Novel compound

Abstract

The present invention relates to novel compounds having the general formula (Ib) or (Ib’) JPEG2025519226000030.jpg118161 (wherein R 1 , R 2 , R 6 , A3, A4, A5, X, Y and W are as described herein), compositions containing the compounds, and methods of using the compounds.

Description

Technical Field

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

[0002] The present invention relates to novel compounds of formula Ib or Ib'

Chemical Formula

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

Background Art

[0004] The NOD-like receptor (NLR) family pyrin domain-containing protein 3 (NLRP3) inflammasome is a component of the inflammatory process, and its abnormal activation is responsible for genetic disorders such as cryopyrin-associated periodic syndrome (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-derived factors, environmental factors, and host-derived factors. When activated, NLRP3 binds to apoptosis-associated speck-like protein (ASC) containing a caspase activation and recruitment domain. Next, ASC polymerizes to form a large aggregate known as the ASC speck. Next, the polymerized ASC interacts with the cysteine protease caspase-1 to form a complex called the inflammasome. As a result, caspase-1 is activated, and the precursor forms of the inflammatory cytokines IL-1β and IL-18 (called pro-IL-1β and pro-IL-18, respectively) are cleaved, and these cytokines are activated. Caspase-1 also mediates a type of inflammatory cell death known as pyroptosis. The ASC speck can also recruit and activate caspase-8 and process pro-IL-1β and pro-IL-18 to induce apoptotic cell death.

[0006] Caspase-1 cleaves pro-IL-1β and pro-IL-18 into their active forms, which are secreted from the cell. Active caspase-1 also cleaves gasdermin-D to induce pyroptosis. Through the 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, resulting in its degradation and enabling the release of IL-1α. In human cells, caspase-1 may also control the processing and secretion of IL-37. Many other caspase-1 substrates, such as components of the cytoskeleton and the glycolytic pathway, may contribute to caspase-1-dependent inflammation.

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

[0008] The active cytokines resulting from NLRP3 inflammasome activation are important drivers of inflammation and interact with other cytokine pathways to shape the immune response 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 act synergistically 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 and to promote a Th1 response.

[0009] 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, defining NLRP3 as an important component of the inflammatory process. NLRP3 is also involved in the etiology of many complex diseases, including metabolic disorders such as type 2 diabetes, atherosclerosis, obesity, and gout.

[0010] The role of NLRP3 in central nervous system diseases is becoming clear, and it has also been shown that lung diseases are also affected by NLRP3. Furthermore, NLRP3 is involved in the development of liver diseases, kidney diseases, and aging. Many of these associations have been elucidated using Nlrp3 - / - mice, but insights into the specific activation of NLRP3 in these diseases have also been obtained. 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.

[0011] Some small molecules have been shown to inhibit the NLRP3 inflammasome. Glyburide inhibits the production of IL-1β at micromolar concentrations in response to NLRP3 activation, but does not respond to the activation of NLRC4 or NLRP1. 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 non-specific.

[0012] Current treatments for NLRP3-related diseases include biological 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 proven successful in the treatment of CAPS, and these biological agents are being used in clinical trials for other IL-1β-related diseases.

[0013] There is a need to provide compounds with improved pharmacological and / or physiological and / or physicochemical properties, and / or compounds that are useful alternatives to known compounds. SUMMARY OF THE INVENTION

[0014] The present invention relates to novel compounds of formula Ib or Ib’ [Chemical] (wherein, A3 is selected from N or CR 3 ; and is selected from A4 is selected from N or CR 4 ; and is selected from A5 is selected from N or CR 5 ; and is selected from Y is selected from N or CH, X is CR 7 or alternatively, X and Y, and the atoms to which they are attached, form a 5-membered heteroaryl ring containing two N heteroatoms, and one of the N heteroatoms is substituted with either H or alkyl; R 1 is selected from alkyl, cyano or H; R 2 is selected from alkyl, cyano, H or halo; R 3 is H; R 4 is selected from H, alkyl, alkoxy or halo; R 5 is selected from H or halo; R 6 is H; R 7 is alkyl or haloalkyl; W is optionally substituted cycloalkyl, or an optionally substituted heterocycle containing a single N heteroatom, the optionally substituted cycloalkyl may be substituted with one or two substituents independently selected from H, OH or alkyl, and the optionally substituted heterocycle containing a single N heteroatom may be substituted with alkyl or haloalkyl); and its pharmaceutically acceptable salts are provided.

[0015] The term "alkyl" represents a monovalent straight-chain or branched saturated hydrocarbon group consisting of 1 to 6 carbon atoms. In some embodiments, unless otherwise specified, alkyl is 1 to 6 carbon atoms (C 1-6-(alkyl) or 1 to 4 carbon atoms (C 1-4 -alkyl). C 1-6 Examples of -alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl and pentyl. Specific alkyl groups include methyl and ethyl. When an alkyl residue having a specific number of carbons is named, all geometric isomers having that number of carbons may be included. Thus, for example, "butyl" may include n-butyl, sec-butyl, iso-butyl and t-butyl, and "propyl" may include n-propyl and isopropyl.

[0016] The term "alkoxy" represents a group of the formula -O-R' where R' is a C 1-6 -alkyl group. C 1-6 Examples of -alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and tert-butoxy.

[0017] The term "cyano" represents a -C≡N group.

[0018] The term "cycloalkyl" represents a monocyclic or polycyclic saturated or partially unsaturated non-aromatic hydrocarbon. In some embodiments, unless otherwise specified, 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. In other embodiments, cycloalkyl contains one or more double bonds (e.g., cycloalkyl fused to an aryl or heteroaryl ring, or a non-aromatic monocyclic hydrocarbon containing one or two double bonds). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, octahydropentalenyl, spiro[3.3]heptanyl, and the like. Bicyclic means a ring system consisting of two saturated carbon rings sharing two carbon atoms in common. Examples of monocyclic cycloalkyl are cyclopropyl, cyclobutanil, cyclopentyl, cyclohexyl, or cycloheptyl.

[0019] The terms "halogen", "halide", and "halo" are used interchangeably herein and represent fluoro, chloro, bromo, or iodo. Specific halogens are fluoro and chloro.

[0020] The term "haloalkyl" represents a C 1-6 -alkyl group in which at least one hydrogen atom of the C 1-6 -alkyl group is replaced by the same or different halogen atoms. A specific example is trifluoromethyl.

[0021] The term "heterocyclic ring" refers to a monocyclic or bicyclic ring system of 4 to 10 or 4 to 9 ring atoms, containing 1, 2 or 3 ring heteroatoms selected from N, O and S, with the remaining ring atoms being carbon, which is monovalent saturated or partially unsaturated. Examples of monocyclic saturated heterocyclic rings are oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl or piperazinyl. Examples of partially unsaturated heterocyclic rings are dihydrofuryl, imidazolinyl, dihydro-oxazolyl, tetrahydro-pyridinyl, or dihydropyranyl. A specific example of a heterocyclic ring is piperidinyl.

[0022] The term "heteroaryl" refers to a monovalent aromatic heterocyclic monocyclic or bicyclic ring system of 5 to 12 ring atoms, containing 1, 2, 3 or 4 heteroatoms selected from N, O and S, with the remaining ring atoms being carbon, either alone or in combination. Examples of heteroaryl groups include pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, triazinyl, azepinyl, diazepinyl, isoxazolyl, benzofuranyl, isothiazolyl, benzothienyl, indolyl, isoindolyl, isobenzofuranyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, and benzothiophenyl.

[0023] The term "pharmaceutically acceptable salt" refers to salts that retain the biological effectiveness and properties of the free base or free acid and are 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, N-acetylcysteine. In addition, these salts can be prepared by adding an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, salts of sodium, potassium, lithium, ammonium, calcium, magnesium. Salts derived from organic bases include 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, salts of polyamine resins, but are not limited to these. The compounds of formula Ib can also exist in zwitterionic form. Particularly preferred pharmaceutically acceptable salts of the compounds of formula Ib are salts formed with formic acid and salts formed with hydrochloric acid that yield hydrochloride, dihydrochloride or trihydrochloride.

[0024] The abbreviation uM means micromole and is equivalent to the symbol μM.

[0025] The abbreviation uL means microliter and is equivalent to the symbol μL.

[0026] The abbreviation ug means microgram and is equivalent to the symbol μg.

[0027] The compounds of formula Ib can contain several asymmetric centers and can exist in the form of optically pure enantiomers, mixtures of enantiomers such as racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereomeric racemates or mixtures of diastereomeric racemates.

[0028] According to the Cahn-Ingold-Prelog rules, the asymmetric carbon atoms can have the "R" or "S" configuration.

[0029] One embodiment of the present invention also provides a compound according to formula Ib described herein, and a pharmaceutically acceptable salt or ester thereof, in particular a compound according to formula Ib described herein, and a pharmaceutically acceptable salt thereof, more specifically, a compound according to formula Ib described herein.

[0030] Also, one embodiment of the present invention provides a compound according to formula Ib' described herein, and a pharmaceutically acceptable salt or ester thereof, in particular a compound according to formula Ib' described herein, and a pharmaceutically acceptable salt thereof, more specifically, a compound according to formula Ib' described herein.

[0031] One embodiment of the present invention is A3 is selected from N or CR 3 ; and A4 is selected from N or CR 4 ; and A5 is selected from N or CR 5 ; and Y is selected from N or CH, X is CR 7 or or X and Y, and the atoms to which they are attached, form a 5-membered heteroaryl ring containing two N heteroatoms, one of the N heteroatoms being substituted by either H or alkyl; R 1 is selected from alkyl, cyano or H; R 2 is selected from alkyl, cyano, H or halo; R 3 is H; R 4 is selected from H, alkyl, alkoxy or halo; R 5 is selected from H or halo; R 6 is H; R 7 is alkyl or haloalkyl; W is optionally substituted cycloalkyl, or an optionally substituted heterocycle containing a single N heteroatom, the optionally substituted cycloalkyl may be substituted with one or two substituents independently selected from H, OH or alkyl, and the optionally substituted heterocycle containing a single N heteroatom may be substituted with alkyl or haloalkyl, a compound of formula Ib as described herein and pharmaceutically acceptable salts thereof are provided.

[0032] One embodiment of the invention provides a compound of formula Ib as described herein, wherein Y is selected from N or CH and X is CR 7 as defined herein.

[0033] One embodiment of the invention provides a compound of formula Ib as described herein, wherein R 1 is H.

[0034] One embodiment of the invention provides a compound of formula Ib as described herein, wherein R 2 is H or halo.

[0035] One embodiment of the invention provides a compound of formula Ib as described herein, wherein A3 is CR 3 as defined herein.

[0036] One embodiment of the invention provides a compound of formula Ib as described herein, wherein A4 is CR 4 as defined herein.

[0037] One embodiment of the invention provides a compound of formula Ib as described herein, wherein A5 is CR 5Provided is a compound according to formula Ib described herein.

[0038] An embodiment of the present invention provides a compound according to formula Ib wherein R 4 is selected from H or halo.

[0039] One embodiment of the present invention provides a compound according to formula Ib wherein R 4 is H.

[0040] One embodiment of the present invention provides a compound according to formula Ib wherein R 5 is H.

[0041] One embodiment of the present invention provides a compound according to formula Ib wherein R 7 is alkyl.

[0042] One embodiment of the present invention provides a compound according to formula Ib wherein W is a piperidine ring substituted with alkyl.

[0043] One embodiment of the present invention is that A3 is CR 3 ; A4 is CR 4 ; A5 is CR 5 ; Y is selected from N or CH, and X is CR 7 ; R 1 is alkyl, cyano, or H; R 2 is alkyl, cyano, H or halo; R 3 is H; R 4 is H or halo; R 5 is H or halo; R 6 is H; R 7 is alkyl or haloalkyl; A compound of formula Ib wherein W is a piperidine ring substituted with alkyl and pharmaceutically acceptable salts thereof are provided.

[0044] One embodiment of the invention is A3 is CR 3 ; A4 is CR 4 ; A5 is CR 5 ; Y is selected from N or CH, and X is CR 7 ; R 1 is H; R 2 is H or halo; R 3 is H; R 4 is H; R 5 is H; R 6 is H; R 7 is alkyl or haloalkyl; A compound of formula Ib wherein W is a piperidine ring substituted with alkyl and pharmaceutically acceptable salts thereof are provided.

[0045] One embodiment of the invention is A3 is CR 3 ; A4 is CR 4 ; A5 is CR 5 ; and Y is selected from N or CH, and X is CR 7 ; R 1 is H; R 2 is H or halo; R 3 is H; R 4 is H; R 5is H; R 6 is H; R 7 is alkyl; a compound of formula Ib wherein W is a piperidine ring substituted with alkyl and pharmaceutically acceptable salts thereof are provided.

[0046] Specific examples of the compounds of formula Ib described herein are N-[(3R)-1-Ethyl-3-piperidinyl]-6-(1H-indol-6-yl)-5-methyl-pyridazin-3-amine; N-[(3R)-1-Ethyl-3-piperidinyl]-6-(3-fluoro-1H-indol-6-yl)-5-methyl-pyridazin-3-amine; N-[(3R)-1-Ethyl-3-piperidinyl]-6-(5-fluoro-1H-indol-6-yl)-5-methyl-pyridazin-3-amine; N-[(3R)-1-Ethyl-3-piperidinyl]-5-methyl-6-(3-methyl-1H-indol-6-yl)pyridazin-3-amine; 6-(3-Chloro-1H-indol-6-yl)-N-[(3R)-1-ethyl-3-piperidinyl]-5-methyl-pyridazin-3-amine; N-[(3R)-1-Ethyl-3-piperidinyl]-5-methyl-6-(2-methyl-1H-indol-6-yl)pyridazin-3-amine; 6-[6-[[(3R)-1-Ethyl-3-piperidinyl]amino]-4-methyl-pyridazin-3-yl]-1H-indole-3-carbonitrile; 6-[6-[[(3R)-1-Ethyl-3-piperidinyl]amino]-4-methyl-pyridazin-3-yl]-1H-indole-2-carbonitrile; 6-(3-Fluoro-1H-indol-6-yl)-5-methyl-N-[(3R)-1-methyl-3-piperidinyl]pyridazin-3-amine; N-[(3R)-1-Ethyl-3-piperidinyl]-6-(1H-indol-6-yl)-5-methyl-pyridazin-3-amine; N-[(3R)-1-Ethyl-3-piperidyl]-6-(3-fluoro-1H-indol-6-yl)-5-(trifluoromethyl)pyridazin-3-amine; 5-Ethyl-N-[(3R)-1-ethyl-3-piperidyl]-6-(3-fluoro-1H-indol-6-yl)pyridazin-3-amine; N-[(3R)-1-Ethyl-3-piperidyl]-6-(1H-indol-6-yl)-5-methyl-1,2,4-triazin-3-amine; N-[(3R)-1-Ethyl-3-piperidyl]-6-(3-fluoro-1H-indol-6-yl)-5-methyl-1,2,4-triazin-3-amine and is selected from its pharmaceutically acceptable salts.

[0047] Other specific examples of formula Ib described herein are N-[(3R)-1-Ethyl-3-piperidyl]-6-(5-methyl-1H-indol-6-yl)pyridazin-3-amine; 3-[[6-(3-Fluoro-1H-indol-6-yl)-5-methyl-pyridazin-3-yl]amino]-1-methyl-cyclobutanol; and is selected from its pharmaceutically acceptable salts.

[0048] Other specific examples of formula Ib described herein are N-[(3R)-1-ethyl-3-piperidyl]-7-(1H-indol-6-yl)-1-methyl-pyrazolo[3,4-d]pyridazin-4-amine and its pharmaceutically acceptable salts.

[0049] Other specific examples of formula Ib described herein are (3aS,7aR)-1-[6-(3-Fluoro-1H-indol-6-yl)-5-methyl-pyridazin-3-yl]-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridine; (3aR,7aS)-1-[6-(3-Fluoro-1H-indol-6-yl)-5-methyl-pyridazin-3-yl]-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridine; and is selected from the pharmaceutically acceptable salts thereof.

[0050] Preferred examples of the compound of formula Ib described herein are N-[(3R)-1-Ethyl-3-piperidyl]-6-(1H-indol-6-yl)-5-methyl-pyridazin-3-amine; N-[(3R)-1-Ethyl-3-piperidyl]-6-(3-fluoro-1H-indol-6-yl)-5-methyl-pyridazin-3-amine; 6-(3-Fluoro-1H-indol-6-yl)-5-methyl-N-[(3R)-1-methyl-3-piperidyl]pyridazin-3-amine; N-[(3R)-1-Ethyl-3-piperidyl]-6-(3-fluoro-1H-indol-6-yl)-5-(trifluoromethyl)pyridazin-3-amine; N-[(3R)-1-Ethyl-3-piperidyl]-6-(1H-indol-6-yl)-5-methyl-1,2,4-triazin-3-amine; N-[(3R)-1-Ethyl-3-piperidyl]-6-(3-fluoro-1H-indol-6-yl)-5-methyl-1,2,4-triazin-3-amine; and is selected from the pharmaceutically acceptable salts thereof.

[0051] The most preferred examples of the compound of formula Ib described herein are N-[(3R)-1-Ethyl-3-piperidyl]-6-(3-fluoro-1H-indol-6-yl)-5-methyl-pyridazin-3-amine; N-[(3R)-1-Ethyl-3-piperidyl]-6-(1H-indol-6-yl)-5-methyl-1,2,4-triazin-3-amine; N-[(3R)-1-Ethyl-3-piperidyl]-6-(3-fluoro-1H-indol-6-yl)-5-methyl-1,2,4-triazin-3-amine; and is selected from the pharmaceutically acceptable salts thereof.

[0052] One embodiment of the present invention provides a compound according to formula I, wherein the compound of formula I is a compound of formula Ib.

Chemical formula

[0053] One embodiment of the present invention A3 is selected from N or CR 3 ; A4 is selected from N or CR 4 ; A5 is selected from N or CR 5 ; Y is selected from N or CH; R 1 is selected from alkyl, cyano or H; R 2 is selected from alkyl, cyano, H or halo; R 3 is H; R 4 is selected from H, alkyl, alkoxy or halo; R 5 is selected from H or halo; R 6 is H; R 7 is alkyl or haloalkyl; W is optionally substituted cycloalkyl, or an optionally substituted heterocycle containing a single N heteroatom, wherein the optionally substituted cycloalkyl may be substituted with 1 or 2 substituents independently selected from H, OH or alkyl, and the optionally substituted heterocycle containing a single N heteroatom may be substituted with alkyl or haloalkyl, a compound according to formula I as described herein and is selected from the pharmaceutically acceptable salts thereof.

[0054] One embodiment of the present invention provides a compound of formula I as described herein, wherein R 1 is H.

[0055] One embodiment of the present invention provides a compound of formula I as described herein, wherein R 2 is H or halo.

[0056] One embodiment of the present invention provides a compound of formula I as described herein, wherein A3 is CR 3 .

[0057] One embodiment of the present invention provides a compound of formula I as described herein, wherein A4 is CR 4 .

[0058] One embodiment of the present invention provides a compound of formula I as described herein, wherein A5 is CR 5 .

[0059] Embodiments of the present invention provide a compound of formula I as described herein, wherein R 4 is selected from H or halo.

[0060] One embodiment of the present invention provides a compound of formula I as described herein, wherein R 4 is H.

[0061] One embodiment of the present invention provides a compound of formula I as described herein, wherein R 5 is H.

[0062] One embodiment of the present invention provides a compound of formula I as described herein, wherein R 7 is alkyl.

[0063] One embodiment of the present invention provides a compound of formula I as described herein, wherein W is a piperidine ring substituted with alkyl.

[0064] One embodiment of the present invention is A3 is CR 3 and; A4 is CR 4 and; A5 is -CR 5 -and; Y is N or CH; R 1 is alkyl, cyano, or H; R 2 is alkyl, cyano, H or halo; R 3 is H; R 4 is H or halo; R 5 is H or halo; R 6 is H; R 7 is alkyl or haloalkyl; W is a piperidine ring substituted with alkyl, a compound of formula I and a pharmaceutically acceptable salt thereof selected from.

[0065] One embodiment of the present invention is A3 is CR 3 and; A4 is CR 4 and; A5 is CR 5 and; Y is N or CH; R 1 is H; R 2 is H or halo; R 3 is H; R 4 is H; R 5 is H; R 6 is H; R 7 is alkyl or haloalkyl; W is a piperidine ring substituted with alkyl, a compound of formula I and is selected from the pharmaceutically acceptable salts thereof.

[0066] One embodiment of the present invention is A3 is CR 3 and; A4 is CR 4 and; A5 is CR 5 and; Y is N or CH; R 1 is H; R 2 is H or halo; R 3 is H; R 4 is H; R 5 is H; R 6 is H; R 7 is alkyl; W is a piperidine ring substituted with alkyl, a compound of formula I and is selected from the pharmaceutically acceptable salts thereof.

[0067] Specific examples of the compounds of formula I described herein are N-[(3R)-1-Ethyl-3-piperidyl]-6-(1H-indol-6-yl)-5-methyl-pyridazine-3-amine; N-[(3R)-1-Ethyl-3-piperidyl]-6-(3-fluoro-1H-indol-6-yl)-5-methyl-pyridazine-3-amine; N-[(3R)-1-Ethyl-3-piperidyl]-6-(5-fluoro-1H-indol-6-yl)-5-methyl-pyridazine-3-amine; N-[(3R)-1-Ethyl-3-piperidyl]-5-methyl-6-(3-methyl-1H-indol-6-yl)pyridazine-3-amine; 6-(3-Chloro-1H-indol-6-yl)-N-[(3R)-1-ethyl-3-piperidyl]-5-methyl-pyridazine-3-amine; N-[(3R)-1-Ethyl-3-piperidyl]-5-methyl-6-(2-methyl-1H-indol-6-yl)pyridazine-3-amine; 6-[6-[[(3R)-1-Ethyl-3-piperidyl]amino]-4-methyl-pyridazin-3-yl]-1H-indole-3-carbonitrile; 6-[6-[[(3R)-1-Ethyl-3-piperidyl]amino]-4-methyl-pyridazin-3-yl]-1H-indole-2-carbonitrile; 6-(3-Fluoro-1H-indol-6-yl)-5-methyl-N-[(3R)-1-methyl-3-piperidyl]pyridazine-3-amine; N-[(3R)-1-Ethyl-3-piperidyl]-6-(1H-indol-6-yl)-5-methyl-pyridazine-3-amine; N-[(3R)-1-Ethyl-3-piperidyl]-6-(3-fluoro-1H-indol-6-yl)-5-(trifluoromethyl)pyridazine-3-amine; 5-Ethyl-N-[(3R)-1-ethyl-3-piperidyl]-6-(3-fluoro-1H-indol-6-yl)pyridazine-3-amine; N-[(3R)-1-Ethyl-3-piperidyl]-6-(1H-indol-6-yl)-5-methyl-1,2,4-triazine-3-amine; N-[(3R)-1-Ethyl-3-piperidyl]-6-(3-fluoro-1H-indol-6-yl)-5-methyl-1,2,4-triazine-3-amine; and is selected from the pharmaceutically acceptable salts thereof.

[0068] Other specific examples of Formula I described herein are N-[(3R)-1-Ethyl-3-piperidyl]-6-(5-methyl-1H-indol-6-yl)pyridazine-3-amine; 3-[[6-(3-Fluoro-1H-indol-6-yl)-5-methyl-pyridazin-3-yl]amino]-1-methyl-cyclobutanol; and is selected from the pharmaceutically acceptable salts thereof.

[0069] Preferred examples of the compounds of formula I described herein are N-[(3R)-1-Ethyl-3-piperidyl]-6-(1H-indol-6-yl)-5-methyl-pyridazin-3-amine; N-[(3R)-1-Ethyl-3-piperidyl]-6-(3-fluoro-1H-indol-6-yl)-5-methyl-pyridazin-3-amine; 6-(3-Fluoro-1H-indol-6-yl)-5-methyl-N-[(3R)-1-methyl-3-piperidyl]pyridazin-3-amine; N-[(3R)-1-Ethyl-3-piperidyl]-6-(3-fluoro-1H-indol-6-yl)-5-(trifluoromethyl)pyridazin-3-amine; N-[(3R)-1-Ethyl-3-piperidyl]-6-(1H-indol-6-yl)-5-methyl-1,2,4-triazin-3-amine; N-[(3R)-1-Ethyl-3-piperidyl]-6-(3-fluoro-1H-indol-6-yl)-5-methyl-1,2,4-triazin-3-amine; and are selected from its pharmaceutically acceptable salts.

[0070] Most preferred examples of the compounds of formula I described herein are N-[(3R)-1-Ethyl-3-piperidyl]-6-(3-fluoro-1H-indol-6-yl)-5-methyl-pyridazin-3-amine; N-[(3R)-1-Ethyl-3-piperidyl]-6-(1H-indol-6-yl)-5-methyl-1,2,4-triazin-3-amine; N-[(3R)-1-Ethyl-3-piperidyl]-6-(3-fluoro-1H-indol-6-yl)-5-methyl-1,2,4-triazin-3-amine; and are selected from its pharmaceutically acceptable salts.

[0071] One embodiment of the invention provides a compound according to formula Ic, wherein the compound of formula Ic is a compound of formula Ib. [Chemical]

[0072] One embodiment of the present invention is A3 is selected from N or CR 3 and; A4 is selected from N or CR 4 and; A5 is selected from N or CR 5 and; R 1 is selected from alkyl, cyano or H; R 2 is selected from alkyl, cyano, H or halo; R 3 is H; R 4 is selected from H, alkyl, alkoxy or halo; R 5 is selected from H or halo; R 6 is H; R 8 is H or alkyl; W is optionally substituted cycloalkyl, or an optionally substituted heterocycle containing a single N heteroatom, the optionally substituted cycloalkyl may be substituted with 1 or 2 substituents independently selected from H, OH or alkyl, and the optionally substituted heterocycle containing a single N heteroatom may be substituted with alkyl or haloalkyl, a compound of formula Ic and pharmaceutically acceptable salts thereof.

[0073] One embodiment of the present invention provides a compound of formula Ic as described herein, wherein R 1 is H.

[0074] One embodiment of the present invention provides a compound of formula Ic as described herein, wherein R 2 is H.

[0075] One embodiment of the present invention is that A3 is CR 3Provided are compounds of formula Ic as described herein.

[0076] One embodiment of the invention is that A4 is CR 4 Provided are compounds of formula Ic as described herein.

[0077] One embodiment of the invention is that A5 is CR 5 Provided are compounds of formula Ic as described herein.

[0078] One embodiment of the invention is R 4 is H, and provided are compounds of formula Ic as described herein.

[0079] One embodiment of the invention is R 5 is H, and provided are compounds of formula Ic as described herein.

[0080] One embodiment of the invention is R 8 is alkyl, and provided are compounds of formula Ic as described herein.

[0081] One embodiment of the invention is that W is a piperidine ring substituted with alkyl, and provided are compounds of formula Ic as described herein.

[0082] One embodiment of the invention is A3 is CR 3 and; A4 is CR 4 and; A5 is CR 5 and R 1 is H; R 2 is H; R 3 is H; R 4 is H; R 5 is H; R 6 is H; R 8 is alkyl or H; A compound according to formula Ic, wherein W is a piperidine ring substituted with alkyl and is selected from the pharmaceutically acceptable salts thereof.

[0083] One embodiment of the present invention is A3 is CR 3 ; A4 is CR 4 ; A5 is CR 5 ; R 1 is H; R 2 is H; R 3 is H; R 4 is H; R 5 is H; R 6 is H; R 8 is alkyl; A compound according to formula Ic, wherein W is a piperidine ring substituted with alkyl and is selected from the pharmaceutically acceptable salts thereof.

[0084] Specific examples of the compounds of formula Ib described herein are N-[(3R)-1-ethyl-3-piperidyl]-7-(1H-indol-6-yl)-1-methyl-pyrazolo[3,4-d]pyridazin-4-amine and pharmaceutically acceptable salts thereof.

[0085] Specific examples of the compounds of formula Ic described herein are N-[(3R)-1-ethyl-3-piperidyl]-7-(1H-indol-6-yl)-1-methyl-pyrazolo[3,4-d]pyridazin-4-amine and pharmaceutically acceptable salts thereof.

[0086] Another embodiment of the present invention provides a pharmaceutical composition or medicament containing a compound of the present invention and a therapeutically inert carrier, diluent or excipient, and a method of using a compound of the present invention for preparing such a composition and medicament. In one example, a compound of formula Ib is formulated into a galenical dosage 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 to the desired degree of purity. The pH of the formulation mainly depends on the particular use and the concentration of the compound, but is preferably in the range of about 3 to about 8. In one example, a compound of formula Ib is formulated in an acetate buffer at pH 5. In another embodiment, a compound of formula Ib is sterile. The compound can be stored, for example, as a solid or amorphous composition, as a lyophilized formulation, or as an aqueous solution.

[0087] The compositions are formulated, dosed, and administered in a manner consistent with good medical practice. Factors to be considered in this regard include the particular disease being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disease, the site to which the agent is to be delivered, the method of administration, the dosing schedule, and other factors known to the medical practitioner.

[0088] The compounds of the present invention can be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intralung, intradermal, intrathecal, epidural, and intranasal, and, if desired in local treatment, intralesional administration. Parenteral injection includes intramuscular, intravenous, intraarterial, intraperitoneal or subcutaneous administration.

[0089] The compounds of the present invention can be administered in any convenient dosage form, such as tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions can contain ingredients conventional in pharmaceutical formulations, such as diluents, carriers, pH adjusters, sweeteners, bulking agents, and additional active agents.

[0090] Typical formulations are prepared by mixing a compound of the present invention with a carrier or additive. 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 & 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 formulations may also contain one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifying agents, flow promoters, processing aids, colorants, sweeteners, flavors, fragrances, diluents, and other known additives for providing an aesthetically pleasing presentation of the drug (i.e., the compound of the present invention or its pharmaceutical composition) or for assisting in the manufacture of a pharmaceutical product (i.e., a medicament).

[0091] The compounds of formula Ib and their pharmaceutically acceptable salts can be processed with pharmaceutically inert, inorganic or organic adjuvants for the production of tablets, coated tablets, dragees, hard gelatin capsules, injection solutions, or topical formulations. Lactose, corn starch or its derivatives, talc, stearic acid or its salts, etc. can be used, for example, as such adjuvants for tablets, dragees and hard gelatin capsules.

[0092] Adjuvants suitable for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid substances, and liquid polyols.

[0093] Adjuvants suitable for the production of liquid and syrup preparations are, for example, water, polyols, sucrose, invert sugar, glucose, and the like.

[0094] Adjuvants suitable for injection solutions are, for example, water, alcohol, polyols, glycerol, vegetable oils, and the like.

[0095] Adjuvants suitable for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols, and the like.

[0096] Adjuvants suitable for topical ophthalmic preparations are, for example, cyclodextrin, mannitol or many other carriers and excipients known in the art.

[0097] Furthermore, the pharmaceutical preparation may contain preservatives, solubilizers, viscosity increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents, salts for changing the osmotic pressure, buffers, masking agents, or antioxidants. They may also further contain other therapeutically valuable substances.

[0098] The dosage can be varied widely and can of course be adapted to the individual requirements of each particular case. Generally, in the case of oral administration, a daily dosage 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 (for example, about 300 mg per person), is preferably divided into 1 to 3 individual doses. This can, if appropriate, be composed of the same amounts, for example. In the case of topical administration, the preparation may contain 0.001 wt% to 15 wt% of the medicament, and the required dosage may be between 0.1 and 25 mg and can be administered once a day or once a week, or by multiple administrations per day (2 to 4 times) or by multiple administrations per week. However, it will be obvious that the upper or lower limits described herein may be exceeded if so indicated.

[0099] One embodiment of the present invention is a compound according to formula Ib described herein for use as a therapeutic active substance.

[0100] One embodiment of the invention is a compound of formula Ib 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.

[0101] One embodiment of the invention is a compound of formula Ib as described herein for the treatment or prevention of a disease, disorder or condition, wherein the disorder or condition is responsive to NLRP3 inhibition.

[0102] As used herein, the term "NLRP3 inhibition" refers to a complete or partial decrease in the activity level of NLRP3 and includes, for example, inhibition of active NLRP3 and / or inhibition of NLRP3 activation.

[0103] There is evidence indicating that NLRP3-induced IL-1 and IL-18 play a role in a number of different disorders or in the resulting inflammatory responses (Menu et al., Clinical and Experimental Immunology, 166:1-15, 2011; Strowig et al., Nature, 481:278-286, 2012).

[0104] In one embodiment, the disease, disorder or condition is selected from: (i) Inflammation; (ii) Autoimmune disease; (iii) Cancer; (iv) Infectious disease; (v) Central nervous system disease; (vi) Metabolic disease; (vii) Cardiovascular disease; (viii) Respiratory disease; (ix) Liver disease; (x) Kidney disease; (xi) Eye disease; (xii) Skin disease; (xiii) Lymphatic symptoms; (xiv) Psychological disorder; (xv) Graft-versus-host disease; (xvi) Allodynia; (xvii) Symptoms associated with diabetes; and (xviii) Diseases in which an individual is determined to have a germline or somatic non-silent mutation in NLRP3.

[0105] In another embodiment, the disease, disorder or symptom is selected from: (i) Cancer; (ii) Infectious disease; (iii) Central nervous system diseases; (iv) Cardiovascular diseases; (v) Liver diseases; (vi) Eye diseases; or (vii) Skin diseases.

[0106] In a further exemplary embodiment of the invention, the disease, disorder or symptom is inflammation. Examples of inflammation that can be treated or prevented include inflammatory responses associated with or resulting from: (i) Skin symptoms 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; (ii) Joint symptoms such as osteoarthritis, systemic juvenile idiopathic arthritis, adult-onset Still's disease, relapsing polychondritis, rheumatoid arthritis, juvenile chronic arthritis, gout, or seronegative spondyloarthropathies (e.g., ankylosing spondylitis, psoriatic arthritis or Reiter's disease); (iii) Muscle symptoms such as polymyositis or myasthenia gravis; (iv) Gastrointestinal symptoms 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 can affect sites distant from the intestine (e.g., migraine, rhinitis or eczema); (v) Respiratory symptoms such as chronic obstructive pulmonary disease (COPD), asthma (including eosinophilic, bronchial, allergic, intrinsic, extrinsic or dust asthma, especially chronic or refractory asthma, such as late-stage asthma and airway hyperresponsiveness), bronchitis, rhinitis (including acute rhinitis, allergic rhinitis, atrophic rhinitis, chronic rhinitis, catarrhal rhinitis, hypertrophic rhinitis, pansinusitis, 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, volcanic ash-induced inflammation, adult respiratory distress syndrome, hypersensitivity pneumonitis, or idiopathic interstitial pneumonia; (vi) Vascular symptoms such as atherosclerosis, Behçet's disease, vasculitis, or Wegener's granulomatosis; (vii) Autoimmune symptoms such as systemic lupus erythematosus, Sjögren's syndrome, systemic sclerosis, Hashimoto's thyroiditis, type I diabetes, idiopathic thrombocytopenic purpura, or Graves' disease; (viii) Ocular symptoms such as uveitis, allergic conjunctivitis, or vernal catarrh; (ix) Neurological symptoms such as multiple sclerosis or encephalomyelitis; (x) Infectious or infection-related symptoms 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 (A, B or C, or other viral hepatitis), peritonitis, pneumonia, laryngotracheitis, malaria, hemorrhagic dengue 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; (xi) Renal symptoms such as mesangial proliferative glomerulonephritis, nephrotic 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 symptoms such as Castleman's disease; (xiii) Symptoms of the immune system, or symptoms involved therein, such as hyper-IgE syndrome, granulomatous Hansen's disease, familial hemophagocytic lymphohistiocytosis, or graft-versus-host disease; (xiv) Liver symptoms such as chronic active hepatitis, non-alcoholic steatohepatitis (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; (xv) Cancers including the above cancers; (xvi) Burns, wounds, traumas, bleeding or strokes; (xvii) Radiation exposure; (xviii) Metabolic diseases such as type 2 diabetes (T2D), atherosclerosis, obesity, gout or pseudogout; and / or (xix) Pains such as inflammatory pain hypersensitivity, pelvic pain, allodynia, neuropathic pain, or cancer-induced bone pain.

[0107] One embodiment of the present invention is the use of a compound of formula Ib described herein in the treatment or prevention of a disease, disorder or symptom selected from Alzheimer's disease and Parkinson's disease.

[0108] One embodiment of the present invention is the use of a compound of formula Ib described herein for use in the treatment or prevention of a disease, disorder or symptom selected from asthma or COPD.

[0109] One embodiment of the present invention is the use of a compound of formula Ib described herein for use in the treatment or prevention of a disease, disorder or symptom selected from inflammatory bowel diseases (including Crohn's disease and ulcerative colitis).

[0110] One embodiment of the present invention is a compound of formula Ib described herein for the treatment or prevention of a disease, disorder or symptom selected from Alzheimer's disease and Parkinson's disease.

[0111] One embodiment of the present invention is a compound of formula Ib as described herein for the treatment or prevention of a disease, disorder or condition selected from asthma or COPD.

[0112] One embodiment of the present invention is a compound of formula Ib as described herein for the treatment or prevention of a disease, disorder or condition selected from inflammatory bowel diseases (including Crohn's disease and ulcerative colitis).

[0113] One embodiment of the present invention is the use of a compound of formula Ib 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.

[0114] One embodiment of the present invention is the use of a compound of formula Ib 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.

[0115] One embodiment of the present invention is the use of a compound of formula Ib as described herein for the preparation of a medicament for the treatment or prevention of a disease, disorder or condition selected from inflammatory bowel diseases (including Crohn's disease and ulcerative colitis).

[0116] 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, the method comprising administering an effective amount of a compound of formula Ib as described herein.

[0117] 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, the method comprising administering an effective amount of a compound of formula Ib as described herein.

[0118] One embodiment of the present invention is a method for the treatment or prevention of a disease, disorder or condition selected from inflammatory bowel diseases (including Crohn's disease and ulcerative colitis), the method comprising administering an effective amount of a compound of formula Ib as described herein.

[0119] One embodiment of the present invention relates to a method of inhibiting NLRP3, which comprises administering an effective amount of a compound of formula Ib described herein.

[0120] Also, one embodiment of the present invention is a compound of formula Ib described herein when manufactured according to any one of the described methods.

[0121] One embodiment of the present invention is a pharmaceutical composition comprising a compound of formula Ib described herein and a therapeutically inert carrier.

[0122] One embodiment of the present invention is a compound of formula Ib described herein for the treatment or prevention of a disease, disorder or condition selected from: (i) Inflammation; (ii) Autoimmune diseases; (iii) Cancer; (iv) Infectious diseases; (v) Central nervous system diseases; (vi) Metabolic diseases; (vii) Cardiovascular diseases; (viii) Respiratory diseases; (ix) Liver diseases; (x) Kidney diseases; (xi) Eye diseases; (xii) Skin diseases; (xiii) Lymphatic conditions; (xiv) Psychological disorders; (xv) Graft-versus-host disease; (xvi) Allodynia; (xvii) Conditions associated with diabetes; and (xviii) Any disease in which an individual is determined to have a germline or somatic non-silent mutation in NLRP3.

[0123] Assay procedure NLRP3 and pyroptosis The activation of NLRP3 leads to pyroptosis, and it is well established that 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 & 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 inflammatory cytokines (e.g., IL-1β) from cells.

[0124] THP-1 cells: Culture and preparation THP-1 cells (ATCC number TIB-202) were grown in RPMI supplemented with 10% fetal bovine serum (FBS) (Sigma number F0804), 1 mM sodium pyruvate (Sigma number S8636), and L-glutamine (Gibco number 11835) supplemented with penicillin (100 units / ml) / streptomycin (0.1 mg / ml) (Sigma number P4333). The cells were passaged regularly and confluent (about 10 6The cells were grown to a density of

[0125] THP-1 Cell Pyroptosis Assay For compound screening, a stepwise assay of the following method was followed. 1. Seed THP-1 cells (25,000 cells / well) containing 1.0 μg / ml of LPS 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 number 734-0317). 2. Add 5 μl of the compound (8-point semi-log dilution using a maximum dose of 10 μM) or vehicle (DMSO 0.1% FAC) to the appropriate wells. 3. Incubate at 37 °C and 5% CO2 for 3 hours. 4. Add 5 μl of nigericin (Sigma number N7143) (FAC 5 μM) to all wells. 5. Incubate at 37 °C and 5% CO2 for 1 hour. 6. At the end of the incubation period, spin the plate at 300 × g for 3 minutes and remove the supernatant. 7. Then add 50 μl of resazurin (Sigma number R7017) (FAC 100 μM resazurin in RPMI medium without FBS) and incubate the plate at 37 °C and 5% CO2 for an additional 1 - 2 hours. 8. Read the plate on an Envision reader at Ex 560 nm and Em 590 nm. 9. IC 50Fit the data to a non-linear regression equation (logarithmic inhibitor vs. response variable gradient 4-parameter)

[0126] Summarize the results of the apoptosis assay as THP IC 50 in Table 1 below.

[0127] Human whole blood IL-1β release assay For systemic delivery, the ability of the compound to inhibit NLRP3 when present in the bloodstream is of great importance. Therefore, the NLRP3 inhibitory activity of a number of compounds in human whole blood was investigated according to the following protocol.

[0128] Human whole blood in Li-heparin tubes was collected from healthy donors in the volunteer donor population. Plate out 80 μl of whole blood containing 1 μg / ml of LPS in a 96-well clear-bottom cell culture plate (Corning number 3585) Add 10 μl of the compound (8-point half-log dilution at a maximum dose of 10 μM) or vehicle (0.1% FAC in DMSO) to the appropriate wells Incubate at 37 °C, 5% CO2 for 3 hours Add 10 μl of nigericin (Sigma number N7143) (10 μM FAC) to all wells Incubate at 37 °C, 5% CO2 for 1 hour At the end of the incubation period, spin the plate at 300 × 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 later analysis) Measure IL-1β according to the manufacturer's protocol (Perkin Elmer - AlphaLisa IL-1 Kit AL220F-5000) 8. IC 50 Fit the data to a non-linear regression equation (logarithmic inhibitor vs. response variable gradient 4-parameter)

[0129] The results of the human whole blood assay are summarized in Table 1 below as HWB IC 50 and are shown as follows in Table 1 below.

Table 1

[0130] From this, the present invention will be described by the following examples which have no limiting features.

[0131] When the preparation example is obtained as a mixture of enantiomers, the pure enantiomers can be obtained by the methods described herein or methods known to those skilled in the art, such as chiral chromatography or crystallization.

Examples

[0132] Unless otherwise specified, all examples and intermediates were prepared under a nitrogen atmosphere.

[0133] Abbreviations

Table 2

[0134] Example 1: N-[(3R)-1-Ethyl-3-piperidyl]-6-(1H-indol-6-yl)-5-methyl-pyridazine-3-amine

Chemical formula

[0135] Step A: tert-Butyl (3R)-3-[(6-chloro-5-methyl-pyridazin-3-yl)amino]piperidine-1-carboxylate A suspension of 3,6-dichloro-4-methyl-pyridazine (CAS No. 19064-64-3, 1.60 g, 9.82 mmol, 1.00 equiv) and tert-butyl (3R)-3-aminopiperidine-1-carboxylate (CAS No. 188111-79-7, 3.93 g, 19.6 mmol, 2.00 equiv) was added to DIPEA (3.26 g, 4.4 mL, 25.2 mmol, 2.57 equiv). The reaction mixture was stirred at 120 °C for 72 h. The reaction mixture was cooled to room temperature and then extracted with ethyl acetate and water. The organic layer was washed with water and brine. The aqueous layer was back-extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 120 g, gradient: 0% - 5% methanol in dichloromethane) to give the title compound (1.77 g, 52% yield) as a pale yellow oil. LCMS: m / z 327.2 [M+H] + , ESI positive.

[0136] Step B: 6-chloro-5-methyl-N-[(3R)-3-piperidyl]pyridazine-3-amine hydrochloride To a solution of tert-butyl (3R)-3-[(6-chloro-5-methyl-pyridazin-3-yl)amino]piperidine-1-carboxylate (Example 1, Step A) (1.65 g, 4.79 mmol, 1.00 equiv) in dichloromethane (12 mL) and methanol (6.0 mL) was added 4 M HCl in dioxane (12 mL, 48.0 mmol, 10.0 equiv) dropwise. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo to give the title compound (1.33 g, 95% yield, 90% purity) as an off-white solid, which was used without further purification. LCMS: m / z 227.2 [M+H] + , ESI positive.

[0137] Step C: 6-chloro-N-[(3R)-1-ethyl-3-piperidyl]-5-methyl-pyridazine-3-amine 6-Chloro-5-methyl-N-[(3R)-3-piperidyl]pyridazin-3-amine hydrochloride (Example 1, Step B) (1.32 g, 4.51 mmol, 1.00 equiv., purity 90%) in dichloromethane (20 mL) was suspended, and acetaldehyde (405.7 mg, 0.460 mL, 9.21 mmol, 2.04 equiv.) was added, followed by sodium acetate (741 mg, 9.03 mmol, 2.00 equiv.) under ice-bath cooling. Sodium triacetoxyborohydride (1.44 g, 6.77 mmol, 1.50 equiv.) was added in three portions at 0 °C. The reaction mixture was stirred at 0 °C for 30 minutes and at room temperature for 2.5 hours. The reaction mixture was quenched with saturated aqueous NaHCO3 and extracted three times with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 40 g, gradient: 0% - 10% methanol in dichloromethane) to give the title compound (901 mg, 74% yield) as a yellow oily substance. LCMS: m / z 255.2 [M+H] + , ESI positive.

[0138] Step D: N-[(3R)-1-Ethyl-3-piperidyl]-6-(1H-indol-6-yl)-5-methyl-pyridazin-3-amine In 1,4-dioxane (2.0 mL) and water (1.0 mL), a mixture of 6-chloro-N-[(3R)-1-ethyl-3-piperidyl]-5-methyl-pyridazine-3-amine (Example 1, Step C) (80 mg, 0.30 mmol, 1.00 equiv), 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (CAS No. 642494-36-8, 130 mg, 0.51 mmol, 1.70 equiv), potassium carbonate (195 mg, 1.41 mmol, 4.73 equiv) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(ii) dichloride dichloromethane complex (28 mg, 0.03 mmol, 0.11 equiv) was flushed with argon and stirred at 90 °C for 16 h. The reaction mixture was cooled to room temperature and extracted with ethyl acetate and water. The aqueous layer was back-extracted with ethyl acetate. The organic layer was washed twice with water and once with brine. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient: 0% - 100% in dichloromethane (dichloromethane:methanol:NH4OH 9:1:0.05)). The residue was adsorbed onto ISOLUTE HM-N and purified again by flash chromatography (silica gel, 12 g, gradient: 0% - 20% methanol in dichloromethane). All fractions containing the product were combined and concentrated in vacuo to give the title compound (61 mg, 58% yield) as a light brown foamy substance. LCMS: m / z 336.3 [M+H] + , ESI positive.

[0139] Example 2: N-[(3R)-1-Ethyl-3-piperidyl]-6-(3-fluoro-1H-indol-6-yl)-5-methyl-pyridazine-3-amine

Chemical Structure

[0140] Step A: 3-Fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole To a solution of commercially available 6-bromo-3-fluoro-1H-indole (CAS No. 2568045-20-3, 296 mg, 1.31 mmol, 1.00 equiv) and bis(pinacolato)diboron (400 mg, 1.58 mmol, 1.20 equiv) in 1,4-dioxane (3.1 mL) was added potassium acetate (387 mg, 3.94 mmol, 3.00 equiv), followed by the addition of 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (109 mg, 0.13 mmol, 0.10 equiv). The reaction mixture was flushed with argon and stirred at 90 °C for 16 h. The reaction mixture was then cooled to room temperature, adsorbed onto ISOLUTE HM-N, and purified by flash chromatography (silica gel, 25 g, 0% - 10% ethyl acetate in heptane) to afford the title compound (224 mg, 62% yield) as a dark brown solid. LCMS: m / z 262.1 [M+H] + , ESI positive.

[0141] Step B: N-[(3R)-1-Ethyl-3-piperidyl]-6-(3-fluoro-1H-indol-6-yl)-5-methyl-pyridazin-3-amine The above-mentioned 6-chloro-N-[(3R)-1-ethyl-3-piperidyl]-5-methyl-pyridazine-3-amine (Example 1, Step C) (75 mg, 0.28 mmol, 1.00 equivalent), 3-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (Example 2, Step A) (124 mg, 0.45 mmol, 1.61 equivalents), potassium carbonate (180 mg, 1.30 mmol, 4.66 equivalents) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(ii) dichloride dichloromethane complex (28 mg, 0.03 mmol, 0.12 equivalent) in 1,4-dioxane (1.8 mL) and water (0.90 mL) were flushed with argon and stirred at 90 °C for 16 hours. The reaction mixture was cooled to room temperature and extracted with ethyl acetate and water. The aqueous layer was back-extracted with ethyl acetate. The organic layer was washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient: 0% to 100% in dichloromethane (dichloromethane:methanol:NH4OH 9:1:0.05)). All fractions containing the product were combined and concentrated in vacuo to give the title compound (77 mg, 74% yield) as a brown foamy substance. LCMS: m / z 354.2 [M+H] + , ESI positive.

[0142] Example 3: N-[(3R)-1-ethyl-3-piperidyl]-6-(5-fluoro-1H-indol-6-yl)-5-methyl-pyridazine-3-amine

Chemical Structure

[0143] Step A: 5-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole 6-Bromo-5-fluoro-1H-indole (500 mg, 2.34 mmol, 1.0 equiv), potassium 2-ethylhexanoate (937 mg, 5.14 mmol, 2.2 equiv), palladium(II) acetate (10.7 mg, 0.05 mmol, 0.02 equiv) and Xphos (44.5 mg, 0.09 mmol, 0.04 equiv) were dissolved in isopropyl acetate (7.5 mL). The reaction mixture was degassed with argon and stirred at 80 °C for 2 h. After cooling to room temperature, the mixture was filtered through a syringe filter and the solvent was evaporated in vacuo. The title compound was used in the next step without further purification. LCMS: m / z = 261.9 [M+H] + , ESI positive.

[0144] Step B: N-[(3R)-1-Ethyl-3-piperidyl]-6-(5-fluoro-1H-indol-6-yl)-5-methyl-pyridazin-3-amine A mixture of the above 5-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (Example 3, Step A) (53.0 mg, 0.30 mmol, 1.5 equiv), the above 6-chloro-N-[(3R)-1-ethyl-3-piperidyl]-5-methyl-pyridazin-3-amine (Example 1, Step C) (50.0 mg, 0.20 mmol, 1.0 equiv), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (14.3 mg, 0.02 mmol, 0.10 equiv) and cesium carbonate (191 mg, 0.59 mmol, 3.0 equiv) in 1,4-dioxane (2.1 mL) and water (1.0 mL) was purged with argon and stirred at 90 °C. After 5 h, the reaction mixture was cooled to room temperature, extracted with ethyl acetate, washed with water and brine. The combined organic phases were dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. Purification of the crude product by preparative HPLC (column: YMC-Triart C 18 , 12 nm, 5 μm, 100×30 mm, MeCN / water + 0.1% TEA, gradient 20 - 80% MeCN) gave the title compound (18 mg, 23% yield). LC-MS: m / z = 354.2 [M+H] +, ESI positive.

[0145] Example 4: N-[(3R)-1-Ethyl-3-piperidyl]-5-methyl-6-(3-methyl-1H-indol-6-yl)pyridazine-3-amine [Chemical formula] To a 2 mL microwave vial were added 6-chloro-N-[(3R)-1-ethyl-3-piperidyl]-5-methyl-pyridazine-3-amine (Example 1, Step C) (50 mg, 0.196 mmol, 1.00 equivalent) in methanol (1.7 mL), commercially available 3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (CAS No. 1300582-52-8, 60.6 mg, 0.236 mmol, 1.200 equivalents), 1,1'-bis(diphenylphosphino)ferrocene-palladium(ii) dichloride dichloromethane complex (8.01 mg, 0.010 mmol, 0.050 equivalent), and potassium carbonate (2.25 M aqueous solution) (260 μL, 0.585 mmol, 2.98 equivalents). The reaction mixture was sparged with argon while sonicating for 5 minutes. The vial was capped and heated in a microwave at 80 °C for 2 hours. The progress of the reaction was monitored by LCMS, showing a conversion rate of 54%. The reaction mixture was diluted with MeOH and filtered through a syringe filter to obtain a red solution, which was fractionated. Purification by HPLC (Gemini NX, ACN / water (Et3N), basic mode) gave the title compound (21.7 mg, yield 31%) as a white lyophilized powder. LCMS: m / z = 350.3 [M+H] + , ESI positive.

[0146] Example 5: 6-(3-Chloro-1H-indol-6-yl)-N-[(3R)-1-ethyl-3-piperidyl]-5-methyl-pyridazine-3-amine [Chemical formula] To a 2 mL microwave vial, 6-chloro-N-[(3R)-1-ethyl-3-piperidyl]-5-methyl-pyridazine-3-amine (Example 1, Step C) (50 mg, 0.196 mmol, 1.000 equiv), commercially available 3-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (CAS No. 2304635-36-5, 70.8 mg, 0.255 mmol, 1.30 equiv), 1,1'-bis(diphenylphosphino)ferrocene-palladium(ii) dichloride dichloromethane complex (16.0 mg, 0.020 mmol, 0.10 equiv) and potassium carbonate (2.25 M aqueous solution) (436.1 μL, 0.981 mmol, 5.0 equiv) were added in 1,4-dioxane (1.78 mL). The reaction mixture was sparged with argon while sonicating for 5 minutes. The vial was capped and heated in a microwave at 90 °C for 2 hours. The progress of the reaction was monitored by LCMS, which indicated that the reaction was complete. The reaction mixture was filtered through a syringe filter and the solvent was evaporated in a centrifuge. The crude product was purified by preparative HPLC (Gemini NX, ACN / water (Et3N), basic mode) to give the title compound (13.1 mg, 18% yield) as a white lyophilized powder. LCMS: m / z = 368.3 [M-H] - , ESI negative.

[0147] Example 6: N-[(3R)-1-ethyl-3-piperidyl]-5-methyl-6-(2-methyl-1H-indol-6-yl)pyridazine-3-amine [Chemical Structure] To a 5 mL microwave vial were added 6-chloro-N-[(3R)-1-ethyl-3-piperidyl]-5-methyl-pyridazin-3-amine (Example 1, Step C) (50 mg, 0.196 mmol, 1.000 equiv) in methanol (3 mL), commercially available 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (CAS No. 1650548-44-9, 60.56 mg, 0.236 mmol, 1.20 equiv), 1,1'-bis(diphenylphosphino)ferrocene-palladium(ii) dichloride dichloromethane complex (16.0 mg, 0.020 mmol, 0.100 equiv), and potassium carbonate (2.25 M aqueous solution) (261.7 μL, 0.589 mmol, 3.000 equiv). The reaction mixture was sparged with argon while sonicating for 3 minutes. The vial was capped and heated in a microwave at 80 °C for 4 hours. The progress of the reaction was monitored by LCMS, showing a conversion of 71%. The reaction mixture was filtered through a syringe filter, and the solvent was evaporated using a centrifuge. The crude product was purified by preparative HPLC (YMC Triart, ACN / water (HCOOH), acidic mode) to give the title compound (7.0 mg, yield 10%) as a light brown solid. LCMS: m / z = 350.2 [M+H] + , ESI positive.

[0148] Example 7: 6-[6-[[(3R)-1-Ethyl-3-piperidyl]amino]-4-methyl-pyridazin-3-yl]-1H-indole-3-carbonitrile [Chemical formula]

[0149] Step A: (3R)-3-[(6-Bromo-5-methyl-pyridazin-3-yl)amino]piperidine-1-carboxylic acid tert-butyl ester In a sealed tube, a mixture of commercially available 3-bromo-6-chloro-4-methyl-pyridazine (CAS number 89283-90-9, 3.0 g, 14.5 mmol, 1.0 equivalent), DIPEA (4.67 g, 6.31 mL, 36.2 mmol, 2.5 equivalents) and (3R)-3-aminopiperidine-1-carboxylic acid tert-butyl ester (CAS number 188111-79-7, 5.79 g, 5.57 mL, 28.9 mmol, 2.0 equivalents) was stirred at 120 °C for 18 hours. The reaction mixture was cooled to room temperature and extracted with EtOAc and water. The aqueous layer was back-extracted with EtOAc. The organic layer was washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 140 g, gradient: 0% - 2% methanol in dichloromethane). Combining all fractions containing the product and concentrating in vacuo gave the title compound (988 mg, 18% yield) as a white powder. LCMS: m / z: 371.2 ([{79Br}M+H] + ), 373.2 ([{81Br}M+H] + ), ESI positive.

[0150] Step B: (6-Bromo-5-methyl-pyridazin-3-yl)-[(3R)-3-piperidyl]amine. 1:1 hydrogen chloride (3R)-3-[(6-Bromo-5-methyl-pyridazin-3-yl)amino]piperidine-1-carboxylic acid tert-butyl ester (Example 7, Step A) (988 mg, 2.66 mmol, 1.0 equivalent) in dichloromethane (18 mL) and methanol (9 mL) was added dropwise with 4M hydrochloric acid in 1,4-dioxane (6.65 mL, 26.6 mmol, 10.0 equivalents) at room temperature. The reaction mixture was stirred at 23 °C for 16 hours. Then the reaction mixture was concentrated in vacuo to give the crude title compound (886 mg, 97%) as a pale yellow powder. LCMS: m / z: 271.1 ([{79Br}M+H] + ), 273.1 ([{81Br}M+H] + ), ESI positive.

[0151] Project C: (6-Bromo-5-methyl-pyridazin-3-yl)-[(3R)-1-ethyl-3-piperidyl]amine (6-Bromo-5-methyl-pyridazin-3-yl)-[(3R)-3-piperidyl]amine, 1:1 hydrogen chloride (Example 7, Step B) (886 mg, 2.88 mmol, 1.0 equiv) in a suspension in ultradry dichloromethane (13 mL), acetaldehyde (317.2 mg, 404.07 μL, 7.2 mmol, 2.5 equiv) was added, followed by sodium acetate (590.7 mg, 7.20 mmol, 2.5 equiv) under ice bath cooling. Sodium triacetoxyborohydride (1.10 g, 5.18 mmol, 1.8 equiv) was added at 0 °C. The reaction mixture was stirred at 0 °C for 15 minutes and at room temperature for 2 hours. The reaction mixture was carefully basified with NaHCO3 solution (50 mL) and then extracted with dichloromethane (3 × 80 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to give the title compound (667 mg, 74% yield) as an orange viscous oil. LCMS: m / z 299.1 ([{ 35 Cl}M+H]+), 301.1 ([{ 37 Cl}M+H]+), ESI positive.

[0152] Preparation of boronic ester: 6-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-3-carbonitrile A solution of commercially available 6-bromo-1H-indole-3-carbonitrile (CAS No. 224434-83-7, 500 mg, 2.26 mmol, 1.0 equiv) and bis(pinacolato)diboron (689.3 mg, 2.71 mmol, 1.2 equiv) in 1,4-dioxane (5.25 mL) was added with potassium acetate (666 mg, 548.13 μL, 6.79 mmol, 3.0 equiv), followed by [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (165.51 mg, 0.226 mmol, 0.1 equiv). The reaction mixture was flushed with argon and stirred at 90 °C overnight. The reaction mixture was cooled to room temperature, adsorbed onto ISOLUTE HM-N, and purified by flash chromatography (silica gel, 25 g, 0% - 50% EtOAc in heptane) to give the title compound (372 mg, 61%) as a white powder. LCMS: m / z 269.1 [M+H]+, ESI positive.

[0153] Step D: 6-[6-[[(3R)-1-Ethyl-3-piperidyl]amino]-4-methyl-pyridazin-3-yl]-1H-indole-3-carbonitrile (6-Bromo-5-methyl-pyridazin-3-yl)-[(3R)-1-ethyl-3-piperidyl]amine (80.0 mg, 0.267 mmol, 1.0 eq), 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-3-carbonitrile (Example 7, see above) (100.4 mg, 0.374 mmol, 1.4 eq), potassium carbonate (166.3 mg, 1.2 mmol, 4.5 eq) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(ii) dichloromethane adduct (32.8 mg, 0.040 mmol, 0.150 eq) in 1,4-dioxane (1 mL) and water (0.5 mL) were flushed with argon and stirred at 95 °C overnight. The residue was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient: 0% - 20% in dichloromethane (dichloromethane:methanol:NH4OH 9:1:0.05)). All fractions containing the product were combined and concentrated in vacuo. Trituration of the residue with EtOAc / heptane gave the title compound (69 mg, 68.01% yield) as a pale pink powder. LCMS: m / z: [M-H] + = 359.3, ESI negative.

[0154] Example 8: 6-[6-[[(3R)-1-Ethyl-3-piperidyl]amino]-4-methyl-pyridazin-3-yl]-1H-indole-2-carbonitrile

Chemical Structure

[0155] Step A: 6-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-2-carbonitrile A solution of 6-bromo-1H-indole-2-carbonitrile (CAS No. 1420537-60-5, 500 mg, 2.26 mmol, 1.0 equiv) and bis(pinacolato)diboron (688.3 mg, 2.71 mmol, 1.2 equiv) in 1,4-dioxane (5.25 mL) was treated with potassium acetate (665.2 mg, 6.78 mmol, 3.0 equiv), followed by 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (187.2 mg, 0.226 mmol, 0.1 equiv). The reaction mixture was flushed with argon and stirred at 90 °C overnight. The reaction mixture was then cooled to room temperature (not completely converted), adsorbed onto ISOLUTE HM-N, and purified by flash chromatography (silica gel, 25 g, 0% - 50% ethyl acetate in heptane) to afford the title compound (85 mg, 14%) as pale yellow crystals. LCMS: m / z 267.1 [M-H]+, ESI negative.

[0156] Step B: 6-[6-[[(3R)-1-Ethyl-3-piperidyl]amino]-4-methyl-pyridazin-3-yl]-1H-indole-2-carbonitrile (6-Bromo-5-methyl-pyridazin-3-yl)-[(3R)-1-ethyl-3-piperidyl]amine (80.0 mg, 0.267 mmol, 1.0 equiv), 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-2-carbonitrile (Example 10, Step A) (86.0 mg, 0.321 mmol, 1.2 equiv), potassium carbonate (166.3 mg, 1.20 mmol, 4.50 equiv) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(ii) dichloromethane adduct (32.8 mg, 0.040 mmol, 0.15 equiv) in 1,4-dioxane (1 mL) and water (0.5 mL) were flushed with argon and stirred at 95 °C overnight. The residue was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient (dichloromethane:methanol:NH4OH 9:1:0.05)). All fractions containing the product were combined and concentrated in vacuo. Trituration of the residue with EtOAc / heptane gave the title compound (49 mg, 48% yield) as a light brown powder. LCMS: m / z: [M-H] + = 359.3, ESI negative.

[0157] Example 9: 6-(3-Fluoro-1H-indol-6-yl)-5-methyl-N-[(3R)-1-methyl-3-piperidyl]pyridazine-3-amine [Chemical formula] 6-Chloro-5-methyl-N-[(3R)-1-methyl-3-piperidyl]pyridazin-3-amine (CAS No. 2557359-57-4, 50 mg, 0.20 mmol, 1.00 equivalent), 3-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (Example 2, Step A) (82 mg, 0.30 mmol, 1.51 equivalents), potassium carbonate (130 mg, 0.94 mmol, 4.77 equivalents) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(ii) dichloride dichloromethane complex (20 mg, 0.02 mmol, 0.12 equivalents) in 1,4-dioxane (1.3 mL) and water (0.65 mL) were flushed with argon and stirred at 90 °C for 16 h. The reaction mixture was cooled to room temperature and extracted with ethyl acetate and water. The aqueous layer was back-extracted with ethyl acetate. The organic layer was washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, gradient: 0% - 100% in dichloromethane (dichloromethane:methanol:NH4OH 9:1:0.05)). All fractions containing the product were combined and concentrated in vacuo. The residue was adsorbed onto ISOLUTE HM-N and re-purified by flash chromatography (Si-amine, 12 g, gradient: 0% - 5% methanol in ethyl acetate) to give the title compound (40 mg, 57% yield) as a brown foamy substance. LCMS: m / z 340.2 [M+H] + , ESI positive.

[0158] Example 10: N-[(3R)-1-Ethyl-3-piperidyl]-6-(7-fluoro-1H-indol-6-yl)-5-methyl-pyridazin-3-amine [Chemical formula]

[0159] Step A: 7-Fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole Commercially available 6-bromo-5-fluoro-1H-indole (CAS No. 936901-94-9, 500 mg, 2.34 mmol, 1.0 equivalent), commercially available potassium 2-ethylhexanoate (CAS No. 3164-85-0, 936.9 mg, 5.14 mmol, 2.2 equivalents), palladium acetate (10.7 mg, 0.05 mmol, 0.020 equivalent) and Xphos (44.5 mg, 0.093 mmol, 0.04 equivalent) were dissolved in isopropyl acetate (7.5 mL). The mixture was first purged with argon and then stirred at 80 °C for 1 hour. Then, the reaction mixture was filtered through a syringe filter and the solvent was evaporated using a centrifuge. The crude product was used in the next step without further purification. LCMS: m / z = 262.0 [M+H] + , ESI positive.

[0160] Step B: N-[(3R)-1-Ethyl-3-piperidyl]-6-(1H-indol-6-yl)-5-methyl-pyridazin-3-amine A mixture of the above 7-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (Example 11, Step A) (97.6 mg, 0.54 mmol, 1.0 equivalent), 6-chloro-N-[(3R)-1-ethyl-3-piperidyl]-5-methyl-pyridazin-3-amine (Example 1, Step C) (97 mg, 0.38 mmol, 0.7 equivalent), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(ii) (20 mg, 0.03 mmol, 0.05 equivalent) and cesium carbonate (533 mg, 1.6 mmol, 3.0 equivalents) in 1,4-dioxane (5.8 mL) and water (2.9 mL) was flushed with argon and stirred at 90 °C. After cooling to room temperature, the mixture was passed through a syringe filter and the solvent was removed under reduced pressure. Then, the same amounts of the above reagents and solvents were added again and the reaction was heated at 90 °C for 5 days. Then, the reaction mixture was extracted with ethyl acetate and washed twice with water. The aqueous layer was back-extracted with EtOAc. The crude product was purified by preparative HPLC (column: YMC-Triart C 18, 12 nm, 5 μm, 100 × 30 mm, purified with MeCN / (water + 0.1% trimethylamine, gradient: 20% - 50% MeCN), the title compound (34.3 mg, yield 16%) was obtained. LCMS: m / z = 354.3 [M+H] + .

[0161] Example 11: N-[(3R)-1-Ethyl-3-piperidyl]-6-(3-fluoro-1H-indol-6-yl)-5-(trifluoromethyl)pyridazine-3-amine

Chemical formula

[0162] Step A: tert-Butyl (3R)-3-[[6-chloro-5-(trifluoromethyl)pyridazin-3-yl]amino]piperidine-1-carboxylate and tert-butyl (3R)-3-[[6-chloro-4-(trifluoromethyl)pyridazin-3-yl]amino]piperidine-1-carboxylate Commercially available 3,6-dichloro-4-(trifluoromethyl)pyridazine (CAS No. 1057672-68-0, 1.72 g, 7.93 mmol, 1.00 equivalent) and commercially available tert-butyl (3R)-3-aminopiperidine-1-carboxylate (CAS No. 188111-79-7, 3.18 g, 15.9 mmol, 2.00 equivalents) in neat mixture in N,N-diisopropylethylamine (2.56 g, 3.46 mL, 19.8 mmol, 2.50 equivalents) was stirred in a sealed tube at 130 °C for 24 h. The warm mixture (ca. 50 °C) was poured into a 500 mL Erlenmeyer flask, the oily mixture was transferred using ethyl acetate (100 mL), and water (100 mL) was added. The mixture was stirred at room temperature for 20 min to dissolve all components. The mixture was then extracted with ethyl acetate and washed twice with water. The aqueous layer was back-extracted with EtOAc and finally with brine. The residue was purified by flash chromatography (SiO2, 0 - 50% ethyl acetate in heptane) to give two title compounds: tert-butyl (3R)-3-[[6-chloro-5-(trifluoromethyl)pyridazin-3-yl]amino]piperidine-1-carboxylate as a pale yellow foamy substance (1.67 g, 55%), and tert-butyl (3R)-3-[[6-chloro-4-(trifluoromethyl)pyridazin-3-yl]amino]piperidine-1-carboxylate as a pale yellow foamy substance (1.07 g, 35%). LCMS: m / z = 381.1 ([{35Cl}M+H] + ), 383.1 ([{37Cl}M+H] + ), ESI positive.

[0163] Step B: 6-Chloro-N-[(3R)-3-piperidyl]-5-(trifluoromethyl)pyridazin-3-amine; hydrochloride To a solution of tert-butyl (3R)-3-[[6-chloro-5-(trifluoromethyl)pyridazin-3-yl]amino]piperidine-1-carboxylate (Example 11, Step A, Fraction 1) (1.67 g, 4.39 mmol, 1.00 eq) in dichloromethane (20 mL) and methanol (10 mL) was added 4M HCl (in dioxane) (13.2 g, 10.96 mL, 43.9 mmol, 10.0 eq) via syringe. The clear yellow reaction solution was stirred at 23 °C for 16 h. Concentration of the reaction mixture in vacuo gave the title compound as a pale yellow foamy solid as a 1:1 hydrogen chloride salt (1.51 g, 98%). LCMS: m / z = 281.1 ([{35Cl}M+H]+), 283.1 ([{37Cl}M+H]+), ESI positive.

[0164] Step C: 6-Chloro-N-[(3R)-1-ethyl-3-piperidyl]-5-(trifluoromethyl)pyridazin-3-amine The above-mentioned 6-chloro-N-[(3R)-piperidin-3-yl]-5-(trifluoromethyl)pyridazin-3-amine; hydrochloride (Example 11, Step B) (1.51 g, 4.29 mmol, 1.00 equivalent) was suspended in ultradry dichloromethane (30 mL). Acetaldehyde (471.9 mg, 597.38 μL, 10.7 mmol, 2.50 equivalents) was added thereto, followed by sodium acetate (878.8 mg, 10.7 mmol, 2.50 equivalents) under cooling in an ice bath. Then, sodium triacetoxyborohydride (1.63 g, 7.71 mmol, 1.800 equivalents) was added at 0 °C. The reaction mixture was stirred at 0 °C for 15 minutes and at room temperature for 2 hours (pale yellow suspension). LCMS indicated complete conversion to the product. The reaction mixture was carefully basified with NaHCO3 solution (50 mL) and then extracted with dichloromethane (3 × 80 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product (1.4 g) was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (SiO2, gradient: 0% - 100% in dichloromethane (dichloromethane:methanol:NH4OH 110:10:1)) to obtain the title compound (1.03 g, 76%) as a light brown oily substance. LCMS: m / z = 309.1 ([{35Cl}M+H] + ), 311.0 ([{37Cl}M+H] + ), ESI positive.

[0165] Step D: N-[(3R)-1-Ethyl-3-piperidinyl]-6-(3-fluoro-1H-indol-6-yl)-5-(trifluoromethyl)pyridazin-3-amine The above-mentioned 6-chloro-N-[(3R)-1-ethyl-3-piperidyl]-5-(trifluoromethyl)pyridazine-3-amine (Example 11, Step C) (40 mg, 129.6 μmol, 1.00 equivalent), 3-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (Example 2, Step A) (50.7 mg, 194.3 μmol, 1.50 equivalents), potassium carbonate (85.95 mg, 621.9 μmol, 4.800 equivalents) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(ii) dichloride dichloromethane complex (15.9 mg, 19.4 μmol, 0.15 equivalent) in 1,4-dioxane (1 mL) and water (500 μL) were flushed with argon and stirred at 90 °C overnight. Complete conversion to the product was shown by LCMS. The reaction mixture was cooled to room temperature and extracted with about 30 mL of ethyl acetate and about 15 mL of water. The aqueous layer was back-extracted with about 30 mL of ethyl acetate. The organic layer was washed with about 15 mL of water and about 15 mL of brine. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by RP HPLC (Gemini NX, 12 nm, 5 μm, 100×30 mm, CAN / water + 0.1% TEA) to give the title product (24 mg, 43%) as a light grey amorphous freeze-dried solid. LCMS: m / z = 408.2 [M+H]+, ESI positive.

[0166] Example 12: 5-Ethyl-N-[(3R)-1-ethyl-3-piperidyl]-6-(3-fluoro-1H-indol-6-yl)pyridazine-3-amine

Chemical formula

[0167] Step A: (3R)-3-[(6-chloro-5-ethyl-pyridazin-3-yl)amino]piperidine-1-carboxylic acid tert-butyl ester and (3R)-3-[(6-chloro-4-ethyl-pyridazin-3-yl)amino]piperidine-1-carboxylic acid tert-butyl ester A neat mixture of (3R)-3-aminopiperidine-1-carboxylic acid tert-butyl ester (CAS No. 188111-79-7, 4.53 g, 22.6 mmol, 2.00 equiv) and 3,6-dichloro-4-ethyl-pyridazine (2.0 g, 11.3 mmol, 1.00 equiv) in DIPEA (3.65 g, 4.93 mL, 28.2 mmol, 2.50 equiv) was sealed in a sealed tube and stirred at 130 °C (preheated oil bath) for 3 h. By LCMS, some product was shown at rt = 1.16 min and the starting material still remaining at rt = 0.95 min. The brown neat reaction mixture was sealed again and stirring was continued at 130 °C (preheated oil bath) for 16 h (overnight). By LCMS, complete conversion to two positional isomers was shown at rt = 1.17 min and rt = 1.23 min. The viscous brown reaction mixture was poured into warm (ca. 50 °C) water (ca. 100 mL) and the oily mixture was transferred using ethyl acetate (ca. 50 mL). The brown reaction solution was stirred for 10 min, transferred to a separatory funnel and extracted twice with ethyl acetate (2 × ca. 100 mL). The organic layer was washed with water (ca. 50 mL) and brine (ca. 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The brown crude product was absorbed onto ISOLUTE HM-N and purified by flash chromatography (SiO2, 0% - 40% ethyl acetate in heptane) to give (3R)-3-[(6-chloro-5-ethyl-pyridazin-3-yl)amino]piperidine-1-carboxylic acid tert-butyl ester (1.32 g, 34%) as a pale yellow foamy substance. LCMS: m / z = 341.1 ([{35Cl}M+H]+), 341.1 ([{37Cl}M+H]+), ESI positive. Further, (3R)-3-[(6-chloro-4-ethyl-pyridazin-3-yl)amino]piperidine-1-carboxylic acid tert-butyl ester (545 mg, 13%) was obtained as a pale yellow foamy substance. LCMS: m / z = 341.1 ([{35Cl}M+H]+), 341.1 ([{37Cl}M+H]+), ESI positive.

[0168] Step B: (6-Chloro-5-ethyl-pyridazin-3-yl)-[(3R)-3-piperidyl]amine; hydrochloride To a solution of tert-butyl (3R)-3-[(6-chloro-5-ethyl-pyridazin-3-yl)amino]piperidine-1-carboxylate (Example 12, Step A) (943 mg, 2.77 mmol, 1.00 equiv) in dichloromethane (10 mL) and methanol (5 mL) was added 4M HCl in 1,4-dioxane (8.30 g, 6.92 mL, 27.7 mmol, 10.0 equiv) dropwise at ambient temperature. The reaction mixture was stirred at 23 °C for 16 h. Complete conversion to the product was shown by LCMS. Evaporation of the reaction mixture afforded the title product as a pale yellow solid of 1:1 hydrogen chloride (786 mg, 97.37%). LCMS: m / z = 241.1 ([{35Cl}M+H] + ), 243.1 ([{37Cl}M+H] + ), ESI positive.

[0169] Step C: (6-Chloro-5-ethyl-pyridazin-3-yl)-[(3R)-1-ethyl-3-piperidyl]amine A suspension of (6-chloro-5-ethyl-pyridazin-3-yl)-[(3R)-piperidin-3-yl]amine; hydrochloride (Example 12, Step B) (400 mg, 1.44 mmol, 1.00 equiv) in ultradry dichloromethane (15 mL) was treated with acetaldehyde (158.9 mg, 203.7 μL, 3.61 mmol, 2.50 equiv), followed by sodium acetate (295.9 mg, 3.61 mmol, 2.50 equiv) added under ice-bath cooling. Sodium triacetoxyborohydride (562.6 mg, 2.65 mmol, 1.80 equiv) was added at 0 °C. The reaction mixture was stirred at 0 °C for 5 minutes and at room temperature for 3 hours (the reaction mixture changed to a brownish color). Complete conversion to the product was indicated by LCMS. The reaction mixture was carefully basified with NaHCO3 solution (25 mL), then extracted with dichloromethane (3 × 60 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (SiO2, gradient: 0% to 100% in dichloromethane (dichloromethane:methanol:NH4OH 110:10:1)) to give the title compound (204 mg, 52.6% yield) as a pale brown oily substance. LCMS: m / z = 269.1 ([{35Cl}M+H]+), 271.1 ([{37Cl}M+H]+), ESI positive.

[0170] Step D: 5-Ethyl-N-[(3R)-1-ethyl-3-piperidyl]-6-(3-fluoro-1H-indol-6-yl)pyridazin-3-amine (6-Chloro-5-ethyl-pyridazin-3-yl)-[(3R)-1-ethyl-piperidin-3-yl]amine (65 mg, 241.82 μmol, 1.0 eq), 3-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (Example 2, Step A) (97.64 mg, 362.74 μmol, 1.5 eq), potassium carbonate (160.43 mg, 1.16 mmol, 4.8 eq) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(ii) dichloride dichloromethane complex (29.62 mg, 36.27 μmol, 0.15 eq) in 1,4-dioxane (2 mL) and water (1 mL) were flushed with argon and stirred at 90 °C for 4 h. The reaction mixture was cooled to room temperature and extracted with ethyl acetate (30 mL) and water (30 mL). The aqueous layer was back-extracted with ethyl acetate (30 mL). The organic layer was washed with water (20 mL) and brine (20 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, gradient: 0% - 100% in dichloromethane (dichloromethane:methanol:NH4OH 110:10:1)), followed by crystallization from heptane / ethyl acetate (1:1) to give the title compound (22 mg, 24% yield) as a light brown solid. LCMS m / z: 368.2 [M+H] + , ESI positive.

[0171] Example 13: N-[(3R)-1-Ethyl-3-piperidyl]-6-(1H-indol-6-yl)-5-methyl-1,2,4-triazin-3-amine

Chemical Structure

[0172] Step A: 6-Chloro-N-[(3R)-1-ethyl-3-piperidyl]-5-methyl-1,2,4-triazin-3-amine A mixture of 3,6-dichloro-5-methyl-1,2,4-triazine (CAS No. 132434-82-3, 1.00 g, 6.1 mmol, 1.0 eq) and [(3R)-1-ethyl-3-piperidyl]amine (CAS No. 1020396-26-2, 1.24 g, 9.15 mmol, 1.5 eq) in 1,4-dioxane (20 mL) was added with N,N-diisopropylethylamine (814 mg, 1.1 mL, 6.3 mmol, 1.03 eq). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was extracted with dichloromethane and water. The organic layer was washed with brine. The aqueous layer was back-extracted twice with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 40 g, gradient: 0% - 10% methanol in dichloromethane) to give the title compound (1.32 g, 80% yield) as a green solid. m / z 256.3 [M+H]+, ESI positive. This step was repeated as described above and the next step was proceeded.

[0173] Step B: N-[(3R)-1-Ethyl-3-piperidyl]-6-(1H-indol-6-yl)-5-methyl-1,2,4-triazin-3-amine The above-mentioned 6-chloro-N-[(3R)-1-ethyl-3-piperidyl]-5-methyl-1,2,4-triazine-3-amine (Example 13, Step A) (50 mg, 196 μmol, 1.00 equivalent), 1H-indol-6-ylboronic acid (47 mg, 293 μmol, 1.50 equivalents, CAS No. 147621-18-9), cesium carbonate (191 mg, 587 μmol, 3.0 equivalents) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(ii) dichloride dichloromethane complex (14 mg, 19.6 μmol, 0.1 equivalent) were dissolved in 1,4-dioxane (2.0 mL) and water (1.0 mL). The mixture was flushed with argon and stirred at 90 °C until consumption of the starting material was indicated by LCMS. The reaction mixture was cooled to room temperature and extracted with ethyl acetate (30 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. Purification of the crude material by preparative HPLC (Gemini NX, 12 nm, 5 μm, 100×30 mm, MeCN / water + 0.1% TEA) gave the title compound (24.6 mg, 37% yield). LCMS: m / z = 337.3 [M+H] + , ESI positive.

[0174] Example 14: N-[(3R)-1-ethyl-3-piperidyl]-6-(3-fluoro-1H-indol-6-yl)-5-methyl-1,2,4-triazine-3-amine [Chemical formula] The above-mentioned 6-chloro-N-[(3R)-1-ethyl-3-piperidyl]-5-methyl-1,2,4-triazine-3-amine (Example 13, Step A) (79 mg, 308.9 μmol, 1.00 equivalent), 3-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (Example 2, Step A) (124.7 mg, 463.3 μmol, 1.50 equivalents), potassium carbonate (204.9 mg, 1.48 mmol, 4.80 equivalents) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(ii) dichloride dichloromethane complex (37.8 mg, 46.3 μmol, 0.15 equivalent) in 1,4-dioxane (2.38 mL) and water (1.19 mL) were flushed with argon and stirred at 90 °C overnight. Complete conversion to the product was shown by LCMS. The reaction mixture was cooled to room temperature and extracted with ethyl acetate (30 mL) and water (30 mL). The aqueous layer was back-extracted with ethyl acetate (30 mL). The organic layer was washed with water (20 mL) and brine (20 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (SiO2, gradient: 0% - 100% in dichloromethane (dichloromethane:methanol:NH4OH 110:10:1)), followed by crystallization from heptane / ethyl acetate (1:1) to give the title compound (52 mg, 45% yield) as a grey solid. LCMS: m / z = 355.2 [M+H] + , ESI positive.

[0175] Example 15: N-[(3R)-1-ethyl-3-piperidyl]-7-(1H-indol-6-yl)-1-methyl-pyrazolo[3,4-d]pyridazin-4-amine [Chemical Structure]

[0176] Step A: Diethyl 2-methylpyrazole-3,4-dicarboxylate To a solution of diethyl 1H-pyrazole-4,5-dicarboxylate (4.00 g, 18.9 mmol, 1.0 equiv) in MeCN (60 mL) was added potassium carbonate (5.21 g, 37.7 mmol, 2.0 equiv). The mixture was stirred at 20 °C for 0.5 h, then iodomethane (4.01 g, 28.3 mmol, 1.5 equiv) was added to the mixture. The mixture was stirred at 20 °C for 12 h. When the reaction was complete (TLC: PE:EtOAc = 3:1), the mixture was quenched with H2O (100 mL) and extracted with EtOAc (100 mL × 3). The organic phase was washed with brine (100 mL × 2), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate, 5:1~2:1) to give the title compound (1.35 g, yield 32%) as a colorless oily substance. 1 1H NMR (400 MHz, DMSO-d6) δ = 7.88 (s, 1H), 4.37, 4.21 (q, 2H each), 3.94 (s, 3H), 1.34 - 1.21 (m, 6H).

[0177] Step B: 1-Methylpyrazolo[3,4-d]pyridazine-4,7-diol To a solution of diethyl 2-methylpyrazole-3,4-dicarboxylate (1.1 g, 4.86 mmol, 1.0 equiv) in methanol (20 mL) was added hydrazine monohydrate (0.71 mL, 14.6 mmol, 3.0 equiv). The mixture was stirred at 20 °C for 24 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by RP flash (CombiFlash (0.1% NH3.H2O aqueous-MeCN condition)) and then lyophilized to give the title compound (100 mg, yield 12%) as a white solid. LCMS: m / z 167.1 [M + H] + , ESI positive.

[0178] Step C: 4,7-Dichloro-1-methyl-pyrazolo[3,4-d]pyridazine A mixture of the above 1-methylpyrazolo[3,4-d]pyridazine-4,7-diol (200 mg, 1.20 mmol, 1.0 equiv) in POCl3 (2.0 mL) was stirred at 60 °C for 12 h. Upon completion of the reaction, the mixture was concentrated under reduced pressure to afford the title compound (220 mg, 90% yield) as a yellow solid. LCMS: m / z 202.8 [M+H]+, ESI positive.

[0179] Step D: 7-chloro-N-[(3R)-1-ethyl-3-piperidyl]-1-methyl-pyrazolo[3,4-d]pyridazin-4-amine To a solution of the above 4,7-dichloro-1-methyl-pyrazolo[3,4-d]pyridazine (200 mg, 0.99 mmol, 1.0 equiv) and (3R)-1-ethylpiperidin-3-amine (CAS No. 1020396-26-2, 152 mg, 1.18 mmol, 1.20 equiv) in NMP (1 mL) was added potassium carbonate (272 mg, 1.97 mmol, 2.0 equiv). The mixture was heated to 85 °C and stirred under N2 for 16 h. Upon completion of the reaction, the reaction mixture was cooled to 20 °C and purified by reverse-phase flash (CombiFlash 0.1% TFA aqueous-ACN conditions), followed by lyophilization to afford the title compound (70 mg, 24% yield) as a yellow solid. LCMS: m / z 295.0 [M+H] + , ESI positive. The synthesis was repeated as described above.

[0180] Step E: N-[(3R)-1-ethyl-3-piperidyl]-7-(1H-indol-6-yl)-1-methyl-pyrazolo[3,4-d]pyridazin-4-amine 7-chloro-N-[(3R)-1-ethyl-3-piperidyl]-1-methyl-pyrazolo[3,4-d]pyridazin-4-amine (100 mg, 0.34 mmol, 1.00 equivalent), 1H-indol-6-ylboronic acid (CAS No. 147621-18-9, 100 mg, 0.62 mmol, 1.83 equivalents), potassium carbonate (225 mg, 1.63 mmol, 4.80 equivalents) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(ii) dichloride dichloromethane complex (42 mg, 0.05 mmol, 0.15 equivalent) in 1,4-dioxane (2.0 mL) and water (1.0 mL) were flushed with argon and stirred at 95 °C for 16 h. The reaction mixture was cooled to room temperature and then extracted with ethyl acetate and water. The aqueous layer was back-extracted with ethyl acetate. The organic layer was washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient: 0% - 100% in dichloromethane (dichloromethane:methanol:NH4OH 9:1:0.05)). All fractions containing the product were combined and concentrated in vacuo. The residue was adsorbed onto ISOLUTE HM-N and purified again by flash chromatography (Si-amine, 12 g, gradient: 0% - 5% methanol in ethyl acetate) to give the title compound (70 mg, 52% yield) as an off-white foamy substance. LCMS: m / z 376.3 [M+H] + , ESI positive.

[0181] Example 16: N-[(3R)-1-ethyl-3-piperidyl]-6-(5-methyl-1H-indol-6-yl)pyridazin-3-amine [Chemical formula]

[0182] Step A: 6-chloro-N-[(3R)-1-ethyl-3-piperidyl]pyridazin-3-amine A mixture of 3,6-dichloropyridazine (CAS number 141-30-0, 0.600 g, 4.03 mmol, 1.00 equiv) and (3R)-1-ethylpiperidin-3-amine (CAS number 1020396-26-2, 620 mg, 4.84 mmol, 1.20 equiv) in N-methyl-2-pyrrolidinone (3.4 mL) was added N,N-diisopropylethylamine (1.33 g, 1.8 mL, 10.3 mmol, 2.56 equiv). The reaction mixture was stirred at 120 °C for 16 h. The reaction mixture was cooled to room temperature and extracted with ethyl acetate and 5% aqueous LiCl solution. The aqueous layer was back-extracted with ethyl acetate. The organic layer was washed twice with 5% aqueous LiCl solution, once with water and once with brine. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE HM and purified by flash chromatography (silica gel, 25 g, gradient: 0% - 100% in dichloromethane (dichloromethane:methanol:NH4OH 9:1:0.05)) to give the title compound (567 mg, 56% yield) as a pale yellow solid. LCMS: m / z 241.1 [M+H] + , ESI positive.

[0183] Step B: 5-Methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole A solution of 6-bromo-5-methyl-1H-indole (CAS number 248602-16-6, 330 mg, 1.57 mmol, 1.00 equivalent) and bis(pinacolato)diboron (478 mg, 1.88 mmol, 1.20 equivalents) in 1,4-dioxane (3.7 mL) was treated with potassium acetate (462 mg, 4.71 mmol, 3.00 equivalents), followed by 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (130 mg, 0.16 mmol, 0.10 equivalent). The reaction mixture was flushed with argon and stirred at 90 °C for 16 h. The reaction mixture was cooled to room temperature, adsorbed onto ISOLUTE HM-N, and purified by flash chromatography (silica gel, 25 g, gradient: 0% - 20% ethyl acetate in heptane) to afford the title compound (182 mg, 43% yield) as a pale yellow solid. LCMS: m / z 258.0 [M+H] + , ESI positive.

[0184] Step C: N-[(3R)-1-Ethyl-3-piperidyl]-6-(5-methyl-1H-indol-6-yl)pyridazin-3-amine 6-Chloro-N-[(3R)-1-ethyl-3-piperidyl]pyridazine-3-amine (Example 16, Step A) (60 mg, 0.24 mmol, 1.00 equiv), 5-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (Example 15, Step B) (100 mg, 0.37 mmol, 1.56 equiv), potassium carbonate (156 mg, 1.13 mmol, 4.77 equiv) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (24 mg, 0.03 mmol, 0.12 equiv) in 1,4-dioxane (1.6 mL) and water (0.80 mL) were flushed with argon and stirred at 100 °C for 4 h. The reaction mixture was cooled to room temperature and extracted with ethyl acetate and water. The aqueous layer was back-extracted with ethyl acetate. The organic layer was washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient: 0% - 100% in dichloromethane (dichloromethane:methanol:NH4OH 9:1:0.05)). All fractions containing the product were combined and concentrated in vacuo. Trituration of the residue with ethyl acetate gave the title compound (50 mg, 60% yield) as a dark brown solid. LCMS: m / z 336.3 [M+H] + , ESI positive.

[0185] Example 17: 3-[[6-(3-Fluoro-1H-indol-6-yl)-5-methyl-pyridazin-3-yl]amino]-1-methyl-cyclobutanol

Chemical formula

[0186] Step A: 3-[(6-Chloro-5-methyl-pyridazin-3-yl)amino]-1-methyl-cyclobutanol and 3-[(6-chloro-4-methyl-pyridazin-3-yl)amino]-1-methyl-cyclobutanol A solution of 3,6-dichloro-4-methyl-pyridazine (CAS No. 19064-64-3, 300 mg, 1.84 mmol, 1.00 eq) in N-methyl-2-pyrrolidinone (3.0 mL) was added with N,N-diisopropylethylamine (962 mg, 1.3 mL, 7.44 mmol, 4.04 eq) and cis-3-amino-1-methyl-cyclobutanol hydrochloride (CAS No. 1523606-23-6, 253 mg, 1.84 mmol, 1.00 eq). The mixture was stirred at 180 °C for 2 h under microwave irradiation. The reaction mixture was extracted with ethyl acetate and 10% aqueous LiCl solution. The aqueous layer was back-extracted with ethyl acetate. The organic layer was washed twice with 10% aqueous LiCl solution, once with water, and once with brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 24 g, gradient: 0% - 5% methanol in dichloromethane) to give 3-[(6-chloro-5-methyl-pyridazin-3-yl)amino]-1-methyl-cyclobutanol (100 mg, yield 23%) as an off-white solid; LCMS: m / z 228.0 [M+H] + , ESI positive, and 3-[(6-chloro-4-methyl-pyridazin-3-yl)amino]-1-methyl-cyclobutanol (70 mg, yield 16%) was obtained as an off-white solid; LCMS: m / z 228.1 [M+H] + , ESI positive.

[0187] Step B: 3-[[6-(3-Fluoro-1H-indol-6-yl)-5-methyl-pyridazin-3-yl]amino]-1-methyl-cyclobutanol 3-[(6-Chloro-5-methyl-pyridazin-3-yl)amino]-1-methyl-cyclobutanol (Example 17, Step A) (60 mg, 0.25 mmol, 1.00 equivalent), 3-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (Example 2, Step A) (110 mg, 0.40 mmol, 1.60 equivalents), potassium carbonate (175 mg, 1.27 mmol, 5.06 equivalents) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (28 mg, 0.03 mmol, 0.14 equivalents) in 1,4-dioxane (1.6 mL) and water (0.80 mL) were flushed with argon and stirred at 90 °C for 16 hours. The reaction mixture was cooled to room temperature and extracted with ethyl acetate and water. The aqueous layer was back-extracted with ethyl acetate. The organic layer was washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient: 0% - 100% in dichloromethane (dichloromethane:methanol:NH4OH 9:1:0.05)) to give the title compound (52 mg, 57% yield) as a brown foamy substance. LCMS: m / z 327.1 [M+H] + , ESI positive.

[0188] Examples 18A and 18B: (3aS,7aR)-1-[6-(3-Fluoro-1H-indol-6-yl)-5-methyl-pyridazin-3-yl]-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridine and (3aR,7aS)-1-[6-(3-Fluoro-1H-indol-6-yl)-5-methyl-pyridazin-3-yl]-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridine

Chemical Structure

[0189] Project A: tert-Butyl 1-(6-chloro-5-methyl-pyridazin-3-yl)-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridine-6-carboxylate 1,2,3,3a,4,5,7,7a-octahydropyrrolo[2,3- c pyridine-6-carboxylic acid tert-butyl ester (CAS No. 1196147-27-9, 2.33 g, 10.31 mmol, 1.4 eq), 3,6-dichloro-4-methyl-pyridazine (CAS No. 19064-64-3, 1.2 g, 7.36 mmol, 1.0 eq) and N,N-diisopropylethylamine (2.57 mL, 14.7 mmol, 2.0 eq) in N-methyl-2-pyrrolidinone (3 mL) were stirred at 130 °C for 24 h. The reaction mixture was extracted with ethyl acetate (2 × 80 mL) and semi-saturated NaHCO3. The organic layer was washed with water (80 mL) and brine (80 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. Purification of the residue by flash column chromatography (silica gel, 0% - 50% ethyl acetate in heptane) gave the title compound (1.49 g, 57% yield) as a pale yellow solid. LCMS: m / z 353.3 ([{ 35 Cl}M+H]+), 355.3 ([{ 37 Cl}M+H] + )), ESI positive.

[0190] Project B: 1-(6-Chloro-5-methyl-pyridazin-3-yl)-2,3,3a,4,5,6,7,7a-octahydropyrrolo[2,3-c]pyridine hydrochloride tert-Butyl 1-(6-chloro-5-methyl-pyridazin-3-yl)-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridine-6-carboxylate (1.48 g, 4.19 mmol, 1.0 equiv) was dissolved in dichloromethane (12.7 mL) and methanol (6.4 mL). 4M HCl in 1,4-dioxane (9.4 mL, 37.8 mmol, 9.0 equiv) was added dropwise to the reaction mixture, and the mixture was stirred at 23 °C for 3 h. Concentration of the reaction mixture in vacuo gave the title compound (1.40 g, 99% yield) as an orange solid. LCMS: m / z 253.2 [M+H] + , ESI positive.

[0191] Step C: 1-(6-Chloro-5-methyl-pyridazin-3-yl)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridine 1-(6-Chloro-5-methyl-pyridazin-3-yl)-2,3,3a,4,5,6,7,7a-octahydropyrrolo[2,3-c]pyridine hydrochloride (1.4 g, 4.16 mmol, 1.0 equiv) was dissolved in 1,2-dichloroethane (40.0 mL), and triethylamine (649 mg, 0.89 mL, 6.41 mmol, 1.54 equiv) was added. The reaction mixture was stirred at 23 °C for 5 min. Then, formaldehyde (37% aqueous solution, 758 mg, 0.70 mL, 9.33 mmol, 2.24 equiv) was added, followed by the addition of sodium triacetoxyborohydride (CAS No. 56553-60-7, 3.53 g, 16.7 mmol, 4.0 equiv) in portions. The reaction mixture was stirred at room temperature for 1 h. Thereafter, the reaction mixture was carefully quenched with saturated aqueous NaHCO3 and extracted with dichloromethane (5 × 30 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Purification of the crude product by flash chromatography (silica gel, gradient: 0% - 5% methanol in dichloromethane) gave the title compound (1.2 g, 97% yield) as a pale yellow solid. LCMS m / z 267.2 [M+H] + , ESI positive.

[0192] Project D: (3aS,7aR)-1-[6-(3-Fluoro-1H-indol-6-yl)-5-methyl-pyridazin-3-yl]-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridine (A) and (3aR,7aS)-1-[6-(3-Fluoro-1H-indol-6-yl)-5-methyl-pyridazin-3-yl]-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridine (B)

Chemical formula

[0193] Example A The compound of formula Ib can be used as an active ingredient in a manner known per se to produce tablets of the following composition: Per tablet Active ingredient 200 mg Microcrystalline cellulose 155 mg Corn starch 25 mg Talc 25 mg Hydroxypropylmethylcellulose 20mg 425 mg

[0194] Example B The compound of formula Ib can be used as an active ingredient in a manner known per se to produce capsules of the following composition: Per capsule Active ingredient 100.0 mg Corn starch 20.0 mg Lactose 95.0 mg Talc 4.5 mg Magnesium stearate 0.5mg 220.0 mg

Claims

1. Expression Ib or Ib' 【Chemistry 1】 (In the formula, A ３ is N or CR ３ Selected from; A ４ is N or CR ４ Selected from; A ５ is N or CR ５ Selected from; Y is selected from N or CH, and X is CR ７ Is it, Alternatively, X and Y, and the atoms to which they are bonded, form a five-membered heteroaryl ring containing two N heteroatoms, where one N heteroatom is substituted with either H or an alkyl group; R １ is selected from alkyl, cyano, or H; R ２ is selected from alkyl, cyano, H or halo; R ３ H is; R ４ is selected from H, alkyl, alkoxy, or halo; R ５ is selected from H or halo; R ６ H is; R ７ is alkyl or haloalkyl; W is an optionally substituted cycloalkyl group or an optionally substituted heterocyclic ring containing a single N heteroatom, where the optionally substituted cycloalkyl group may be substituted with one or two substituents independently selected from H, OH, or alkyl, and the optionally substituted heterocyclic ring containing a single N heteroatom may be substituted with alkyl or haloalkyl groups. The compound indicated by, or a pharmaceutically acceptable salt thereof.

2. Formula Ib 【Chemistry 2】 The compound according to claim 1, as shown in [the provided text], or a pharmaceutically acceptable salt thereof.

3. A ３ However, CR ３ And; A ４ However, CR ４ And; A ５ However, CR ５ And; Y is selected from N or CH, and X is CR ７ And; R １ However, it is alkyl, cyano, or H; R ２ However, it is alkyl, cyano, H, or halo; R ３ However, it is H; R ４ However, it is H or halo; R ５ However, it is H or halo; R ６ However, it is H; R ７ However, it is alkyl or haloalkyl; W is an alkyl-substituted piperidine ring. The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

4. N-[(3R)-1-ethyl-3-piperidyl]-6-(1H-indole-6-yl)-5-methylpyridazine-3-amine; N-[(3R)-1-ethyl-3-piperidyl]-6-(3-fluoro-1H-indole-6-yl)-5-methylpyridazine-3-amine; N-[(3R)-1-ethyl-3-piperidyl]-6-(5-fluoro-1H-indole-6-yl)-5-methylpyridazine-3-amine; N-[(3R)-1-ethyl-3-piperidyl]-5-methyl-6-(3-methyl-1H-indole-6-yl)pyridazine-3-amine; 6-(3-chloro-1H-indole-6-yl)-N-[(3R)-1-ethyl-3-piperidyl]-5-methylpyridazine-3-amine; N-[(3R)-1-ethyl-3-piperidyl]-5-methyl-6-(2-methyl-1H-indole-6-yl)pyridazine-3-amine; 6-[6-[[(3R)-1-ethyl-3-piperidyl]amino]-4-methylpyridazine-3-yl]-1H-indole-3-carbonitrile; 6-[6-[[(3R)-1-ethyl-3-piperidyl]amino]-4-methylpyridazine-3-yl]-1H-indole-2-carbonitrile; 6-(3-fluoro-1H-indole-6-yl)-5-methyl-N-[(3R)-1-methyl-3-piperidyl]pyridazine-3-amine; N-[(3R)-1-ethyl-3-piperidyl]-6-(1H-indole-6-yl)-5-methylpyridazine-3-amine; N-[(3R)-1-ethyl-3-piperidyl]-6-(3-fluoro-1H-indole-6-yl)-5-(trifluoromethyl)pyridazine-3-amine; 5-Ethyl-N-[(3R)-1-ethyl-3-piperidyl]-6-(3-fluoro-1H-indole-6-yl)pyridazine-3-amine; N-[(3R)-1-ethyl-3-piperidyl]-6-(1H-indole-6-yl)-5-methyl-1,2,4-triazine-3-amine; and N-[(3R)-1-ethyl-3-piperidyl]-6-(3-fluoro-1H-indole-6-yl)-5-methyl-1,2,4-triazine-3-amine A compound according to claim 1, selected from, or a pharmaceutically acceptable salt thereof.

5. N-[(3R)-1-ethyl-3-piperidyl]-6-(1H-indole-6-yl)-5-methylpyridazine-3-amine; N-[(3R)-1-ethyl-3-piperidyl]-6-(3-fluoro-1H-indole-6-yl)-5-methylpyridazine-3-amine; 6-(3-fluoro-1H-indole-6-yl)-5-methyl-N-[(3R)-1-methyl-3-piperidyl]pyridazine-3-amine; N-[(3R)-1-ethyl-3-piperidyl]-6-(3-fluoro-1H-indole-6-yl)-5-(trifluoromethyl)pyridazine-3-amine; N-[(3R)-1-ethyl-3-piperidyl]-6-(1H-indole-6-yl)-5-methyl-1,2,4-triazine-3-amine; and N-[(3R)-1-ethyl-3-piperidyl]-6-(3-fluoro-1H-indole-6-yl)-5-methyl-1,2,4-triazine-3-amine A compound according to claim 1, selected from, or a pharmaceutically acceptable salt thereof.

6. N-[(3R)-1-ethyl-3-piperidyl]-6-(3-fluoro-1H-indole-6-yl)-5-methylpyridazine-3-amine; N-[(3R)-1-ethyl-3-piperidyl]-6-(1H-indole-6-yl)-5-methyl-1,2,4-triazine-3-amine; and N-[(3R)-1-ethyl-3-piperidyl]-6-(3-fluoro-1H-indole-6-yl)-5-methyl-1,2,4-triazine-3-amine A compound according to claim 1, selected from, or a pharmaceutically acceptable salt thereof.

7. The compound according to claim 1, which is N-[(3R)-1-ethyl-3-piperidyl]-7-(1H-indole-6-yl)-1-methyl-pyrazolo[3,4-d]pyridazine-4-amine, or a pharmaceutically acceptable salt thereof.

8. N-[(3R)-1-ethyl-3-piperidyl]-6-(5-methyl-1H-indole-6-yl)pyridazine-3-amine; and 3-[[6-(3-fluoro-1H-indole-6-yl)-5-methylpyridazine-3-yl]amino]-1-methylcyclobutanol A compound according to claim 1, selected from, or a pharmaceutically acceptable salt thereof.

9. (3aS,7aR)-1-[6-(3-fluoro-1H-indole-6-yl)-5-methylpyridazine-3-yl]-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridine; and (3aR,7aS)-1-[6-(3-fluoro-1H-indole-6-yl)-5-methylpyridazine-3-yl]-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridine A compound according to claim 1, selected from, or a pharmaceutically acceptable salt thereof.

10. A compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, for use as a therapeutically active substance.

11. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, for use in the treatment or prevention of a disease, disorder or condition, wherein the disease, disorder or condition is responsive to NLRP3 inhibition.

12. A compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, for the treatment or prevention of a disease, disorder or condition selected from asthma or COPD.

13. A compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, for the treatment or prevention of a disease, disorder or condition selected from Parkinson's disease or Alzheimer's disease.

14. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof.

15. A pharmaceutical composition according to claim 14 for the treatment or prevention of a disease, disorder or condition, wherein the disease, disorder or condition is responsive to NLRP3 inhibition.

16. The pharmaceutical composition according to claim 14 for treating or preventing a disease, disorder, or condition selected from asthma or COPD.

17. The pharmaceutical composition according to claim 14 for treating or preventing a disease, disorder, or condition selected from Parkinson's disease or Alzheimer's disease.

18. Use of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9 for the preparation of a medicament for the treatment or prevention of a disease, disorder or condition, wherein the disease, disorder or condition is responsive to NLRP3 inhibition.

19. Use of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9 for the preparation of a medicament for the treatment or prevention of a disease, disorder or condition selected from asthma or COPD.

20. Use of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9 for the preparation of a medicament for the treatment or prevention of a disease, disorder or condition selected from Parkinson's disease or Alzheimer's disease.

21. An NLRP3 inhibitor comprising the compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof.

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