Triazinone derivatives as NLRP3 inhibitors

Abstract

The present invention relates to a compound of general formula (I): TIFF2025537238000022.tif47161 (In the formula, R 1 , R 2 , R 3 , R 4a , R 4b and R 5 are as described herein) The present invention relates to novel compounds having the formula:

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present invention relates to organic compounds useful for therapy and / or prophylaxis in mammals, in particular compounds that modulate NLRP3 inhibition.

[0002] The present invention relates to a compound of formula I: [ka] (In the formula, R 1 is H, acetyl, SF5, halo, alkyl, alkoxy, haloalkyl, haloalkoxy or cyano; R 5 is H; or R 1 and R 5 and the atoms to which they are attached form any 4-6 membered heterocycle containing only one O heteroatom, 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 4-6 membered cycloalkyl ring optionally substituted with 1-2 substituents independently selected from halo and alkyl; R 2 is H, halo, alkyl, alkoxy, alkoxyalkyl, haloalkyl, or cycloalkyl, wherein cycloalkyl is optionally substituted with halo; R 3 is H or alkyl; R 4a is a heterocycle optionally substituted with 1 to 3 substituents independently selected from halo, alkyl, haloalkyl, hydroxyalkyl, —OH, oxo, —COH, cycloalkylalkyl, or cycloalkyl optionally substituted with halo; R 4b is H; or R 4a and R 4band the N to which they are attached form a 9-membered heterocycle containing 1 or 2 N heteroatoms optionally substituted with 1 or 2 substituents independently selected from alkyl, —OH, or halo. and pharmaceutically acceptable salts thereof.

[0003] Furthermore, the present invention includes all racemic mixtures, all their corresponding enantiomers and / or optical isomers. [Background technology]

[0004] Background of the Invention The NOD-like receptor (NLR) family pyrin domain-containing protein 3 (NLRP3) inflammasome is a component of the inflammatory process, and its aberrant 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.

[0005] NLRP3 is an intracellular signaling molecule that senses many pathogen-, environmental, and host-derived factors. Upon activation, NLRP3 binds to apoptosis-associated speck-like proteins containing a caspase activation and recruitment domain (ASC). ASC then polymerizes to form large aggregates known as ASC specks. Polymerized 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 (pro-IL-1β and pro-IL-18, respectively), thereby activating these cytokines. Caspase-1 also mediates a type of inflammatory cell death known as pyroptosis. ASC specks can also recruit and activate caspase-8, which processes pro-IL-1β and pro-IL-18, leading to apoptotic cell death.

[0006] Caspase-1 cleaves pro-IL-1β and pro-IL-18 to their active forms, which are secreted from cells. Active caspase-1 also cleaves gasdermin-D, causing pyroptosis. Through its control of the pyroptotic cell death pathway, caspase-1 also mediates the release of alarmin molecules such as IL-33 and high-mobility group box 1 protein (HMGB1). Caspase-1 also cleaves intracellular IL-1R2, leading to its degradation and enabling the release of IL-1α. In human cells, caspase-1 can also regulate the processing and secretion of IL-37. Several other caspase-1 substrates, such as components of the cytoskeleton and glycolytic pathways, may contribute to caspase-1-dependent inflammation.

[0007] NLRP3-dependent ASC specks are released into the extracellular milieu where they can activate caspase-1, induce the processing of caspase-1 substrates, and propagate inflammation.

[0008] Active cytokines derived from NLRP3 inflammasome activation are key drivers of inflammation and interact with other cytokine pathways to shape immune responses to infection and injury. For example, IL-1β signaling induces the secretion of the pro-inflammatory cytokines IL-6 and TNF. IL-1β and IL-18 synergize with IL-23 to induce IL-17 production by memory CD4 Th17 cells and γδ T cells in the absence of T cell receptor engagement. IL-18 and IL-12 also act synergistically to induce IFN-γ production from memory T cells and NK cells, driving Th1 responses.

[0009] The inherited CAPS disorders Muckle-Wells syndrome (MWS), familial common cold autoinflammatory syndrome (FCAS), and neonatal-onset multisystem inflammatory disease (NOMID) are caused by gain-of-function mutations in NLRP3, defining it as a key component of the inflammatory process. NLRP3 is also involved in the pathogenesis of several complex diseases, including metabolic disorders such as type 2 diabetes, atherosclerosis, obesity, and gout, among others.

[0010] The role of NLRP3 in central nervous system diseases is becoming clear, and lung diseases have also been shown to be affected by NLRP3. NLRP3 has also been implicated in several central nervous system conditions, including Parkinson's disease (PD), Alzheimer's disease (AD), dementia, Huntington's disease, cerebral malaria, and brain damage due to pneumococcal meningitis (Walsh et al., Nature Reviews, 15:84-97, 2014 and Dempsey et al., Brain. Behav. Immun. 201761:306-316). NLRP3 has also been implicated in several lung diseases, including chronic obstructive pulmonary disorder (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). Furthermore, NLRP3 is involved in the development of liver disease, kidney disease, and aging. Many of these associations are due to the involvement of NLRP3. - / - Although defined using mice, insights into the specific activation of NLRP3 in these diseases also exist. In type 2 diabetes (T2D), deposition of islet amyloid polypeptide in the pancreas activates NLRP3 and IL-1β signaling, leading to cell death and inflammation.

[0011] Several small molecules have been shown to inhibit the NLRP3 inflammasome. Glyburide inhibits IL-1β production at micromolar concentrations in response to NLRP3 activation, but not in response to NLRC4 or NLRP1 activation. Other previously characterized weak NLRP3 inhibitors include parthenolide, 3,4-methylenedioxy-β-nitrostyrene, and dimethyl sulfoxide (DMSO), but these agents have limited potency and are nonspecific.

[0012] Current treatments for NLRP3-related diseases include biologic agents that target IL-1. These include the recombinant IL-1 receptor antagonist anakinra, the neutralizing IL-1β antibody canakinumab, and the soluble decoy IL-1 receptor rilonacept. These approaches have proven successful in treating CAPS, and these biologic agents are being used in clinical trials for other IL-1β-related diseases.

[0013] There is a need to provide compounds that have improved pharmacological and / or physiological and / or physicochemical properties and / or that provide useful alternatives to known compounds. Summary of the Invention

[0014] Summary of the Invention The present invention relates to a compound of formula I: [ka] (In the formula, R 1 is H, acetyl, SF5, halo, alkyl, alkoxy, haloalkyl, haloalkoxy or cyano; R 5 is H; or R 1 and R 5and the atoms to which they are attached form any 4-6 membered heterocycle containing only one O heteroatom, 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 4-6 membered cycloalkyl ring optionally substituted with 1-2 substituents independently selected from halo and alkyl; R 2 is H, halo, alkyl, alkoxy, alkoxyalkyl, haloalkyl, cycloalkyl, wherein cycloalkyl is optionally substituted with halo; R 3 is H or alkyl; R 4a is a heterocycle optionally substituted with 1 to 3 substituents independently selected from halo, alkyl, haloalkyl, hydroxyalkyl, —OH, oxo, —COH, cycloalkylalkyl, or cycloalkyl optionally substituted with halo; R 4b is H; or 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 1 or 2 substituents independently selected from alkyl, —OH, or halo. and pharmaceutically acceptable salts thereof. [Brief explanation of the drawings]

[0015] [Figure 1] 1 is a graph showing the voltage patterns used in the hERG screening assay.

[0016] The term "acetyl" refers to the group -C(=O)CH3.

[0017] The term "alkyl" refers to a monovalent linear or branched saturated hydrocarbon group of 1 to 6 carbon atoms. In some embodiments, unless otherwise specified, alkyl refers to a group having 1 to 6 carbon atoms (C 1~6 -alkyl) or 1 to 4 carbon atoms (C 1~4 -alkyl). 1~6 Examples of alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl and pentyl. Particular alkyl groups include methyl and ethyl.

[0018] The term "alkoxy" refers to a group in which R' is C 1~6 represents a group of formula -O-R', which is an alkyl group. 1~6 Examples of -alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and tert-butoxy.

[0019] The term "cycloalkyl" refers to a monocyclic or polycyclic saturated or partially unsaturated non-aromatic hydrocarbon. In some embodiments, unless otherwise specified, a cycloalkyl contains 3 to 8 carbon atoms, 3 to 6 carbon atoms, or 3 to 5 carbon atoms. In some embodiments, a cycloalkyl is a saturated monocyclic or polycyclic hydrocarbon. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0020] The term "cycloalkylalkyl" refers to 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.

[0021] The terms "halogen," "halide," and "halo" are used interchangeably herein and refer to fluoro, chloro, bromo, or iodo. A particular halogen is fluoro.

[0022] The term "haloalkyl" refers to C 1~6 -C in which at least one hydrogen atom of the alkyl group is replaced by the same or different halogen atom 1~6 represents an alkyl group. Examples of haloalkyl include fluoromethyl, difluoromethyl and trifluoromethyl. A particular example is trifluoromethyl.

[0023] The term "haloalkoxy" refers to C 1~6 -C in which at least one hydrogen atom of the alkoxy group is replaced by the same or different halogen atom 1~6 -represents an alkoxy group. Examples of haloalkoxy are difluoromethoxy, trifluoromethoxy, difluoroethoxy and trifluoroethoxy.

[0024] The term "heterocycle" refers to a monovalent saturated or partially unsaturated monocyclic or bicyclic ring system of 4 to 9 ring atoms containing one, two, or three 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 azaspiroheptanyl, diazaspiroheptanyl, azaspirooctanyl, diazospirooctanyl, diazaspirononanyl, oxaazaspirooctanyl, and oxadiazaspirononanyl. One particular example of a polycyclic heterocycle is hexahydro-pyrrolopyridinyl. Another particular example of a heterocycle is piperidinyl.

[0025] The term "hydroxy" refers to an --OH group.

[0026] The term "hydroxyalkyl" refers to an alkyl group in which at least one hydrogen atom of the alkyl group has been replaced by a hydroxy group. Examples of hydroxyalkyl include hydroxymethyl, hydroxyethyl, hydroxypropyl, 2-hydroxy-1-propyl, 2-hydroxy-2-methyl-1-propyl, 3-hydroxy-1-propyl, and the like. An example of a hydroxyalkyl is hydroxyethyl.

[0027] The term "nitrile" refers to a -C≡N group.

[0028] The term "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness and properties of the free base or free acid and is not biologically or otherwise undesirable.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, and N-acetylcysteine.In addition, these salts can be prepared by adding inorganic or organic bases to the free acid.Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, and polyamine resins.The compound of formula I can also exist in the form of a zwitterion.Particularly preferred pharmaceutically acceptable salts of the compound of formula I are salts formed with formic acid and salts formed with hydrochloric acid to produce hydrochloride, dihydrochloride, or trihydrochloride.

[0029] The abbreviation uM means micromolar and is equivalent to the symbol μM.

[0030] The abbreviation uL means microliter and is equivalent to the symbol μL.

[0031] The abbreviation ug stands for microgram and is equivalent to the symbol μg.

[0032] The compounds of formula I may contain several asymmetric centers and may exist in the form of optically pure enantiomers, mixtures of enantiomers, such as racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates.

[0033] According to the Cahn-Ingold-Prelog rules, the asymmetric carbon atom can be of the "R" or "S" configuration.

[0034] Also, one embodiment of the present invention provides compounds according to formula I as described herein and pharmaceutically acceptable salts or esters thereof, particularly compounds according to formula I as described herein and pharmaceutically acceptable salts thereof, more particularly compounds according to formula I as described herein.

[0035] One embodiment of the present invention is R 1 is halo, haloalkyl, or haloalkoxy; R 5 is H; or R 1 and R 5 and the atom to which they are attached form any 4-6 membered heterocycle containing only one O heteroatom optionally substituted with 1 or 2 substituents independently selected from halo and alkyl, or R 1 and R 5and the atoms to which they are attached form a 4-6 membered cycloalkyl ring, optionally substituted with 1 or 2 substituents independently selected from halo and alkyl.

[0036] One embodiment of the present invention is R 1 is halo, haloalkyl, or haloalkoxy; R 5 is H; or R 1 and R 5 and the atoms to which they are attached form any five-membered heterocycle containing only one O heteroatom, or R 1 and R 5 and the atoms to which they are attached form a 5-membered cycloalkyl ring.

[0037] One embodiment of the present invention is R 1 is halo, haloalkyl, or haloalkoxy.

[0038] One embodiment of the present invention is R 1 is haloalkyl.

[0039] One embodiment of the present invention is R 5 is H or R 1 and R 5 and the atoms to which they are attached form any five-membered heterocycle containing only one O heteroatom, or R 1 and R 5 and the atoms to which they are attached form a 5-membered cycloalkyl ring.

[0040] One embodiment of the present invention is R 5 is H.

[0041] One embodiment of the present invention is R 2 is H or alkyl.

[0042] One embodiment of the present invention is R 2 is alkyl.

[0043] One embodiment of the present invention is R 3 is alkyl.

[0044] One embodiment of the present invention is R 4a is a cycloalkyl-substituted 6-membered heterocycle optionally substituted with alkyl, hydroxyalkyl, cycloalkylalkyl, or halo, and R 4b is H or 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 halo.

[0045] One embodiment of the present invention is R 4a is a 6-membered heterocycle substituted with alkyl, cycloalkylalkyl, or cycloalkyl optionally substituted with halo, and R 4b is H or 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 halo.

[0046] One embodiment of the present invention is R 4a is a 6-membered heterocycle containing only one N heteroatom substituted with alkyl or hydroxyalkyl, and R 4b is H or R 4a and R 4band the N to which they are attached form a 9-membered heterocycle containing 1 or 2 N heteroatoms optionally substituted with alkyl.

[0047] One embodiment of the present invention is R 4a is a 6-membered heterocycle containing only one N heteroatom substituted with alkyl, and R 4b is H or 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.

[0048] One embodiment of the present invention is R 4a is a 6-membered heterocycle containing only one N heteroatom substituted with alkyl, and R 4b is H or R 4a and R 4b and the N to which they are attached form a 9-membered heterocycle containing two N heteroatoms, and the 9-membered heterocycle containing two N heteroatoms is substituted with alkyl.

[0049] One embodiment of the present invention is R 4a is ethylpiperidyl, and R 4b is H.

[0050] One embodiment of the present invention comprises: R 1 is halo, haloalkyl, or haloalkoxy; R 5 is H; or R 1 and R 5 and the atoms to which they are attached form any five-membered heterocycle containing only one O heteroatom, or R 1 and R 5 and the atoms to which they are attached form a 5-membered cycloalkyl ring; R 2 is H, halo, alkyl, haloalkyl, cycloalkyl, wherein cycloalkyl is optionally substituted with halo; R 3 is alkyl; R 4a is a 6-membered heterocycle substituted with alkyl, hydroxyalkyl, cycloalkylalkyl, or cycloalkyl optionally substituted with halo, and R 4b is H, or 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 halo; Provided are compounds according to Formula I, as described herein, and pharmaceutically acceptable salts thereof.

[0051] One embodiment of the present invention comprises: R 1 is halo, haloalkyl, or haloalkoxy; R 5 is H; or R 1 and R 5 and the atoms to which they are attached form any five-membered heterocycle containing only one O heteroatom, or R 1 and R 5 and the atoms to which they are attached form a 5-membered cycloalkyl ring; R 2 is H, halo, alkyl, haloalkyl, cycloalkyl, wherein cycloalkyl is optionally substituted with halo; R 3 is alkyl; R 4a is a 6-membered heterocycle substituted with alkyl, cycloalkylalkyl, or cycloalkyl optionally substituted with halo, and R 4b is H, or R 4a and R 4band the N to which they are attached form a 9-membered heterocycle containing 1 or 2 N heteroatoms optionally substituted with alkyl or halo; Provided are compounds according to Formula I, as described herein, and pharmaceutically acceptable salts thereof.

[0052] One embodiment of the present invention comprises: R 1 is halo, haloalkyl, or haloalkoxy; R 5 is H; or R 1 and R 5 and the atoms to which they are attached form any five-membered heterocycle containing only one O heteroatom, or R 1 and R 5 and the atoms to which they are attached form a 5-membered cycloalkyl ring; R 2 is H or alkyl; R 3 is alkyl; R 4a is a 6-membered heterocycle containing only one N heteroatom substituted with alkyl or hydroxyalkyl, and R 4b is H, or 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; Provided are compounds according to Formula I, as described herein, and pharmaceutically acceptable salts thereof.

[0053] One embodiment of the present invention comprises: R 1 is halo, haloalkyl, or haloalkoxy; R 5 is H; or R 1 and R 5 and the atoms to which they are attached form any five-membered heterocycle containing only one O heteroatom, or R1 and R 5 and the atoms to which they are attached form a 5-membered cycloalkyl ring; R 2 is H or alkyl; R 3 is alkyl; R 4a is a 6-membered heterocycle containing only one N heteroatom substituted with alkyl or hydroxyalkyl, and R 4b is H, or 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; Provided are compounds according to Formula I, as described herein, and pharmaceutically acceptable salts thereof.

[0054] One embodiment of the present invention comprises: R 1 is halo, haloalkyl, or haloalkoxy; R 5 is H; or R 1 and R 5 and the atoms to which they are attached form any five-membered heterocycle containing only one O heteroatom, or R 1 and R 5 and the atoms to which they are attached form a 5-membered cycloalkyl ring; R 2 is alkyl; R 3 is alkyl; R 4a is a 6-membered heterocycle containing only one N heteroatom substituted with alkyl or hydroxyalkyl, and R 4b is H, or 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; Provided are compounds according to Formula I, as described herein, and pharmaceutically acceptable salts thereof.

[0055] One embodiment of the present invention comprises: R 1 is halo, haloalkyl, or haloalkoxy; R 5 is H; or R 1 and R 5 and the atoms to which they are attached form any five-membered heterocycle containing only one O heteroatom, or R 1 and R 5 and the atoms to which they are attached form a 5-membered cycloalkyl ring; R 2 is H or alkyl; R 3 is alkyl; R 4a is a 6-membered heterocycle containing only one N heteroatom substituted with alkyl, and R 4b is H, or 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; Provided are compounds according to Formula I, as described herein, and pharmaceutically acceptable salts thereof.

[0056] One embodiment of the present invention comprises: R 1 is halo, haloalkyl, or haloalkoxy; R 5 is H; or R 1 and R 5 and the atoms to which they are attached form any five-membered heterocycle containing only one O heteroatom, or R 1 and R 5 and the atoms to which they are attached form a 5-membered cycloalkyl ring; R 2 is alkyl; R 3 is alkyl; R 4a is a 6-membered heterocycle containing only one N heteroatom substituted with alkyl, and R 4b is H, or 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; Provided are compounds according to Formula I, as described herein, and pharmaceutically acceptable salts thereof.

[0057] One embodiment of the present invention comprises: R 1 is halo, haloalkyl, or haloalkoxy; R 5 is H; or R 1 and R 5 and the atoms to which they are attached form any five-membered heterocycle containing only one O heteroatom, or R 1 and R 5 and the atoms to which they are attached form a 5-membered cycloalkyl ring; R 2 is H or alkyl; R 3 is alkyl; R 4a is a 6-membered heterocycle containing only one N heteroatom substituted with alkyl or hydroxyalkyl, and R 4b is H, or R 4a and R 4b and the N to which they are attached form a 9-membered heterocycle containing two N heteroatoms, and the 9-membered heterocycle containing two N heteroatoms is substituted with alkyl; Provided are compounds according to Formula I, as described herein, and pharmaceutically acceptable salts thereof.

[0058] One embodiment of the present invention comprises: R 1is halo, haloalkyl, or haloalkoxy; R 5 is H; or R 1 and R 5 and the atoms to which they are attached form any five-membered heterocycle containing only one O heteroatom, or R 1 and R 5 and the atoms to which they are attached form a 5-membered cycloalkyl ring; R 2 is alkyl; R 3 is alkyl; R 4a is a 6-membered heterocycle containing only one N heteroatom substituted with alkyl or hydroxyalkyl, and R 4b is H, or R 4a and R 4b and the N to which they are attached form a 9-membered heterocycle containing two N heteroatoms, and the 9-membered heterocycle containing two N heteroatoms is substituted with alkyl; Provided are compounds according to Formula I, as described herein, and pharmaceutically acceptable salts thereof.

[0059] One embodiment of the present invention comprises: R 1 is halo, haloalkyl, or haloalkoxy; R 5 is H; or R 1 and R 5 and the atoms to which they are attached form any five-membered heterocycle containing only one O heteroatom, or R 1 and R 5 and the atoms to which they are attached form a 5-membered cycloalkyl ring; R 2 is H or alkyl; R 3 is alkyl; R 4a is a 6-membered heterocycle containing only one N heteroatom substituted with alkyl, and R4b is H, or R 4a and R 4b and the N to which they are attached form a 9-membered heterocycle containing two N heteroatoms, and the 9-membered heterocycle containing two N heteroatoms is substituted with alkyl; Provided are compounds according to Formula I, as described herein, and pharmaceutically acceptable salts thereof.

[0060] One embodiment of the present invention comprises: R 1 is halo, haloalkyl, or haloalkoxy; R 5 is H; or R 1 and R 5 and the atoms to which they are attached form any five-membered heterocycle containing only one O heteroatom, or R 1 and R 5 and the atoms to which they are attached form a 5-membered cycloalkyl ring; R 2 is alkyl; R 3 is alkyl; R 4a is a 6-membered heterocycle containing only one N heteroatom substituted with alkyl, and R 4b is H, or R 4a and R 4b and the N to which they are attached form a 9-membered heterocycle containing two N heteroatoms, and the 9-membered heterocycle containing two N heteroatoms is substituted with alkyl; Provided are compounds according to Formula I, as described herein, and pharmaceutically acceptable salts thereof.

[0061] One embodiment of the present invention comprises: R 1 is haloalkyl, R 5 is H; R 2 is H or alkyl; R3 is alkyl; R 4a is ethylpiperidyl, and R 4b is H, Provided are compounds according to Formula I, as described herein, and pharmaceutically acceptable salts thereof.

[0062] One embodiment of the present invention comprises: R 1 is haloalkyl, R 5 is H; R 2 is alkyl; R 3 is alkyl; R 4a is ethylpiperidyl, and R 4b is H, Provided are compounds according to Formula I, as described herein, and pharmaceutically acceptable salts thereof.

[0063] Specific examples of compounds of formula I described herein include: 3-[[(3R)-1-ethyl-3-piperidyl]amino]-6-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5-one; 3-[[(3R)-1-ethyl-3-piperidyl]amino]-6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5-one; and pharmaceutically acceptable salts thereof.

[0064] Other specific examples of compounds of formula I described herein are: 3-[[(3R)-1-ethyl-3-piperidyl]amino]-6-(4-hydroxy-6-methyl-indan-5-yl)-4-methyl-1,2,4-triazin-5-one; 3-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]-6-(4-hydroxy-6-methyl-indan-5-yl)-4-methyl-1,2,4-triazin-5-one; 3-[[(3R)-1-ethyl-3-piperidyl]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-piperidyl]amino]-4-methyl-1,2,4-triazin-5-one; and pharmaceutically acceptable salts thereof.

[0065] A preferred example of a compound of formula I described herein is 3-[[(3R)-1-ethyl-3-piperidyl]amino]-6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5-one and pharmaceutically acceptable salts thereof.

[0066] Other preferred examples of compounds of formula I described herein are 3-[[(3R)-1-ethyl-3-piperidyl]amino]-6-(4-hydroxy-6-methyl-indan-5-yl)-4-methyl-1,2,4-triazin-5-one; 3-[[(3R)-1-ethyl-3-piperidyl]amino]-6-(4-hydroxy-6-methyl-2,3-dihydrobenzofuran-5-yl)-4-methyl-1,2,4-triazin-5-one; and pharmaceutically acceptable salts thereof.

[0067] The processes for the preparation of compounds of formula I described herein are an object of the present invention.

[0068] 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 process described below, which comprises reacting a compound of formula III to provide a compound of formula I by cleaving a protecting group (PG). Preferably, the protecting group is a methyl ether. Preferably, the methyl ether is cleaved by boron tribromide (BBr) in dichloromethane. [ka]

[0069] General synthetic scheme Compounds of general formula I can be prepared using variations of the processes described below according to Scheme 1. Starting materials are commercially available or can be prepared according to known methods.

[0070] Scheme 1: General synthesis of compounds of formula I (GP = protecting group) [ka] Compounds of general formula II were obtained using palladium-mediated Suzuki-Miyaura cross-coupling under conditions well known to those skilled in the art in the presence of intermediate 1 and a boronic acid or ester having the general formula shown in Scheme 1. Subsequently, to prepare compounds of general formula III, nucleophilic aromatic substitution (SNAr) was carried out with a boronic acid or ester of the general formula HNR 4b R 4a (In the formula, R 4a and R 4b The reaction was carried out with an appropriate secondary amine of formula (I) (wherein methyl ether has the meaning given in the claims of the present invention) in the presence of pyridine under heating. Alternatively, the reaction can be carried out under microwave irradiation. Finally, a final step of protecting group cleavage was required. In the case of the methyl ether protecting group, this is usually cleaved with boron tribromide (BBr3) in dichloromethane to deliver the compound of general formula I.

[0071] Scheme 2: Synthesis of Intermediate 1 [ka] Intermediate 1 was synthesized as described in the experimental section by a Sandmeyer-type reaction using commercially available 6-amino-4-methyl-3-methylsulfanyl-1,2,4-triazin-5-one (CAS number 89730-72-3) in the presence of copper(I) chloride and lithium chloride in acetonitrile at 60 °C.

[0072] Another embodiment of the present invention provides pharmaceutical compositions or medicaments containing a compound of the present invention and a therapeutically inert carrier, diluent, or excipient, as well as methods of using the compounds of the present invention to prepare such compositions and medicaments. In one example, a compound of Formula I can be formulated into a galenic dosage form by mixing it at ambient temperature, at an appropriate pH, and to the desired degree of purity with a physiologically acceptable carrier, i.e., a carrier that is nontoxic to recipients at the dosages and concentrations employed. The pH of the formulation will depend primarily on the particular application and the concentration of the compound, but is preferably anywhere in the range of about 3 to about 8. In one example, a 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.

[0073] The compositions are formulated, dosed, and administered in a manner consistent with good medical practice. Factors to consider in this regard 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 agent, the method of administration, the administration schedule, and other factors known to medical practitioners.

[0074] The compounds of the present invention may be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal and epidural, and intranasal, and, if desired for local treatment, intralesional administration. Parenteral administration includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.

[0075] The compounds of the present invention may be administered in any convenient dosage form, such as tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain components conventional in pharmaceutical preparations, such as diluents, carriers, pH adjusters, sweeteners, fillers and additional active agents.

[0076] Typical preparation is prepared by mixing the compound of the present invention with carrier or excipient.Suitable carrier and excipient are well known to those skilled in the art, and are described in detail in, for example, Ansel, Howard C., et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems.Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al., Remington: The Science and Practice of Pharmacy.Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients.Chicago, Pharmaceutical Press, 2005. The formulation may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifying agents, glidants, processing aids, colorants, sweeteners, fragrances, flavorings, diluents, and other known additives to present the drug (i.e., a compound of the present invention or a pharmaceutical composition thereof) aesthetically or to aid in the manufacture of a pharmaceutical product (i.e., a medicament).

[0077] The compounds of formula I and their pharmaceutically acceptable salts can be processed with pharmaceutically inert, inorganic or organic adjuvants for the production of tablets, coated tablets, sugar-coated tablets, hard gelatin capsules, injection solutions or topical preparations.Lactose, corn starch or its derivatives, talc, stearic acid or its salts, etc. can be used as such adjuvants for tablets, sugar-coated tablets and hard gelatin capsules.

[0078] Suitable adjuvants for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semisolids, and liquid polyols.

[0079] Suitable adjuvants for the production of solutions and syrups are, for example, water, polyols, saccharose, invert sugar, glucose etc.

[0080] Suitable adjuvants for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils and the like.

[0081] Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols etc.

[0082] Suitable adjuvants for topical ophthalmic formulations are, for example, cyclodextrins, mannitol, or many other carriers and excipients known in the art.

[0083] In addition, pharmaceutical preparations may contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents, salts for varying osmotic pressure, buffers, masking agents, or antioxidants. They may also contain still other therapeutically valuable substances.

[0084] Dosages can vary widely and will, of course, be adapted to the individual requirements of each particular case. Generally, for oral administration, a daily dose of about 0.1 mg to 20 mg per kg of body weight, preferably about 0.5 mg to 4 mg per kg of body weight (e.g., about 300 mg per person), is preferably divided into 1 to 3 individual doses, which, if appropriate, may be composed of, for example, the same amount. For topical administration, the preparation may contain 0.001% to 15% by weight of the drug, and the required dose, which may be 0.1 to 25 mg, may be administered either in a single dose per day or per week, or in multiple doses (2 to 4 times) per day or multiple doses per week; however, it will be clear that this may exceed the upper or lower limits given herein, if indicated.

[0085] One embodiment of the present invention is a compound according to Formula I as described herein for use as a therapeutically active substance.

[0086] One embodiment of the present invention is a compound according to Formula I as described herein for use in the treatment or prevention of a disease, disorder or condition, wherein the disease, disorder or condition is responsive to NLRP3 inhibition.

[0087] One embodiment of the present invention is a compound according to Formula I as described herein for the treatment or prevention of a disease, disorder or condition, wherein the disorder or condition is responsive to NLRP3 inhibition.

[0088] As used herein, the term "NLRP3 inhibition" refers to a complete or partial reduction in the activity level of NLRP3, including, for example, inhibition of active NLRP3 and / or inhibition of NLRP3 activation.

[0089] There is evidence for a role for NLRP3-induced IL-1 and IL-18 in the inflammatory response associated with or resulting from a number of different disorders (Menu et al., Clinical and Experimental Immunology, 166:1-15, 2011; Strowig et al., Nature, 481:278-286, 2012).

[0090] In one embodiment, the disease, disorder or condition is selected from the following: (i) Inflammation; (ii) autoimmune diseases; (iii) cancer; (iv) infectious diseases; (v) central nervous system disorders; (vi) metabolic diseases; (vii) cardiovascular disease; (viii) respiratory diseases; (ix) liver disease; (x) Kidney disease; (xi) eye diseases; (xii) skin diseases; (xiii) lymphatic symptoms; (xiv) mental disorder; (xv) graft-versus-host disease; (xvi) allodynia; (xvii) symptoms related to diabetes; and (xviii) Any disease in which an individual is determined to have a germline or somatic non-silent mutation in NLRP3.

[0091] In another embodiment, the disease, disorder or condition is selected from the following: (i) Cancer; (ii) infectious diseases; (iii) central nervous system disorders; (iv) cardiovascular disease; (v) liver disease; (vi) eye disease; or (vii) Skin diseases.

[0092] In a further exemplary embodiment of the invention, the disease, disorder or condition is inflammation. Examples of inflammation that may be treated or prevented include inflammatory responses associated with or resulting from: (i) Skin conditions such as contact sensitivity, bullous pemphigoid, sunburn, psoriasis, atopic dermatitis, contact dermatitis, allergic contact dermatitis, seborrheic dermatitis, lichen planus, scleroderma, pemphigus, epidermolysis bullosa, urticaria, erythema, or alopecia; (ii) articular conditions such as osteoarthritis, systemic juvenile idiopathic arthritis, adult-onset Still's disease, relapsing polychondritis, rheumatoid arthritis, juvenile chronic arthritis, gout, or seronegative spondyloarthropathy (e.g., ankylosing spondylitis, psoriatic arthritis, or Reiter's disease); (iii) muscle conditions such as polymyositis or myasthenia gravis; (iv) gastrointestinal conditions 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 have effects remote from the gut (e.g., migraine, rhinitis, or eczema); (v) respiratory conditions such as chronic obstructive pulmonary disease (COPD), asthma (including eosinophilic, bronchial, allergic, intrinsic, extrinsic or dust-induced asthma, especially chronic or refractory asthma, e.g., late-stage asthma and airway hyperresponsiveness), bronchitis, rhinitis (including acute rhinitis, allergic rhinitis, atrophic rhinitis, chronic rhinitis, caseous rhinitis, hypertrophic rhinitis, panlentic rhinitis, rhinitis sicca, rhinitis medicamentosa, membranous rhinitis, seasonal rhinitis, e.g., hay fever and vasomotor rhinitis), sinusitis, idiopathic pulmonary fibrosis (IPF), sarcoidosis, farmer's lung, silicosis, asbestosis, volcanic ash-induced inflammation, adult respiratory distress syndrome, hypersensitivity pneumonitis, or idiopathic interstitial pneumonia; (vi) vascular conditions such as atherosclerosis, Behçet's disease, vasculitis, or Wegener's granulomatosis; (vii) autoimmune conditions such as systemic lupus erythematosus, Sjögren's syndrome, systemic sclerosis, Hashimoto's thyroiditis, type I diabetes, idiopathic thrombocytopenic purpura, or Graves' disease; (viii) ocular conditions such as uveitis, allergic conjunctivitis, or vernal conjunctivitis; (ix) neurological conditions such as multiple sclerosis or encephalomyelitis; (x) an infection or infection-related condition such as acquired immunodeficiency syndrome (AIDS), acute or chronic bacterial infection, acute or chronic parasitic infection, acute or chronic viral infection, acute or chronic fungal infection, meningitis, hepatitis (A, B, or C, or other viral hepatitis), peritonitis, pneumonia, epiglottitis, malaria, hemorrhagic dengue fever, leishmaniasis, streptococcal myositis, mycobacterium tuberculosis (including mycobacterium tuberculosis and HIV co-infection), mycobacterium avium intracellulare, pneumocystis carinii pneumonia, orchitis / epidydimitis, Legionnaires' disease, Lyme disease, influenza A, Epstein-Barr virus infection, viral encephalitis / aseptic meningitis, or pelvic inflammatory disease; (xi) renal conditions such as mesangial proliferative glomerulonephritis, renal syndrome, nephritis, glomerulonephritis, obesity-related glomerulopathy, acute renal failure, acute kidney injury, uremia, nephritic syndrome, renal fibrosis including chronic crystalline nephropathy, or renal hypertension; (xii) lymphatic conditions such as Castleman's disease; (xiii) conditions of or involving the immune system, such as hyper-IgE syndrome, lepromatous leprosy, familial hemophagocytic lymphohistiocytosis, or graft-versus-host disease; (xiv) hepatic conditions such as chronic active hepatitis, nonalcoholic steatohepatitis (NASH), alcohol-induced hepatitis, nonalcoholic fatty liver disease (NAFLD), alcoholic fatty liver disease (AFLD), alcoholic steatohepatitis (ASH), primary biliary cirrhosis, fulminant hepatitis, hepatic fibrosis, or liver failure; (xv) Cancer, including those mentioned above; (xvi) burns, wounds, trauma, hemorrhage, or stroke; (xvii) radiation exposure; (xviii) metabolic diseases such as type 2 diabetes (T2D), atherosclerosis, obesity, gout, or pseudogout; and / or (xix) Pain such as inflammatory hyperalgesia, pelvic pain, allodynia, neuropathic pain, or cancer-induced bone pain.

[0093] One embodiment of the present invention is a compound according to formula I as described herein for the treatment or prevention of a disease, disorder or condition selected from the following: (i) Inflammation; (ii) autoimmune diseases; (iii) cancer; (iv) infectious diseases; (v) central nervous system disorders; (vi) metabolic diseases; (vii) cardiovascular disease; (viii) respiratory diseases; (ix) liver disease; (x) Kidney disease; (xi) eye diseases; (xii) skin diseases; (xiii) lymphatic symptoms; (xiv) mental disorder; (xv) graft-versus-host disease; (xvi) allodynia; (xvii) symptoms related to diabetes; and (xviii) Any disease in which an individual is determined to have a germline or somatic non-silent mutation in NLRP3.

[0094] One embodiment of the present 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, wherein the disease, disorder or condition is responsive to NLRP3 inhibition.

[0095] One embodiment of the present 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.

[0096] One embodiment of the present invention is the use of a compound according to formula I as described herein for use in the treatment or prevention of a disease, disorder or condition selected from asthma or COPD.

[0097] One embodiment of the present 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.

[0098] One embodiment of the present invention is 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.

[0099] 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 the treatment or prevention of a disease, disorder or condition selected from Alzheimer's disease and Parkinson's disease.

[0100] 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 the treatment or prevention of a disease, disorder or condition selected from asthma or COPD.

[0101] One embodiment of the present invention is a method for the treatment or prevention of a disease, disorder, or condition selected from Alzheimer's disease and Parkinson's disease, comprising administering an effective amount of a compound according to Formula I described herein.

[0102] One embodiment of the present invention is a method for the treatment or prevention of a disease, disorder, or condition selected from asthma or COPD, comprising administering an effective amount of a compound according to formula I described herein.

[0103] One embodiment of the present invention relates to a method of inhibiting NLRP3, comprising administering an effective amount of a compound according to Formula I described herein.

[0104] Also, one embodiment of the present invention is a compound of formula I as described herein when prepared according to any one of the processes described.

[0105] One embodiment of the present invention is a pharmaceutical composition comprising a compound according to Formula I described herein and a therapeutically inert carrier.

[0106] Assay procedure NLRP3 and pyroptosis It is well established that activation of NLRP3 leads to cell pyroptosis, a hallmark of which plays a key role in the development of clinical disease (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 & 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 block pyroptosis and the release of pro-inflammatory cytokines (e.g., IL-1β) from cells.

[0107] THP-1 cells: culture and preparation THP-1 cells (ATCC No. TIB-202) were grown in RPMI containing L-glutamine (Gibco No. 11835) supplemented with 1 mM sodium pyruvate (Sigma No. S8636) and penicillin (100 units / ml) / streptomycin (0.1 mg / ml) (Sigma No. P4333) in 10% fetal bovine serum (FBS) (Sigma No. F0804). Cells were passaged periodically until confluent (approximately 10 6 The THP-1 cells were grown to a concentration of 625,000 cells / ml. On the day of the experiment, the cells were harvested and resuspended in RPMI medium (without FBS). The cells were then counted, and viability (>90%) was confirmed using trypan blue (Sigma #T8154). Appropriate dilutions were made to obtain a concentration of 625,000 cells / ml. LPS (Sigma #L4524) was added to this diluted cell solution to obtain a final assay concentration (FAC) of 1 μg / ml. 40 μl of the final preparation was dispensed into each well of a 96-well plate. The plates prepared in this manner were used for compound screening.

[0108] THP-1 cell pyroptosis assay For compound screening, the following method stepwise assay was followed. 1. Seed THP-1 cells (25,000 cells / well) in 40 μl of RPMI medium (without FBS) containing 1.0 μg / ml LPS in a 96-well black-walled, clear-bottom cell culture plate coated with poly-D-lysine (VWR No. 734-0317). Add 2.5 μl of compound (8-point half-log dilutions with the highest dose at 10 μM) or vehicle (DMSO 0.1% FAC) to the appropriate wells. 3. Incubate at 37°C, 5% CO2 for 3 hours. Add 4.5 μl of nigericin (Sigma No. N7143) (FAC 5 μM) to all wells 5. Incubate at 37°C, 5% CO2 for 1 hour. 6. At the end of the incubation period, spin the plate at 300 x g for 3 minutes and remove the supernatant. 7. 50 μl of resazurin (Sigma #R7017) (100 μM resazurin in RPMI medium without FBS) is then added and the plate is incubated at 37°C and 5% CO for a further 1-2 hours. 8. Plates were read on an Envision reader at Ex 560nm and Em 590nm 9.IC 50 Fit the data to a nonlinear regression equation (log inhibitor vs. response variable slope, 4 parameters)

[0109] Pyroptosis assay results were compared with THP IC 50 This is summarized in Table 1 below.

[0110] Human whole blood IL-1β release assay For systemic delivery, the ability of a compound to inhibit NLRP3 when present in the bloodstream is crucial. Therefore, we investigated the NLRP3 inhibitory activity of several compounds in human whole blood according to the following protocol.

[0111] Human whole blood in Li-heparin tubes was obtained from healthy donors from a volunteer donor panel.

[0112] 1. Plate out 80 μl of whole blood containing 1 μg / ml LPS in a 96-well clear-bottom cell culture plate (Corning #3585). 2. Add 10 μl of compound (8-point half-log dilutions at the highest dose of 10 μM) or vehicle (FAC in DMSO 0.1%) to the appropriate wells. 3. Incubate at 37°C, 5% CO2 for 3 hours. 4. Add 10 μl of nigericin (Sigma #N7143) (10 μM FAC) to all wells 5. Incubate at 37°C, 5% CO2 for 1 hour. 6. At the end of the incubation period, spin the plate at 300 x g for 5 minutes to pellet the cells, 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 analysis at a later date.) 7. IL-1β was measured according to the manufacturer's protocol (Perkin Elmer-AlphaLisa IL-1 Kit AL220F-5000). 8.IC 50 Fit the data to a nonlinear regression equation (log inhibitor vs. response variable slope, 4 parameters)

[0113] Human whole blood assay results HWB IC 50 This is summarized in Table 1 below.

[0114] hERG screening assay During the small molecule drug development process, cardiac arrhythmias are one of the most frequent side effects leading to drug failure. Such failures are often related to the drug's ability to inhibit the human ether-a-go-go-related gene (hERG) cardiac potassium channel. Therefore, no or low inhibition of the hERG cardiac potassium channel is considered beneficial.

[0115] cell The CHO-crelox hERG cell line (ATCC reference number PTA-6812, female Chinese hamster cells) was generated and validated at Roche. Ready-to-use frozen instant CHO-hERG cells were cryopreserved at Evotec (Germany) and used directly in the experiments.

[0116] Experimental solution The extracellular solution contained (in mM): NaCl 150; KCl 4; CaCl 1; MgCl 1; HEPES 10; pH 7.2-7.4 with NaOH, osmolarity 290-330 mOsm. The internal solution contained (in mM): KCl 10; KF 100; NaCl 10; HEPES 10; EGTA 20; pH 7.0-7.4 with KOH, osmolarity 260-300 mOsm.

[0117] electrophysiology The effects of compounds on hERG K+-current parameters will be evaluated at two concentrations in at least four cells.

[0118] hERG studies are performed using the automated patch clamp system SynchroPatch® 384 (Nanion Technologies GmbH, Germany). K+ currents are measured using the patch voltage clamp technique in the whole-cell configuration at 35-37°C.

[0119] Cells were held at a resting voltage of -80 mV and stimulated with the voltage pattern shown in Figure 1 to measure outward K (at 35–37 °C). + The pulse pattern used to elicit the current) activated hERG channels at a stimulation frequency of 0.1 Hz (6 bpm) to conduct outward IK hERG currents.

[0120] Data analysis The amplitude of the IKhERG was recorded at each concentration of drug and compared to vehicle control values ​​(set at 100%) to define fractional blocks. The concentration-response data were fitted with the following relationship: [Table 1]

[0121] Concentration-response curves were fitted by nonlinear regression analysis using the EworkBook suite (ID Business Solutions Ltd, UK). Data were fitted using a four-parameter logistic model (fit = (A + (B / (1 + ((x / C)^D)))), where A = 0 and B = 100).

[0122] The results of the hERG assay were analyzed using the hERG IC 20 This is summarized in Table 2 below.

[0123] Intracellular P-gp assay: A typical assay uses transfected LLC-PK1 cells (porcine kidney epithelial cells) overexpressing human P-gp or mouse P-gp cultured on 96-well semi-permeable filter membrane plates, where these cells form a polarized monolayer with tight junctions, which act as a barrier between the apical and basolateral compartments.

[0124] P-gp is expressed in the apical membrane of the monolayer.

[0125] The adhesion of the cell monolayer and the functional activity of P-gp are confirmed by the addition of the cell-impermeable marker Lucifer Yellow and the reference P-gp substrate edoxaban, respectively.

[0126] PAMPA: PAMPA (Parallel Artificial Membrane Permeability Assay) is a first-order selective permeability screen for drug candidates. The PAMPA assay uses artificial phospholipid membranes to mimic intracellular absorption conditions. This assay determines permeability values ​​that can be used for compound optimization and ranking purposes and as input parameters for in silico models predicting intestinal absorption.

[0127] The donor concentration is measured at t-start (baseline) and compared to the donor and acceptor concentrations after a certain time period (t-end), and the extent of compound crossing the membrane is calculated.

[0128] Microsomal stability: Incubations of 1 μM test compound in microsomes (0.5 mg / mL) and the cofactor NADPH are performed in 96-well plates at 37°C using a TECAN (Tecan Group Ltd, Switzerland) automated liquid handling system. After a 10-minute preincubation step between the microsomes and the test compound, the enzymatic reaction is initiated by the addition of the cofactor. Aliquots of the incubation are removed at 1, 3, 6, 9, 15, 25, 35, and 45 minutes and quenched with 1:3 (v / v) acetonitrile containing an internal standard. The samples are then cooled and centrifuged, after which the supernatants are analyzed by LC-MS / MS2.

[0129] Metabolic stability in hepatocytes: Assay Description: Biological materials. Obtain cryopreserved hepatocytes [mouse, rat, rabbit, monkey, and human (mixed sex)]. Hepatocyte viability after reconstitution is at least 80% throughout the study. Obtain ready-to-use rat / human HepatoPac® cultures [long-term hepatocyte co-cultures; pooled (human males n=5 and females n=5)], stromal mouse fibroblasts (negative control; pooled), incubation plates, application medium, and maintenance medium.

[0130] Metabolism by Suspension Hepatocytes. Initially, pooled cryopreserved hepatocytes were reconstituted in prewarmed 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 to a final suspension density of 1 × 10 cells / mL. Incubations were performed automatically using a Liquid Handling System (Tecan) equipped with a CO2 incubator equipped with an orbital shaker. After adding test compound, e.g., 1 μM, to wells (1 × 105 cells / well), the 96-well hepatocyte suspension culture plate was incubated at 37°C with 5% CO2. Samples were quenched at designated time points up to 2 hours by adding acetonitrile (containing an internal standard) to the incubation wells.

[0131] Incubation of test substances (e.g., 1 μM, 0.1% v / v DMSO) in metabolic suspension assays using HepatoPac® is carried out in 96-well plates containing either co-cultures of adherent hepatocytes and mouse fibroblast control cells, or control cells alone (5% CO2 atmosphere and 37°C). The incubation medium for human HepatoPac® is the same as that used for suspension hepatocytes. At designated time points (2, 18, 26, 48, 72, and 96 hours), all wells are quenched with ice-cold acetonitrile containing an internal standard.

[0132] The samples are then appropriately centrifuged and the supernatants are analyzed by LC-MS / MS. Incubations are performed in n=1 or 2. [Table 2] [Table 3]

[0133] The invention will now be illustrated by the following examples, which have no limiting character.

[0134] Where preparations are obtained as mixtures of enantiomers or diastereoisomers, the pure enantiomers or diastereoisomers may be obtained by the methods described herein or by methods known to those skilled in the art, such as, for example, chiral chromatography or crystallization.

[0135] Experimental Method Abbreviation: [Table 4] [Example]

[0136] Unless otherwise specified, all examples and intermediates were prepared under a nitrogen atmosphere.

[0137] Synthesis of intermediates Intermediate 1 6-chloro-4-methyl-3-methylsulfanyl-1,2,4-triazin-5-one [ka] Isoamyl nitrite (2.02 mL, 15.01 mmol, 2.02 equiv.) was added dropwise to a mixture of 6-amino-4-methyl-3-methylsulfanyl-1,2,4-triazin-5-one (CAS no. 89730-72-3, 1.28 g, 7.43 mmol, 1.0 equiv.), benzyltriethylammonium chloride (2.54 g, 11.2 mmol, 1.5 equiv.), copper(I) chloride (1.47 g, 14.9 mmol, 2.0 equiv.), and lithium chloride (472.6 mg, 11.2 mmol, 1.5 equiv.) in MeCN (30 mL) 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 (MgSO), filtered, and concentrated in vacuo. The residue was purified by chromatography on silica gel (40 g cartridge, 0-50% EtOAc / isohexane) to give the title compound (570 mg, 39%) as a white solid. LCMS: m / z 192.3 / 194.0 [M+H] + ,ESI pos.

[0138] Synthesis of Examples Example 1: 3-[[(3R)-1-Ethyl-3-piperidyl]amino]-6-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5-one; Formic acid [ka] Step A: 6-[2-methoxy-4-(trifluoromethyl)phenyl]-4-methyl-3-methylsulfanyl-1,2,4-triazin-5-one To a stirred solution of 6-chloro-4-methyl-3-methylsulfanyl-1,2,4-triazin-5-one intermediate 1 (500 mg, 2.48 mmol, 1.0 equiv), 2-methoxy-4-(trifluoromethyl)-phenylboronic acid (670 mg, 3.02 mmol, 1.22 equiv), and Xphos Pd G3 (215 mg, 0.25 mmol, 0.1 equiv) in 1,4-dioxane (5 mL) was added sodium carbonate (saturated aqueous solution) (0.5 mL, 7.44 mmol, 3.0 equiv). The mixture was degassed three times with N2, and the reaction mixture was stirred at 100 °C for 6 h and then allowed to stand at room temperature overnight. 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 organics were dried (Na2SO4), filtered, and concentrated to dryness. The crude material was purified by flash column chromatography on silica gel (24 g cartridge, 0-100% TBME / isohexane) to afford the title compound (411 mg, 45%) as a pale yellow solid. LCMS m / z 332.0 [M+H] + ESI pos.

[0139] Step B: 3-[[(3R)-1-ethyl-3-piperidyl]amino]-6-[2-methoxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5-one A solution of 6-[2-methoxy-4-(trifluoromethyl)phenyl]-4-methyl-3-methylsulfanyl-1,2,4-triazin-5-one (Step A) (278 mg, 0.76 mmol, 1.0 equiv) and (3R)-1-ethylpiperidin-3-amine (610 mg, 4.76 mmol, 6.3 equiv) 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 (NaSO), and concentrated to dryness. The crude material was purified by flash column chromatography on silica gel (24 g cartridge, DCM loading, 0–10% MeOH (0.7 M NH) / DCM) to afford the title compound (212 mg, 61%) as a dark brown oil. LCMS m / z 412.2[M+H]+ ESI pos.

[0140] Step C: 3-[[(3R)-1-ethyl-3-piperidyl]amino]-6-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5-one; formic acid A solution of boron tribromide (2.9 mL, 2.90 mmol, 1 M in DCM, 5.01 equiv.) was added dropwise to 3-[[(3R)-1-ethyl-3-piperidyl]amino]-6-[2-methoxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5-one (Step B) (238 mg, 0.58 mmol, 1.0 equiv.) in DCM (8 mL) at 0° C. The reaction mixture was stirred for 30 minutes and then quenched with 0.7 M NH3MeOH (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 using Phenomenex Gemini NC-C 18 Preparative column, 110Å, 5 μm, 30 mm x 150 mm, flow rate 42 mL / min -1 The column was purified by reverse-phase preparative HPLC (Gilson) using a column dilution pump to elute with 0.1% formic acid in a water-MeCN gradient over 15 min. -1 Feed MeCN at 100°C for 1.2 min. Gradient information: 0.0-1.0 min, 90% MeCN; 1.0-11.0 min, ramp from 90% MeCN to 65% MeCN; 11.1-14.0 min, ramp from 65% MeCN to 100% MeCN; 14.1-15.0 min, equilibrate with 100% MeCN to 90% MeCN. Evaporate clean fractions in a Genevac to give the title compound (142 mg, 54% yield) as a yellow solid. LCMS m / z 398.4 [M+H] + ESI pos.

[0141] Example 2: 3-[[(3R)-1-Ethyl-3-piperidyl]amino]-6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5-one [ka] Step A: 6-[2-methoxy-6-methyl-4-(trifluoromethyl)phenyl]-4-methyl-3-methylsulfanyl-1,2,4-triazin-5-one To a stirred solution of 6-chloro-4-methyl-3-methylsulfanyl-1,2,4-triazin-5-one intermediate 1 (300 mg, 1.49 mmol, 1.0 equiv.), [2-methoxy-6-methyl-4-(trifluoromethyl)phenyl]boronic acid (423.4 mg, 1.81 mmol, 1.22 equiv.), and Xphos Pd G3 (129.0 mg, 0.15 mmol, 0.1 equiv.) in 1,4-dioxane (3 mL) was added sodium carbonate (saturated aqueous solution) (0.3 mL). The mixture was degassed with N2 three times and stirred under N2 at 90 °C for 12 h. 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 organics were dried (Na2SO4), filtered, and concentrated to dryness. The product was purified by flash column chromatography on silica gel (24 g cartridge, 0-60% TBME / isohexane) to give the title compound (87.0 mg, 16%) as a pale yellow gum. LCMS m / z 346.23[M+H] + ESI pos.

[0142] Step B: 3-[[(3R)-1-ethyl-3-piperidyl]amino]-6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5-one A solution of 6-[2-methoxy-6-methyl-4-(trifluoromethyl)phenyl]-4-methyl-3-methylsulfanyl-1,2,4-triazin-5-one (80.0 mg, 0.23 mmol, 1.0 equiv.) and (3R)-1-ethylpiperidin-3-amine; dihydrochloride (293.5 mg, 1.46 mmol, 6.3 equiv.) 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 NaSO, filtered, and concentrated to dryness. The crude intermediate was then purified by flash column chromatography on silica gel (24 g cartridge, 0–10% MeOH (0.7 M NH) / DCM) to afford 21.0 mg as a brown solid. 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 equiv.) was added, then warmed to room temperature and stirred for 18 h. The reaction mixture was added to a stirred solution of 0.7 M NH in MeOH (10 mL) at 0 °C, and the reaction mixture was warmed 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) and concentrated to dryness. The product was purified by chromatography on silica gel (12 g cartridge, 0–10% MeOH (0.7 M NH) / DCM) to give the title compound (7.0 mg, 7%) as a light brown solid. LCMS m / z 412.24 [M+H] + ESI pos.

[0143] Intermediate 2 6-Iodo-4-methyl-3-methylsulfanyl-1,2,4-triazin-5-one [ka] Isoamyl nitrite (320.0 μL, 2.38 mmol, 2.05 equiv) was added dropwise to a mixture of 6-amino-4-methyl-3-methylsulfanyl-1,2,4-triazin-5-one (CAS no. 89730-72-3; 200.0 mg, 1.16 mmol, 1.0 equiv), tetrabutylammonium iodide (648.0 mg, 1.75 mmol, 1.51 equiv), copper(I) chloride (447.0 mg, 2.35 mmol, 2.02 equiv), and lithium iodide (330.0 mg, 2.47 mmol, 2.12 equiv) in MeCN (4 mL) heated at 60° C. for 3 h. The reaction mixture was cooled, diluted with EtOAc (50 mL), filtered through Celite, and rinsed with EtOAc (2 × 50 mL). The filtrate was diluted with water (100 mL) and the separated aqueous layer was further extracted with EtOAc (2 x 50 mL). The combined organic layers were dried (NaSO) and concentrated to give the crude product. The residue was purified by chromatography on silica gel (40 g cartridge, 0-100% EtOAc / isohexane) to give the title compound (156.0 mg, 46% yield) as a yellow solid. LCMS: m / z 284.0 [M+H] + ,ESI pos.

[0144] Intermediate 3: 2-(4-benzyloxy-6-methyl-indan-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka] Step A: 5-Bromo-6-methyl-indan-4-ol Sodium nitrite (200.0 mg, 2.9 mmol, 1.3 equiv) in water (5 mL) was added dropwise to a stirred solution of 5-bromo-6-methyl-indan-4-amine (500.0 mg, 2.21 mmol, 1.0 equiv, CAS number 2411531-03-6) in sulfuric acid (10.0 mL, 20.0 mmol, 9.0 equiv) (2 M in THF) at 0° C. The reaction was stirred for approximately 30 minutes and then allowed to warm to room temperature over approximately 30 minutes. The reaction mixture was then added dropwise to a stirred solution of sulfuric acid (10.0 mL, 20.0 mmol, 9.0 equiv) (2 M in THF) at 50° C., and the reaction was stirred for an additional 2.5 hours. The reaction was cooled to room temperature and then diluted with water (100 mL) and EtOAc (100 mL). The layers were separated and the aqueous phase was re-extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (1 x 50 mL), dried over MgSO4, and concentrated in vacuo. The crude material 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(500MHz,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).

[0145] Step B: 4-benzyloxy-5-bromo-6-methyl-indan Potassium carbonate (185.0 mg, 1.34 mmol, 2.0 equiv) was added to a stirred solution of 5-bromo-6-methyl-indan-4-ol (150.0 mg, 0.66 mmol, 1.0 equiv) in acetone (5 mL), and the reaction was stirred at room temperature for 5 minutes. Benzyl bromide (0.1 mL, 0.84 mmol, 1.27 equiv) was then added dropwise, and the reaction was stirred for approximately another 36 hours. 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 re-extracted with DCM (2 x 30 mL). The combined organic layers were washed with brine (1 x 30 mL), dried over MgSO4, and concentrated in vacuo. The crude material 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. 1 H NMR(500MHz,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).

[0146] Step C: 2-(4-benzyloxy-6-methyl-indan-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane To a stirred solution of 4-benzyloxy-5-bromo-6-methyl-indane (1.4 g, 4.41 mmol, 1.0 equiv.) and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.35 mL, 6.62 mmol, 1.5 equiv.) in THF (20 mL) was added n-butyllithium (1.6 M in hexanes) (4.41 mL, 7.06 mmol, 1.6 equiv.) dropwise at −78° C., and the reaction was stirred for 3 h. The reaction was quenched by the slow addition of saturated aqueous NH4Cl (20 mL). The mixture was allowed to warm to room temperature over 18 h. The layers were separated, the aqueous layer was extracted with EtOAc (2×20 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) as a light brown solid. 1 H NMR(500MHz,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).

[0147] Example 3: 3-[[(3R)-1-Ethyl-3-piperidyl]amino]-6-(4-hydroxy-6-methyl-indan-5-yl)-4-methyl-1,2,4-triazin-5-one [ka] Step A: 6-(4-benzyloxy-6-methyl-indan-5-yl)-4-methyl-3-methylsulfanyl-1,2,4-triazin-5-one A mixture of 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 equiv.), 6-iodo-4-methyl-3-methylsulfanyl-1,2,4-triazin-5-one intermediate 2 (225.0 mg, 0.79 mmol, 1.0 equiv.), KCO (352.0 mg, 2.55 mmol, 3.2 equiv.), and Pd-170 (111.0 mg, 0.16 mmol, 0.21 equiv.) in MeCN (12 mL) and water (4 mL) was degassed with N for 5 min and then heated to 60 °C for 21 h. A slow stream of N was added to the reaction mixture via a needle to limit the formation of the diMeS by-product. The reaction was cooled, concentrated, and loaded onto Celite. The crude product was purified by column chromatography on C18 silica gel (40 g cartridge, 10-100% [0.1% formic acid MeCN:0.1% formic acid in water]) to afford the title compound (86.0 mg, 24% yield) as a yellow solid. LCMS m / z 394.2 [M+H] + ESI pos.

[0148] Step B: 6-(4-benzyloxy-6-methyl-indan-5-yl)-4-methyl-3-[[(3R)-1-benzyl-3-piperidyl]amino]-1,2,4-triazin-5-one; formate salt 6-(4-Benzyloxy-6-methyl-indan-5-yl)-4-methyl-3-methylsulfanyl-1,2,4-triazin-5-one (70.0 mg, 0.18 mmol, 1.0 equiv.) was added to a small MW vial, and (R)-3-amino-1-benzylpiperidine (170.0 mg, 0.89 mmol, 5.02 equiv.; CAS No. 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 dark 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 cartridge, 10-100% [0.1% formic acid MeCN:0.1% formic acid in water]) to afford the title compound (35.0 mg, 36% yield) as a light brown solid and a further portion of the title compound (18.0 mg, 17% yield) as a dark brown solid. LCMS m / z 536.4 [M+H] + ESI pos.

[0149] Step C: 3-[[(3R)-1-ethyl-3-piperidyl]amino]-6-(4-hydroxy-6-methyl-indan-5-yl)-4-methyl-1,2,4-triazin-5-one Pd / C (type 39) (32.0 mg, 0.02 mmol, 0.25 equiv.) and Pd / C (type 87) (16.0 mg, 0.02 mmol, 0.25 equiv.) were added to a stirred solution of 6-(4-benzyloxy-6-methyl-indan-5-yl)-4-methyl-3-[[(3R)-1-benzyl-3-piperidyl]amino]-1,2,4-triazin-5-one; formate salt (35.0 mg, 0.1 mmol, 1.0 equiv.) in acetonitrile (2.1 mL). The hydrogenation vessel was placed under an atmosphere of hydrogen gas (2 bar) at room temperature and stirred vigorously for 4 h. The reaction was filtered through a plug of Celite, 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 cartridge, 0-10% MeOH (0.7 M NH) / DCM) to give the title compound (20.0 mg, 85% yield) as a pale yellow freeze-dried solid after lyophilization. LCMS m / z 384.3 [M+H] + ESI pos.

[0150] Example 4: 3-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]-6-(4-hydroxy-6-methyl-indan-5-yl)-4-methyl-1,2,4-triazin-5-one [ka] Step A: 6-(4-hydroxy-6-methyl-indan-5-yl)-4-methyl-3-[[(3R)-3-piperidyl]amino]-1,2,4-triazin-5-one Pd / C (type 39) (20.0 mg, 0.01 mmol, 0.29 equiv.) and Pd / C (type 87) (10.0 mg, 0.01 mmol, 0.29 equiv.) were added to a stirred solution of 6-(4-benzyloxy-6-methyl-indan-5-yl)-4-methyl-3-[[(3R)-1-benzyl-3-piperidyl]amino]-1,2,4-triazin-5-one; formate salt (Step B of Example 3) (19.0 mg, 0.03 mmol, 1.0 equiv.) in 1,4-dioxane (3 mL). The hydrogenation vessel was placed under an atmosphere of hydrogen gas (2 bar) at room temperature and stirred vigorously for 18 h. Additional Pd / C (type 39) (20.0 mg, 0.01 mmol, 0.29 equiv.) and Pd / C (type 87) (10.0 mg, 0.01 mmol, 0.29 equiv.) were added, and the reaction was resubmitted to these conditions for 24 h. The reaction was filtered through a plug of Celite, rinsed with EtOH, and concentrated to dryness to give 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.

[0151] Step B: 3-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]-6-(4-hydroxy-6-methyl-indan-5-yl)-4-methyl-1,2,4-triazin-5-one To a stirred solution of 6-(4-hydroxy-6-methyl-indan-5-yl)-4-methyl-3-[[(3R)-3-piperidyl]amino]-1,2,4-triazin-5-one (7.0 mg, 0.02 mmol, 1.0 equiv.) and DIPEA (5.15 µL, 0.03 mmol, 1.5 equiv.) in DMF (0.30 mL), 2-iodoethanol (3.39 mg, 0.02 mmol, 1.0 equiv.) in DMF (0.100 mL) was added dropwise at room temperature, and the reaction mixture was stirred for 3 days. The reaction mixture was concentrated to dryness and then loaded onto Celite. The crude product was then purified by reverse-phase flash column chromatography (C18 13 g cartridge, 10–100% MeCN / 10 mM NH4HCO3 in water) to afford the title compound (2.0 mg, 24% yield) as an off-white solid after lyophilization. LCMS m / z 400.5[M+H] + ESI pos.

[0152] Example 5: 3-[[(3R)-1-Ethyl-3-piperidyl]amino]-6-(4-hydroxy-6-methyl-2,3-dihydrobenzofuran-5-yl)-4-methyl-1,2,4-triazin-5-one [ka] Step A: 6-(4-benzyloxy-6-methyl-2,3-dihydrobenzofuran-5-yl)-4-methyl-3-methylsulfanyl-1,2,4-triazin-5-one A mixture of 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 equiv., CAS number 2923540-53-6), 6-iodo-4-methyl-3-methylsulfanyl-1,2,4-triazin-5-one intermediate 2 (150.0 mg, 0.53 mmol, 1.0 equiv.), KCO (220.0 mg, 1.59 mmol, 3.0 equiv.) and Pd-170 (71.0 mg, 0.11 mmol, 0.2 equiv.) in MeCN (10 mL) and water (2 mL) was degassed with N for 5 min and then heated to 60 °C for 2 h. A slow stream of N2 was added to the reaction mixture via needle to limit the formation of the diMeS by-product. The reaction was left stirring at room temperature for approximately 4 days. The reaction was cooled, concentrated, and loaded onto Celite. The crude product was purified by column chromatography on C18 silica gel (40 g cartridge, 10-100% [0.1% formic acid MeCN:0.1% formic acid in water]) to afford the title compound (36.0 mg, 17% yield) as a yellow solid. LCMS m / z 395.8 [M+H] + ESI pos.

[0153] Step B: 6-(4-benzyloxy-6-methyl-2,3-dihydrobenzofuran-5-yl)-4-methyl-3-[[(3R)-1-benzyl-3-piperidyl]amino]-1,2,4-triazin-5-one; formate salt 6-(4-benzyloxy-6-methyl-2,3-dihydrobenzofuran-5-yl)-4-methyl-3-methylsulfanyl-1,2,4-triazin-5-one (35.0 mg, 0.09 mmol, 1.0 equiv.) was added to a small MW vial, and (R)-3-amino-1-benzylpiperidine (160.0 mg, 0.84 mmol, 9.5 equiv.; CAS No. 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 dark 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 cartridge, 10-100% [0.1% formic acid MeCN:0.1% formic acid in water]) to give the title compound (30.0 mg, 54% yield) as a brown solid. LCMS m / z 538.4 [M+H] + ESI pos.

[0154] Step C: 3-[[(3R)-1-ethyl-3-piperidyl]amino]-6-(4-hydroxy-6-methyl-2,3-dihydrobenzofuran-5-yl)-4-methyl-1,2,4-triazin-5-one Pd / C (Type 39) (24.0 mg, 0.01 mmol, 0.26 equiv.) and Pd / C (Type 87) (12.0 mg, 0.01 mmol, 0.26 equiv.) were added to a stirred solution of 6-(4-benzyloxy-6-methyl-2,3-dihydrobenzofuran-5-yl)-4-methyl-3-[[(3R)-1-benzyl-3-piperidyl]amino]-1,2,4-triazin-5-one; formate salt (30.0 mg, 0.04 mmol, 1.0 equiv.) in acetonitrile (3.0 mL). The hydrogenation vessel was placed under an atmosphere of hydrogen gas (2 bar) at room temperature and stirred vigorously for 18 h. The reaction was filtered through a plug of Celite, rinsed with EtOH, and concentrated to dryness to give the crude product (14 mg). The crude product was purified by column chromatography on silica gel (12 g cartridge, 0-10% MeOH (0.7 M NH) / DCM) to give the title compound (8.0 mg, 47% yield) as a pale yellow freeze-dried solid after lyophilization. LCMS m / z 386.2 [M+H] + ESI pos.

[0155] Example 6: 6-(4-chloro-2-hydroxy-6-methyl-phenyl)-3-[[(3R)-1-ethyl-3-piperidyl]amino]-4-methyl-1,2,4-triazin-5-one [ka] Step A: 6-(4-chloro-2-hydroxy-6-methyl-phenyl)-4-methyl-3-methylsulfanyl-1,2,4-triazin-5-one A mixture of (4-chloro-2-hydroxy-6-methyl-phenyl)boronic acid (200.0 mg, 1.07 mmol, 1.03 equiv., CAS No. 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 equiv.), KCO (430.0 mg, 3.11 mmol, 2.99 equiv.), and Pd-170 (140.0 mg, 0.21 mmol, 0.2 equiv.) in MeCN (12 mL) and water (3 mL) was degassed with N for 5 minutes and then heated to 60° C. for 20 hours. The reaction was cooled, concentrated, and loaded onto Celite. The crude product was purified by column chromatography on C18 silica gel (40 g cartridge, 10-100% [0.1% formic acid MeCN:0.1% formic acid in water]) to give the title compound (132.0 mg, 39% yield) as a pale yellow solid. LCMS m / z 298.1 / 300.1 [M+H] + ESI pos.

[0156] Step B: 6-(4-chloro-2-hydroxy-6-methyl-phenyl)-3-[[(3R)-1-ethyl-3-piperidyl]amino]-4-methyl-1,2,4-triazin-5-one A 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 equiv.) and (3R)-1-ethylpiperidin-3-amine (121.0 mg, 0.94 mmol, 4.32 equiv.) was irradiated at 180 °C for 0.5 h, showing nearly complete conversion. The reaction mixture was concentrated to dryness and then loaded onto Celite. The crude material was then purified by reverse-phase flash column chromatography (C18 13 g cartridge, 10–100% MeCN / 10 mM NH4HCO3 in water) to afford the title compound (35.0 mg, 40% yield) as a pale yellow solid. LCMS m / z 378.3 / 380.2 [M+H] + ,ESI pos.

[0157] Example A The compound of formula I can be used in a manner known per se as the active ingredient to produce tablets of the following composition: Per tablet Active ingredient 200mg Microcrystalline cellulose 155mg Cornstarch 25mg Talc 25mg Hydroxypropyl methylcellulose 20mg 425mg

[0158] Example B The compound of formula I can be used in a manner known per se as the active ingredient to produce capsules of the following composition: Per capsule Active ingredient 100.0mg Cornstarch 20.0mg Lactose 95.0mg Talc 4.5mg Magnesium stearate 0.5mg 220.0mg

Claims

1. Formula I: 【Chemistry 1】 (In the formula, R １ is H, acetyl, SF ５ , halo, alkyl, alkoxy, haloalkyl, haloalkoxy, or cyano; R ５ is H; or R １ and R ５ and the atoms to which they are attached form any 4-6 membered heterocyclic ring containing only one O heteroatom, optionally substituted with 1 or 2 substituents independently selected from halo and alkyl, or R １ and R ５ and the atoms to which they are attached form a 4-6 membered cycloalkyl ring, optionally substituted with 1-2 substituents independently selected from halo and alkyl; R ２ is H, halo, alkyl, alkoxy, alkoxyalkyl, haloalkyl, cycloalkyl, wherein cycloalkyl is optionally substituted with halo; R ３ is H or alkyl; R ４ａ is halo, alkyl, haloalkyl, hydroxyalkyl, —OH, oxo, —CO ２ a heterocyclic ring optionally substituted with 1 to 3 substituents independently selected from H, cycloalkylalkyl, or cycloalkyl optionally substituted with halo, and R ４ｂ is H, or 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 1 or 2 substituents independently selected from alkyl, —OH, or halo. and pharmaceutically acceptable salts thereof.

2. 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 any 4-6 membered heterocyclic ring containing only one O heteroatom optionally substituted with 1 or 2 substituents independently selected from halo and alkyl, or R １ and R ５ and the atoms to which they are attached form a 4-6 membered cycloalkyl ring, optionally substituted with 1-2 substituents independently selected from halo and alkyl.

3. 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 any 5-membered heterocyclic ring containing only one O heteroatom, or R １ and R ５ and the atoms to which they are attached form a 5-membered cycloalkyl ring.

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

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

6. R ５ is H or R １ and R ５ and the atoms to which they are attached form any 5-membered heterocyclic ring containing only one O heteroatom, or R １ and R ５ and the atoms to which they are attached form a 5-membered cycloalkyl ring.

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

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

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

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

11. R ４ａ is a 6-membered heterocyclic ring containing only one N heteroatom substituted with alkyl or hydroxyalkyl, and R ４ｂ is H or 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.

12. R ４ａ is a 6-membered heterocyclic ring containing only one N heteroatom substituted with alkyl, and R ４ｂ is H or 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.

13. R ４ａ is a 6-membered heterocyclic ring containing only one N heteroatom substituted with alkyl, and R ４ｂ is H or R ４ａ and R ４ｂ and the N to which they are attached form a 9-membered heterocycle containing two N heteroatoms, and the 9-membered heterocycle containing two N heteroatoms is substituted with alkyl.

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

15. R １ is halo, haloalkyl, or haloalkoxy; R ５ is H; or R １ and R ５ and the atoms to which they are attached form any 5-membered heterocyclic ring containing only one O heteroatom, or R １ and R ５ and the atoms to which they are attached form a 5-membered cycloalkyl ring; R ２ is H, halo, alkyl, haloalkyl, cycloalkyl, wherein cycloalkyl is optionally substituted with halo; R ３ is alkyl; R ４ａ is a 6-membered heterocyclic ring substituent having alkyl, hydroxyalkyl, cycloalkylalkyl, or cycloalkyl optionally substituted with halo, and R ４ｂ is H, or 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 halo; 10. The compound of claim 1 and pharmaceutically acceptable salts thereof.

16. R １ is halo, haloalkyl, or haloalkoxy; R ５ is H; or R １ and R ５ and the atoms to which they are attached form any 5-membered heterocyclic ring containing only one O heteroatom, or R １ and R ５ and the atoms to which they are attached form a 5-membered cycloalkyl ring; R ２ is H or alkyl; R ３ is alkyl; R ４ａ is a 6-membered heterocyclic ring containing only one N heteroatom substituted with alkyl or hydroxyalkyl, and R ４ｂ is H, or 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; 10. The compound of claim 1 and pharmaceutically acceptable salts thereof.

17. R １ is halo, haloalkyl, or haloalkoxy; R ５ is H; or R １ and R ５ and the atoms to which they are attached form any 5-membered heterocyclic ring containing only one O heteroatom, or R １ and R ５ and the atoms to which they are attached form a 5-membered cycloalkyl ring; R ２ is H or alkyl; R ３ is alkyl; R ４ａ is a 6-membered heterocyclic ring containing only one N heteroatom substituted with alkyl or hydroxyalkyl, and R ４ｂ is H, or R ４ａ and R ４ｂ and the N to which they are attached form a 9-membered heterocycle containing two N heteroatoms, said 9-membered heterocycle containing two N heteroatoms being substituted with alkyl; 10. The compound of claim 1 and pharmaceutically acceptable salts thereof.

18. R １ is halo, haloalkyl, or haloalkoxy; R ５ is H; or R １ and R ５ and the atoms to which they are attached form any 5-membered heterocyclic ring containing only one O heteroatom, or R １ and R ５ and the atoms to which they are attached form a 5-membered cycloalkyl ring; R ２ is H or alkyl; R ３ is alkyl; R ４ａ is a 6-membered heterocyclic ring containing only one N heteroatom substituted with alkyl, and R ４ｂ is H, or 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; 10. The compound of claim 1 and pharmaceutically acceptable salts thereof.

19. R １ is halo, haloalkyl, or haloalkoxy; R ５ is H; or R １ and R ５ and the atoms to which they are attached form any 5-membered heterocyclic ring containing only one O heteroatom, or R １ and R ５ and the atoms to which they are attached form a 5-membered cycloalkyl ring; R ２ is H or alkyl; R ３ is alkyl; R ４ａ is a 6-membered heterocyclic ring containing only one N heteroatom substituted with alkyl, and R ４ｂ is H, or R ４ａ and R ４ｂ and the N to which they are attached form a 9-membered heterocycle containing two N heteroatoms, said 9-membered heterocycle containing two N heteroatoms being substituted with alkyl; 10. The compound of claim 1 and pharmaceutically acceptable salts thereof.

20. R １ is halo, haloalkyl, or haloalkoxy; R ５ is H; or R １ and R ５ and the atoms to which they are attached form any 5-membered heterocyclic ring containing only one O heteroatom, or R １ and R ５ and the atoms to which they are attached form a 5-membered cycloalkyl ring; R ２ is alkyl; R ３ is alkyl; R ４ａ is a 6-membered heterocyclic ring containing only one N heteroatom substituted with alkyl, and R ４ｂ is H, or R ４ａ and R ４ｂ and the N to which they are attached form a 9-membered heterocycle containing two N heteroatoms, said 9-membered heterocycle containing two N heteroatoms being substituted with alkyl; 10. The compound of claim 1 and pharmaceutically acceptable salts thereof.

21. 3-[[(3R)-1-ethyl-3-piperidyl]amino]-6-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5-one; 3-[[(3R)-1-ethyl-3-piperidyl]amino]-6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5-one; 21. The compound of any one of claims 1 to 20, selected from: and pharmaceutically acceptable salts thereof.

22. 3-[[(3R)-1-ethyl-3-piperidyl]amino]-6-(4-hydroxy-6-methyl-indan-5-yl)-4-methyl-1,2,4-triazin-5-one; 3-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]-6-(4-hydroxy-6-methyl-indan-5-yl)-4-methyl-1,2,4-triazin-5-one; 3-[[(3R)-1-ethyl-3-piperidyl]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-piperidyl]amino]-4-methyl-1,2,4-triazin-5-one; 21. The compound of any one of claims 1 to 20, selected from: and pharmaceutically acceptable salts thereof.

23. The compound according to any one of claims 1 to 21, which is 3-[[(3R)-1-ethyl-3-piperidyl]amino]-6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-4-methyl-1,2,4-triazin-5-one or a pharmaceutically acceptable salt thereof.

24. 3-[[(3R)-1-ethyl-3-piperidyl]amino]-6-(4-hydroxy-6-methyl-indan-5-yl)-4-methyl-1,2,4-triazin-5-one; 3-[[(3R)-1-ethyl-3-piperidyl]amino]-6-(4-hydroxy-6-methyl-2,3-dihydrobenzofuran-5-yl)-4-methyl-1,2,4-triazin-5-one; 23. The compound of any one of claims 1 to 20 or 22, selected from: and pharmaceutically acceptable salts thereof.

25. 25. A process for preparing a compound according to any one of claims 1 to 24, comprising reacting a compound of formula III to provide a compound of formula I by cleavage of the protecting group (PG). 【Chemistry 2】

26. A compound according to any one of claims 1 to 24 for use as a therapeutically active substance.

27. 25. A compound according to any one of claims 1 to 24 for use in the treatment or prevention of a disease, disorder or condition, wherein the disease, disorder or condition is responsive 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. 25. Use of a compound according to any one of claims 1 to 24 for the treatment or prevention of a disease, disorder or condition, wherein said disease, disorder or condition is responsive to NLRP3 inhibition.

30. 25. A compound according to any one of claims 1 to 24 for use in the treatment or prevention of a disease, disorder or condition selected from Alzheimer's disease and Parkinson's disease.

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

32. 25. Use of a compound according to any one of claims 1 to 24 for the preparation of a medicament for the treatment or prevention of a disease, disorder or condition selected from Alzheimer's disease and Parkinson's disease.

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

34. 25. A method for the treatment or prevention of a disease, disorder or condition, 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 when produced according to the method of claim 25.

36. 10. The invention as hereinbefore described.

Images