heteroatoms optionally substituted with alkyl;

[0122] and its pharmaceutically acceptable salts.

[0123] An embodiment of the present invention provides a compound according to formula I as described herein, wherein

[0124] R 1 is halogen, haloalkyl or haloalkoxy;

[0125] R 5 is H;

[0126] Or R 1 and R 5 and the atoms to which they are attached form a 5-membered heterocycle containing a single O heteroatom, or R 1 and R 5 and the atoms to which they are attached form a 5-membered cycloalkyl ring;

[0127] R 2 is alkyl;

[0128] R 3 is alkyl;

[0129] R 4a is a 6-membered heterocycle containing a single N heteroatom substituted with alkyl, and R4b is H, or

[0130] R 4a and R 4b and the N to which they are attached form an optionally alkyl-substituted 9-membered heterocycle containing 1 or 2 N heteroatoms;

[0131] and their pharmaceutically acceptable salts.

[0132] One embodiment of the present invention provides a compound according to formula I as described herein, wherein

[0133] R 1 is halo, haloalkyl or haloalkoxy;

[0134] R 5 is H;

[0135] or R 1 and R 5 and the atoms to which they are attached form a 5-membered heterocycle containing a single O heteroatom, or R 1 and R 5 and the atoms to which they are attached form a 5-membered cycloalkyl ring;

[0136] R 2 is H or alkyl;

[0137] R 3 is alkyl;

[0138] R 4a is a 6-membered heterocycle containing a single N heteroatom substituted with alkyl or hydroxyalkyl, and R 4b is H, or

[0139] R 4a and R 4b and the N to which they are attached form a 9-membered heterocycle containing 2 N heteroatoms, wherein the 9-membered heterocycle containing 2 N heteroatoms is alkyl-substituted;

[0140] and their pharmaceutically acceptable salts.

[0141] One embodiment of the present invention provides a compound according to formula I as described herein, wherein

[0142] R 1 is halo, haloalkyl or haloalkoxy;

[0143] R 5 is H;

[0144] or R 1 and R 5 and the atoms to which they are attached form a 5-membered heterocycle containing a single O heteroatom, or R 1 and R 5and the atoms to which they are bonded form a 5-membered cycloalkyl ring;

[0145] R 2 is alkyl;

[0146] R 3 is alkyl;

[0147] R 4a is a 6-membered heterocycle containing a single N heteroatom substituted with alkyl or hydroxyalkyl, and R 4b is H, or

[0148] R 4a and R 4b and the N to which they are bonded form a 9-membered heterocycle containing two N heteroatoms, wherein the 9-membered heterocycle containing two N heteroatoms is substituted with alkyl;

[0149] and their pharmaceutically acceptable salts.

[0150] One embodiment of the present invention provides a compound according to formula I as described herein, wherein

[0151] R 1 is halo, haloalkyl or haloalkoxy;

[0152] R 5 is H;

[0153] or R 1 and R 5 and the atoms to which they are bonded form a 5-membered heterocycle containing a single O heteroatom, or R 1 and R 5 and the atoms to which they are bonded form a 5-membered cycloalkyl ring;

[0154] R 2 is H or alkyl;

[0155] R 3 is alkyl;

[0156] R 4a is a 6-membered heterocycle containing a single N heteroatom substituted with alkyl, and R 4b is H, or

[0157] R 4a and R 4b and the N to which they are bonded form a 9-membered heterocycle containing two N heteroatoms, wherein the 9-membered heterocycle containing two N heteroatoms is substituted with alkyl;

[0158] and their pharmaceutically acceptable salts.

[0159] One embodiment of the present invention provides a compound according to formula I as described herein, wherein

[0160] R 1 is halo, haloalkyl or haloalkoxy;

[0161] R 5 is H;

[0162] or R 1 and R 5 and the atoms to which they are attached form a 5-membered heterocycle containing a single O heteroatom, or R 1 and R 5 and the atoms to which they are attached form a 5-membered cycloalkyl ring;

[0163] R 2 is alkyl;

[0164] R 3 is alkyl;

[0165] R 4a is a 6-membered heterocycle containing a single N heteroatom substituted by alkyl, and R 4b is H, or

[0166] R 4a and R 4b and the N to which they are attached form a 9-membered heterocycle containing 2 N heteroatoms, wherein the 9-membered heterocycle containing 2 N heteroatoms is substituted by alkyl;

[0167] and its pharmaceutically acceptable salts.

[0168] One embodiment of the present invention provides a compound according to formula I as described herein, wherein

[0169] R 1 is haloalkyl;

[0170] R 5 is H;

[0171] R 2 is H or alkyl;

[0172] R 3 is alkyl;

[0173] R 4a is ethylpiperidinyl and R 4b is H;

[0174] and its pharmaceutically acceptable salts.

[0175] One embodiment of the present invention provides a compound according to formula I as described herein, wherein

[0176] R 1 is haloalkyl;

[0177] R 5 is H;

[0178] R 2 is an alkyl group;

[0179] R 3 is an alkyl group;

[0180] R 4a is ethylpiperidinyl and R 4b is H;

[0181] and its pharmaceutically acceptable salts.

[0182] Particular examples of the compounds of formula I as described herein are selected from

[0183] 3-[[(3R)-1-Ethyl-3-piperidinyl]amino]-6-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5-one;

[0184] 3-[[(3R)-1-Ethyl-3-piperidinyl]amino]-6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5-one;

[0185] and its pharmaceutically acceptable salts.

[0186] Other specific examples of the compounds of formula I as described herein are selected from

[0187] 3-[[(3R)-1-Ethyl-3-piperidinyl]amino]-6-(4-hydroxy-6-methyl-indan-5-yl)-4-methyl-1,2,4-triazin-5-one;

[0188] 3-[[(3R)-1-(2-Hydroxyethyl)-3-piperidinyl]amino]-6-(4-hydroxy-6-methyl-indan-5-yl)-4-methyl-1,2,4-triazin-5-one;

[0189] 3-[[(3R)-1-Ethyl-3-piperidinyl]amino]-6-(4-hydroxy-6-methyl-2,3-dihydrobenzofuran-5-yl)-4-methyl-1,2,4-triazin-5-one;

[0190] 6-(4-Chloro-2-hydroxy-6-methyl-phenyl)-3-[[(3R)-1-ethyl-3-piperidinyl]amino]-4-methyl-1,2,4-triazin-5-one;

[0191] and its pharmaceutically acceptable salts.

[0192] A preferred example of the compounds of formula I as described herein is 3-[[(3R)-1-ethyl-3-piperidinyl]amino]-6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5-one and its pharmaceutically acceptable salts.

[0193] Other preferred examples of the compounds of formula I as described herein are selected from

[0194] 3-[[(3R)-1-Ethyl-3-piperidinyl]amino]-6-(4-hydroxy-6-methyl-indan-5-yl)-4-methyl-1,2,4-triazin-5-one;

[0195] 3-[[(3R)-1-Ethyl-3-piperidinyl]amino]-6-(4-hydroxy-6-methyl-2,3-dihydrobenzofuran-5-yl)-4-methyl-1,2,4-triazin-5-one;

[0196] and their pharmaceutically acceptable salts.

[0197] A method for preparing the compounds of formula I as described herein is an object of the present invention.

[0198] The compounds of formula I of the present invention and their pharmaceutically acceptable salts can be prepared by methods known in the art, for example, by the following method, which comprises reacting a compound of formula III to provide a compound of formula I by cleavage of a protecting group (PG). Preferably, the protecting group is a methyl ether. Preferably, boron tribromide (BBr in dichloromethane is used to cleave the methyl ether. 3 ) to cleave the methyl ether.

[0199]

[0200] General synthetic scheme

[0201] Compounds of general formula I can be prepared in variant forms according to Scheme 1 by the following method. The starting materials are commercially available or can be prepared according to known methods.

[0202] Scheme 1: General synthesis of compounds of general formula I (GP = protecting group)

[0203]

[0204] Compounds of general formula II are obtained using a palladium-mediated Suzuki-Miyaura cross-coupling reaction under conditions well known to those skilled in the art in the presence of intermediate 1 and a boric acid or ester of the general formula shown in Scheme 1. Subsequently, to prepare a compound of general formula III, in the presence of pyridine, under heating, a suitable secondary amine of general formula HNR 4b R 4a is used for nucleophilic aromatic substitution (SNAr), where R 4a and R 4b have the meanings given in the claims of the present invention. Alternatively, the reaction can also be carried out under microwave irradiation. Finally, the last step of protecting group cleavage is required. In the case of a methyl ether protecting group, boron tribromide (BBr in dichloromethane is usually used.3 ) By cleavage, a compound of general formula I is obtained.

[0205] Scheme 2 : Synthesis of Intermediate 1

[0206]

[0207] Intermediate 1 is synthesized by a Sandmeyer-type reaction as described in the experimental section, using commercially available 6-amino-4-methyl-3-methylthio-1,2,4-triazin-5-one (CAS# 89730-72-3), at 60 °C in acetonitrile, in the presence of copper(I) chloride and lithium chloride.

[0208] Another embodiment of the present invention provides a pharmaceutical composition or a medicament containing the compound of the present invention and a therapeutically inert carrier, diluent or excipient, and a method for using the compound of the present invention to prepare such compositions and medicaments. In one example, the compound of formula I can be formulated into a galenical administration form by mixing it with a physiologically acceptable carrier (i.e., a carrier that is non-toxic to the recipient at the dosage and concentration used) at ambient temperature at an appropriate pH and desired purity. The pH of the formulation depends mainly on the specific use and concentration of the compound, but is preferably in the range of about 3 to about 8. In one example, the compound of formula I is formulated in an acetate buffer at pH 5. In another embodiment, the compound of formula I is sterile. The compound can be stored, for example, as a solid or amorphous composition, as a lyophilized formulation or as an aqueous solution.

[0209] The composition is formulated, dosed and administered in a manner consistent with good medical practice. Factors to be considered in this case include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the medicament, the method of administration, the timing of administration, and other factors known to the practicing physician.

[0210] The compounds of the present invention can be administered by any suitable means, including orally, topically (including buccal and sublingual), rectally, vaginally, transdermally, parenterally, subcutaneously, intraperitoneally, intratracheally, intradermally, intrathecally and epidurally, and intranasally, and (if required for local treatment) intralesionally. Parenteral infusion includes intramuscular, intravenous, intraarterial, intraperitoneal or subcutaneous administration.

[0211] The compounds of the present invention can be administered in any convenient form of administration, for example, tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions can contain conventional components in pharmaceutical formulations, for example, diluents, carriers, pH regulators, sweeteners, fillers and other active agents.

[0212] Conventional formulations are prepared by mixing the compounds of the present invention with carriers or excipients. Suitable carriers and excipients are well known to those skilled in the art and are described in detail, for example, in Ansel, Howard C. et al., Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams and Wilkins, 2004; Gennaro, Alfonso R. et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams and Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. The formulations may also contain one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifying agents, glidants, processing aids, colorants, sweeteners, flavoring agents, diluents, and other known additives to provide an aesthetic presentation of the medicament (e.g., the compounds of the present invention or their pharmaceutical compositions) or to facilitate the preparation of the pharmaceutical product (e.g., the drug).

[0213] The compounds of formula I and their pharmaceutically acceptable salts can be processed together with pharmaceutically inert inorganic or organic auxiliaries for the production of tablets, coated tablets, dragees, hard gelatin capsules, injections, or topical preparations. For example, lactose, corn starch or its derivatives, talc, stearic acid or its salts, etc. can be used as such auxiliaries for tablets, dragees, and hard gelatin capsules.

[0214] Suitable auxiliaries for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid substances, and liquid polyols, etc.

[0215] Suitable auxiliaries for the preparation of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose, etc.

[0216] Suitable auxiliaries for injections are, for example, water, alcohols, polyols, glycerol, vegetable oils, etc.

[0217] Suitable auxiliaries for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols, etc.

[0218] Suitable auxiliaries for topical ophthalmic preparations are, for example, cyclodextrins, mannitol, or many other carriers and excipients known in the art.

[0219] In addition, the pharmaceutical preparation may contain preservatives, solubilizers, thickening substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, fragrances, salts for altering the osmotic pressure, buffering agents, masking agents or antioxidants. They may also contain other therapeutically valuable substances.

[0220] The dosage can vary within a wide range and will of course be suitable for the various requirements in each specific case. Generally speaking, in the case of oral administration, a daily dosage of about 0.1 mg to 20 mg per kg body weight, preferably about 0.5 mg to 4 mg per kg body weight (for example, about 300 mg per person), should be appropriate, and it is preferably divided into 1 to 3 separate dosages (which may consist of, for example, the same amount). In the case of topical administration, the formulation may contain 0.001% to 15% by weight of the drug, and the required dosage can be 0.1 mg to 25 mg, administered once a day or once a week, or several times a day (2 to 4 times), or several times a week. However, it is obvious that when shown to be applicable, the upper or lower limits given herein may be exceeded.

[0221] One embodiment of the invention is a compound according to formula I as described herein, which is used as a therapeutically active substance.

[0222] One embodiment of the invention is a compound according to formula I as described herein, which is used for treating or preventing a disease, disorder or condition, wherein the disease, disorder or condition responds to NLRP3 inhibition.

[0223] One embodiment of the invention is a compound according to formula I as described herein, which is used for treating or preventing a disease, disorder or condition, wherein the disorder or condition responds to NLRP3 inhibition.

[0224] As used herein, the term "NLRP3 inhibition" refers to a complete or partial reduction in the level of NLRP3 activity and includes, for example, inhibiting active NLRP3 and / or inhibiting the activation of NLRP3.

[0225] There is evidence that NLRP3-induced IL-1 and IL-18 play a role in the inflammatory responses associated with or caused by a variety of different disorders (Menu et al., Clinical and Experimental Immunology, 166:1-15, 2011; Strowig et al., Nature, 481:278-286, 2012).

[0226] In one embodiment, the disease, disorder or condition is selected from:

[0227] (i) Inflammation;

[0228] (ii) Autoimmune diseases;

[0229] (iii) Cancer;

[0230] (iv) Infection;

[0231] (v) Central nervous system diseases;

[0232] (vi) Metabolic diseases;

[0233] (vii) Cardiovascular diseases;

[0234] (viii) Respiratory diseases;

[0235] (ix) Liver diseases;

[0236] (x) Kidney diseases;

[0237] (xi) Eye diseases;

[0238] (xii) Skin diseases;

[0239] (xiii) Lymphatic disorders;

[0240] (xiv) Psychological disorders;

[0241] (xv) Graft-versus-host disease;

[0242] (xvi) Abnormal pain;

[0243] (xvii) Conditions associated with diabetes; and

[0244] (xviii) Any disease in which an individual has been determined to carry a germline or somatic non-silent mutation in NLRP3

[0245] In another embodiment, the disease, disorder or condition is selected from:

[0246] (i) Cancer;

[0247] (ii) Infection;

[0248] (iii) Central nervous system diseases;

[0249] (iv) Cardiovascular diseases;

[0250] (v) Liver diseases;

[0251] (vi) Eye diseases; or

[0252] (vii) Skin diseases.

[0253] In yet another exemplary embodiment of the present invention, the disease, disorder or condition is inflammation. Examples of inflammation that can be treated or prevented include inflammatory responses associated with or caused by the following diseases:

[0254] (i) Skin diseases such as contact hypersensitivity, bullous pemphigoid, sunburn, psoriasis, atopic dermatitis, contact dermatitis, allergic contact dermatitis, seborrheic dermatitis, lichen planus, scleroderma, pemphigus, epidermolysis bullosa, urticaria, erythema or alopecia;

[0255] (ii) Arthropathies such as osteoarthritis, systemic juvenile idiopathic arthritis, adult-onset Still's disease, relapsing polychondritis, rheumatoid arthritis, juvenile chronic arthritis, gout or seronegative spondyloarthropathies (such as ankylosing spondylitis, psoriatic arthritis or Reiter's disease);

[0256] (iii) Muscle diseases such as polymyositis or myasthenia gravis;

[0257] (iv) Gastrointestinal diseases such as inflammatory bowel disease (including Crohn's disease and ulcerative colitis), colitis, gastric ulcer, celiac disease, proctitis, pancreatitis, eosinophilic gastroenteritis, mastocytosis, antiphospholipid syndrome, or food-related allergies that may affect areas outside the gut (such as migraine, rhinitis or eczema);

[0258] (v) Respiratory diseases such as chronic obstructive pulmonary disease (COPD), asthma (including eosinophilic asthma, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma or dust asthma, and especially chronic or refractory asthma such as late asthma and airway hyperreactivity), bronchitis, rhinitis (including acute rhinitis, allergic rhinitis, atrophic rhinitis, chronic rhinitis, caseous rhinitis, hypertrophic rhinitis, pustular rhinitis, dry rhinitis, drug-induced rhinitis, membranous rhinitis, seasonal rhinitis such as hay fever and vasomotor rhinitis), sinusitis, idiopathic pulmonary fibrosis (IPF), sarcoidosis, farmer's lung, silicosis, asbestosis, inflammation caused by volcanic ash, adult respiratory distress syndrome, allergic pneumonia or idiopathic interstitial pneumonia;

[0259] (vi) Vascular diseases such as atherosclerosis, Behçet's disease, vasculitis or Wegener's granulomatosis;

[0260] (vii) Autoimmune diseases such as systemic lupus erythematosus, Sjögren's syndrome, systemic sclerosis, Hashimoto's thyroiditis, type I diabetes, idiopathic thrombocytopenic purpura or Graves' disease;

[0261] (viii) Ocular diseases such as uveitis, allergic conjunctivitis or vernal conjunctivitis;

[0262] (ix) Neurological diseases such as multiple sclerosis or encephalomyelitis;

[0263] (x) Infections or infection-related diseases, such as acquired immunodeficiency syndrome (AIDS), acute or chronic bacterial infections, acute or chronic parasitic infections, acute or chronic viral infections, acute or chronic fungal infections, meningitis, hepatitis (hepatitis A, B, C or other viral hepatitis), peritonitis, pneumonia, epiglottitis, malaria, dengue hemorrhagic fever, leishmaniasis, streptococcal myositis, Mycobacterium tuberculosis (including co-infection with Mycobacterium tuberculosis and HIV), Mycobacterium avium-intracellulare, Pneumocystis carinii pneumonia, orchitis / epididymitis, Legionella, Lyme disease, influenza A, Epstein-Barr virus infection, viral encephalitis / aseptic meningitis or pelvic inflammatory disease;

[0264] (xi) Kidney diseases, such as mesangial proliferative glomerulonephritis, nephrotic syndrome, nephritis, glomerulonephritis, obesity-related glomerulopathy, acute renal failure, acute kidney injury, uremia, nephrotic syndrome, renal fibrosis (including chronic crystalline nephropathy) or renal hypertension;

[0265] (xii) Lymphatic diseases, such as Castleman disease;

[0266] (xiii) Diseases of the immune system or diseases involving the immune system, such as hyper IgE syndrome, leprosy, familial hemophagocytic lymphohistiocytosis or graft-versus-host disease;

[0267] (xiv) Liver diseases, such as chronic active hepatitis, non-alcoholic fatty liver disease (NASH), alcoholic hepatitis, non-alcoholic fatty liver disease (NAFLD), alcoholic fatty liver disease (AFLD), alcoholic steatohepatitis (ASH), primary biliary cirrhosis, fulminant hepatitis, liver fibrosis or liver failure;

[0268] (xv) Cancers, including those listed above;

[0269] (xvi) Burns, trauma, injuries, bleeding or stroke;

[0270] (xvii) Radiation exposure;

[0271] (xviii) Metabolic diseases, such as type 2 diabetes (T2D), atherosclerosis, obesity, gout or pseudogout; and / or

[0272] (xix) Pain, such as inflammatory hyperalgesia, pelvic pain, allodynia, neuropathic pain or bone pain caused by cancer.

[0273] One embodiment of the present invention is a compound according to formula I as described herein, which is used for treating or preventing a disease, disorder or condition selected from the following:

[0274] (i) Inflammation;

[0275] (ii) Autoimmune diseases;

[0276] (iii) Cancers;

[0277] (iv) Infections;

[0278] (v) Central nervous system diseases;

[0279] (vi) Metabolic diseases;

[0280] (vii) Cardiovascular diseases;

[0281] (viii) Respiratory diseases;

[0282] (ix) Liver diseases;

[0283] (x) Kidney diseases;

[0284] (xi) Eye diseases;

[0285] (xii) Skin diseases;

[0286] (xiii) Lymphatic disorders;

[0287] (xiv) Psychological disorders;

[0288] (xv) Graft-versus-host disease;

[0289] (xvi) Abnormal pain;

[0290] (xvii) Conditions associated with diabetes; and

[0291] (xviii) Any disease in which an individual has been determined to carry a germline or somatic non-silent mutation in NLRP3.

[0292] An embodiment of the invention is the use of a compound according to formula I as described herein for the treatment or prevention of a disease, disorder or condition, wherein the disease, disorder or condition responds to NLRP3 inhibition.

[0293] An embodiment of the invention is the use of a compound according to formula I as described herein in the treatment or prevention of a disease, disorder or condition selected from Alzheimer's disease and Parkinson's disease.

[0294] An embodiment of the invention is the use of a compound according to formula I as described herein for the treatment or prevention of a disease, disorder or condition selected from asthma or COPD.

[0295] An embodiment of the invention is a compound according to formula I as described herein for the treatment or prevention of a disease, disorder or condition selected from Alzheimer's disease and Parkinson's disease.

[0296] One embodiment of the present invention is a compound according to formula I as described herein, which is used for treating or preventing a disease, disorder or condition selected from asthma or COPD.

[0297] One embodiment of the present invention is the use of a compound according to formula I as described herein for the preparation of a medicament for treating or preventing a disease, disorder or condition selected from Alzheimer's disease and Parkinson's disease.

[0298] One embodiment of the present invention is the use of a compound according to formula I as described herein for the preparation of a medicament for treating or preventing a disease, disorder or condition selected from asthma or COPD.

[0299] One embodiment of the present invention is a method for treating or preventing a disease, disorder or condition selected from Alzheimer's disease and Parkinson's disease, the method comprising administering an effective amount of a compound according to formula I as described herein.

[0300] One embodiment of the present invention is a method for treating or preventing a disease, disorder or condition selected from asthma or COPD, the method comprising administering an effective amount of a compound according to formula I as described herein.

[0301] One embodiment of the present invention relates to a method for inhibiting NLRP3, the method comprising administering an effective amount of a compound according to formula I as described herein.

[0302] Another embodiment of the present invention is a compound of formula I as described herein, which is manufactured according to any one of the said methods.

[0303] One embodiment of the present invention is a pharmaceutical composition comprising a compound according to formula I as described herein and a therapeutically inert carrier.

[0304] Determination procedure

[0305] NLRP3 and pyroptosis

[0306] It is well known that the activation of NLRP3 leads to pyroptosis, and this feature plays an important role in the manifestation of clinical diseases (Yan-gang Liu et al., Cell Death & Disease, 2017, 8(2), e2579; Alexander Wree et al., Hepatology, 2014, 59(3), 898-910; Alex Baldwin et al., Journal of Medicinal Chemistry, 2016, 59(5), 1691-1710; Ema Ozaki et al., Journal of Inflammation Research, 2015, 8, 15-27; Zhen Xie and Gang Zhao, Neuroimmunology Neuroinflammation, 2014, 1(2), 60-65; Mattia Cocco et al., Journal of Medicinal Chemistry, 2014, 57(24), 10366-10382; T. Satoh et al., Cell Death & Disease, 2013, 4, e644). Therefore, inhibitors of NLRP3 are expected to prevent pyroptosis and the release of pro-inflammatory cytokines (such as IL-1β) from cells.

[0307] THP-1 cells: Culture and preparation

[0308] THP-1 cells (ATCC#TIB-202) were grown in RPMI containing L-glutamine (Gibco#11835) supplemented with 1 mM sodium pyruvate (Sigma#S8636) and penicillin (100 units / ml) / streptomycin (0.1 mg / ml) (Sigma#P4333) in 10% fetal bovine serum (FBS) (Sigma#F0804). Cells were passaged routinely and grown to confluence (about 10 6 cells / ml). On the day of the experiment, THP-1 cells were harvested and resuspended in RPMI medium (without FBS). Then the cells were counted and viability was checked by trypan blue (Sigma#T8154) (>90%). Appropriate dilutions were made to obtain a concentration of 625,000 cells / ml. LPS (Sigma#L4524) was added to the diluted cell solution to obtain a final assay concentration (FAC) of 1 μg / ml. 40 μl of the final preparation was aliquoted into each well of a 96-well plate. The plates thus prepared were used for compound screening.

[0309] THP-1 cell pyroptosis assay

[0310] Compound screening was carried out step by step according to the following method.

[0311] 1. THP-1 cells (25,000 cells / well) containing 1.0 μg / ml LPS were seeded in 40 μl of RPMI medium (without FBS) in a 96-well, black-walled, clear-bottom cell culture plate coated with poly-D-lysine (VWR#734-0317).

[0312] 2. 5 μl of the compound (8-point semi-log dilution, 10 μM highest dose) or vehicle (0.1% DMSO in FAC) was added to the appropriate wells.

[0313] 3. Incubate at 37 °C, 5% CO 2 for 3 hours.

[0314] 4. 5 μl of nigericin (Sigma#N7143) (5 μM in FAC) was added to all wells.

[0315] 5. Incubate at 37 °C, 5% CO 2 for 1 hour.

[0316] 6. At the end of the incubation period, spin the plate at 300 x g for 3 minutes and remove the supernatant.

[0317] 7. Then 50 μl of resazurin (Sigma#R7017) (100 μM resazurin in FAC, dissolved in RPMI medium without FBS) was added, and the plate was incubated for an additional 1 - 2 hours at 37 °C and 5% CO. 2

[0318] 8. Read the plate in an Envision reader at Ex 560 nm and Em 590 nm.

[0319] 9. IC 50 The data fit a non-linear regression equation (log inhibitor vs. response variable slope 4-parameter).

[0320] The results of the pyroptosis assay are summarized in Table 1 below as THP IC 50 .

[0321] Human whole blood IL-1β release assay

[0322] For systemic delivery, the ability to inhibit NLRP3 when the compound is present in the bloodstream is very important. For this reason, the NLRP3 inhibitory activity of multiple compounds in human whole blood was investigated according to the following protocol.

[0323] Human whole blood in lithium heparin tubes was obtained from healthy donors from a panel of volunteer donors.

[0324] ​1. Place 80 μl of whole blood containing 1 μg / ml LPS into a 96-well clear-bottom cell culture plate (Corning #3585).

[0325] 2. Add 10 μl of the compound (8-point half-log dilution, 10 μM highest dose) or vehicle (DMSO 0.1% FAC) to the appropriate wells.

[0326] 3. Incubate at 37 °C, 5% CO 2 for 3 hours.

[0327] 4. Add 10 μl of nigericin (Sigma #N7143) (10 μM FAC) to all wells.

[0328] 5. Incubate at 37 °C, 5% CO 2 for 1 hour.

[0329] 6. At the end of the incubation period, centrifuge the plate at 300 x g for 5 minutes to pellet the cells and remove 20 μl of the supernatant, and add it to a 96-well V-bottom plate for IL-1β analysis (Note: These plates containing the supernatant can be stored at -80 °C for later analysis).

[0330] 7. IL-1β was measured according to the manufacturer's protocol (Perkin Elmer - AlphaLisa IL-1 Kit AL220F-5000).

[0331] 8. IC 50 Data was fit to a non-linear regression equation (log inhibitor vs. response variable slope 4-parameter).

[0332] The results of the human whole blood assay are summarized in Table 1 below as HWB IC 50 .

[0333] hERG screening assay

[0334] During the development of small molecule drugs, one of the most common adverse side effects leading to drug failure is arrhythmia. Such failures are usually associated with the ability of the drug to inhibit the human ether-à-go-go related gene (hERG) cardiac potassium channel. Therefore, no or low inhibition of the hERG cardiac potassium channel is considered beneficial.

[0335] Cells

[0336] The CHO crelox hERG cell line (ATCC reference number PTA-6812, female Chinese hamster cells) was generated and validated by Roche. Ready-to-use frozen CHO-hERG cells were cryopreserved at Evotec (Germany) and used directly in the experiments.

[0337] Experimental solution

[0338] The extracellular solution contains (in mM): NaCl 150; KCl 4; CaCl 2 1; MgCl 2 1; HEPES 10; pH 7.2 - 7.4, containing NaOH, osmotic pressure 290 - 330 mOsm. The intracellular solution contains (in mM): KCl, 10; KF, 100; NaCl, 10; HEPES, 10; EGTA, 20; pH = 7.0 - 7.4, containing KOH, osmotic pressure 260 - 300 mOsm.

[0339] Electrophysiology

[0340] The effects of the compound on hERG K+ current parameters will be evaluated at two concentrations in at least 4 cells.

[0341] The hERG experiment was performed using an automated patch - clamp system 384 (Nanion Technologies GmbH, Germany). At 35 - 37 °C, K+ current was measured using the patch - voltage - clamp technique in the whole - cell configuration.

[0342] The cells were held at a resting voltage of - 80 mV and were stimulated by In Figure 1 the voltage pattern shown (pulse pattern for eliciting outward K + current at 35 - 37 °C) to activate the hERG channel and conduct the IKhERG current outward, with a stimulation frequency of 0.1 Hz (6 bpm)

[0343] Data analysis

[0344] The amplitude of IKhERG at each drug concentration was recorded and compared with the vehicle control value (recorded as 100%) to determine partial block. The concentration - response data were fitted with the following relationship:

[0345]

[0346] The concentration - response curve was fitted using non - linear regression analysis of the EworkBook suite (ID Business Solutions Ltd, UK). Data fitting was performed using a 4 - parameter logistic model (fit = (A+(B / (1+((x / C)^D)))), where A = 0 and B = 100).

[0347] The results of the hERG assay are summarized in Table 2 below as hERG IC 20 .

[0348] Transcellular P-gp assay:

[0349] For general assays, transfected LLC-PK1 cells (porcine kidney epithelial cells) overexpressing human or mouse P-gp are used and cultured on 96-well semi-permeable filter plates, where they form a polarized monolayer with tight junctions and act as a barrier between the apical and basolateral compartments.

[0350] P-gp is expressed in the apical membrane of the monolayer.

[0351] The tightness of the cell monolayer and the functional activity of P-gp are confirmed by adding the cell-impermeable marker fluorescein and the reference P-gp substrate edoxaban, respectively.

[0352] PAMPA :

[0353] PAMPA (Parallel Artificial Membrane Permeability Assay) is a first-line permeability screen for candidate drugs. The PAMPA assay uses an artificial phospholipid membrane to simulate transcellular absorption conditions. This assay determines permeability values that can be used for compound optimization and ranking purposes and input parameters for computer models to predict intestinal absorption.

[0354] The donor concentration is measured at the start time (reference) and compared with the donor and acceptor concentrations after a certain time (end time) to calculate the extent of compound passage through the membrane.

[0355] Microsomal stability :

[0356] Incubate the test compound (0.5 mg / mL) at 1 μM and the cofactor NADPH in microsomes in 96-well plates at 37 °C on a TECAN (Tecan Group Ltd, Switzerland) automated liquid handling system. After a 10-minute pre-incubation step of the test compound with microsomes, the enzymatic reaction is initiated by adding the cofactor. At 1, 3, 6, 9, 15, 25, 35, and 45 minutes, aliquots of the culture are taken and quenched with 1:3 (v / v) acetonitrile containing an internal standard. Subsequently, the samples are cooled and centrifuged, and the supernatant is then analyzed by LC-MS / MS2.

[0357] Metabolic stability in hepatocytes :

[0358] Assay description:

[0359] Biomaterials. Obtain cryopreserved hepatocytes [mouse, rat, rabbit, monkey, and human (male and female; mixed)]. Throughout the study, the viability of the reconstituted hepatocytes is at least 80%. Ready-to-use rat / human with matrix mouse fibroblasts (negative control; pooled) The culture [long-term hepatocyte co-culture; pooled (for humans, n = 5 males, n = 5 females)] is incubated with the plate, and it is necessary to apply the culture medium and maintain the culture medium.

[0360] Metabolism of suspended hepatocytes. Primary pooled cryopreserved hepatocytes are reconstituted in pre-warmed William’s E medium containing 10% FCS, 0.05 mg / mL streptomycin and 50 U / mL penicillin, and 0.4 mM L-glutamine; and 0.01 mg / mL gentamicin, 0.048 mg / mL hydrocortisone and 0.004 mg / mL insulin, with a final suspension density of 1×106 cells / mL. Cultivation is carried out fully automatically using a liquid handling system (Tecan) equipped with a CO2 incubator and an orbital shaker. After adding the test compound (e.g., 1 μM) to the wells (1×105 cells / well), the 96-well hepatocyte suspension culture plate is incubated at 37 °C and 5% CO2. Samples are quenched by adding acetonitrile (including the internal standard) to the incubation wells at specified time points up to 2 h.

[0361] By metabolism. Incubation of the test substance (e.g., 1 μM, 0.1% v / v DMSO) in the suspension assay is carried out in a 96-well plate containing a co-culture of adherent hepatocytes and mouse fibroblast control cells or separate control cells (5% CO2 atmosphere and 37 °C). The incubation medium in humans is the same as the incubation medium in suspended hepatocytes. At the specified time points (2, 18, 26, 48, 72, and 96 h), the entire well is quenched with ice-cold acetonitrile containing the internal standard.

[0362] Subsequently, the samples are centrifuged appropriately, and the supernatant is analyzed by LC-MS / MS. Incubation is carried out with n = 1 or 2.

[0363] Table 1: NLRP3 inhibitory activity

[0364]

[0365]

[0366] Table 2: hERG inhibition assay

[0367]

[0368] The present invention will now be illustrated by the following examples, which are not limiting.

[0369] If the preparation example is obtained in the form of a mixture of enantiomers or diastereomers, the pure enantiomers or diastereomers can be obtained by the methods described herein or methods known to those skilled in the art such as, for example, chiral chromatography or crystallization.

[0370] Experimental methods

[0371] Abbreviations:

[0372]

[0373]

[0374] Examples

[0375] Unless otherwise stated, all examples and intermediates were prepared under a nitrogen atmosphere.

[0376] Synthesis of intermediates:

[0377] Intermediate 1

[0378] 6-Chloro-4-methyl-3-methylthio-1,2,4-triazin-5-one

[0379]

[0380] Isopentyl nitrite (2.02 mL, 15.01 mmol, 2.02 eq) was added dropwise to a mixture of 6-amino-4-methyl-3-methylthio-1,2,4-triazin-5-one (CAS# 89730-72-3, 1.28 g, 7.43 mmol, 1.0 eq), benzyltriethylammonium chloride (2.54 g, 11.2 mmol, 1.5 eq), copper(I) chloride (1.47 g, 14.9 mmol, 2.0 eq) and lithium chloride (472.6 mg, 11.2 mmol, 1.5 eq) in MeCN (30 mL), and the mixture was heated at 60 °C for 2 h. The reaction mixture was cooled, diluted with TBME (50 ml) and filtered through celite. The filtrate was washed with water (50 ml), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (40 g column, 0-50% EtOAc / isohexane) to afford the title compound (570 mg, 39%), which was a white solid. LCMS: m / z 192.3 / 194.0 [M+H] + , ESI pos.

[0381] Synthesis of examples

[0382] Example 1:

[0383] 3-[[(3R)-1-Ethyl-3-piperidinyl]amino]-6-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5-one; formic acid

[0384]

[0385] Step A: 6-[2-Methoxy-4-(trifluoromethyl)phenyl]-4-methyl-3-methylthio-1,2,4-triazin-5-one

[0386] To a stirred solution of 6-chloro-4-methyl-3-methylthio-1,2,4-triazin-5-one intermediate 1 (500 mg, 2.48 mmol, 1.0 eq), 2-methoxy-4-(trifluoromethyl)-phenylboronic acid (670 mg, 3.02 mmol, 1.22 eq) and Xphos Pd G3 (215 mg, 0.25 mmol, 0.1 eq) in 1,4-dioxane (5 mL) was added sodium carbonate (saturated aqueous solution) (0.5 mL, 7.44 mmol, 3.0 eq). Using N 2 The mixture was degassed three times and the reaction mixture was stirred at 100 °C for 6 h and then left to stand overnight at room temperature. The reaction mixture was diluted with water (15 mL) and EtOAc (40 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2 × 15 mL). The combined organic layers were dried (Na 2 SO 4 )), filtered and concentrated to dryness. The crude product was purified by flash column chromatography on silica gel (24 g column, 0% to 100% TBME / isohexane) to give the title compound (411 mg, 45%) as a pale yellow solid. LCMS m / z 332.0 [M+H] + ESI pos.

[0387] Step B: 3-[[(3R)-1-Ethyl-3-piperidinyl]amino]-6-[2-methoxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5-one

[0388] A solution of 6-[2-methoxy-4-(trifluoromethyl)phenyl]-4-methyl-3-methylthio-1,2,4-triazin-5-one (step A) (278 mg, 0.76 mmol, 1.0 eq) and (3R)-1-ethylpiperidin-3-amine (610 mg, 4.76 mmol, 6.3 eq) in pyridine (2 mL) was heated at 90 °C for 72 h. The reaction mixture was cooled and diluted with DCM (50 mL) and water (10 mL). The layers were separated and the organic layer was washed with brine (3 × 10 mL), dried (Na 2SO 4 ) Filter and concentrate to dryness. Then purify the crude product by flash column chromatography on silica gel (24 g column, eluting with DCM loaded with 0% to 10% MeOH (0.7 M NH 3 ) / DCM) to afford the title compound (212 mg, 61%), which is a thick brown oil. LCMS m / z 412.2 [M+H] + ESI pos.

[0389] Step C: 3-[[(3R)-1-Ethyl-3-piperidinyl]amino]-6-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5-one; formic acid

[0390] At 0 °C, boron tribromide solution (2.9 mL, 2.90 mmol, 1 M in DCM, 5.01 eq) was added dropwise to a solution of 3-[[(3R)-1-ethyl-3-piperidinyl]amino]-6-[2-methoxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5-one (Step B) (238 mg, 0.58 mmol, 1.0 eq) in DCM (8 mL). The reaction mixture was stirred for 30 minutes and then quenched with 0.7 M NH 3 MeOH (10 mL) and stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. The crude product was dissolved in DMSO (8 mL), filtered, and purified by reversed-phase preparative HPLC (Gilson) using a Phenomenex Gemini NC-C 18 preparative column, 5 μm, 30 mm X 150 mm, flow rate 42 mL min-1, eluting with a gradient of 0.1% formic acid in water - MeCN for 15 minutes. A column dilution pump provided 5 mL min -1 MeCN for 1.2 minutes. Gradient information: 0.0 - 1.0 minute, 90% MeCN; 1.0 - 11.0 minutes, changing linearly from 90% MeCN to 65% MeCN; 11.1 to 14.0 minutes, changing linearly from 65% MeCN to 100% MeCN; 14.1–15.0 minutes, equilibrating from 100% to 90% MeCN. The clear fractions were evaporated in a Genevac to afford the title compound (142 mg, 54% yield), which is a yellow solid. LCMS m / z 398.4 [M+H] + ESI pos.

[0391] Example 2:

[0392] 3-[[(3R)-1-Ethyl-3-piperidinyl]amino]-6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5-one

[0393]

[0394] Step A: 6-[2-Methoxy-6-methyl-4-(trifluoromethyl)phenyl]-4-methyl-3-methylthio-1,2,4-triazin-5-one

[0395] To a stirred solution of 6-chloro-4-methyl-3-methylthio-1,2,4-triazin-5-one intermediate 1 (300 mg, 1.49 mmol, 1.0 eq), [2-methoxy-6-methyl-4-(trifluoromethyl)phenyl]boronic acid (423.4 mg, 1.81 mmol, 1.22 eq), and XphosPd G3 (129.0 mg, 0.15 mmol, 0.1 eq) in 1,4-dioxane (3 mL) was added sodium carbonate (saturated aqueous solution) (0.3 mL). The mixture was degassed three times and stirred at 90 °C for 12 h under N 2 and. 2 Water (15 mL) and EtOAc (40 mL) were added. The layers were separated and the aqueous layer was extracted with EtOAc (2 × 15 mL). The combined organic layers were dried (Na 2 SO 4 ), filtered, and concentrated to dryness. The product was purified by flash column chromatography on silica gel (24 g column, 0-60% TBME / isohexane) to afford the title compound (87.0 mg, 16%) as a pale yellow gum.

[0396] LCMS m / z 346.23 [M+H] + ESI pos.

[0397] Step B: 3-[[(3R)-1-Ethyl-3-piperidinyl]amino]-6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5-one

[0398] A solution of 6-[2-methoxy-6-methyl-4-(trifluoromethyl)phenyl]-4-methyl-3-methylthio-1,2,4-triazin-5-one (80.0 mg, 0.23 mmol, 1.0 eq) and (3R)-1-ethylpiperidin-3-amine dihydrochloride (293.5 mg, 1.46 mmol, 6.3 eq) in pyridine (2 mL) was heated at 90 °C for 4 days. The reaction mixture was cooled to room temperature and DCM (50 mL) and water (10 mL) were added. The layers were separated and the organic layer was washed with brine (3 × 10 mL), dried over Na 2 SO 4 , filtered and concentrated to dryness. The crude intermediate was then purified by flash column chromatography on silica gel (24 g column, 0 - 10% MeOH (0.7 M NH 3 ) / DCM) to afford a brown solid (21.0 mg). The brown solid was dissolved in DCM (2 mL) cooled to 0 °C and boron tribromide (1 M in DCM) (1.16 mL, 1.16 mmol, 5.0 eq) was added and the mixture was then allowed to warm to room temperature and stirred for 18 h. The reaction mixture was added to a stirred solution of 0.7 M NH3 in MeOH (10 mL) at 0 °C, allowed to warm to room temperature overnight and then concentrated. The brown residue was dissolved in DCM (25 mL) and water (10 mL), the layers were separated and the organic layer was dried (MgSO 4 ) and concentrated to dryness. The product was purified by chromatography on silica gel (12 g column, 0 - 10% MeOH (0.7 M NH 3 ) / DCM) to afford the title compound (7.0 mg, 7%) as a light brown solid. LCMS m / z 412.24 [M+H] + ESI pos.

[0399] Intermediate 2

[0400] 6-Iodo-4-methyl-3-methylthio-1,2,4-triazin-5-one

[0401]

[0402] Amyl nitrite (320.0 μL, 2.38 mmol, 2.05 eq) was added dropwise to a mixture of 6-amino-4-methyl-3-methylthio-1,2,4-triazin-5-one (CAS# 89730-72-3; 200.0 mg, 1.16 mmol, 1.0 eq), tetrabutylammonium iodide (648.0 mg, 1.75 mmol, 1.51 eq), cuprous iodide (447.0 mg, 2.35 mmol, 2.02 eq) and lithium iodide (330.0 mg, 2.47 mmol, 2.12 eq) in MeCN (4 mL), and the mixture was heated at 60 °C for 3 h. The reaction mixture was cooled, diluted with EtOAc (50 mL) and filtered through celite, rinsed with EtOAc (2 x 50 mL). The filtrate was diluted with water (100 mL) and the separated aqueous phase was further extracted with EtOAc (2 × 50 mL). The combined organic layers were dried (Na 2 SO 4 ), filtered and evaporated to give the crude product. The residue was purified by chromatography on silica gel (40 g column, 0-100% EtOAc / isohexane) to give the title compound (156.0 mg, 46% yield), which was a yellow solid. LCMS: m / z 284.0 [M+H] + , ESI pos.

[0403] Intermediate 3:

[0404] 2-(4-Benzyloxy-6-methyl-indan-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0405]

[0406] Step A: 5-Bromo-6-methyl-indan-4-ol

[0407] At 0 °C, sodium nitrite (200.0 mg, 2.9 mmol, 1.3 eq) in water (5 mL) was added dropwise to 5-bromo-6-methyl-indan-4-amine (500.0 mg, 2.21 mmol, 1.0 eq, CAS#2411531-03-6) (2 M in THF) in sulfuric acid (10.0 mL, 20.0 mmol, 9.0 eq). The reaction was stirred for about 30 minutes and then allowed to warm to room temperature over about 30 minutes. Then, at 50 °C, the reaction mixture was added dropwise to a stirred solution of sulfuric acid (10.0 mL, 20.0 mmol, 9.0 eq) (2 M in THF) and the reaction was stirred for an additional 2.5 h. The reaction was allowed to cool to room temperature and then diluted with water (100 mL) and EtOAc (100 mL). The layers were separated and the aqueous phase was extracted again with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (1 x 50 mL), dried over MgSO 4 and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (0 - 20% EtOAc / isohexane) to afford the title compound (211.3 mg, 42% yield) as an off-white solid. 1 H NMR (500 MHz, DMSO) δ 9.13 (br s, 1H), 6.70 (s, 1H), 2.80 (t, 2H), 2.76 (t, 2H), 2.27 (s, 3H), 1.97 (p, 2H).

[0408] Step B : 4-benzyloxy-5-bromo-6-methylindane

[0409] Potassium carbonate (185.0 mg, 1.34 mmol, 2.0 eq) was added to a stirred solution of 5-bromo-6-methyl-indan-4-ol (150.0 mg, 0.66 mmol, 1.0 eq) in acetone (5 mL) and the reaction was stirred at room temperature for 5 minutes. Then benzyl bromide (0.1 mL, 0.84 mmol, 1.27 eq) was added dropwise and the reaction was stirred for an additional ~36 h. The reaction mixture was concentrated in vacuo and then dissolved in DCM (30 mL) and water (30 mL). The organic layer was separated and the aqueous layer was extracted again with DCM (2 x 30 mL). The combined organic layers were washed with brine (1 x 30 mL), dried over MgSO 4 and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (0 - 10% EtOAc / isohexane) to afford the title compound (191.3 mg, 90% yield) as a pale yellow oil. 11H NMR (500 MHz, DMSO) δ 7.54–7.48 (m, 2H), 7.44–7.38 (m, 2H), 7.38–7.32 (m, 1H), 7.01 (s, 1H), 4.95 (s, 2H), 2.89 (t, 2H), 2.80 (t, 2H), 2.33 (s, 3H), 2.06–1.95 (m, 2H).

[0410] Step C: 2-(4-Benzyloxy-6-methyl-indan-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0411] At -78 °C, n-butyllithium (1.6 M in hexanes) (4.41 mL, 7.06 mmol, 1.6 eq) was added dropwise to a stirred solution of 4-benzyloxy-5-bromo-6-methyl-indane (1.4 g, 4.41 mmol, 1.0 eq) and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.35 mL, 6.62 mmol, 1.5 eq) in THF (20 mL), and the reaction was stirred for 3 h. The reaction was quenched by slow addition of saturated NH 4 Cl aqueous solution (20 mL). The mixture was allowed to warm to room temperature over 18 h. The layers were separated, and the aqueous layer was extracted with EtOAc (2 x 20 mL), and then the combined organic layers were concentrated in vacuo. The crude product was purified by silica gel chromatography (0 - 5% (heptane / EtOAc)) to afford the title compound (975.0 mg, 60% yield), which was a light brown solid. 1 1H NMR (500 MHz, DMSO) δ 7.48–7.42 (m, 2H), 7.41–7.35 (m, 2H), 7.35–7.30 (m, 1H), 6.81 (s, 1H), 4.91 (s, 2H), 2.83 (dt, 4H), 2.25 (s, 3H), 1.97 (p, 2H), 1.22 (s, 12H).

[0412] Example 3:

[0413] 3-[[(3R)-1-Ethyl-3-piperidinyl]amino]-6-(4-hydroxy-6-methyl-indan-5-yl)-4-methyl-1,2,4-triazin-5-one

[0414]

[0415] Step A: 6-(4-Benzyloxy-6-methyl-indan-5-yl)-4-methyl-3-methylthio-1,2,4-triazin-5-one

[0416] 2-(4-benzyloxy-6-methyl-indan-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane intermediate 3 (322.0 mg, 0.88 mmol, 1.11 eq), 6-iodo-4-methyl-3-methylthio-1,2,4-triazin-5-one intermediate 2 (225.0 mg, 0.79 mmol, 1.0 eq), K 2 CO 3 (352.0 mg, 2.55 mmol, 3.2 eq) and Pd-170 (111.0 mg, 0.16 mmol, 0.21 eq) in a mixture of MeCN (12 mL) and water (4 mL) were degassed with N 2 for 5 minutes and then heated to 60 °C for 21 hours. A slow stream of N 2 was added to the reaction mixture through a needle to minimize the formation of the diMeS byproduct. The reaction was cooled, concentrated and loaded onto celite. The crude product was purified by column chromatography on C18 silica gel (40 g column, 10 - 100% [0.1% formic acid in MeCN: 0.1% formic acid in aqueous solution]) to afford the title compound (86.0 mg, 24% yield), which was a yellow solid. LCMS m / z 394.2 [M+H] + ESI pos.

[0417] Step B : 6-(4-benzyloxy-6-methyl-indan-5-yl)-4-methyl-3-[[(3R)-1-benzyl-3-piperidinyl]amino]-1,2,4-triazin-5-one; formate

[0418] 6-(4-benzyloxy-6-methyl-indan-5-yl)-4-methyl-3-methylthio-1,2,4-triazin-5-one (70.0 mg, 0.18 mmol, 1.0 eq) was added to an MW vial and (R)-3-amino-1-benzylpiperidine (170.0 mg, 0.89 mmol, 5.02 eq; CAS# 168466-84-0) was added. The mixture was then irradiated at 180 °C for 2 hours. The reaction was cooled to room temperature and the resulting thick black residue was dissolved in DCM and loaded onto celite. The crude product was purified by reverse-phase column chromatography on C18 silica gel (26 g column, 10 - 100% [0.1% formic acid in MeCN: 0.1% formic acid in aqueous solution]) to afford the title compound (35.0 mg, 36% yield), which was a light brown solid, and another portion of the title compound (18.0 mg, 17% yield), which was a dark brown solid. LCMS m / z 536.4 [M+H] + ESI pos.

[0419] Step C : 3-[[(3R)-1-Ethyl-3-piperidinyl]amino]-6-(4-hydroxy-6-methyl-indan-5-yl)-4-methyl-1,2,4-triazin-5-one

[0420] Pd / C (type 39) (32.0 mg, 0.02 mmol, 0.25 eq) and Pd / C (type 87) (16.0 mg, 0.02 mmol, 0.25 eq) were added to a stirred solution of 6-(4-benzyloxy-6-methyl-indan-5-yl)-4-methyl-3-[[(3R)-1-benzyl-3-piperidinyl]amino]-1,2,4-triazin-5-one; formate (35.0 mg, 0.1 mmol, 1.0 eq) in acetonitrile (2.1 mL). At room temperature, the hydrogenation vessel was placed under a hydrogen atmosphere (2 bar) and stirred vigorously for 4 hours. The reaction was filtered through a Celite plug, rinsed with EtOH and concentrated to dryness to give the crude product. The crude product was purified by column chromatography on silica gel (24 g column, 0 - 10% MeOH(0.7M NH 3 ) / DCM), and after lyophilization, the title compound (20.0 mg, 85% yield) was obtained as a light yellow lyophilized solid. LCMS m / z 384.3 [M+H] + ESI pos.

[0421] Example 4:

[0422] 3-[[(3R)-1-(2-Hydroxyethyl)-3-piperidinyl]amino]-6-(4-hydroxy-6-methyl-indan-5-yl)-4-methyl-1,2,4-triazin-5-one

[0423]

[0424] Step A : 6-(4-Hydroxy-6-methyl-indan-5-yl)-4-methyl-3-[[(3R)-3-piperidinyl]amino]-1,2,4-triazin-5-one

[0425] Pd / C (type 39) (20.0 mg, 0.01 mmol, 0.29 eq) and Pd / C (type 87) (10.0 mg, 0.01 mmol, 0.29 eq) were added to a stirred solution of 6-(4-benzyloxy-6-methyl-indan-5-yl)-4-methyl-3-[[(3R)-1-benzyl-3-piperidinyl]amino]-1,2,4-triazin-5-one; formate Example 3 Step B (19.0 mg, 0.03 mmol, 1.0 eq) in 1,4-dioxane (3 mL). At room temperature, the hydrogenation vessel was placed under a hydrogen atmosphere (2 bar) and stirred vigorously for 18 h. Additional Pd / C (type 39) (20.0 mg, 0.01 mmol, 0.29 eq) and Pd / C (type 87) (10.0 mg, 0.01 mmol, 0.29 eq) were added and the reaction was placed under these conditions again for 24 h. The reaction was filtered through a Celite plug, rinsed with EtOH and concentrated to dryness to afford the title compound (7 mg, 42% yield), which was used in the next step without further purification. LCMS m / z 356.3 [M+H] + ESI pos.

[0426] Step B : 3-[[(3R)-1-(2-Hydroxyethyl)-3-piperidinyl]amino]-6-(4-hydroxy-6-methyl-indan-5-yl)-4-methyl-1,2,4-triazin-5-one

[0427] At room temperature, 2-iodoethanol (3.39 mg, 0.02 mmol, 1.0 eq) in DMF (0.100 mL) was added dropwise to a stirred solution of 6-(4-hydroxy-6-methyl-indan-5-yl)-4-methyl-3-[[(3R)-3-piperidinyl]amino]-1,2,4-triazin-5-one (7.0 mg, 0.02 mmol, 1.0 eq) and DIPEA (5.15 uL, 0.03 mmol, 1.5 eq) in DMF (0.30 mL), and the reaction mixture was stirred for 3 days. The reaction mixture was concentrated to dryness, then loaded onto Celite. The crude product was then purified by reverse phase flash column chromatography (C18 13 g column, 10-100% MeCN / 10 mM NH 4 HCO 3 aqueous solution), and after lyophilization, the title compound (2.0 mg, 24% yield) was obtained as an off-white solid. LCMS m / z 400.5 [M+H] + ESI pos.

[0428] Example 5:

[0429] 3-[[(3R)-1-ethyl-3-piperidinyl]amino]-6-(4-hydroxy-6-methyl-2,3-dihydrobenzofuran-5-yl)-4-methyl-1,2,4-triazine-5-one

[0430]

[0431] Step A :6-(4-benzyloxy-6-methyl-2,3-dihydrobenzofuran-5-yl)-4-methyl-3-methylsulfanyl-1,2,4-triazine-5-one

[0432] 2-(4-benzyloxy-6-methyl-2,3-dihydrobenzofuran-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (217.0 mg, 0.59 mmol, 1.12 eq, CAS#2923540-53-6), 6-iodo-4-methyl-3-methylsulfanyl-1,2,4-triazine-5-one intermediate 2 (150.0 mg, 0.53 mmol, 1.0 eq), K 2 CO 3 A mixture of daptomycin (220.0 mg, 1.59 mmol, 3.0 eq) and Pd-170 (71.0 mg, 0.11 mmol, 0.2 eq) in MeCN (10 mL) and water (2 mL) was stirred with N 2 Degas for 5 minutes and then heat to 60 °C for 2 hours. N 2 A slow stream of 20% NH 2-(2-(4-(2-methyl-1-oxo-2-yl)-4-nitropropene) was added to the reaction mixture to limit the formation of diMeS byproducts as much as possible. The reaction was stirred for about 4 days. The reaction was cooled, concentrated and loaded onto diatomaceous earth. The crude product was purified by column chromatography on C18 silica gel (40 g column, 10-100% [0.1% formic acid MeCN: 0.1% formic acid in water] to give the title compound (36.0 mg, 17% yield) as a yellow solid. LCMS m / z 395.8 [M+H] + ESIpos.

[0433] Step B :6-(4-Benzyloxy-6-methyl-2,3-dihydrobenzofuran-5-yl)-4-methyl-3-[[(3R)-1-benzyl-3-piperidinyl]amino]-1,2,4-triazine-5-one; formate

[0434] 6-(4-benzyloxy-6-methyl-2,3-dihydrobenzofuran-5-yl)-4-methyl-3-methylthio-1,2,4-triazin-5-one (35.0 mg, 0.09 mmol, 1.0 eq) was added to an MW vial and (R)-3-amino-1-benzylpiperidine (160.0 mg, 0.84 mmol, 9.5 eq; CAS# 168466-84-0) was added. The mixture was then irradiated at 180 °C for 1 hour. The reaction was cooled to room temperature and the resulting thick black residue was dissolved in DCM and loaded onto diatomaceous earth. The crude product was purified by reverse-phase column chromatography on C18 silica gel (26 g column, 10 - 100% [0.1% formic acid in MeCN: 0.1% aqueous formic acid]) to afford the title compound (30.0 mg, 54% yield), which was a brown solid. LCMS m / z 538.4 [M+H] + ESI pos.

[0435] Step C : 3-[[(3R)-1-ethyl-3-piperidinyl]amino]-6-(4-hydroxy-6-methyl-2,3-dihydrobenzofuran-5-yl)-4-methyl-1,2,4-triazin-5-one

[0436] Pd / C (type 39) (24.0 mg, 0.01 mmol, 0.26 eq) and Pd / C (type 87) (12.0 mg, 0.01 mmol, 0.26 eq) were added to a stirred solution of 6-(4-benzyloxy-6-methyl-2,3-dihydrobenzofuran-5-yl)-4-methyl-3-[[(3R)-1-benzyl-3-piperidinyl]amino]-1,2,4-triazin-5-one; formate (30.0 mg, 0.04 mmol, 1.0 eq) in acetonitrile (3.0 mL). At room temperature, the hydrogenation vessel was placed under a hydrogen atmosphere (2 bar) and stirred vigorously for 18 hours. The reaction was filtered through a plug of diatomaceous earth, rinsed with EtOH and concentrated to dryness to afford the crude product (14 mg). The crude product was purified by column chromatography on silica gel (12 g column, 0 - 10% MeOH (0.7 M NH 3 ) / DCM), and after lyophilization, the title compound (8.0 mg, 47% yield) was obtained as a pale yellow lyophilized solid. LCMS m / z 386.2 [M+H] + ESI pos.

[0437] Example 6:

[0438] 6-(4-chloro-2-hydroxy-6-methyl-phenyl)-3-[[(3R)-1-ethyl-3-piperidinyl]amino]-4-methyl-1,2,4-triazin-5-one

[0439]

[0440] Step A : 6-(4-chloro-2-hydroxy-6-methyl-phenyl)-4-methyl-3-methylsulfanyl-1,2,4-triazin-5-one

[0441] (4-Chloro-2-hydroxy-6-methyl-phenyl)boronic acid (200.0 mg, 1.07 mmol, 1.03 eq; CAS# 1207961-50-9), 6-iodo-4-methyl-3-methylsulfanyl-1,2,4-triazin-5-one intermediate 2 (295.0 mg, 1.04 mmol, 1.0 eq), K 2 CO 3 (430.0 mg, 3.11 mmol, 2.99 eq) and Pd-170 (140.0 mg, 0.21 mmol, 0.2 eq) in a solution of MeCN (12 mL) and water (3 mL) were degassed with N 2 for 5 minutes and then heated at 60 °C for 20 hours. The reaction was cooled, concentrated and loaded onto diatomaceous earth. The crude product was purified by column chromatography on C18 silica gel (40 g column, 10 - 100% [0.1% formic acid in MeCN: 0.1% formic acid aqueous solution]) to give the title compound (132.0 mg, 39% yield), which was a pale yellow solid. LCMS m / z 298.1 / 300.1 [M+H] + ESI pos.

[0442] Step B : 6-(4-chloro-2-hydroxy-6-methyl-phenyl)-3-[[(3R)-1-ethyl-3-piperidinyl]amino]-4-methyl-1,2,4-triazin-5-one

[0443] An MW vial containing 6-(4-chloro-2-hydroxy-6-methyl-phenyl)-4-methyl-3-methylsulfanyl-1,2,4-triazin-5-one (65.0 mg, 0.22 mmol, 1.0 eq) and (3R)-1-ethylpiperidin-3-amine (121.0 mg, 0.94 mmol, 4.32 eq) was irradiated at 180 °C for 0.5 hour, during which almost complete conversion was observed. The reaction mixture was concentrated to dryness and then loaded onto diatomaceous earth. The crude product was then purified by reverse phase flash column chromatography (C18 13 g column, 10 - 100% MeCN / 10 mM NH 4 HCO 3 aqueous solution) to give the title compound (35.0 mg, 40% yield), which was a pale yellow solid. LCMS m / z 378.3 / 380.2 [M+H] + , ESI pos.

[0444] Example A

[0445] The compound of formula I can be used as an active ingredient for producing tablets composed of the following in a manner known per se:

[0446]

[0447]

[0448] Example B

[0449] The compound of formula I can be used as an active ingredient for producing capsules composed of the following in a manner known per se:

Claims

1. A compound of formula I, wherein R 1 is H, acetyl, SF 5 , halogenated, alkyl, alkoxy, haloalkyl, haloalkoxy or cyano; R 5 is H; or R 1 and R 5 and the atoms to which they are bonded form a 4- to 6-membered heterocycle containing a single O heteroatom, said heterocycle being optionally substituted with one or two substituents independently selected from halo and alkyl, or R 1 and R 5 and the atoms to which they are bonded form a 4- to 6-membered cycloalkyl ring optionally substituted with 1 to 2 substituents independently selected from halo and alkyl; R 2 is H, halogen, alkyl, alkoxy, alkoxyalkyl, haloalkyl, cycloalkyl, where the cycloalkyl is optionally substituted by halogen; R 3 is H or an alkyl group; R 4a is a heterocycle optionally substituted with 1 to 3 substituents independently selected from the following: halogen, alkyl, haloalkyl, hydroxyalkyl, -OH, oxo, -CO 2 H, cycloalkylalkyl or cycloalkyl optionally substituted with halogen, and R 4b is H, or R 4a and R 4b and N to which they are bonded form a 9-membered heterocycle containing 1 or 2 N heteroatoms, which heterocycle is optionally substituted with 1 or 2 substituents independently selected from alkyl, -OH or halo; and its pharmaceutically acceptable salts.

2. The compound according to claim 1, wherein R 1 is halogenated, haloalkyl or haloalkoxy and R 5 is H; or R 1 and R 5 and the atoms to which they are bonded form a 4- to 6-membered heterocycle containing a single O heteroatom, the heterocycle being optionally substituted with one or two substituents independently selected from halogenated and alkyl, or R 1 and R 5 and the atoms to which they are bonded form a 4- to 6-membered cycloalkyl ring optionally substituted with 1 to 2 substituents independently selected from halogenated and alkyl.

3. The compound according to claim 1 or claim 2, wherein R 1 is halogenated, haloalkyl or haloalkoxy and R 5 is H; or R 1 and R 5 and the atoms to which they are bonded form a 5-membered heterocycle containing a single O heteroatom, or R 1 and R 5 and the atoms to which they are bonded form a 5-membered cycloalkyl ring.

4. The compound according to any one of claims 1 to 3, wherein R 1 is halogenated, haloalkyl or haloalkoxy.

5. The compound according to any one of claims 1 to 4, wherein R 1 is a haloalkyl group.

6. The compound according to any one of claims 1 to 5, wherein R 5 is H, or R 1 and R 5 and the atoms to which they are attached form a 5-membered heterocycle containing a single O heteroatom, or R 1 and R 5 and the atoms to which they are attached form a 5-membered cycloalkyl ring.

7. The compound according to any one of claims 1 to 6, wherein R 5 is H.

8. The compound according to any one of claims 1 to 7, wherein R 2 is H or alkyl.

9. The compound according to any one of claims 1 to 8, wherein R 2 is H.

10. The compound according to any one of claims 1 to 9, wherein R 3 is an alkyl group.

11. The compound according to any one of claims 1 to 10, wherein R 4a is a 6-membered heterocycle containing a single N heteroatom substituted by alkyl or hydroxyalkyl, and R 4b is H, or R 4a and R 4b and the N to which they are bonded form a 9-membered heterocycle containing 1 or 2 N heteroatoms optionally substituted by alkyl.

12. The compound according to any one of claims 1 to 11, wherein R 4a is a 6-membered hetero ring containing a single N heteroatom substituted by an alkyl group, and R 4b is H, or R 4a and R 4b and the N to which they are bonded form a 9-membered hetero ring optionally substituted by an alkyl group and containing 1 or 2 N heteroatoms.

13. The compound according to any one of claims 1 to 12, wherein R 4a is a 6-membered hetero ring containing a single N heteroatom substituted by an alkyl group, and R 4b is H, or R 4a and R 4b and the N to which they are bonded form a 9-membered hetero ring containing 2 N heteroatoms, wherein the 9-membered hetero ring containing 2 N heteroatoms is substituted by an alkyl group.

14. A compound according to any one of claims 1 to 13, wherein R 4a is ethylpiperidyl and R 4b is H.

15. The compound according to claim 1, wherein R 1 is halogen, haloalkyl or haloalkoxy; R 5 is H; or R 1 and R 5 and the atoms to which they are bonded form a 5-membered hetero ring containing a single O heteroatom, or R 1 and R 5 and the atoms to which they are bonded form a 5-membered cycloalkyl ring; R 2 is H, halogen, alkyl, haloalkyl, cycloalkyl, where the cycloalkyl is optionally substituted with halogen; R 3 is an alkyl group; R 4a is a 6-membered heterocycle substituted by the following: alkyl, hydroxyalkyl, cycloalkylalkyl or cycloalkyl optionally substituted by halogen, and R 4b is H, or R 4a and R 4b and the N to which they are bonded form an optionally alkyl- or halo-substituted 9-membered heterocycle containing 1 or 2 N heteroatoms; and its pharmaceutically acceptable salts.

16. The compound according to claim 1, wherein R 1 is halogenated, haloalkyl or haloalkoxy; R 5 is H; or R 1 and R 5 and the atoms to which they are bonded form a 5-membered heterocycle containing a single O heteroatom, or R 1 and R 5 and the atoms to which they are bonded form a 5-membered cycloalkyl ring; R 2 is H or an alkyl group; R 3 is an alkyl group; R 4a is a 6-membered heterocycle containing a single N heteroatom substituted by an alkyl or hydroxyalkyl group, and R 4b is H, or R 4a and R 4b and the N to which they are bonded form an optionally alkyl-substituted 9-membered heterocycle containing 1 or 2 N heteroatoms; and its pharmaceutically acceptable salts.

17. The compound according to claim 1, wherein R 1 is halogen, haloalkyl or haloalkoxy; R 5 is H; or R 1 and R 5 and the atoms to which they are bonded form a 5-membered heterocycle containing a single O heteroatom, or R 1 and R 5 and the atoms to which they are bonded form a 5-membered cycloalkyl ring; R 2 is H or an alkyl group; R 3 is an alkyl group; R 4a is a 6-membered heterocycle containing a single N heteroatom substituted by an alkyl or hydroxyalkyl group, and R 4b is H, or R 4a and R 4b and the N to which they are bonded form a 9-membered heterocycle containing 2 N heteroatoms, wherein the 9-membered heterocycle containing 2 N heteroatoms is substituted with an alkyl group; and its pharmaceutically acceptable salts.

18. The compound according to claim 1, wherein R 1 is halogenated, haloalkyl or haloalkoxy; R 5 is H; or R 1 and R 5 and the atoms to which they are bonded form a 5-membered heterocycle containing a single O heteroatom, or R 1 and R 5 and the atoms to which they are bonded form a 5-membered cycloalkyl ring; R 2 is H or an alkyl group; R 3 is an alkyl group; R 4a is an alkyl-substituted 6-membered heterocycle containing a single N heteroatom, and R 4b is H, or R 4a and R 4b and the N to which they are bonded form an optionally alkyl-substituted 9-membered heterocycle containing 1 or 2 N heteroatoms; and its pharmaceutically acceptable salts.

19. The compound according to claim 1, wherein R 1 is halogen, haloalkyl or haloalkoxy; R 5 is H; or R 1 and R 5 and the atoms to which they are bonded form a 5-membered heterocycle containing a single O heteroatom, or R 1 and R 5 and the atoms to which they are bonded form a 5-membered cycloalkyl ring; R 2 is H or an alkyl group; R 3 is an alkyl group; R 4a is an alkyl-substituted 6-membered heterocycle containing a single N heteroatom, and R 4b is H, or R 4a and R 4b and the N to which they are bonded form a 9-membered heterocycle containing 2 N heteroatoms, wherein the 9-membered heterocycle containing 2 N heteroatoms is substituted with an alkyl group; and its pharmaceutically acceptable salts.

20. The compound according to claim 1, wherein R 1 is halogen, haloalkyl or haloalkoxy; R 5 is H; or R 1 and R 5 and the atoms to which they are bonded form a 5-membered heterocycle containing a single O heteroatom, or R 1 and R 5 and the atoms to which they are bonded form a 5-membered cycloalkyl ring; R 2 is an alkyl group; R 3 is an alkyl group; R 4a is an alkyl-substituted 6-membered heterocycle containing a single N heteroatom, and R 4b is H, or R 4a and R 4b and the N to which they are bonded form a 9-membered heterocycle containing 2 N heteroatoms, wherein the 9-membered heterocycle containing 2 N heteroatoms is alkyl-substituted; and its pharmaceutically acceptable salts.

21. The compound according to any one of claims 1 to 20, which is selected from 3-[[(3R)-1-Ethyl-3-piperidinyl]amino]-6-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5-one; 3-[[(3R)-1-Ethyl-3-piperidinyl]amino]-6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5-one; and its pharmaceutically acceptable salts.

22. The compound according to any one of claims 1 to 20, which is selected from 3-[[(3R)-1-Ethyl-3-piperidinyl]amino]-6-(4-hydroxy-6-methyl-indan-5-yl)-4-methyl-1,2,4-triazin-5-one; 3-[[(3R)-1-(2-Hydroxyethyl)-3-piperidinyl]amino]-6-(4-hydroxy-6-methyl-indan-5-yl)-4-methyl-1,2,4-triazin-5-one; 3-[[(3R)-1-Ethyl-3-piperidinyl]amino]-6-(4-hydroxy-6-methyl-2,3-dihydrobenzofuran-5-yl)-4-methyl-1,2,4-triazin-5-one; 6-(4-Chloro-2-hydroxy-6-methyl-phenyl)-3-[[(3R)-1-ethyl-3-piperidinyl]amino]-4-methyl-1,2,4-triazin-5-one; and its pharmaceutically acceptable salts.

23. The compound according to any one of claims 1 to 21, wherein the compound is 3-[[(3R)-1-Ethyl-3-piperidinyl]amino]-6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5-one or its pharmaceutically acceptable salt.

24. The compound according to any one of claims 1 to 20 or 22, wherein the compound is selected from 3-[[(3R)-1-Ethyl-3-piperidinyl]amino]-6-(4-hydroxy-6-methyl-indan-5-yl)-4-methyl-1,2,4-triazin-5-one; 3-[[(3R)-1-Ethyl-3-piperidinyl]amino]-6-(4-hydroxy-6-methyl-2,3-dihydrobenzofuran-5-yl)-4-methyl-1,2,4-triazin-5-one; and its pharmaceutically acceptable salts.

25. A process for preparing the compound according to any one of claims 1 to 24, the process comprising reacting a compound of formula III to provide a compound of formula I by cleavage of a protecting group (PG), 26. A compound according to any one of claims 1 to 24, which is used as a therapeutic active substance.

27. A compound according to any one of claims 1 to 24, which is used for treating or preventing a disease, disorder or condition, wherein the disease, disorder or condition responds to NLRP3 inhibition.

28. A pharmaceutical composition comprising a compound according to any one of claims 1 to 24 and a therapeutically inert carrier.

29. Use of a compound according to any one of claims 1 to 24 for treating or preventing a disease, disorder or condition, wherein the disease, disorder or condition responds to NLRP3 inhibition.

30. A compound according to any one of claims 1 to 24, which is used for treating or preventing a disease, disorder or condition selected from Alzheimer's disease and Parkinson's disease.

31. Use of a compound according to any one of claims 1 to 24 in treating or preventing a disease, disorder or condition selected from Alzheimer's disease and Parkinson's disease.

32. Use of a compound according to any one of claims 1 to 24 for preparing a medicament for treating or preventing a disease, disorder or condition selected from Alzheimer's disease and Parkinson's disease.

33. A method of inhibiting NLRP3, the method comprising administering an effective amount of a compound as claimed in any one of claims 1 to 24 to inhibit NLRP3.

34. A method for treating or preventing a disease, disorder or condition, the method comprising administering an effective amount of a compound according to any one of claims 1 to 24, wherein the disease, disorder or condition is selected from Alzheimer's disease and Parkinson's disease.

35. A compound according to any one of claims 1 to 24, which is manufactured according to the method of claim 25.

36. The present invention as described above.

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