Novel compounds

Abstract

The present invention relates to novel compounds (Ib) or (Ib ') having the general formula (Ib) or (Ib') # imgabs0 # wherein R1, R2, R6, A3, A4, A5, X, Y and W are as described herein, compositions including the compounds, and methods of using the compounds.

Description

Technical Field

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

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

[0003]

[0004] in

[0005] A3 is selected from N or CR 3 ;

[0006] A4 is selected from N or CR 4 ;

[0007] A5 is selected from N or CR 5 ;

[0008] Y is selected from N or CH, and X is CR 7 ,

[0009] or X and Y and the atoms to which they are attached form a 5-membered heteroaryl ring containing 2 N heteroatoms, one of which is substituted with H or alkyl;

[0010] R 1 is selected from alkyl, cyano or H;

[0011] R 2 is selected from alkyl, cyano, H or halo;

[0012] R 3 is H;

[0013] R 4 Selected from H, alkyl, alkoxy or halo;

[0014] R 5 Selected from H or halo;

[0015] R 6 is H;

[0016] R 7 is an alkyl group or a halogenated alkyl group;

[0017] W is optionally substituted cycloalkyl or 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;

[0018] and pharmaceutically acceptable salts thereof.

[0019] Furthermore, the present invention includes all racemic mixtures, all corresponding enantiomers and / or optical isomers thereof. Background Art

[0020] The NOD-like receptor (NLR) family (pyrin domain-containing protein 3 (NLRP3) inflammasome) is integral to the inflammatory process and its aberrant activity is pathogenic in inherited disorders such as cryopyrin-associated periodic syndrome (CAPS) and complex diseases such as multiple sclerosis, type 2 diabetes, Alzheimer's disease and atherosclerosis.

[0021] NLRP3 is an intracellular signaling molecule that senses many pathogen-derived, environmental, and host-derived factors. After activation, NLRP3 binds to apoptosis-associated speck-like proteins, which contain caspase activation and recruitment domains (ASC). ASC then polymerizes to form large aggregates known as ASC specks. Polymerized ASC then interacts with the cysteine ​​protease caspase-1 to form a complex known as an inflammasome. This causes the activation of caspase-1, which cleaves the precursor forms of proinflammatory cytokines IL-1β and IL-18 (referred to as pro-IL-1β and pro-IL-18, respectively), thereby activating these cytokines. Caspase-1 also mediates a class of inflammatory cell death known as pyroptosis. ASC specks can also recruit and activate caspase-8, which can process pro-IL-1β and pro-IL-18 and trigger apoptotic cell death.

[0022] Caspase-1 cleaves pro-IL-1β and pro-IL-18 into their active forms, which are secreted by cells. Active caspase-1 also cleaves gasdermin-D to trigger cell pyroptosis. Caspase-1 can also mediate the release of alarmin molecules such as IL-33 and high mobility group protein 1 (HMGB1) by controlling the pyroptosis cell death pathway. Caspase-1 also cleaves intracellular IL-1R2, causing its degradation and releasing IL-1α. In human cells, caspase-1 can also control the processing and secretion of IL-37. Many other caspase-1 substrates such as components of the cytoskeleton and glycolytic pathways may contribute to caspase-1-dependent inflammation.

[0023] NLRP3-dependent ASC specks are released into the extracellular milieu, where they can activate caspase-1, induce processing of caspase-1 substrates, and propagate inflammation.

[0024] Active cytokines derived 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 proinflammatory cytokines IL-6 and TNF. IL-1β and IL-18 synergize with IL-23 to induce IL-17 production by memory CD4 Th17 cells and γδ T cells in the absence of T cell receptor engagement. IL-18 and IL-12 also synergize to induce IFN-γ production from memory T cells and NK cells that drive Th1 responses.

[0025] The inherited CAPS disorders 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 a key component of the inflammatory process. NLRP3 has also been implicated in the pathogenesis of many complex diseases, notably metabolic disorders such as type 2 diabetes, atherosclerosis, obesity, and gout.

[0026] The role of NLRP3 in central nervous system diseases is emerging, and lung diseases have also been shown to be affected by NLRP3. In addition, NLRP3 has a role in the development of liver disease, kidney disease and aging. Many of these associations are made using Nlrp3 - / - Although the role of NLRP3 in these diseases has been defined in mice, there are also insights into the specific activation of NLRP3 in these diseases. In type 2 diabetes (T2D), deposition of amylin in the pancreas activates NLRP3 and IL-1β signaling, leading to cell death and inflammation.

[0027] Several small molecules have been demonstrated to inhibit the NLRP3 inflammasome. Glibenclamide inhibits IL-1β production at micromolar concentrations in response to activation of NLRP3, but not NLRC4 or NLRP1. Other previously characterized weak NLRP3 inhibitors include parthenolide, 3,4-methylenedioxy-β-nitrostyrene, and dimethyl sulfoxide (DMSO), although these agents have limited potency and are nonspecific.

[0028] Current treatments for NLRP3-related diseases include biologic agents that target IL-1. These are the recombinant IL-1 receptor antagonist anakinra, the neutralizing IL-1β antibody canakinumab, and the soluble decoy IL-1 receptor rilonacept. These approaches have been shown to successfully treat CAPS, and these biologic agents have been used in clinical trials for other IL-1β-related diseases.

[0029] There is a need to provide compounds having improved pharmacological and / or physiological and / or physicochemical properties, and / or compounds which provide useful alternatives to known compounds. Summary of the invention

[0030] The present invention provides novel compounds of formula Ib or Ib'

[0031]

[0032] in

[0033] A3 is selected from N or CR 3 ;

[0034] A4 is selected from N or CR 4 ;

[0035] A5 is selected from N or CR 5 ;

[0036] Y is selected from N or CH, and X is CR 7 ,

[0037] or X and Y and the atoms to which they are attached form a 5-membered heteroaryl ring containing 2 N heteroatoms, one of which is substituted with H or alkyl;

[0038] R 1 is selected from alkyl, cyano or H;

[0039] R 2 is selected from alkyl, cyano, H or halo;

[0040] R 3 is H;

[0041] R 4 Selected from H, alkyl, alkoxy or halo;

[0042] R 5 Selected from H or halo;

[0043] R 6 is H;

[0044] R 7 is an alkyl group or a halogenated alkyl group;

[0045] W is optionally substituted cycloalkyl or 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;

[0046] and pharmaceutically acceptable salts thereof.

[0047] The term "alkyl" refers to a monovalent straight or branched saturated hydrocarbon group having 1 to 6 carbon atoms. In some embodiments, if not otherwise specified, the alkyl group contains 1 to 6 carbon atoms (C 1-6 -alkyl) or 1 to 4 carbon atoms (C 1-4 -alkyl). 1-6 Examples of -alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and amyl. Particular alkyl groups include methyl and ethyl. When an alkyl residue with a specific carbon number is indicated, all geometric isomers with that carbon number may be encompassed. Thus, for example, "butyl" may include n-butyl, sec-butyl, isobutyl and tert-butyl, and "propyl" may include n-propyl and isopropyl.

[0048] The term "alkoxy" refers to a group of formula -O-R', wherein R' is C 1-6 -alkyl group. 1-6 Examples of -alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and tert-butoxy.

[0049] The term "cyano" refers to a -C≡N group.

[0050] The term "cycloalkyl" refers to a monocyclic or polycyclic saturated or partially unsaturated non-aromatic hydrocarbon. In certain embodiments, unless otherwise described, cycloalkyl includes 3 to 8 carbon atoms, 3 to 6 carbon atoms or 3 to 5 carbon atoms. In certain embodiments, cycloalkyl is a saturated monocyclic or polycyclic hydrocarbon. In other embodiments, cycloalkyl includes one or more double bonds (e.g., a cycloalkyl fused to an aryl or heteroaryl ring, or a non-aromatic monocyclic hydrocarbon including one or two double bonds). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, octahydropentalenyl, spiro [3.3] heptyl, etc. Bicyclic means a ring system consisting of two saturated carbocyclic rings with two common carbon atoms. Examples of monocyclic cycloalkyls are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

[0051] The terms "halogen", "halide" and "halo" are used interchangeably herein and refer to fluorine, chlorine, bromine or iodine. Particular halogens are fluorine and chlorine.

[0052] The term "haloalkyl" refers to a group in which C 1-6 -alkyl radical wherein at least one hydrogen atom has been replaced by the same or different halogen atoms 1-6 -alkyl group. A particular example is trifluoromethyl.

[0053] The term "heterocycle" means a monovalent saturated or partially unsaturated monocyclic or bicyclic system of 4 to 10 ring atoms, or 4 to 9 ring atoms, comprising 1, 2 or 3 heteroatoms selected from N, O and S, and the remaining ring atoms are carbon. Examples of monocyclic saturated heterocycles are oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl or piperazinyl. Examples of partially unsaturated heterocycles are dihydrofuranyl, imidazolinyl, dihydrooxazolyl, tetrahydropyridinyl or dihydropyranyl. A special example of heterocycle is piperidinyl.

[0054] The term "heteroaryl", alone or in combination, denotes a monovalent aromatic heterocyclic mono- or bicyclic ring system of 5 to 12 ring atoms containing 1, 2, 3 or 4 heteroatoms selected from N, O and S, the remaining ring atoms being carbon. 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, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, and benzothienyl.

[0055] The term "pharmaceutical salt" refers to those salts that retain the biological effect and properties of free alkali or free acid, which are not undesirable in biology or other aspects. These salts are formed by inorganic acids such as trifluoroacetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid (particularly 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 inorganic bases or organic bases to free acids. Salts derived from inorganic bases include but are not limited to sodium, potassium, lithium, ammonium, calcium, magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, 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, polyamine resins). The compound of formula Ib may also exist in the form of zwitterions. Particularly preferred pharmaceutically acceptable salts of the compound of formula Ib are salts formed from formic acid and salts formed from hydrochloric acid to produce hydrochlorides, dihydrochlorides or trihydrochlorides.

[0056] The abbreviation uM means micromolar, and is equivalent to the symbol μM.

[0057] The abbreviation uL means microliter, and is equivalent to the symbol μL.

[0058] The abbreviation ug means microgram, and is equivalent to the symbol μg.

[0059] The compounds of formula Ib may contain several asymmetric centers and may be present as optically pure enantiomers, mixtures of enantiomers (such as, for example, racemates), optically pure diastereomers, mixtures of diastereomers, diastereomeric racemates or mixtures of diastereomeric racemates.

[0060] According to the Cahn-Ingold-Prelog convention, asymmetric carbon atoms can be in either the "R" or "S" configuration.

[0061] Another embodiment of the present invention provides a compound according to formula Ib as described herein and a pharmaceutically acceptable salt or ester thereof, in particular a compound according to formula Ib as described herein and a pharmaceutically acceptable salt thereof, more particularly a compound according to formula Ib as described herein.

[0062] Yet another embodiment of the present invention provides a compound according to formula Ib' as described herein and a pharmaceutically acceptable salt or ester thereof, in particular a compound according to formula Ib' as described herein and a pharmaceutically acceptable salt thereof, more particularly a compound according to formula Ib' as described herein.

[0063] One embodiment of the present invention provides a compound according to formula Ib as described herein, wherein

[0064] A3 is selected from N or CR 3 ;

[0065] A4 is selected from N or CR 4 ;

[0066] A5 is selected from N or CR 5 ;

[0067] Y is selected from N or CH, and X is CR 7 ,

[0068] or X and Y and the atoms to which they are attached form a 5-membered heteroaryl ring containing 2 N heteroatoms, one of which is substituted with H or alkyl;

[0069] R 1 is selected from alkyl, cyano or H;

[0070] R 2 is selected from alkyl, cyano, H or halo;

[0071] R 3 is H;

[0072] R 4Selected from H, alkyl, alkoxy or halo;

[0073] R 5 Selected from H or halo;

[0074] R 6 is H;

[0075] R 7 is an alkyl group or a halogenated alkyl group;

[0076] W is optionally substituted cycloalkyl or 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;

[0077] and pharmaceutically acceptable salts thereof.

[0078] One embodiment of the present invention provides a compound according to formula Ib as described herein, wherein Y is selected from N or CH, and X is CR 7 .

[0079] One embodiment of the present invention provides a compound according to formula Ib as described herein, wherein R 1 For H.

[0080] One embodiment of the present invention provides a compound according to formula Ib as described herein, wherein R 2 is H or halogenated.

[0081] One embodiment of the present invention provides a compound according to formula Ib as described herein, wherein A3 is CR 3 .

[0082] One embodiment of the present invention provides a compound according to formula Ib as described herein, wherein A4 is CR 4 .

[0083] One embodiment of the present invention provides a compound according to formula Ib as described herein, wherein A5 is CR 5 .

[0084] One embodiment of the present invention provides a compound according to formula Ib as described herein, wherein R 4 Selected from H or halo.

[0085] One embodiment of the present invention provides a compound according to formula Ib as described herein, wherein R 4 For H.

[0086] One embodiment of the present invention provides a compound according to formula Ib as described herein, wherein R 5 For H.

[0087] One embodiment of the present invention provides a compound according to formula Ib as described herein, wherein R 7 It is an alkyl group.

[0088] One embodiment of the present invention provides a compound according to formula Ib as described herein, wherein W is an alkyl substituted piperidine ring.

[0089] One embodiment of the present invention provides a compound according to formula Ib, wherein

[0090] A3 is CR 3 ;

[0091] A4 to CR 4 ;

[0092] A5 is CR 5 ;

[0093] Y is selected from N or CH, and X is CR 7 ;

[0094] R 1 is alkyl, cyano or H;

[0095] R 2 is alkyl, cyano, H or halo;

[0096] R 3 is H;

[0097] R 4 is H or halogenated;

[0098] R 5 is H or halogenated;

[0099] R 6 is H;

[0100] R 7 is an alkyl group or a halogenated alkyl group;

[0101] W is a piperidine ring substituted with an alkyl group;

[0102] and pharmaceutically acceptable salts thereof.

[0103] One embodiment of the present invention provides a compound according to formula Ib, wherein

[0104] A3 is CR 3 ;

[0105] A4 to CR 4 ;

[0106] A5 is CR 5 ;

[0107] Y is selected from N or CH, and X is CR 7 ;

[0108] R 1 is H;

[0109] R 2 is H or halogenated;

[0110] R 3 is H;

[0111] R 4 is H;

[0112] R 5 is H;

[0113] R 6 is H;

[0114] R 7 is an alkyl group or a halogenated alkyl group;

[0115] W is a piperidine ring substituted with an alkyl group;

[0116] and pharmaceutically acceptable salts thereof.

[0117] One embodiment of the present invention provides a compound according to formula Ib, wherein

[0118] A3 is CR 3 ;

[0119] A4 to CR 4 ;

[0120] A5 is CR 5 ;

[0121] Y is selected from N or CH, and X is CR 7 ;

[0122] R 1 is H;

[0123] R 2 is H or halogenated;

[0124] R 3 is H;

[0125] R 4 is H;

[0126] R 5 is H;

[0127] R 6 is H;

[0128] R 7 is an alkyl group;

[0129] W is a piperidine ring substituted with an alkyl group;

[0130] and pharmaceutically acceptable salts thereof.

[0131] Particular examples of compounds of formula Ib as described herein are selected from

[0132] N-[(3R)-1-ethyl-3-piperidinyl]-6-(1H-indol-6-yl)-5-methyl-pyridazin-3-amine;

[0133] N-[(3R)-1-ethyl-3-piperidinyl]-6-(3-fluoro-1H-indol-6-yl)-5-methyl-pyridazin-3-amine;

[0134] N-[(3R)-1-ethyl-3-piperidinyl]-6-(5-fluoro-1H-indol-6-yl)-5-methyl-pyridazin-3-amine;

[0135] N-[(3R)-1-ethyl-3-piperidinyl]-5-methyl-6-(3-methyl-1H-indol-6-yl)pyridazin-3-amine;

[0136] 6-(3-Chloro-1H-indol-6-yl)-N-[(3R)-1-ethyl-3-piperidinyl]-5-methyl-pyridazin-3-amine;

[0137] N-[(3R)-1-ethyl-3-piperidinyl]-5-methyl-6-(2-methyl-1H-indol-6-yl)pyridazin-3-amine;

[0138] 6-[6-[[(3R)-1-ethyl-3-piperidinyl]amino]-4-methyl-pyridazin-3-yl]-1H-indole-3-carbonitrile;

[0139] 6-[6-[[(3R)-1-ethyl-3-piperidinyl]amino]-4-methyl-pyridazin-3-yl]-1H-indole-2-carbonitrile;

[0140] 6-(3-Fluoro-1H-indol-6-yl)-5-methyl-N-[(3R)-1-methyl-3-piperidinyl]pyridazin-3-amine;

[0141] N-[(3R)-1-ethyl-3-piperidinyl]-6-(1H-indol-6-yl)-5-methyl-pyridazin-3-amine;

[0142] N-[(3R)-1-ethyl-3-piperidinyl]-6-(3-fluoro-1H-indol-6-yl)-5-(trifluoromethyl)pyridazin-3-amine;

[0143] 5-ethyl-N-[(3R)-1-ethyl-3-piperidinyl]-6-(3-fluoro-1H-indol-6-yl)pyridazin-3-amine;

[0144] N-[(3R)-1-ethyl-3-piperidinyl]-6-(1H-indol-6-yl)-5-methyl-1,2,4-triazin-3-amine;

[0145] N-[(3R)-1-ethyl-3-piperidinyl]-6-(3-fluoro-1H-indol-6-yl)-5-methyl-1,2,4-triazin-3-amine;

[0146] and pharmaceutically acceptable salts thereof.

[0147] Other specific examples of Formula Ib as described herein are selected from

[0148] N-[(3R)-1-ethyl-3-piperidinyl]-6-(5-methyl-1H-indol-6-yl)pyridazin-3-amine;

[0149] 3-[[6-(3-Fluoro-1H-indol-6-yl)-5-methyl-pyridazin-3-yl]amino]-1-methyl-cyclobutanol;

[0150] and pharmaceutically acceptable salts thereof.

[0151] Other particular examples of Formula Ib as described herein are N-[(3R)-1-ethyl-3-piperidinyl]-7-(1H-indol-6-yl)-1-methyl-pyrazolo[3,4-d]pyridazin-4-amine and pharmaceutically acceptable salts thereof.

[0152] Other specific examples of Formula Ib as described herein are selected from

[0153] (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;

[0154] (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;

[0155] and pharmaceutically acceptable salts thereof.

[0156] Preferred examples of compounds of formula Ib as described herein are selected from

[0157] N-[(3R)-1-ethyl-3-piperidinyl]-6-(1H-indol-6-yl)-5-methyl-pyridazin-3-amine;

[0158] N-[(3R)-1-ethyl-3-piperidinyl]-6-(3-fluoro-1H-indol-6-yl)-5-methyl-pyridazin-3-amine;

[0159] 6-(3-Fluoro-1H-indol-6-yl)-5-methyl-N-[(3R)-1-methyl-3-piperidinyl]pyridazin-3-amine;

[0160] N-[(3R)-1-ethyl-3-piperidinyl]-6-(3-fluoro-1H-indol-6-yl)-5-(trifluoromethyl)pyridazin-3-amine;

[0161] N-[(3R)-1-ethyl-3-piperidinyl]-6-(1H-indol-6-yl)-5-methyl-1,2,4-triazin-3-amine;

[0162] N-[(3R)-1-ethyl-3-piperidinyl]-6-(3-fluoro-1H-indol-6-yl)-5-methyl-1,2,4-triazin-3-amine;

[0163] and pharmaceutically acceptable salts thereof.

[0164] Most preferred examples of compounds of formula Ib as described herein are selected from

[0165] N-[(3R)-1-ethyl-3-piperidinyl]-6-(3-fluoro-1H-indol-6-yl)-5-methyl-pyridazin-3-amine;

[0166] N-[(3R)-1-ethyl-3-piperidinyl]-6-(1H-indol-6-yl)-5-methyl-1,2,4-triazin-3-amine;

[0167] N-[(3R)-1-ethyl-3-piperidinyl]-6-(3-fluoro-1H-indol-6-yl)-5-methyl-1,2,4-triazin-3-amine;

[0168] and pharmaceutically acceptable salts thereof.

[0169] 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

[0170]

[0171] One embodiment of the present invention provides a compound according to formula I as described herein, wherein

[0172] A3 is selected from N or CR 3 ;

[0173] A4 is selected from N or CR 4 ;

[0174] A5 is selected from N or CR 5 ;

[0175] Y is selected from N or CH;

[0176] R 1 is selected from alkyl, cyano or H;

[0177] R 2 is selected from alkyl, cyano, H or halo;

[0178] R 3 is H;

[0179] R 4 Selected from H, alkyl, alkoxy or halo;

[0180] R 5 Selected from H or halo;

[0181] R 6 is H;

[0182] R 7 is an alkyl group or a halogenated alkyl group;

[0183] W is optionally substituted cycloalkyl or 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;

[0184] and pharmaceutically acceptable salts thereof.

[0185] One embodiment of the present invention provides a compound according to formula I as described herein, wherein R 1 For H.

[0186] One embodiment of the present invention provides a compound according to formula I as described herein, wherein R 2 is H or halogenated.

[0187] One embodiment of the present invention provides a compound according to formula I as described herein, wherein A3 is CR 3 .

[0188] One embodiment of the present invention provides a compound according to formula I as described herein, wherein A4 is CR 4 .

[0189] One embodiment of the present invention provides a compound according to formula I as described herein, wherein A5 is CR 5 .

[0190] One embodiment of the present invention provides a compound according to formula I as described herein, wherein R 4 Selected from H or halo.

[0191] One embodiment of the present invention provides a compound according to formula I as described herein, wherein R 4 For H.

[0192] One embodiment of the present invention provides a compound according to formula I as described herein, wherein R 5 For H.

[0193] One embodiment of the present invention provides a compound according to formula I as described herein, wherein R 7 It is an alkyl group.

[0194] One embodiment of the present invention provides a compound according to formula I as described herein, wherein W is an alkyl substituted piperidine ring.

[0195] One embodiment of the present invention provides a compound according to formula I, wherein

[0196] A3 is CR 3 ;

[0197] A4 to CR 4 ;

[0198] A5 is CR 5 ;

[0199] Y is N or CH;

[0200] R 1 is alkyl, cyano or H;

[0201] R 2 is alkyl, cyano, H or halo;

[0202] R 3 is H;

[0203] R 4 is H or halogenated;

[0204] R 5 is H or halogenated;

[0205] R 6 is H;

[0206] R 7 is an alkyl group or a halogenated alkyl group;

[0207] W is a piperidine ring substituted with an alkyl group;

[0208] and pharmaceutically acceptable salts thereof.

[0209] One embodiment of the present invention provides a compound according to formula I, wherein

[0210] A3 is CR 3 ;

[0211] A4 to CR 4 ;

[0212] A5 is CR 5 ;

[0213] Y is N or CH;

[0214] R 1 is H;

[0215] R 2 is H or halogenated;

[0216] R 3 is H;

[0217] R 4 is H;

[0218] R 5 is H;

[0219] R 6 is H;

[0220] R 7 is an alkyl group or a halogenated alkyl group;

[0221] W is a piperidine ring substituted with an alkyl group;

[0222] and pharmaceutically acceptable salts thereof.

[0223] One embodiment of the present invention provides a compound according to formula I, wherein

[0224] A3 is CR 3 ;

[0225] A4 to CR 4 ;

[0226] A5 is CR 5 ;

[0227] Y is N or CH;

[0228] R 1 is H;

[0229] R 2 is H or halogenated;

[0230] R 3 is H;

[0231] R 4 is H;

[0232] R 5 is H;

[0233] R 6 is H;

[0234] R 7 is an alkyl group;

[0235] W is a piperidine ring substituted with an alkyl group;

[0236] and pharmaceutically acceptable salts thereof.

[0237] Particular examples of compounds of formula I as described herein are selected from

[0238] N-[(3R)-1-ethyl-3-piperidinyl]-6-(1H-indol-6-yl)-5-methyl-pyridazin-3-amine;

[0239] N-[(3R)-1-ethyl-3-piperidinyl]-6-(3-fluoro-1H-indol-6-yl)-5-methyl-pyridazin-3-amine;

[0240] N-[(3R)-1-ethyl-3-piperidinyl]-6-(5-fluoro-1H-indol-6-yl)-5-methyl-pyridazin-3-amine;

[0241] N-[(3R)-1-ethyl-3-piperidinyl]-5-methyl-6-(3-methyl-1H-indol-6-yl)pyridazin-3-amine;

[0242] 6-(3-Chloro-1H-indol-6-yl)-N-[(3R)-1-ethyl-3-piperidinyl]-5-methyl-pyridazin-3-amine;

[0243] N-[(3R)-1-ethyl-3-piperidinyl]-5-methyl-6-(2-methyl-1H-indol-6-yl)pyridazin-3-amine;

[0244] 6-[6-[[(3R)-1-ethyl-3-piperidinyl]amino]-4-methyl-pyridazin-3-yl]-1H-indole-3-carbonitrile;

[0245] 6-[6-[[(3R)-1-ethyl-3-piperidinyl]amino]-4-methyl-pyridazin-3-yl]-1H-indole-2-carbonitrile;

[0246] 6-(3-Fluoro-1H-indol-6-yl)-5-methyl-N-[(3R)-1-methyl-3-piperidinyl]pyridazin-3-amine;

[0247] N-[(3R)-1-ethyl-3-piperidinyl]-6-(1H-indol-6-yl)-5-methyl-pyridazin-3-amine;

[0248] N-[(3R)-1-ethyl-3-piperidinyl]-6-(3-fluoro-1H-indol-6-yl)-5-(trifluoromethyl)pyridazin-3-amine;

[0249] 5-ethyl-N-[(3R)-1-ethyl-3-piperidinyl]-6-(3-fluoro-1H-indol-6-yl)pyridazin-3-amine;

[0250] N-[(3R)-1-ethyl-3-piperidinyl]-6-(1H-indol-6-yl)-5-methyl-1,2,4-triazin-3-amine;

[0251] N-[(3R)-1-ethyl-3-piperidinyl]-6-(3-fluoro-1H-indol-6-yl)-5-methyl-1,2,4-triazin-3-amine;

[0252] and pharmaceutically acceptable salts thereof.

[0253] Other specific examples of Formula I as described herein are selected from

[0254] N-[(3R)-1-ethyl-3-piperidinyl]-6-(5-methyl-1H-indol-6-yl)pyridazin-3-amine;

[0255] 3-[[6-(3-Fluoro-1H-indol-6-yl)-5-methyl-pyridazin-3-yl]amino]-1-methyl-cyclobutanol; and pharmaceutically acceptable salts thereof.

[0256] Preferred examples of compounds of formula I as described herein are selected from

[0257] N-[(3R)-1-ethyl-3-piperidinyl]-6-(1H-indol-6-yl)-5-methyl-pyridazin-3-amine;

[0258] N-[(3R)-1-ethyl-3-piperidinyl]-6-(3-fluoro-1H-indol-6-yl)-5-methyl-pyridazin-3-amine;

[0259] 6-(3-Fluoro-1H-indol-6-yl)-5-methyl-N-[(3R)-1-methyl-3-piperidinyl]pyridazin-3-amine;

[0260] N-[(3R)-1-ethyl-3-piperidinyl]-6-(3-fluoro-1H-indol-6-yl)-5-(trifluoromethyl)pyridazin-3-amine;

[0261] N-[(3R)-1-ethyl-3-piperidinyl]-6-(1H-indol-6-yl)-5-methyl-1,2,4-triazin-3-amine;

[0262] N-[(3R)-1-ethyl-3-piperidinyl]-6-(3-fluoro-1H-indol-6-yl)-5-methyl-1,2,4-triazin-3-amine;

[0263] and pharmaceutically acceptable salts thereof.

[0264] Most preferred examples of compounds of formula I as described herein are selected from

[0265] N-[(3R)-1-ethyl-3-piperidinyl]-6-(3-fluoro-1H-indol-6-yl)-5-methyl-pyridazin-3-amine;

[0266] N-[(3R)-1-ethyl-3-piperidinyl]-6-(1H-indol-6-yl)-5-methyl-1,2,4-triazin-3-amine;

[0267] N-[(3R)-1-ethyl-3-piperidinyl]-6-(3-fluoro-1H-indol-6-yl)-5-methyl-1,2,4-triazin-3-amine;

[0268] and pharmaceutically acceptable salts thereof.

[0269] One embodiment of the present invention provides a compound according to formula Ic, wherein the compound of formula Ic is a compound of formula Ib

[0270]

[0271] One embodiment of the present invention provides a compound according to formula Ic as described herein, wherein

[0272] A3 is selected from N or CR 3 ;

[0273] A4 is selected from N or CR 4 ;

[0274] A5 is selected from N or CR 5 ;

[0275] R 1 is selected from alkyl, cyano or H;

[0276] R 2 is selected from alkyl, cyano, H or halo;

[0277] R 3 is H;

[0278] R 4 Selected from H, alkyl, alkoxy or halo;

[0279] R 5 Selected from H or halo;

[0280] R 6 is H;

[0281] R 8 is H or alkyl;

[0282] W is optionally substituted cycloalkyl or 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;

[0283] and pharmaceutically acceptable salts thereof.

[0284] One embodiment of the present invention provides a compound according to formula Ic as described herein, wherein R 1 For H.

[0285] One embodiment of the present invention provides a compound according to formula Ic as described herein, wherein R 2 For H.

[0286] One embodiment of the present invention provides a compound according to formula Ic as described herein, wherein A3 is CR 3 .

[0287] One embodiment of the present invention provides a compound according to formula Ic as described herein, wherein A4 is CR 4 .

[0288] One embodiment of the present invention provides a compound according to formula Ic as described herein, wherein A5 is CR 5 .

[0289] One embodiment of the present invention provides a compound according to formula Ic as described herein, wherein R 4 For H.

[0290] One embodiment of the present invention provides a compound according to formula Ic as described herein, wherein R 5 For H.

[0291] One embodiment of the present invention provides a compound according to formula Ic as described herein, wherein R 8 It is an alkyl group.

[0292] One embodiment of the present invention provides a compound according to formula Ic as described herein, wherein W is an alkyl substituted piperidine ring.

[0293] One embodiment of the present invention provides a compound according to formula Ic, wherein

[0294] A3 is CR 3 ;

[0295] A4 to CR 4 ;

[0296] A5 is CR 5 ;

[0297] R 1is H;

[0298] R 2 is H;

[0299] R 3 is H;

[0300] R 4 is H;

[0301] R 5 is H;

[0302] R 6 is H;

[0303] R 8 is alkyl or H;

[0304] W is a piperidine ring substituted with an alkyl group;

[0305] and pharmaceutically acceptable salts thereof.

[0306] One embodiment of the present invention provides a compound according to formula Ic, wherein

[0307] A3 is CR 3 ;

[0308] A4 to CR 4 ;

[0309] A5 is CR 5 ;

[0310] R 1 is H;

[0311] R 2 is H;

[0312] R 3 is H;

[0313] R 4 is H;

[0314] R 5 is H;

[0315] R 6 is H;

[0316] R 8 is an alkyl group;

[0317] W is a piperidine ring substituted with an alkyl group;

[0318] and pharmaceutically acceptable salts thereof.

[0319] Particular examples of compounds of formula Ib as described herein are N-[(3R)-1-ethyl-3-piperidinyl]-7-(1H-indol-6-yl)-1-methyl-pyrazolo[3,4-d]pyridazin-4-amine and pharmaceutically acceptable salts thereof.

[0320] Particular examples of compounds of formula Ic as described herein are N-[(3R)-1-ethyl-3-piperidinyl]-7-(1H-indol-6-yl)-1-methyl-pyrazolo[3,4-d]pyridazin-4-amine and pharmaceutically acceptable salts thereof.

[0321] Another embodiment of the present invention provides a pharmaceutical composition or medicine containing the compounds of this invention and a therapeutic inert carrier, diluent or excipient, and methods for preparing such compositions and medicines using the compounds of this invention. In one example, the compound of formula Ib can be formulated as a galenical administration form by mixing with a physiologically acceptable carrier (i.e., a carrier that is nontoxic to the recipient at the dose and concentration used) at ambient temperature, at an appropriate pH, and at a desired purity. The pH of the preparation depends primarily on the specific use and concentration of the compound, but is preferably in the range of about 3 to about 8. In one example, the compound of formula Ib is formulated in acetate buffer at pH 5. In another embodiment, the compound of formula Ib is sterile. The compound can be stored, for example, as a solid or amorphous composition, as a lyophilized preparation, or as an aqueous solution.

[0322] The compositions are formulated, dosed, and administered in a manner consistent with good medical practice. Factors to be considered in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the timing of administration, and other factors known to practitioners.

[0323] 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, intrapulmonary, intradermal, intrathecal and epidural and intranasal, and (if necessary for local treatment) intralesional administration. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal or subcutaneous administration.

[0324] The compounds of the present invention can be administered in any convenient administration form, for example, tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain conventional components of pharmaceutical preparations, for example, diluents, carriers, pH adjusters, sweeteners, fillers and other active agents.

[0325] The usual formulations are prepared by mixing the compounds of the invention with carriers or excipients. Suitable carriers and excipients are well known to those skilled in the art and are described in, for example, Ansel, Howard C. et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams and Wilkins, 2004; Gennaro, Alfonso R. et al., Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams and Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. The formulation may also contain one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, sweeteners, flavoring agents, flavoring agents, diluents and other known additives to provide an aesthetically pleasing display of the drug (e.g., a compound of the present invention or a pharmaceutical composition thereof) or to facilitate the preparation of a pharmaceutical product (e.g., a drug).

[0326] The compound of formula Ib and its pharmaceutically acceptable salt can be processed with pharmaceutically inert inorganic or organic adjuvants for the production of tablets, coated tablets, dragees, hard gelatin capsules, injections or topical preparations. For example, lactose, corn starch or its derivatives, talcum powder, stearic acid or its salts, etc. can be used as such adjuvants for tablets, dragees and hard gelatin capsules.

[0327] Suitable adjuvants for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semisolid substances and liquid polyols and the like.

[0328] Suitable adjuvants for the preparation of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose and the like.

[0329] Suitable adjuvants for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils and the like.

[0330] Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols and the like.

[0331] Suitable adjuvants for topical ophthalmic preparations are, for example, cyclodextrins, mannitol or numerous other carriers and excipients known in the art.

[0332] In addition, the pharmaceutical preparations may contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorings, salts for varying the osmotic pressure, buffer masking agents or antioxidants. They may also contain other therapeutically valuable substances.

[0333] Dosage can vary over a wide range, and will certainly be suitable for various requirements in each particular case. Generally speaking, in the case of oral administration, a daily dose of about 0.1 mg to 20 mg per kg body weight, preferably about 0.5 mg to 4 mg per kg body weight (e.g., about 300 mg per person) should be suitable, and it is preferably divided into 1 to 3 separate doses (which may be composed of, for example, the same amount). In the case of topical administration, the formulation may include 0.001% to 15% of the drug by weight, and the desired dose may be 0.1 mg to 25 mg, a single application every day or every week, or multiple applications every day (2 to 4 times), or multiple applications every week. However, it is apparent that, when shown as applicable, the upper or lower limits given herein may be exceeded.

[0334] One embodiment of the present invention is a compound according to formula Ib as described herein for use as therapeutically active substance.

[0335] One embodiment of the present invention is a compound according to formula Ib as described herein for use in treating or preventing a disease, disorder or condition, wherein the disease, disorder or condition is responsive to NLRP3 inhibition.

[0336] One embodiment of the present invention is a compound according to formula Ib as described herein for use in treating or preventing a disease, disorder or condition, wherein the disease or condition is responsive to NLRP3 inhibition.

[0337] 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 activation of NLRP3.

[0338] There is evidence that NLRP3-induced IL-1 and IL-18 play a role in inflammatory responses associated with or due to a variety of different diseases (Menu et al., Clinical and Experimental Immunology, 166:1-15, 2011; Strowig et al., Nature, 481:278-286, 2012).

[0339] In one embodiment, the disease, disorder or condition is selected from:

[0340] (i) Inflammation;

[0341] (ii) Autoimmune diseases;

[0342] (iii) cancer;

[0343] (iv) infection;

[0344] (v) central nervous system diseases;

[0345] (vi) metabolic diseases;

[0346] (vii) cardiovascular disease;

[0347] (viii) respiratory diseases;

[0348] (ix) liver disease;

[0349] (x) Kidney disease;

[0350] (xi) eye diseases;

[0351] (xii) skin diseases;

[0352] (xiii) lymphatic disorders;

[0353] (xiv) mental disorders;

[0354] (xv) graft-versus-host disease;

[0355] (xvi) allodynia;

[0356] (xvii) conditions associated with diabetes; and

[0357] (xviii) any disease in which the individual has been identified as carrying a germline or somatic non-silent mutation in NLRP3.

[0358] In another embodiment, the disease, disorder or condition is selected from:

[0359] (i) Cancer;

[0360] (ii) infection;

[0361] (iii) central nervous system diseases;

[0362] (iv) cardiovascular disease;

[0363] (v) liver disease;

[0364] (vi) eye disease; or

[0365] (vii) Skin diseases.

[0366] In another typical embodiment of the present invention, the disease, illness or condition is inflammation. Examples of inflammation that can be treated or prevented include inflammatory reactions associated with or occurring due to:

[0367] (i) skin disorders 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;

[0369] (ii) joint disorders 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

[0370] sick);

[0371] (iii) muscle disorders, such as polymyositis or myasthenia gravis;

[0372] (iv) gastrointestinal disorders such as inflammatory bowel disease (including Crohn's disease and ulcerative colitis), colitis, gastric ulcers, celiac disease, proctitis, pancreatitis, eosinophilic gastroenteritis, mastocytosis, antiphospholipid syndrome, or food-related allergies that may have effects distal to the intestine (e.g., migraines, rhinitis, or eczema);

[0373] (v) respiratory disorders, such as chronic obstructive pulmonary disease (COPD), asthma (including eosinophilic asthma, bronchial asthma, allergic asthma, intrinsic asthma, exogenous asthma or dust asthma, and in particular chronic or refractory asthma, such as delayed asthma and airway hyperresponsiveness), bronchitis, rhinitis (including acute rhinitis, allergic rhinitis, atrophic rhinitis, chronic rhinitis, caseous rhinitis, hypertrophic rhinitis, pustular rhinitis, dry rhinitis, drug-induced rhinitis, membranous rhinitis, seasonal rhinitis such as hay fever and vasomotor rhinitis), sinusitis, idiopathic pulmonary fibrosis (IPF), sarcoidosis, farmer's lung, silicosis, asbestosis, inflammation caused by volcanic ash, adult respiratory distress syndrome, hypersensitivity pneumonitis or idiopathic rhinitis.

[0374] interstitial pneumonia;

[0375] (vi) vascular disorders such as atherosclerosis, Behcet's disease, vasculitis or Wegener's granulomatosis;

[0376] (vii) autoimmune disorders such as systemic lupus erythematosus, Sjögren's syndrome, systemic sclerosis, Hashimoto's thyroiditis, type I diabetes mellitus, idiopathic thrombocytopenic purpura, or Graves' disease;

[0377] (viii) ocular disorders such as uveitis, allergic conjunctivitis or vernal conjunctivitis;

[0378] (ix) neurological disorders, such as multiple sclerosis or encephalomyelitis;

[0379] (x) infection or infection-related condition, such as acquired immunodeficiency syndrome (AIDS), acute or chronic bacterial infection, acute or chronic parasitic infection, acute or chronic viral infection, acute or chronic fungal infection, meningitis, hepatitis (A, B or C, or other viral hepatitis), peritonitis, pneumonia, epiglottitis, malaria, dengue hemorrhagic fever, leishmaniasis, streptococcal myositis, Mycobacterium tuberculosis (including Mycobacterium tuberculosis and HIV co-infection), 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;

[0380] (xi) renal disorders 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;

[0381] (xii) lymphatic system disorders such as Castleman's disease;

[0382] (xiii) immune system disorders or disorders involving the immune system, such as hyper-IgE syndrome, lepromatous leprosy, familial hemophagocytic lymphohistiocytosis, or graft-versus-host disease;

[0383] (xiv) liver disorders such as chronic active hepatitis, nonalcoholic steatohepatitis (NASH), alcoholic hepatitis, nonalcoholic fatty liver disease (NAFLD), alcoholic fatty liver disease (AFLD), alcoholic steatohepatitis (ASH), primary biliary cirrhosis, fulminant hepatitis, liver fibrosis or liver failure;

[0384] (xv) cancer, including those listed above;

[0385] (xvi) burns, wounds, trauma, hemorrhage or stroke;

[0386] (xvii) radiation exposure;

[0387] (xviii) metabolic diseases, such as type 2 diabetes (T2D), atherosclerosis, obesity, gout or pseudogout; and / or

[0388] (xix) Pain, such as inflammatory hyperalgesia, pelvic pain, allodynia, neuropathic pain or bone pain caused by cancer.

[0389] One embodiment of the present invention is the use of a compound according to formula Ib as described herein in the treatment or prevention of a disease, disorder or condition selected from Alzheimer's disease and Parkinson's disease.

[0390] One embodiment of the present invention is the use of a compound according to formula Ib as described herein in the treatment or prevention of a disease, disorder or condition selected from asthma or COPD.

[0391] One embodiment of the present invention is the use of a compound according to formula Ib as described herein for use in the treatment or prevention of a disease, disorder or condition selected from inflammatory bowel disease including Crohn's disease and ulcerative colitis.

[0392] One embodiment of the present invention is a compound according to formula Ib as described herein for use in the treatment or prevention of a disease, disorder or condition selected from Alzheimer's disease and Parkinson's disease.

[0393] One embodiment of the present invention is a compound according to formula Ib as described herein for use in treating or preventing a disease, disorder or condition selected from asthma or COPD.

[0394] One embodiment of the present invention is a compound according to formula Ib as described herein for use in the treatment or prevention of a disease, disorder or condition selected from inflammatory bowel disease including Crohn's disease and ulcerative colitis.

[0395] One embodiment of the present invention is the use of a compound according to 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.

[0396] One embodiment of the present invention is the use of a compound according to 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.

[0397] One embodiment of the present invention is the use of a compound according to 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 disease (including Crohn's disease and ulcerative colitis).

[0398] One embodiment of the present invention is a method of treating or preventing a disease, disorder or condition selected from Alzheimer's disease and Parkinson's disease, the method comprising administering an effective amount of a compound according to formula Ib as described herein.

[0399] One embodiment of the present invention is a method of treating or preventing a disease, disorder or condition selected from asthma or COPD, the method comprising administering an effective amount of a compound according to formula Ib as described herein.

[0400] One embodiment of the present invention is a method of treating or preventing a disease, disorder or condition selected from inflammatory bowel disease (including Crohn's disease and ulcerative colitis), the method comprising administering an effective amount of a compound according to formula Ib as described herein.

[0401] One embodiment of the present invention relates to a method of inhibiting NLRP3, the method comprising administering an effective amount of a compound according to formula Ib as described herein.

[0402] Yet another embodiment of the present invention is a compound of formula Ib as described herein when manufactured according to any of the methods described.

[0403] One embodiment of the present invention is a pharmaceutical composition comprising a compound according to formula Ib as described herein and a therapeutically inert carrier.

[0404] One embodiment of the present invention is a compound according to formula Ib as described herein for use in treating or preventing a disease, disorder or condition selected from:

[0405] (i) Inflammation;

[0406] (ii) Autoimmune diseases;

[0407] (iii) cancer;

[0408] (iv) infection;

[0409] (v) central nervous system diseases;

[0410] (vi) metabolic diseases;

[0411] (vii) cardiovascular disease;

[0412] (viii) respiratory diseases;

[0413] (ix) liver disease;

[0414] (x) Kidney disease;

[0415] (xi) eye diseases;

[0416] (xii) skin diseases;

[0417] (xiii) lymphatic disorders;

[0418] (xiv) mental disorders;

[0419] (xv) graft-versus-host disease;

[0420] (xvi) allodynia;

[0421] (xvii) conditions associated with diabetes; and

[0422] (xviii) any disease in which the individual has been identified as carrying a germline or somatic non-silent mutation in NLRP3.

[0423] Determination procedure

[0424] NLRP3 and pyroptosis

[0425] It is well recognized that activation of NLRP3 leads to pyroptosis and 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; Xie Zhen & Zhao Gang, Neuroimmunology Neuroinflammation, 2014, 1(2), 60-65; Mattia Cocco et al., Journal of Medicinal Chemistry, 2014, 57(24), 10366-10382; T. Satoh et al., Cell Death & Disease, 2013, 4, e644). Therefore, inhibitors of NLRP3 are expected to prevent pyroptosis and the release of proinflammatory cytokines (such as IL-1β) from cells.

[0426] THP-1 cells: culture and preparation

[0427] THP-1 cells (ATCC #TIB-202) were grown in RPMI containing L-glutamine (Gibco #11835), supplemented with 1 mM sodium pyruvate (Sigma #S8636) in 10% fetal bovine serum (FBS) (Sigma #F0804) and penicillin (100 units / ml) / streptomycin (0.1 mg / ml) (Sigma #P4333). Cells were routinely passaged and grown to confluence (approximately 10 6Cells / ml). On the day of the experiment, THP-1 cells were harvested and resuspended in RPMI medium (without FBS). The cells were then counted and checked for viability (>90%) by trypan blue (Sigma #T8154). Appropriate dilutions were made to obtain a concentration of 625,000 cells / ml. LPS (Sigma #L4524) was added to the diluted cell solution to obtain a final assay concentration (FAC) of 1 μg / ml. 40 μl of the final preparation was aliquoted into each well of a 96-well plate. The plates thus prepared were used for compound screening.

[0428] THP-1 cell pyroptosis assay

[0429] The following method was followed to perform a step-by-step assay for compound screening.

[0430] 1. Seed THP-1 cells (25,000 cells / well) containing 1.0 μg / ml LPS in 40 μl RPMI medium (without FBS) in a 96-well, black-walled, clear-bottom cell culture plate coated with poly-D-lysine (VWR#734-0317).

[0431] 2. Add 5 μl of compound (8-point half-log dilution, highest dose is 10 μM) or vehicle (DMSO 0.1% FAC) to appropriate wells

[0432] 3. Incubate at 37°C, 5% CO2 for 3 hours

[0433] 4. Add 5 μl of nigericin (Sigma #N7143) (FAC 5 μM) to all wells

[0434] 5. Incubate at 37°C, 5% CO2 for 1 hour

[0435] 6. At the end of the incubation period, spin the plate at 300 x g for 3 min and remove the supernatant.

[0436] 7. Then add 50 μl of Resazurin (Sigma #R7017) (FAC 100 μM Resazurin in RPMI medium without FBS) and incubate the plate for another 1-2 hours at 37°C and 5% CO2

[0437] 8. Read the plate in the Envision reader at Ex 560nm and Em 590nm

[0438] 9.IC 50 Data were fitted to a nonlinear regression equation (log inhibitor vs. response variable slope 4 parameters)

[0439] Results of pyroptosis assay as THP IC 50This is summarized in Table 1 below.

[0440] Human whole blood IL-1β release assay

[0441] For systemic delivery, the ability of the compound to inhibit NLRP3 when present in the bloodstream is very important. To this end, the NLRP3 inhibitory activity of various compounds in human whole blood was investigated according to the following protocol.

[0442] Human whole blood in lithium heparin tubes was obtained from healthy donors from a volunteer donor panel.

[0443] 1. Deposit 80 μl of whole blood containing 1 μg / ml LPS in a 96-well clear bottom cell culture plate (Corning #3585).

[0444] 2. Add 10 μl of compound (8-point half-log dilution, highest dose is 10 μM) or vehicle (DMSO 0.1% FAC) to appropriate wells

[0445] 3. Incubate at 37°C, 5% CO2 for 3 hours

[0446] 4. Add 10 μl of nigericin (Sigma #N7143) (10 μM FAC) to all wells

[0447] 5. Incubate at 37°C, 5% CO2 for 1 hour

[0448] 6. At the end of the incubation period, spin the plate at 300 x g for 5 min to pellet the cells and remove 20 μl of supernatant and add to 96-well v-bottom plates for IL-1β analysis (Note: these plates containing supernatant can be stored at -80°C for analysis at a later time)

[0449] 7. IL-1β was measured according to the manufacturer's protocol (Perkin Elmer-AlphaLisa IL-1Kit AL220F-5000)

[0450] 8.IC 50 Data were fitted to a nonlinear regression equation (log inhibitor vs. response variable slope 4 parameters)

[0451] The results of human whole blood assay are used as HWB IC 50 This is summarized in Table 1 below.

[0452] Table 1: NLRP3 inhibitory activity

[0453]

[0454]

[0455] The invention will now be illustrated by the following examples, which are not limiting.

[0456] If preparations are obtained as mixtures of enantiomers, the pure enantiomers may be obtained by methods described herein or by methods known to those skilled in the art such as, for example, chiral chromatography or crystallization.

[0457] Examples

[0458] If not stated otherwise, all examples and intermediates were prepared under nitrogen atmosphere.

[0459] abbreviation

[0460]

[0461]

[0462] Example 1: N-[(3R)-1-ethyl-3-piperidinyl]-6-(1H-indol-6-yl)-5-methyl-pyridazin-3-amine

[0463]

[0464] Step A: (3R)-3-[(6-chloro-5-methyl-pyridazin-3-yl)amino]piperidine-1-carboxylic acid tert-butyl ester

[0465] To a suspension of 3,6-dichloro-4-methyl-pyridazine (CAS#19064-64-3, 1.60 g, 9.82 mmol, 1.00 eq) and (3R)-3-aminopiperidine-1-carboxylic acid tert-butyl ester (CAS#188111-79-7, 3.93 g, 19.6 mmol, 2.00 eq) was added DIPEA (3.26 g, 4.4 mL, 25.2 mmol, 2.57 eq). The reaction mixture was stirred at 120 ° C for 72 hours. 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 water layer was stripped with dichloromethane. The combined organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was adsorbed on ISOLUTE HM-N and purified by flash chromatography (silica gel, 120 g, gradient 0% to 5% methanol in dichloromethane) to give the title compound (1.77 g, 52% yield) as a light yellow oil. LCMS: m / z 327.2 [M+H] + ,ESI pos.

[0466] Step B: 6-Chloro-5-methyl-N-[(3R)-3-piperidinyl]pyridazin-3-amine hydrochloride

[0467] To a solution of (3R)-3-[(6-chloro-5-methyl-pyridazin-3-yl)amino]piperidine-1-carboxylic acid tert-butyl ester (Example 1, Step A) (1.65 g, 4.79 mmol, 1.00 eq) in dichloromethane (12 mL) and methanol (6.0 mL) was added dropwise a solution of 4M HCl in dioxane (12 mL, 48.0 mmol, 10.0 eq). The reaction mixture was stirred at room temperature for 16 hours. 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 pos.

[0468] Step C: 6-Chloro-N-[(3R)-1-ethyl-3-piperidinyl]-5-methyl-pyridazin-3-amine

[0469] To a suspension of 6-chloro-5-methyl-N-[(3R)-3-piperidinyl]pyridazine-3-amine hydrochloride (Example 1, Step B) (1.32 g, 4.51 mmol, 1.00 eq, purity 90%) in dichloromethane (20 mL) was added acetaldehyde (405.7 mg, 0.460 mL, 9.21 mmol, 2.04 eq), followed by sodium acetate (741 mg, 9.03 mmol, 2.00 eq) under ice bath cooling. Sodium triacetoxyborohydride (1.44 g, 6.77 mmol, 1.50 eq) 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 NaHCO aqueous solution 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 on ISOLUTE HM-N and purified by flash chromatography (silica gel, 40 g, gradient 0% to 10% methanol in dichloromethane) to give the title compound (901 mg, 74% yield) as a yellow oil. LCMS: m / z 255.2 [M+H] + ,ESI pos.

[0470] Step D: N-[(3R)-1-ethyl-3-piperidinyl]-6-(1H-indol-6-yl)-5-methyl-pyridazin-3-amine

[0471] A mixture of 6-chloro-N-[(3R)-1-ethyl-3-piperidinyl]-5-methyl-pyridazin-3-amine (Example 1, Step C) (80 mg, 0.30 mmol, 1.00 eq), 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (CAS#642494-36-8, 130 mg, 0.51 mmol, 1.70 eq), potassium carbonate (195 mg, 1.41 mmol, 4.73 eq) and 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(ii) dichloromethane complex (28 mg, 0.03 mmol, 0.11 eq) in 1,4-dioxane (2.0 mL) and water (1.0 mL) was 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 is back extracted with ethyl acetate. The organic layer is washed twice with water and once with brine. The combined organic layer is dried over sodium sulfate, filtered and concentrated in vacuo. The crude product is adsorbed on ISOLUTE HM-N and purified by flash chromatography (silica gel, 12g, gradient 0% to 100% (dichloromethane: methanol: NH4OH 9:1:0.05) in dichloromethane). The residue is adsorbed on ISOLUTE HM-N and purified again by flash chromatography (silica gel, 12g, gradient 0% to 20% methanol in dichloromethane). All fractions containing the product are combined and concentrated in vacuo to obtain the title compound (61mg, yield 58%), which is a light brown foam. LCMS: m / z 336.3[M+H] + ,ESIpos.

[0472] Example 2: N-[(3R)-1-ethyl-3-piperidinyl]-6-(3-fluoro-1H-indol-6-yl)-5-methyl-pyridazin-3-amine

[0473]

[0474] Step A: 3-Fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole

[0475] To a solution of commercially available 6-bromo-3-fluoro-1H-indole (CAS#2568045-20-3, 296 mg, 1.31 mmol, 1.00 eq) and bis(pinacol)diboron (400 mg, 1.58 mmol, 1.20 eq) in 1,4-dioxane (3.1 mL) was added potassium acetate (387 mg, 3.94 mmol, 3.00 eq) followed by 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex (109 mg, 0.13 mmol, 0.10 eq). The reaction mixture was flushed with argon and stirred at 90 °C for 16 hours. The reaction mixture was then cooled to room temperature, adsorbed on ISOLUTE HM-N, and purified by flash chromatography (silica gel, 25 g, 0% to 10% ethyl acetate in heptane) to give the title compound (224 mg, 62% yield) as a dark brown solid. LCMS: m / z 262.1 [M+H] + ,ESI pos.

[0476] Step B: N-[(3R)-1-ethyl-3-piperidinyl]-6-(3-fluoro-1H-indol-6-yl)-5-methyl-pyridazin-3-amine

[0477] A mixture of the above 6-chloro-N-[(3R)-1-ethyl-3-piperidinyl]-5-methyl-pyridazin-3-amine (Example 1, Step C) (75 mg, 0.28 mmol, 1.00 eq), 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 eq), potassium carbonate (180 mg, 1.30 mmol, 4.66 eq) and 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(ii) dichloromethane complex (28 mg, 0.03 mmol, 0.12 eq) in 1,4-dioxane (1.8 mL) and water (0.90 mL) was 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 on ISOLUTE HM-N and purified by flash chromatography (silica gel, 12g, gradient 0% to 100% (dichloromethane: methanol: NH4OH 9: 1: 0.05) in dichloromethane). All fractions containing the product were combined and concentrated in vacuo to obtain the title compound (77mg, 74% yield), which was a brown foam. LCMS: m / z 354.2[M+H] + ,ESI pos.

[0478] Example 3:N-[(3R)-1-ethyl-3-piperidinyl]-6-(5-fluoro-1H-indol-6-yl)-5-methyl-pyridazin-3-amine

[0479]

[0480] Step A: 5-Fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole

[0481] 6-Bromo-5-fluoro-1H-indole (500 mg, 2.34 mmol, 1.0 eq), potassium 2-ethylhexanoate (937 mg, 5.14 mmol, 2.2 eq), palladium acetate (10.7 mg, 0.05 mmol, 0.02 eq) and Xphos (44.5 mg, 0.09 mmol, 0.04 eq) 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 using 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 pos.

[0482] Step B: N-[(3R)-1-ethyl-3-piperidinyl]-6-(5-fluoro-1H-indol-6-yl)-5-methyl-pyridazin-3-amine

[0483] 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 eq), the above 6-chloro-N-[(3R)-1-ethyl-3-piperidinyl]-5-methyl-pyridazin-3-amine (Example 1, Step C) (50.0 mg, 0.20 mmol, 1.0 eq), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(ii) (14.3 mg, 0.02 mmol, 0.10 eq) and cesium carbonate (191 mg, 0.59 mmol, 3.0 eq) in 1,4-dioxane (2.1 mL) and water (1.0 mL) was purged with argon and stirred at 90° C. After 5 hours, the reaction mixture was cooled to room temperature and extracted with ethyl acetate and washed with water and brine. The combined organic phases were dried over sodium sulfate, filtered, and the solvent was removed under reduced pressure. The crude product was purified by preparative HPLC (column: YMC-Triart C 18 , 12 nm, 5 μm, 100 x 30 mm, MeCN / water + 0.1% TEA, gradient 20%-80% MeCN) to obtain the title compound (18 mg, yield 23%). LC-MS: m / z = 354.2 [M+H] + ,ESI pos.

[0484] Example 4:N-[(3R)-1-ethyl-3-piperidinyl]-5-methyl-6-(3-methyl-1H-indol-6-yl)pyridazin-3-amine

[0485]

[0486] To a 2 mL microwave vial was added a solution of 6-chloro-N-[(3R)-1-ethyl-3-piperidinyl]-5-methyl-pyridazin-3-amine (Example 1, Step C) described above (50 mg, 0.196 mmol, 1.00 eq), commercially available 3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (CAS #1300582-52-8, 60.6 mg, 0.236 mmol, 1.200 eq), 1,1'-bis(diphenylphosphino)ferrocene-palladium(ii) chloride dichloromethane complex (8.01 mg, 0.010 mmol, 0.050 eq) and potassium carbonate (2.25 M in water) (260 μL, 0.585 mmol, 2.98 eq) in methanol (1.7 mL). The reaction mixture was purged with argon and ultrasonically treated for 5 min. The vial was capped and heated in a microwave oven at 80 ° C for 2 h. The reaction progress was monitored by LCMS and a conversion rate of 54% was shown. The reaction mixture was diluted with MeOH and filtered using a syringe filter to produce a red solution, which was purified by preparative HPLC (Gemini NX, ACN / water (Et3N), alkaline mode) to obtain the title compound (21.7 mg, yield 31%), which was a white lyophilized powder. LCMS: m / z=350.3[M+H] + ESI pos.

[0487] Example 5 :6-(3-Chloro-1H-indol-6-yl)-N-[(3R)-1-ethyl-3-piperidinyl]-5-methyl-pyridazin-3-amine

[0488]

[0489] To a 2 mL microwave vial was added a solution of 6-chloro-N-[(3R)-1-ethyl-3-piperidinyl]-5-methyl-pyridazin-3-amine (Example 1, Step C) (50 mg, 0.196 mmol, 1.000 eq), commercially available 3-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (CAS #2304635-36-5, 70.8 mg, 0.255 mmol, 1.30 eq), 1,1'-bis(diphenylphosphino)ferrocene-palladium(ii) chloride dichloromethane complex (16.0 mg, 0.020 mmol, 0.10 eq) and potassium carbonate (2.25 M in water) (436.1 μL, 0.981 mmol, 5.0 eq) in 1,4-dioxane (1.78 mL). The reaction mixture was purged with argon and ultrasonically treated for 5 min. The vial was capped and heated at 90 ° C in a microwave oven for 2 h. The reaction progress was monitored by LCMS and the reaction was shown to be complete. The reaction mixture was filtered using a syringe filter and the solvent was evaporated in a centrifuge. The crude product was purified by preparative HPLC (Gemini NX, ACN / water (Et3N), alkaline mode) to obtain the title compound (13.1 mg, yield 18%), which was a white lyophilized powder. LCMS: m / z=368.3[MH] - ,ESI neg.

[0490] Example 6 :N-[(3R)-1-ethyl-3-piperidinyl]-5-methyl-6-(2-methyl-1H-indol-6-yl)pyridazin-3-amine

[0491]

[0492] To a 5 mL microwave vial was added a solution of 6-chloro-N-[(3R)-1-ethyl-3-piperidinyl]-5-methyl-pyridazin-3-amine (Example 1, Step C) (50 mg, 0.196 mmol, 1.000 eq), commercially available 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (CAS #1650548-44-9, 60.56 mg, 0.236 mmol, 1.20 eq), 1,1'-bis(diphenylphosphino)ferrocene-palladium(ii) chloride dichloromethane complex (16.0 mg, 0.020 mmol, 0.100 eq) and potassium carbonate (2.25 M in water) (261.7 μL, 0.589 mmol, 3.000 eq) in methanol (3 mL). The reaction mixture was purged with argon and ultrasonicated for 3 min. The vial was capped and heated at 80 ° C in a microwave oven for 4 h. The reaction progress was monitored by LCMS and showed a conversion of 71%. The reaction mixture was filtered using a syringe filter and the solvent was evaporated in a centrifuge. The crude product was purified by preparative HPLC (YMC Triart, ACN / water (HCOOH), acidic mode) to obtain the title compound (7.0 mg, yield 10%), which was a light brown solid. LCMS: m / z=350.2[M+H] + ,ESI pos.

[0493] Example 7 :6-[6-[[(3R)-1-ethyl-3-piperidinyl]amino]-4-methyl-pyridazin-3-yl]-1H-indole-3-carbonitrile

[0494]

[0495] Step A: (3R)-3-[(6-Bromo-5-methyl-pyridazin-3-yl)amino]piperidine-1-carboxylic acid tert-butyl ester

[0496] In a sealed tube, a mixture of commercially available 3-bromo-6-chloro-4-methyl-pyridazine (CAS#89283-90-9, 3.0 g, 14.5 mmol, 1.0 eq), DIPEA (4.67 g, 6.31 mL, 36.2 mmol, 2.5 eq) and (3R)-3-aminopiperidine-1-carboxylic acid tert-butyl ester (CAS#188111-79-7, 5.79 g, 5.57 mL, 28.9 mmol, 20. eq) was stirred at 120 ° C for 18 h. The reaction mixture was cooled to room temperature and extracted with EtOAc and water. The aqueous layer was stripped 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 on ISOLUTE HM-N and purified by flash chromatography (silica gel, 140 g, gradient: 0% to 2% methanol in dichloromethane). All fractions containing product were combined and concentrated in vacuo to give the title compound (988 mg, 18%) as a white powder. LCMS: m / z: 371.2 ([{79Br}M+H] + ),373.2([{81Br}M+H] + ),ESI pos.

[0497] Step B: (6-Bromo-5-methyl-pyridazin-3-yl)-[(3R)-3-piperidinyl]amine. 1:1 Hydrogen chloride

[0498] To a solution of (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 eq) in dichloromethane (18 mL) and methanol (9 mL) was added dropwise 4 M hydrochloric acid in 1,4-dioxane (6.65 mL, 26.6 mmol, 10.0 eq) at room temperature. The reaction mixture was stirred at 23 ° C for 16 h. The reaction mixture was then concentrated in vacuo to give the crude title compound (886 mg, 97%) as a light yellow powder. LCMS: m / z: 271.1 ([{79Br}M+H] + ),273.1([{81Br}M+H] + ),ESI pos.

[0499] Step C: (6-Bromo-5-methyl-pyridazin-3-yl)-[(3R)-1-ethyl-3-piperidinyl]amine

[0500] To a suspension of (6-bromo-5-methyl-pyridazin-3-yl)-[(3R)-3-piperidinyl]amine.1:1 hydrochloric acid (Example 7, Step B) (886 mg, 2.88 mmol, 1.0 eq) in ultra-dry dichloromethane (13 mL) was added acetaldehyde (317.2 mg, 404.07 μL, 7.2 mmol, 2.5 eq) followed by sodium acetate (590.7 mg, 7.20 mmol, 2.5 eq) under ice bath cooling. Sodium triacetoxyborohydride (1.10 g, 5.18 mmol, 1.8 eq) was added at 0°C. The reaction mixture was stirred at 0°C for 15 min and at room temperature for 2 h. The reaction mixture was carefully basified with NaHCO3 solution (50 mL) and then extracted with dichloromethane (3 x 80 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude title compound (667 mg, 74%) as an orange viscous oil. LCMS: m / z 299.1 ([{ 35 Cl}M+H]+),301.1([{ 37 Cl}M+H]+), ESI pos.

[0501] Preparation of boric acid esters: 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-3-yl Formonitrile

[0502] To a solution of commercially available 6-bromo-1H-indole-3-carbonitrile (CAS# 224434-83-7, 500 mg, 2.26 mmol, 1.0 eq) and bis(pinacol)diboron (689.3 mg, 2.71 mmol, 1.2 eq) in 1,4-dioxane (5.25 mL) was added potassium acetate (666 mg, 548.13 μL, 6.79 mmol, 3.0 eq) followed by [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(ii) (165.51 mg, 0.226 mmol, 0.1 eq). 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% to 50% EtOAc in heptane) to give the title compound (372 mg, 61%) as a white powder. LCMS: m / z 269.1 [M+H]+, ESI pos.

[0503] Step D: 6-[6-[[(3R)-1-ethyl-3-piperidinyl]amino]-4-methyl-pyridazin-3-yl]-1H-indole-3-yl Formonitrile

[0504] A mixture of (6-bromo-5-methyl-pyridazin-3-yl)-[(3R)-1-ethyl-3-piperidinyl]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) was flushed with argon and stirred at 95°C overnight. The residue was adsorbed on ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient 0% to 20% (dichloromethane: methanol: NH4OH 9: 1: 0.05) in dichloromethane). All fractions containing the product were combined and concentrated in vacuo. The residue was triturated with EtOAc / heptane to give the title compound (69 mg, 68.01%) as a pink powder. LCMS: m / z: [MH] + =359.3,ESI neg.

[0505] Example 8 :6-[6-[[(3R)-1-ethyl-3-piperidinyl]amino]-4-methyl-pyridazin-3-yl]-1H-indole-2-carbonitrile

[0506]

[0507] Step A: 6-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-2-carbonitrile

[0508] To a solution of 6-bromo-1H-indole-2-carbonitrile (CAS#1420537-60-5, 500 mg, 2.26 mmol, 1.0 eq) and bis(pinacol)diboron (688.3 mg, 2.71 mmol, 1.2 eq) in 1,4-dioxane (5.25 mL) was added potassium acetate (665.2 mg, 6.78 mmol, 3.0 eq) followed by 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex (187.2 mg, 0.226 mmol, 0.1 eq). The reaction mixture was flushed with argon and stirred at 90°C overnight. The reaction mixture was then cooled to room temperature (incomplete conversion), adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 25 g, 0% to 50% ethyl acetate in heptane) to give the title compound (85 mg, 14%) as pale yellow crystals. LCMS: m / z 267.1 [MH]+, ESI neg.

[0509] Step B: 6-[6-[[(3R)-1-ethyl-3-piperidinyl]amino]-4-methyl-pyridazin-3-yl]-1H-indole-2-yl Formonitrile

[0510] A mixture of the above (6-bromo-5-methyl-pyridazin-3-yl)-[(3R)-1-ethyl-3-piperidinyl]amine (80.0 mg, 0.267 mmol, 1.0 eq), 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 eq), potassium carbonate (166.3 mg, 1.20 mmol, 4.50 eq) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(ii) dichloromethane adduct (32.8 mg, 0.040 mmol, 0.15 eq) in 1,4-dioxane (1 mL) and water (0.5 mL) was flushed with argon and stirred at 95°C overnight. The residue was adsorbed on ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient (dichloromethane:methanol:NH4OH 9:1:0.05) in dichloromethane). All fractions containing the product were combined and concentrated in vacuo. The residue was triturated with EtOAc / heptane to give the title compound (49 mg, 48%) as a light brown powder. LCMS: m / z: [MH] + =359.3,ESI neg.

[0511] Example 9 :6-(3-Fluoro-1H-indol-6-yl)-5-methyl-N-[(3R)-1-methyl-3-piperidinyl]pyridazin-3-amine

[0512]

[0513] A mixture of 6-chloro-5-methyl-N-[(3R)-1-methyl-3-piperidinyl]pyridazin-3-amine (CAS#2557359-57-4, 50 mg, 0.20 mmol, 1.00 eq), 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 eq), potassium carbonate (130 mg, 0.94 mmol, 4.77 eq) and 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(ii) dichloromethane complex (20 mg, 0.02 mmol, 0.12 eq) in 1,4-dioxane (1.3 mL) and water (0.65 mL) was 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 is back extracted with ethyl acetate. The organic layer is washed with water and brine. The combined organic layer is dried over sodium sulfate, filtered and concentrated in vacuo. The crude product is adsorbed on ISOLUTE HM-N and purified by flash chromatography (silica gel, gradient 0% to 100% (dichloromethane: methanol: NH4OH 9: 1: 0.05) in dichloromethane). All fractions containing the product are combined and concentrated in vacuo. The residue is adsorbed on ISOLUTE HM-N and purified again by flash chromatography (Si-amine, 12g, gradient 0% to 5% methanol in ethyl acetate) to obtain the title compound (40mg, yield 57%), which is brown foam. LCMS: m / z 340.2[M+H] + ,ESI pos.

[0514] Example 10 :N-[(3R)-1-ethyl-3-piperidinyl]-6-(7-fluoro-1H-indol-6-yl)-5-methyl-pyridazin-3-amine

[0515]

[0516] Step A: 7-Fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole

[0517] Commercially available 6-bromo-5-fluoro-1H-indole (CAS#936901-94-9, 500 mg, 2.34 mmol, 1.0 eq), commercially available potassium 2-ethylhexanoate (CAS#3164-85-0, 936.9 mg, 5.14 mmol, 2.2 eq), palladium acetate (10.7 mg, 0.05 mmol, 0.020 eq) and Xphos (44.5 mg, 0.093 mmol, 0.04 eq) were dissolved in isopropyl acetate (7.5 mL). The mixture was first purged with argon and then stirred at 80 ° C for 1 h. Afterwards, the reaction mixture was filtered using a syringe filter, and the solvent was evaporated in vacuo. The crude product was used for the next step without further purification. LCMS: m / z=262.0[M+H] + ,ESI pos.

[0518] Step B: N-[(3R)-1-ethyl-3-piperidinyl]-6-(1H-indol-6-yl)-5-methyl-pyridazin-3-amine

[0519] 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 eq), 6-chloro-N-[(3R)-1-ethyl-3-piperidinyl]-5-methyl-pyridazin-3-amine (Example 1, Step C) (97 mg, 0.38 mmol, 0.7 eq), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(ii) (20 mg, 0.03 mmol, 0.05 eq) and cesium carbonate (533 mg, 1.6 mmol, 3.0 eq) 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 amount of reagents and solvents as above were added again, and the reaction was heated at 90°C for 5 d. 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, 100x30 mm, MeCN / (water + 0.1% trimethylamine), gradient 20% to 50% MeCN) to give the title compound (34.3 mg, yield 16%). LCMS: m / z=354.3 [M+H] + .

[0520] Example 11: N-[(3R)-1-ethyl-3-piperidinyl]-6-(3-fluoro-1H-indol-6-yl)-5-(trifluoromethyl)pyridazin-3-amine

[0521]

[0522] Step A: (3R)-tert-butyl 3-[[6-chloro-5-(trifluoromethyl)pyridazin-3-yl]amino]piperidine-1-carboxylate and (3R)-tert-Butyl 3-[[6-chloro-4-(trifluoromethyl)pyridazin-3-yl]amino]piperidine-1-carboxylate

[0523] Commercially available 3,6-dichloro-4-(trifluoromethyl)pyridazine (CAS#1057672-68-0, 1.72 g, 7.93 mmol, 1.00 eq) and commercially available (3R)-3-aminopiperidine-1-carboxylic acid tert-butyl ester (CAS#188111-79-7, 3.18 g, 15.9 mmol, 2.00 eq) in N,N-diisopropylethylamine (2.56 g, 3.46 mL, 19.8 mmol, 2.50 eq) pure mixture was stirred at 130 ° C for 24 h in a sealed tube. The warm mixture (about 50 ° C) was poured into a 500 mL conical flask, the oily mixture was transferred using ethyl acetate (100 mL), and water (100 mL) was added. Stir at room temperature for 20 min to dissolve all ingredients. Then, the mixture was extracted with ethyl acetate and washed twice with water. The water layer was extracted with EtOAc and finally with saline. The residue was purified by flash chromatography (SiO2, 0%-50% ethyl acetate in heptane) to give two title compounds: (3R)-tert-butyl 3-[[6-chloro-5-(trifluoromethyl)pyridazin-3-yl]amino]piperidine-1-carboxylate as a light yellow foam (1.67 g, 55%) and (3R)-tert-butyl 3-[[6-chloro-4-(trifluoromethyl)pyridazin-3-yl]amino]piperidine-1-carboxylate as a light yellow oil (1.07 g, 35%). LCMS: m / z=381.1 ([{35Cl}M+H] + ),383.1([{37Cl}M+H] + ),ESI pos.

[0524] Step B: 6-Chloro-N-[(3R)-3-piperidinyl]-5-(trifluoromethyl)pyridazin-3-amine; hydrochloride

[0525] To a solution of the above (3R)-tert-butyl 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 clean, yellow reaction solution was stirred at 23 °C for 16 hours. The reaction mixture was concentrated in vacuo to give the title compound as 1:1 hydrochloric acid (1.51 g, 98%) as a light yellow foam. LCMS: m / z=281.1 ([{35Cl}M+H]+), 283.1 ([{37Cl}M+H]+), ESI pos.

[0526] Step C: 6-Chloro-N-[(3R)-1-ethyl-3-piperidinyl]-5-(trifluoromethyl)pyridazin-3-amine

[0527] To the suspension of the above-mentioned 6-chloro-N-[(3R)-3-piperidinyl]-5-(trifluoromethyl)pyridazine-3-amine; hydrochloride (Example 11, Step B) (1.51 g, 4.29 mmol, 1.00 eq) in ultra-dry dichloromethane (30 mL), acetaldehyde (471.9 mg, 597.38 μL, 10.7 mmol, 2.50 eq) was added, followed by sodium acetate (878.8 mg, 10.7 mmol, 2.50 eq) under ice bath cooling. Then, sodium triacetoxyborohydride (1.63 g, 7.71 mmol, 1.800 eq) was added at 0 ° C. The reaction mixture was stirred at 0 ° C for 15 min, and stirred at room temperature for 2 h (light yellow suspension). LCMS showed complete conversion to product. The reaction mixture was carefully alkalized via a syringe with NaHCO solution (50 mL), and then extracted with dichloromethane (3 x 80 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product (1.4 g) was adsorbed on ISOLUTE HM-N and purified by flash chromatography (SiO2, gradient 0% to 100% dichloromethane solution (dichloromethane: methanol: NH4OH is 110: 10: 1) in dichloromethane) to give the title compound (1.03 g, yield 76%) as a light brown oil. LCMS: m / z = 309.1 ([{35Cl}M+H] + ),311.0([{37Cl}M+H] + ),ESI pos.

[0528] Step D: N-[(3R)-1-ethyl-3-piperidinyl]-6-(3-fluoro-1H-indol-6-yl)-5-(trifluoromethyl)pyridinium Oxazine-3-amine

[0529] A mixture of the above 6-chloro-N-[(3R)-1-ethyl-3-piperidinyl]-5-(trifluoromethyl)pyridazin-3-amine (Example 11, Step C) (40 mg, 129.6 μmol, 1.00 eq), 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 eq), potassium carbonate (85.95 mg, 621.9 μmol, 4.800 eq) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(ii) dichloromethane complex (15.9 mg, 19.4 μmol, 0.15 eq) in 1,4-dioxane (1 mL) and water (500 μL) was flushed with argon and stirred at 90°C overnight. LCMS shows that it is completely converted into product.The reaction mixture is cooled to room temperature and extracted with about 30mL ethyl acetate and about 15mL water.The water layer is stripped with about 30mL ethyl acetate.The organic layer is washed with about 15mL water and about 15mL brine.The combined organic layer is dried over sodium sulfate, filtered and concentrated in vacuo.The crude product is purified by RP HPLC (Gemini NX, 12nm, 5μm, 100x30 mm, CAN / water+0.1% TEA) to obtain the title product (24mg, 43%), which is a light grey amorphous freeze-dried solid.LCMS:m / z=408.2[M+H]+,ESI pos.

[0530] Example 12 :5-ethyl-N-[(3R)-1-ethyl-3-piperidinyl]-6-(3-fluoro-1H-indol-6-yl)pyridazin-3-amine

[0531]

[0532] 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

[0533] In a sealed tube, a neat mixture of (3R)-tert-butyl 3-aminopiperidine-1-carboxylate (CAS#188111-79-7, 4.53 g, 22.6 mmol, 2.00 eq) and 3,6-dichloro-4-ethylpyridazine (2.0 g, 11.3 mmol, 1.00 eq) in DIPEA (3.65 g, 4.93 mL, 28.2 mmol, 2.50 eq) was sealed and stirred at 130 °C (preheated oil bath) for 3 h. LCMS showed some product at rt = 1.16 min, and starting material was still remaining at rt = 0.95 min. The brown pure reaction mixture was sealed again and stirred at 130 °C (preheated oil bath) for 16 h (overnight). LCMS showed complete conversion to 2 regioisomers at rt = 1.17 min and rt = 1.23 min. The viscous brown reaction mixture was poured onto water (about 100 mL) with warm (about 50 ° C), and the oily mixture was transferred using ethyl acetate (about 50 mL). The brown reaction solution was stirred for 10 min, transferred to a separatory funnel and extracted twice with ethyl acetate (2x about 100 mL). The organic layer was washed with water (about 50 mL) and brine (about 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The brown crude product was adsorbed on ISOLUTE HM-N and purified by flash chromatography (SiO2, 0%-40% heptane solution of ethyl acetate) to obtain (3R)-3-[(6-chloro-5-ethyl-pyridazine-3-yl)amino]piperidine-1-carboxylic acid tert-butyl ester (1.32 g, 34%), which was a light yellow foam. LCMS: m / z=341.1 ([{35Cl}M+H]+), 341.1 ([{37Cl}M+H]+), ESI pos. And (3R)-tert-butyl 3-[(6-chloro-4-ethyl-pyridazin-3-yl)amino]piperidine-1-carboxylate (545 mg, 13%) as a light yellow foam. LCMS: m / z=341.1 ([{35Cl}M+H]+), 341.1 ([{37Cl}M+H]+), ESI pos.

[0534] Step B: (6-Chloro-5-ethyl-pyridazin-3-yl)-[(3R)-3-piperidinyl]amine; hydrochloride

[0535] At room temperature, to the aforementioned (3R) -3- [(6- chloro-5-ethyl-pyridazine-3-yl) amino] piperidine -1- carboxylic acid tert-butyl ester (Example 12, step A) (943mg, 2.77mmol, 1.00eq) in dichloromethane (10mL) and methanol (5mL) solution was added dropwise 4M HCl in 1,4-dioxane (8.30g, 6.92mL, 27.7mmol, 10.0eq) solution. The reaction mixture was stirred at 23 ° C for 16h. LCMS showed complete conversion to product. Evaporation of the reaction mixture gave the title product, which was 1: 1 hydrogen chloride (786mg, 97.37%), as a light yellow solid. LCMS: m / z = 241.1 ([{35Cl} M + H] + ),243.1([{37Cl}M+H] + ),ESIpos.

[0536] Step C: (6-Chloro-5-ethyl-pyridazin-3-yl)-[(3R)-1-ethyl-3-piperidinyl]amine

[0537] To a suspension of the above (6-chloro-5-ethyl-pyridazine-3-yl)-[(3R)-3-piperidinyl]amine; hydrochloride (Example 12, Step B) (400 mg, 1.44 mmol, 1.00 eq) in ultra-dry dichloromethane (15 mL) was added acetaldehyde (158.9 mg, 203.7 μL, 3.61 mmol, 2.50 eq), followed by sodium acetate (295.9 mg, 3.61 mmol, 2.50 eq) under ice bath cooling. Sodium triacetoxyborohydride (562.6 mg, 2.65 mmol, 1.80 eq) was added at 0 ° C. The reaction mixture was stirred at 0 ° C for 5 min and at room temperature for 3 h (the reaction mixture became slightly brown). LCMS showed complete conversion to product. The reaction mixture was carefully basified with NaHCO solution (25 mL) via a syringe and then extracted with dichloromethane (3 x 60 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was adsorbed on ISOLUTE HM-N and purified by flash chromatography (SiO2, gradient 0% to 100% (dichloromethane: methanol: NH4OH 110: 10: 1) in dichloromethane) to afford the title compound (204 mg, 52.6% yield) as a light brown oil. LCMS: m / z = 269.1 ([{35Cl}M+H]+), 271.1 ([{37Cl}M+H]+), ESI pos.

[0538] Step D: 5-ethyl-N-[(3R)-1-ethyl-3-piperidinyl]-6-(3-fluoro-1H-indol-6-yl)pyridazin-3-amine

[0539] A mixture of the above (6-chloro-5-ethyl-pyridazin-3-yl)-[(3R)-1-ethyl-3-piperidinyl]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-dichloropalladium(ii) dichloromethane complex (29.62 mg, 36.27 μmol, 0.15 eq) in 1,4-dioxane (2 mL) and water (1 mL) was flushed with argon and stirred at 90°C for 4 hours. Then, the reaction mixture was cooled to room temperature and extracted with ethyl acetate (30mL) and water (30mL). The water layer was stripped with ethyl acetate (30mL). The organic layer was washed with water (20mL) and brine (20mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated in a vacuum. The crude product was adsorbed on ISOLUTE HM-N and purified by flash chromatography (silica gel, gradient 0% to 100% (dichloromethane: methanol: NH4OH 110: 10: 1) dichloromethane solution), then crystallized with heptane / ethyl acetate (1: 1), to obtain the title compound (22mg, yield 24%), which was a light brown solid. LCMS m / z: 368.2[M+H] + , ESI pos.

[0540] Example 13: N-[(3R)-1-ethyl-3-piperidinyl]-6-(1H-indol-6-yl)-5-methyl-1,2,4-triazin-3-amine

[0541]

[0542] Step A: 6-Chloro-N-[(3R)-1-ethyl-3-piperidinyl]-5-methyl-1,2,4-triazine-3-amine

[0543] To a mixture of 3,6-dichloro-5-methyl-1,2,4-triazine (CAS#132434-82-3, 1,00 g, 6.1 mmol, 1.0 eq) and [(3R)-1-ethyl-3-piperidinyl]amine (CAS#1020396-26-2, 1.24 g, 9.15 mmol, 1.5 eq) in 1,4-dioxane (20 mL) was added N,N-diisopropylethylamine (814 mg, 1.1 mL, 6.3 mmol, 1.03 eq). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was extracted with dichloromethane and water. The organic layer was washed with brine. The aqueous layer was stripped twice with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was adsorbed on ISOLUTE HM-N and purified by flash chromatography (silica gel, 40 g, gradient 0% to 10% methanol in dichloromethane) to afford the title compound (1.32 g, 80% yield) as a green solid. m / z 256.3 [M+H]+, ESI pos. This step was repeated as described above to proceed to the next step.

[0544] Step B: N-[(3R)-1-ethyl-3-piperidinyl]-6-(1H-indol-6-yl)-5-methyl-1,2,4-triazine-3-yl amine

[0545] The above 6-chloro-N-[(3R)-1-ethyl-3-piperidinyl]-5-methyl-1,2,4-triazine-3-amine (Example 13, Step A) (50 mg, 196 μmol, 1.00 eq), 1H-indol-6-ylboronic acid (47 mg, 293 μmol, 1.50 eq, CAS#147621-18-9), cesium carbonate (191 mg, 587 μmol, 3.0 eq) and 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(ii) dichloromethane complex (14 mg, 19.6 μmol, 0.1 eq) 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 LCMS showed consumption of the starting material. The reaction mixture was cooled to room temperature and extracted with ethyl acetate (30 mL). The combined organic phases were washed with brine and water, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by preparative HPLC (column: Gemini NX, 12 nm, 5 μm, 100 x 30 mm, MeCN / water + 0.1% TEA) to give the title compound (24.6 mg, yield 37%). LCMS: m / z = 337.3 [M+H] + ,ESI pos.

[0546] Example 14:N-[(3R)-1-ethyl-3-piperidinyl]-6-(3-fluoro-1H-indol-6-yl)-5-methyl-1,2,4-triazin-3-amine

[0547]

[0548] A mixture of the above 6-chloro-N-[(3R)-1-ethyl-3-piperidinyl]-5-methyl-1,2,4-triazine-3-amine (Example 13, Step A) (79 mg, 308.9 μmol, 1.00 eq), 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 eq), potassium carbonate (204.9 mg, 1.48 mmol, 4.80 eq) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(ii) dichloromethane complex (37.8 mg, 46.3 μmol, 0.15 eq) in 1,4-dioxane (2.38 mL) and water (1.19 mL) was flushed with argon and stirred at 90°C overnight. LCMS shows complete conversion to product. The reaction mixture is cooled to room temperature and extracted with ethyl acetate (30mL) and water (30mL). The water layer is stripped with ethyl acetate (30mL). The organic layer is washed with water (20mL) and brine (20mL). The combined organic layer is dried over sodium sulfate, filtered and concentrated in vacuo. The crude product is adsorbed on ISOLUTE HM-N and purified by flash chromatography (SiO2, gradient 0% to 100% (dichloromethane: methanol: NH4OH 110: 10: 1) dichloromethane solution), then by crystallization with heptane / ethyl acetate (1: 1), to obtain the title compound (52mg, yield 45%), which is a gray solid. LCMS: m / z=355.2[M+H] + ,ESI pos.

[0549] Example 15: N-[(3R)-1-ethyl-3-piperidinyl]-7-(1H-indol-6-yl)-1-methyl-pyrazolo[3,4-d]pyridazin-4-amine

[0550]

[0551] Step A: Diethyl 2-methylpyrazole-3,4-dicarboxylate

[0552] Potassium carbonate (5.21 g, 37.7 mmol, 2.0 eq) was added to a solution of 1H-pyrazole-4,5-dicarboxylic acid diethyl ester (4.00 g, 18.9 mmol, 1.0 eq) in MeCN (60 mL). The mixture was stirred at 20 ° C for 0.5 hours, and then iodomethane (4.01 g, 28.3 mmol, 1.5 eq) was added to the mixture. The mixture was stirred at 20 ° C for 12 hours. After the reaction was completed (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 (SiO 2 , petroleum ether / ethyl acetate, 5:1 to 2:1) to give the title compound (1.35 g, yield 32%) as a colorless oil. 1 H NMR (400MHz, DMSO-d6) δ = 7.88 (s, 1H), 4.37, 4.21 (q, 2H each), 3.94 (s, 3H), 1.34-1.21 (m, 6H).

[0553] Step B: 1-Methylpyrazolo[3,4-d]pyridazine-4,7-diol

[0554] To a solution of diethyl 2-methylpyrazole-3,4-dicarboxylate (1.1 g, 4.86 mmol, 1,0 eq) in methanol (20 mL) was added hydrazine monohydrate (0.71 mL, 14.6 mmol, 3.0 eq). The mixture was stirred at 20 ° C for 24 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by RP fast (CombiFlash (0.1% NH3.H2O aqueous solution-MeCN conditions) and then lyophilized to give the title compound (100 mg, yield 12%) as a white solid. LCMS: m / z 167.1 [M+H] + ,ESI pos.

[0555] Step C: 4,7-Dichloro-1-methyl-pyrazolo[3,4-d]pyridazine

[0556] A mixture of the above 1-methylpyrazolo[3,4-d]pyridazine-4,7-diol (200 mg, 1.20 mmol, 1.0 eq) in POCl3 (2.0 mL) was stirred at 60°C for 12 hours. After the reaction was completed, the mixture was concentrated under reduced pressure to give the title compound (220 mg, yield 90%) as a yellow solid. LCMS: m / z 202.8 [M+H]+, ESI pos.

[0557] Step D: 7-Chloro-N-[(3R)-1-ethyl-3-piperidinyl]-1-methyl-pyrazolo[3,4-d]pyridazin-4-amine

[0558] To the above-mentioned 4,7-dichloro-1-methyl-pyrazolo[3,4-d]pyridazine (200 mg, 0.99 mmol, 1.0 eq) and (3R)-1-ethylpiperidin-3-amine (CAS#1020396-26-2, 152 mg, 1.18 mmol, 1.20 eq) in NMP (1 mL) was added potassium carbonate (272 mg, 1.97 mmol, 2.0 eq). The mixture was heated to 85 ° C and stirred for 16 hours under N2. After the reaction was completed, the reaction mixture was cooled to 20 ° C and purified by reverse phase fast (CombiFlash 0.1% TFA aqueous solution-ACN conditions), and then freeze-dried to obtain the title compound (70 mg, yield 24%), which was a yellow solid. LCMS: m / z 295.0[M+H] + ,ESI pos. The synthesis was repeated as described above.

[0559] Step E: N-[(3R)-1-ethyl-3-piperidinyl]-7-(1H-indol-6-yl)-1-methyl-pyrazolo[3,4-d] Pyridazine-4-amine

[0560] A mixture of 7-chloro-N-[(3R)-1-ethyl-3-piperidinyl]-1-methyl-pyrazolo[3,4-d]pyridazin-4-amine (100 mg, 0.34 mmol, 1.00 eq), 1H-indol-6-ylboronic acid (CAS#147621-18-9, 100 mg, 0.62 mmol, 1.83 eq), potassium carbonate (225 mg, 1.63 mmol, 4.80 eq) and 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(ii) dichloromethane complex (42 mg, 0.05 mmol, 0.15 eq) in 1,4-dioxane (2.0 mL) and water (1.0 mL) was flushed with argon and stirred at 95° C. for 16 hours. 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 on ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient 0% to 100% (dichloromethane: methanol: NH4OH 9: 1: 0.05) in dichloromethane). All fractions containing the product were combined and concentrated in vacuo. The residue was adsorbed on ISOLUTE HM-N and repurified by flash chromatography (Si-amine, 12 g, gradient 0% to 5% methanol in ethyl acetate) to give the title compound (70 mg, yield 52%) as an off-white foam. LCMS: m / z 376.3 [M+H] + ,ESI pos.

[0561] Example 16:N-[(3R)-1-ethyl-3-piperidinyl]-6-(5-methyl-1H-indol-6-yl)pyridazin-3-amine

[0562]

[0563] Step A: 6-Chloro-N-[(3R)-1-ethyl-3-piperidinyl]pyridazin-3-amine

[0564] To a mixture of 3,6-dichloropyridazine (CAS#141-30-0, 0.600 g, 4.03 mmol, 1.00 eq) and (3R)-1-ethylpiperidin-3-amine (CAS#1020396-26-2, 620 mg, 4.84 mmol, 1.20 eq) in N-methyl-2-pyrrolidone (3.4 mL) was added N,N-diisopropylethylamine (1.33 g, 1.8 mL, 10.3 mmol, 2.56 eq). 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% LiCl-aqueous solution. The aqueous layer was back-extracted with ethyl acetate. The organic layer was washed twice with 5% LiCl-aqueous solution, once with water, and once with brine. The combined organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was adsorbed on ISOLUTE HM-N and purified by flash chromatography (silica gel, 25 g, gradient 0% to 100% (dichloromethane:methanol:NH4OH 9:1:0.05) in dichloromethane) to afford the title compound (567 mg, yield 56%) as a light yellow solid. LCMS: m / z 241.1 [M+H] + ,ESI pos.

[0565] Step B: 5-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole

[0566] To a solution of 6-bromo-5-methyl-1H-indole (CAS#248602-16-6, 330 mg, 1.57 mmol, 1.00 eq) and bis(pinacol)diboron (478 mg, 1.88 mmol, 1.20 eq) in 1,4-dioxane (3.7 mL) was added potassium acetate (462 mg, 4.71 mmol, 3.00 eq) followed by 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex (130 mg, 0.16 mmol, 0.10 eq). The reaction mixture was flushed with argon and stirred at 90 °C for 16 hours. The reaction mixture was cooled to room temperature, adsorbed on ISOLUTE HM-N, and purified by flash chromatography (silica gel, 25 g, gradient 0% to 20% ethyl acetate in heptane) to give the title compound (182 mg, 43% yield) as a pale yellow solid. LCMS: m / z 258.0 [M+H] +,ESI pos.

[0567] Step C: N-[(3R)-1-ethyl-3-piperidinyl]-6-(5-methyl-1H-indol-6-yl)pyridazin-3-amine

[0568] A mixture of 6-chloro-N-[(3R)-1-ethyl-3-piperidinyl]pyridazine-3-amine (Example 16, Step A) (60 mg, 0.24 mmol, 1.00 eq), 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 eq), potassium carbonate (156 mg, 1.13 mmol, 4.77 eq) and 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex (24 mg, 0.03 mmol, 0.12 eq) in 1,4-dioxane (1.6 mL) and water (0.80 mL) was flushed with argon and stirred at 100° C. for 4 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 on ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient 0% to 100% (dichloromethane: methanol: NH4OH 9: 1: 0.05) in dichloromethane). All fractions containing the product were combined and concentrated in vacuo. The residue was ground with ethyl acetate to obtain the title compound (50 mg, yield 60%) as a dark brown solid. LCMS: m / z 336.3 [M+H] + ,ESI pos.

[0569] Example 17 :3-[[6-(3-Fluoro-1H-indol-6-yl)-5-methyl-pyridazin-3-yl]amino]-1-methyl-cyclobutanol

[0570]

[0571] Step A: 3-[(6-chloro-5-methyl-pyridazin-3-yl)amino]-1-methyl-cyclobutanol and 3-[(6-chloro-4-methyl- [3-pyridazin-3-yl)amino]-1-methyl-cyclobutanol

[0572] To a solution of 3,6-dichloro-4-methyl-pyridazine (CAS#19064-64-3, 300 mg, 1.84 mmol, 1.00 eq) in N-methyl-2-pyrrolidone (3.0 mL) was added N,N-diisopropylethylamine (962 mg, 1.3 mL, 7.44 mmol, 4.04 eq) and cis-3-amino-1-methyl-cyclobutanol hydrochloride (CAS#1523606-23-6, 253 mg, 1.84 mmol, 1.00 eq). The mixture was stirred at 180 ° C for 2 hours under microwave radiation. The reaction mixture was extracted with ethyl acetate and 10% LiCl-aqueous solution. The aqueous layer was back-extracted with ethyl acetate. The organic layer was washed twice with 10% LiCl-aqueous solution, once with water, and once with brine. The combined organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was adsorbed on ISOLUTE HM-N and purified by flash chromatography (silica gel, 24 g, gradient 0% to 5% methanol in dichloromethane) to give 3-[(6-chloro-5-methyl-pyridazin-3-yl)amino]-1-methyl-cyclobutanol (100 mg, 23% yield) as an off-white solid; LCMS: m / z 228.0 [M+H] + , ESI pos; and 3-[(6-chloro-4-methyl-pyridazin-3-yl)amino]-1-methyl-cyclobutanol (70 mg, yield 16%) as an off-white solid; LCMS: m / z 228.1 [M+H] + ,ESI pos.

[0573] Step B: 3-[[6-(3-Fluoro-1H-indol-6-yl)-5-methyl-pyridazin-3-yl]amino]-1-methyl-cyclobutanol

[0574] A mixture of 3-[(6-chloro-5-methyl-pyridazin-3-yl)amino]-1-methyl-cyclobutanol (Example 17, Step A) (60 mg, 0.25 mmol, 1.00 eq), 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 eq), potassium carbonate (175 mg, 1.27 mmol, 5.06 eq) and 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex (28 mg, 0.03 mmol, 0.14 eq) in 1,4-dioxane (1.6 mL) and water (0.80 mL) 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 with water and brine. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was adsorbed on ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient 0% to 100% (dichloromethane: methanol: NH4OH 9: 1: 0.05) in dichloromethane) to give the title compound (52 mg, 57% yield) as a brown foam. LCMS: m / z 327.1 [M+H] + ,ESI pos.

[0575] Examples 18A and 18B:

[0576] (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

[0577]

[0578] Step A: 1-(6-Chloro-5-methyl-pyridazin-3-yl)-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyrrolidone tert-Butylpyridine-6-carboxylate

[0579] 1,2,3,3a,4,5,7,7a-octahydropyrrolo[2,3- cA mixture of tert-butyl pyridine-6-formate (CAS#1196147-27-9, 2.33 g, 10.31 mmol, 1.4 eq), 3,6-dichloro-4-methyl-pyridazine (CAS#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-pyrrolidone (3 mL) was stirred at 130 ° C for 24 h. The reaction mixture was extracted with ethyl acetate (2x 80 mL) and half-saturated NaHCO. The organic layer was washed with water (80 mL) and brine (80 mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 0% to 50% ethyl acetate in heptane) to give the title compound (1.49 g, 57% yield) as a light yellow solid. LCMS: m / z 353.3 ([{ 35 Cl}M+H]+),355.3([{ 37 Cl}M+H] + ),ESI pos.

[0580] Step B: 1-(6-Chloro-5-methyl-pyridazin-3-yl)-2,3,3a,4,5,6,7,7a-octahydropyrrolo[2,3-c]pyridin-3-yl Imidazolidine hydrochloride

[0581] 1-(6-chloro-5-methyl-pyridazine-3-yl)-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridine-6-carboxylic acid tert-butyl ester (1.48 g, 4.19 mmol, 1.0 eq) was dissolved in dichloromethane (12.7 mL) and methanol (6.4 mL). A 4M HCl solution in 1,4-dioxane (9.4 mL, 37.8 mmol, 9.0 eq) was added dropwise to the reaction mixture and stirred at 23 ° C for 3 h. The reaction mixture was concentrated in vacuo to give the title compound (1.40 g, yield 99%) as an orange solid. LCMS: m / z 253.2 [M+H] + ,ESI pos.

[0582] Step C: 1-(6-Chloro-5-methyl-pyridazin-3-yl)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo

[0147] [2,3-c]pyridine

[0583] 1-(6-chloro-5-methyl-pyridazine-3-yl)-2,3,3a,4,5,6,7,7a-octahydropyrrolo[2,3-c]pyridine hydrochloride (1.4 g, 4.16 mmol, 1.0 eq) was dissolved in 1,2-dichloroethane (40.0 mL) and triethylamine (649 mg, 0.89 mL, 6.41 mmol, 1.54 eq) was added. The reaction mixture was stirred at 23 ° C for 5 minutes. Then, formaldehyde (37% aqueous solution, 758 mg, 0.70 mL, 9.33 mmol, 2.24 eq) was added, followed by sodium triacetoxyborohydride (CAS#56553-60-7, 3.53 g, 16.7 mmol, 4.0 eq) in batches. The reaction mixture was stirred at room temperature for 1 h. Afterwards, the reaction mixture was carefully quenched with saturated NaHCO3 aqueous solution and extracted with dichloromethane (5 x 30 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, gradient 0% to 5% methanol in dichloromethane) to give the title compound (1.2 g, yield 97%) as a light yellow solid. LCMS m / z 267.2 [M+H] + ,ESIpos.

[0584] Step 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)

[0585]

[0586] A mixture of the above 1-(6-chloro-5-methyl-pyridazin-3-yl)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridine (84 mg, 0.30 mmol, 1.0 eq), 3-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (113 mg, 0.42 mmol, 1.40 eq), potassium carbonate (198 mg, 1.44 mmol, 4.80 eq) and 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(ii) dichloromethane complex (CAS#95464-05-4, 37 mg, 0.045 mmol, 0.15 eq) in 1,4-dioxane (2 mL) and water (1 mL) was flushed with argon and stirred at 90°C for 6 h. The reaction mixture is cooled to room temperature and extracted with ethyl acetate (30mL) and water (30mL). The water layer is stripped with ethyl acetate (30mL). The organic layer is washed with water (20mL) and brine (20mL). The combined organic layer is dried over sodium sulfate, filtered and concentrated in a vacuum. The product is purified by flash chromatography (silica gel, gradient 0% to 100% (dichloromethane: methanol: NH4OH 110: 10: 1) dichloromethane solution) to obtain the title compound (84mg, yield 73%), which is a light brown solid. Chiral separation is carried out by SFC (column chirality AD-H, 5 μm, 250x20mm; elution: 35% methanol CO2 solution) to obtain the first eluted title compound A (28mg, yield 34%), which is a light brown solid; and the second eluted title compound B (32mg, yield 39%), which is a light brown solid. LCMS: m / z 366.3 [M+H] + ,ESI pos.

[0587] Example A

[0588] The compound of formula Ib can be used in a manner known per se as active ingredient for the production of tablets of the following composition:

[0589]

[0590] Example B

[0591] The compound of formula Ib can be used in a manner known per se as active ingredient for the production of capsules of the following composition:

[0592]

Claims

1. A compound of formula Ib or Ib′ in 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, and X is CR 7 , or X and Y and the atoms to which they are attached form a 5-membered heteroaryl ring containing 2 N heteroatoms, one of which is substituted with H or alkyl; R 1 is selected from alkyl, cyano or H; R 2 Selected from alkyl, cyano, H or halo; R 3 is H; R 4 Selected from H, alkyl, alkoxy or halo; R 5 Selected from H or halo; R 6 is H; R 7 is an alkyl group or a halogenated alkyl group; W is optionally substituted cycloalkyl or 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; and pharmaceutically acceptable salts thereof.

2. A compound of formula Ib in 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, and X is CR 7 , or X and Y and the atoms to which they are attached form a 5-membered heteroaryl ring containing 2 N heteroatoms, one of which is substituted with H or alkyl; R 1 is selected from alkyl, cyano or H; R 2 Selected from alkyl, cyano, H or halo; R 3 is H; R 4 Selected from H, alkyl, alkoxy or halo; R 5 Selected from H or halo; R 6 is H; R 7 is an alkyl group or a halogenated alkyl group; W is optionally substituted cycloalkyl or 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; and pharmaceutically acceptable salts thereof.

3. The compound according to claim 1 or 2, wherein Y is selected from N or CH, and X is CR 7 .

4. A compound according to any one of claims 1 to 3, wherein R 1 For H.

5. A compound according to any one of claims 1 to 4, wherein R 2 is H or halogenated.

6. The compound according to any one of claims 1 to 5, wherein A3 is CR 3 .

7. A compound according to any one of claims 1 to 6, wherein A4 is CR 4 .

8. A compound according to any one of claims 1 to 7, wherein A5 is CR 5 .

9. A compound according to any one of claims 1 to 8, wherein R 4 Selected from H or halo.

10. A compound according to any one of claims 1 to 9, wherein R 4 For H.

11. A compound according to any one of claims 1 to 10, wherein R 5 For H.

12. A compound according to any one of claims 1 to 11, wherein R 7 It is an alkyl group.

13. The compound according to any one of claims 1 to 12, wherein W is an alkyl-substituted piperidine ring.

14. The compound according to claim 1, wherein A3 is CR 3 ; A4 to 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 halogenated; R 5 is H or halogenated; R 6 is H; R 7 is an alkyl group or a halogenated alkyl group; W is a piperidine ring substituted with an alkyl group; and pharmaceutically acceptable salts thereof.

15. The compound according to claim 1, wherein A3 is CR 3 ; A4 to CR 4 ; A5 is CR 5 ; Y is selected from N or CH, and X is CR7; R 1 is H; R 2 is H or halogenated; R 3 is H; R 4 is H; R 5 is H; R 6 is H; R 7 is an alkyl group or a halogenated alkyl group; W is a piperidine ring substituted with an alkyl group; and pharmaceutically acceptable salts thereof.

16. The compound according to claim 1, wherein A3 is CR 3 ; A4 to CR 4 ; A5 is CR 5 ; Y is selected from N or CH, and X is CR7; R 1 is H; R 2 is H or halogenated; R 3 is H; R 4 is H; R 5 is H; R 6 is H; R 7 is an alkyl group; W is a piperidine ring substituted with an alkyl group; and pharmaceutically acceptable salts thereof.

17. A compound according to any one of claims 1 to 16, wherein the compound is selected from 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-piperidinyl]-6-(3-fluoro-1H-indol-6-yl)-5-(trifluoromethyl)pyridazin-3-amine; 5-ethyl-N-[(3R)-1-ethyl-3-piperidinyl]-6-(3-fluoro-1H-indol-6-yl)pyridazin-3-amine; N-[(3R)-1-ethyl-3-piperidinyl]-6-(1H-indol-6-yl)-5-methyl-1,2,4-triazin-3-amine; N-[(3R)-1-ethyl-3-piperidinyl]-6-(3-fluoro-1H-indol-6-yl)-5-methyl-1,2,4-triazin-3-amine; and pharmaceutically acceptable salts thereof.

18. A compound according to any one of claims 1 to 17, wherein the compound is selected from 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; 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-(3-fluoro-1H-indol-6-yl)-5-(trifluoromethyl)pyridazin-3-amine; N-[(3R)-1-ethyl-3-piperidinyl]-6-(1H-indol-6-yl)-5-methyl-1,2,4-triazin-3-amine; N-[(3R)-1-ethyl-3-piperidinyl]-6-(3-fluoro-1H-indol-6-yl)-5-methyl-1,2,4-triazine-3-amine; and pharmaceutically acceptable salts thereof.

19. A compound according to any one of claims 1 to 18, wherein the compound is selected from 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-(1H-indol-6-yl)-5-methyl-1,2,4-triazin-3-amine; N-[(3R)-1-ethyl-3-piperidinyl]-6-(3-fluoro-1H-indol-6-yl)-5-methyl-1,2,4-triazin-3-amine; and pharmaceutically acceptable salts thereof.

20. The compound according to claim 1, wherein the compound is N-[(3R)-1-ethyl-3-piperidinyl]-7-(1H-indol-6-yl)-1-methyl-pyrazolo[3,4-d]pyridazin-4-amine and a pharmaceutically acceptable salt thereof.

21. The compound according to any one of claims 1, wherein the compound is selected from N-[(3R)-1-ethyl-3-piperidinyl]-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 pharmaceutically acceptable salts thereof.

22. The compound according to claim 1, wherein the compound is selected from (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 pharmaceutically acceptable salts thereof.

23. Compounds according to any one of claims 1 to 22 for use as therapeutically active substances.

24. A compound according to any one of claims 1 to 22 for use in treating or preventing a disease, disorder or condition, wherein the disease, disorder or condition is responsive to NLRP3 inhibition.

25. A pharmaceutical composition comprising a compound according to any one of claims 1 to 22 and a therapeutically inert carrier.

26. Use of a compound according to any one of claims 1 to 22 for treating or preventing a disease, disorder or condition, wherein the disease, disorder or condition is responsive to NLRP3 inhibition.

27. A compound according to any one of claims 1 to 22 for use in the treatment or prevention of a disease, disorder or condition selected from asthma or COPD.

28. A compound according to any one of claims 1 to 22 for use in the treatment or prevention of a disease, disorder or condition selected from Parkinson's disease or Alzheimer's disease.

29. Use of a compound according to any one of claims 1 to 22 in the treatment or prevention of a disease, disorder or condition selected from asthma or COPD.

30. Use of a compound according to any one of claims 1 to 22 in the treatment or prevention of a disease, disorder or condition selected from Parkinson's disease or Alzheimer's disease.

31. Use of a compound according to any one of claims 1 to 22 for the preparation of a medicament for the treatment or prevention of a disease, disorder or condition selected from asthma or COPD.

32. Use of a compound according to any one of claims 1 to 22 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.

33. A method of inhibiting NLRP3, the method comprising administering an effective amount of a compound as claimed in any one of claims 1 to 22 to inhibit NLRP3.

34. A method for treating or preventing a disease, disorder or condition comprising administering an effective amount of a compound according to any one of claims 1 to 22, wherein the disease, disorder or condition is selected from asthma or COPD.

35. A method for treating or preventing a disease, disorder or condition, the method comprising administering an effective amount of a compound according to any one of claims 1 to 22, wherein the disease, disorder or condition is selected from Parkinson's disease or Alzheimer's disease.

36. The invention as herein described.

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