Pyridazine derivatives as inhibitors of NLRP3

Abstract

The present application relates to a compound of general formula (Ib) TIFF2024540525000049.tif42161 The present invention relates to pyridazine derivatives of the formula: ##STR1## and pharmaceutical compositions containing the compounds and their use in the treatment of diseases and conditions such as asthma, COPD, Parkinson's disease and Alzheimer's disease. The compounds act as inhibitors of NLRP3.

Description

[Technical field]

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

[0002] The present invention relates to novel compounds of formula Ib [ka] [In the formula, R X is selected from H, alkyl and haloalkyl; R Y is selected from H, alkyl, alkoxyalkyl, and halo, with the proviso that R X If is H, then R Y is not H; Z is the system R, S, and T [ka] wherein the systems S and T may be further substituted with OH, halo, alkyl or cyano; R 6 is H or alkyl; Y is CH2, O or NR 7 and; R 7 is H or alkyl; W is a substituted 4-6 membered cycloalkyl ring or a substituted heterocycle of ring system A, where the substituted cycloalkyl is substituted with 1 or 2 substituents selected from OH, halo, and alkyl, and ring system A is [ka] and; R 1 is H and R 2 is alkyl, or R 1 and R 2 and the atoms to which they are attached, taken together, form a 5-membered ring which may be substituted with OH or halo; R3 is H, OH or halo. and pharma- ceutically acceptable salts thereof.

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

[0004] The NOD-like receptor (NLR) family pyrin domain-containing protein 3 (NLRP3) inflammasome is a component of inflammatory processes and its aberrant activity is pathogenic in genetic disorders such as cryopyrin-associated periodic syndromes (CAPS) and complex diseases such as multiple sclerosis, type 2 diabetes, Alzheimer's disease, and atherosclerosis.

[0005] NLRP3 is an intracellular signaling molecule that senses many pathogen-derived, environmental, and host-derived factors. Upon activation, NLRP3 binds to apoptosis-associated speck-like proteins that contain a caspase activation and recruitment domain (ASC). ASC then polymerizes to form large aggregates known as ASC specks. Polymerized ASC then interacts with the cysteine ​​protease caspase-1 to form a complex called the inflammasome. This leads to the activation of caspase-1, which cleaves the precursor forms of the proinflammatory cytokines IL-1β and IL-18 (termed pro-IL-1β and pro-IL-18, respectively), thereby activating these cytokines. Caspase-1 also mediates a type of inflammatory cell death known as pyroptosis. ASC specks can also recruit and activate caspase-8, which can process pro-IL-1β and pro-IL-18 to trigger apoptotic cell death.

[0006] Caspase-1 cleaves pro-IL-1β and pro-IL-18 to produce their active forms, which are secreted from the cell. Active caspase-1 also cleaves gasdermin-D to cause pyroptosis. Through its control of the pyroptotic cell death pathway, caspase-1 also mediates the release of alarmin molecules such as IL-33 and high mobility group box 1 protein (HMGB1). Caspase-1 also cleaves intracellular IL-1R2, resulting in its degradation, allowing IL-1α to be liberated. 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, can contribute to caspase-1-dependent inflammation.

[0007] 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.

[0008] Active cytokines derived from NLRP3 inflammasome activation are key drivers of inflammation and interact with other cytokine pathways to shape immune responses to infection and injury. For example, IL-1β signaling induces secretion of the 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 act synergistically to induce IFN-γ production from memory T cells and NK cells that drive Th1 responses.

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

[0010] The role of NLRP3 in diseases of the central nervous system is becoming clear, and lung diseases have also been shown to be affected by NLRP3. NLRP3 has also been implicated in many central nervous system conditions, including Parkinson's disease (PD), Alzheimer's disease (AD), dementia, Huntington's disease, cerebral malaria, and brain damage due to pneumococcal meningitis (Walsh et al., Nature Reviews, 15:84-97, 2014 and Dempsey et al. Brain. Behav. Immun. 201761:306-316). NLRP3 has also been shown to be involved in many lung diseases, such as chronic obstructive pulmonary disorder (COPD), asthma (including steroid-resistant asthma), asbestosis, and silicosis (De Nardo et al., Am. J. Pathol., 184:42-54, 2014 and Kim et al. Am J Respir Crit Care Med. 2017 196(3):283-97). In addition, NLRP3 has been implicated in the development of liver disease, kidney disease, and aging. Many of these associations are due to the involvement of NLRP3. - / - Although defined in mice, there are also insights into the specific activation of NLRP3 in these diseases. In type 2 diabetes (T2D), deposition of islet amyloid polypeptide in the pancreas activates NLRP3 and IL-1β signaling, leading to cell death and inflammation.

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

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

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

[0014] The present invention relates to novel compounds of formula Ib [ka] [In the formula, R X is selected from H, alkyl and haloalkyl; R Y is selected from H, alkyl, alkoxyalkyl, and halo, with the proviso that R X If is H, then R Y is not H; Z is the system R, S, and T [ka] wherein the systems S and T may be further substituted with OH, halo, alkyl or cyano; R 6 is H or alkyl; Y is CH2, O or NR 7 and; R 7 is H or alkyl; W is a substituted 4-6 membered cycloalkyl ring or substituted heterocycle of ring system A, where the substituted cycloalkyl is substituted with 1 or 2 substituents selected from OH, halo, and alkyl, and ring system A is [ka] and; R 1 is H and R 2 is alkyl, or R 1 and R 2 and the atoms to which they are attached, taken together, form a 5-membered ring which may be substituted with OH or halo; R 3 is H, OH or halo. and pharma- ceutically acceptable salts thereof.

[0015] The term "alkyl" refers to a monovalent linear or branched saturated hydrocarbon group of 1 to 6 carbon atoms. In some embodiments, unless otherwise specified, alkyl refers to a group having 1 to 6 carbon atoms (C 1~6 alkyl) or 1 to 4 carbon atoms (C 1~4 Contains alkyl. 1~6 Examples of alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl and pentyl. Particular alkyl groups include methyl and ethyl.

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

[0017] The term "alkoxyalkyl" means 1~6 At least one hydrogen atom of the alkyl group is C 1~6 C replaced by an alkoxy group 1~6 Represents an alkyl group.

[0018] The term "cyano" refers to the group -C≡N.

[0019] The terms "halogen", "halide" and "halo" are used interchangeably herein and refer to fluoro, chloro, bromo or iodo. A particular halo is fluoro.

[0020] The term "haloalkyl" means C 1~6 At least one hydrogen atom of the alkyl group is replaced by the same or different halogen atom. 1~6 represents an alkyl group. A specific example of haloalkyl is trifluoromethyl.

[0021] The term "cycloalkyl" refers to a monocyclic or polycyclic saturated or partially unsaturated non-aromatic hydrocarbon. In some embodiments, unless otherwise stated, a cycloalkyl contains 3 to 8 carbon atoms, 3 to 6 carbon atoms, or 3 to 5 carbon atoms. In some embodiments, a cycloalkyl is a saturated monocyclic or polycyclic hydrocarbon. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, octahydropentalenyl, spiro[3.3]heptanyl, and the like. A specific example is cyclobutyl.

[0022] The term "heterocycle" refers to a monovalent saturated or partially unsaturated monocyclic or bicyclic ring system of 4 to 10 ring atoms or 4 to 9 ring atoms containing 1, 2 or 3 ring heteroatoms selected from N, O and S, with the remaining ring atoms being carbon. 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 dihydrofuryl, imidazolinyl, dihydro-oxazolyl, tetrahydro-pyridinyl or dihydropyranyl. A specific example of a heterocycle is piperidyl.

[0023] The term "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness and properties of the free base or free acid, and is not biologically or otherwise undesirable. Salts are formed with inorganic acids, such as trifluoroacetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, especially hydrochloric acid, and organic acids, such as formic acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcysteine. Furthermore, these salts can be prepared from the addition of an inorganic or organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyamine resins. Compounds of formula I can also exist in the form of zwitterions. Particularly preferred pharmaceutically acceptable salts of compounds of formula I are salts formed with formic acid and with hydrochloric acid to produce hydrochloride, dihydrochloride or trihydrochloride salts.

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

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

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

[0027] The compounds of formula Ib may contain one or several asymmetric centers and may exist in the form of optically pure enantiomers, mixtures of enantiomers, e.g. racemates, optically pure diastereoisomers, mixtures of diastereoisomers.

[0028] The compounds of formula I may contain one or several asymmetric centers and may exist in the form of optically pure enantiomers, mixtures of enantiomers, e.g. racemates, optically pure diastereoisomers and mixtures of diastereoisomers.

[0029] According to the Cahn-Ingold-Prelog rules, the asymmetric carbon atom can be of the "R" or "S" configuration.

[0030] Certain embodiments of the present invention also provide compounds according to formula Ib as described herein and pharma- ceutically acceptable salts or esters thereof, particularly compounds according to formula I as described herein and pharma- ceutically acceptable salts thereof, more particularly compounds according to formula Ib as described herein.

[0031] Certain embodiments of the present invention also provide compounds according to formula I as described herein and pharma- ceutically acceptable salts or esters thereof, particularly compounds according to formula I as described herein and pharma- ceutically acceptable salts thereof, more particularly compounds according to formula I as described herein.

[0032] In one embodiment of the present invention, R X is H or alkyl.

[0033] In one embodiment of the present invention, R Y is H or alkyl.

[0034] In one embodiment of the present invention, R X is selected from H, alkyl and haloalkyl; R Y is selected from H or alkyl, with the proviso that RX If is H, then R Y is not H.

[0035] In one embodiment of the present invention, R X is selected from H or alkyl, R Y is selected from H or alkyl, with the proviso that R X If is H, then R Y is not H.

[0036] One embodiment of the present invention provides a compound of formula Ib as described herein, wherein Z is system R or system S.

[0037] One embodiment of the present invention provides a compound of formula Ib as described herein, wherein Z is the system S.

[0038] In one embodiment of the present invention, R 6 is alkyl.

[0039] One embodiment of the present invention provides a compound of formula Ib as described herein, wherein W is a 4-membered cycloalkyl ring substituted with alkyl and OH, or W is a substituted heterocycle of ring system A.

[0040] One embodiment of the invention is where W is a 4-membered cycloalkyl ring substituted with alkyl and OH, or W is a substituted heterocycle of ring system A, where R 1 is H and R 2 is alkyl, and R 3 is H.

[0041] One embodiment of the present invention provides a compound of formula Ib as described herein, wherein W is a substituted heterocycle of ring system A.

[0042] In one embodiment of the present invention, R 1 is H and R 2 is alkyl, and R 3is H or alkyl.

[0043] In one embodiment of the present invention, R 1 is H and R 2 is alkyl, and R 3 is H.

[0044] One embodiment of the present invention comprises: R X is selected from H, alkyl and haloalkyl; R Y is selected from H and alkyl, with the proviso that R X If is H, then R Y is not H; Z is a system of R and S [ka] Selected from; R 6 is alkyl; W is a substituted 4-membered cycloalkyl ring substituted with alkyl and OH, or W is a ring system A [ka] is a substituted heterocycle of the formula: R 1 is H and R 2 is alkyl; R 3 is H; Provided herein is a compound of formula Ib, or a pharma- ceutically acceptable salt thereof.

[0045] One embodiment of the present invention comprises: R X is selected from H or alkyl, R Y is selected from H and alkyl, with the proviso that R X If is H, then R Y is not H; Z is a system of R and S [ka] Selected from; R 6 is alkyl; W is ring system A [ka] is a substituted heterocycle of the formula: R 1 is H and R 2 is alkyl; R 3 is H; Provided herein is a compound of formula Ib, or a pharma- ceutically acceptable salt thereof.

[0046] One embodiment of the present invention comprises: R X is selected from H and alkyl; R Y is selected from H and alkyl, with the proviso that R X If is H, then R Y is not H; Z is the system S [ka] Selected from; R 6 is alkyl; Provided herein is a compound of formula Ib, or a pharma- ceutically acceptable salt thereof.

[0047] Specific examples of compounds of formula Ib described herein are 4-[6-[[(3R)-1-ethyl-3-piperidyl]amino]pyridazin-3-yl]-3-hydroxy-5-methyl-benzonitrile; 4-[6-[[(3R)-1-ethyl-3-piperidyl]amino]-4-(trifluoromethyl)pyridazin-3-yl]-3-hydroxy-benzonitrile; 3-Hydroxy-4-[6-[(3-hydroxy-3-methyl-cyclobutyl)amino]-4-methyl-pyridazin-3-yl]benzonitrile; 4-[6-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-hydroxy-5-methyl-benzonitrile or 4-[6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-hydroxy-5-methyl-benzonitrile; 4-[6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-hydroxy-5-methyl-benzonitrile or 4-[6-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-hydroxy-5-methyl-benzonitrile; and pharma- ceutically acceptable salts thereof.

[0048] Specific examples of compounds of formula Ib described herein are also 4-[6-[(3aS,7aR)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-hydroxy-5-methyl-benzonitrile or 4-[6-[(3aR,7aS)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-hydroxy-5-methyl-benzonitrile; 4-[6-[(3aR,7aS)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-hydroxy-5-methyl-benzonitrile or 4-[6-[(3aS,7aR)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-hydroxy-5-methyl-benzonitrile; 3-Hydroxy-4-[4-methyl-6-(6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl)pyridazin-3-yl]benzonitrile; 4-[6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-4-methyl-pyridazin-3-yl]-3-hydroxy-benzonitrile or 4-[6-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-4-methyl-pyridazin-3-yl]-3-hydroxy-benzonitrile; 4-[6-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-4-methyl-pyridazin-3-yl]-3-hydroxy-benzonitrile or 4-[6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-4-methyl-pyridazin-3-yl]-3-hydroxy-benzonitrile; 4-[4-ethyl-6-[[(3R)-1-ethyl-3-piperidyl]amino]pyridazin-3-yl]-3-hydroxy-benzonitrile; and pharma- ceutically acceptable salts thereof.

[0049] Preferred examples of compounds of formula Ib described herein are 4-[6-[[(3R)-1-ethyl-3-piperidyl]amino]pyridazin-3-yl]-3-hydroxy-5-methyl-benzonitrile; 4-[6-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-hydroxy-5-methyl-benzonitrile or 4-[6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-hydroxy-5-methyl-benzonitrile; 4-[6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-hydroxy-5-methyl-benzonitrile or 4-[6-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-hydroxy-5-methyl-benzonitrile; and pharma- ceutically acceptable salts thereof.

[0050] Preferred examples of compounds of formula Ib described herein are also 4-[6-[(3aS,7aR)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-hydroxy-5-methyl-benzonitrile or 4-[6-[(3aR,7aS)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-hydroxy-5-methyl-benzonitrile; 4-[6-[(3aR,7aS)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-hydroxy-5-methyl-benzonitrile or 4-[6-[(3aS,7aR)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-hydroxy-5-methyl-benzonitrile; 3-Hydroxy-4-[4-methyl-6-(6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl)pyridazin-3-yl]benzonitrile; 4-[6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-4-methyl-pyridazin-3-yl]-3-hydroxy-benzonitrile or 4-[6-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-4-methyl-pyridazin-3-yl]-3-hydroxy-benzonitrile; 4-[6-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-4-methyl-pyridazin-3-yl]-3-hydroxy-benzonitrile or 4-[6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-4-methyl-pyridazin-3-yl]-3-hydroxy-benzonitrile; 4-[4-ethyl-6-[[(3R)-1-ethyl-3-piperidyl]amino]pyridazin-3-yl]-3-hydroxy-benzonitrile; and pharma- ceutically acceptable salts thereof.

[0051] The most preferred examples of compounds of formula Ib described herein are 4-[6-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-hydroxy-5-methyl-benzonitrile or 4-[6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-hydroxy-5-methyl-benzonitrile; 4-[6-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-hydroxy-5-methyl-benzonitrile or 4-[6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-hydroxy-5-methyl-benzonitrile; and pharma- ceutically acceptable salts thereof.

[0052] The most preferred examples of compounds of formula Ib described herein are also 4-[6-[(3aS,7aR)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-hydroxy-5-methyl-benzonitrile or 4-[6-[(3aR,7aS)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-hydroxy-5-methyl-benzonitrile; 4-[6-[(3aR,7aS)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-hydroxy-5-methyl-benzonitrile or 4-[6-[(3aS,7aR)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-hydroxy-5-methyl-benzonitrile; 3-Hydroxy-4-[4-methyl-6-(6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl)pyridazin-3-yl]benzonitrile; 4-[6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-4-methyl-pyridazin-3-yl]-3-hydroxy-benzonitrile or 4-[6-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-4-methyl-pyridazin-3-yl]-3-hydroxy-benzonitrile; 4-[6-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-4-methyl-pyridazin-3-yl]-3-hydroxy-benzonitrile or 4-[6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-4-methyl-pyridazin-3-yl]-3-hydroxy-benzonitrile; and pharma- ceutically acceptable salts thereof.

[0053] One embodiment of the invention is a compound of formula I, wherein the compound of formula I is a compound of formula Ib [ka] [In the formula, R x is alkyl; W is a substituted 4-6 membered cycloalkyl ring or a substituted heterocycle of ring system A, where the substituted cycloalkyl is substituted with 1 or 2 substituents selected from OH, halo, and alkyl, and ring system A is [ka] and; Where: R 1 is H; R 2 is alkyl; or R 1 and R 2 and the atoms to which they are attached, taken together, form a five-membered ring; R 3 is OH or halo] and pharma- ceutically acceptable salts thereof.

[0054] In one embodiment of the present invention, R X is methyl of ethyl.

[0055] In one embodiment of the present invention, R X is methyl.

[0056] One embodiment of the invention is wherein W is selected from methylcyclobutanol, cyclohexanol, or ring system A, where R 1 is H; R 2 is alkyl; or R 1 and R 2 are joined together to form a five-membered ring; R 3 is H, OH or halo; Provided are compounds according to formula I described herein.

[0057] One embodiment of the invention is wherein W is the ring system A, wherein R 1 is H; R 2 is methyl or ethyl; or R 1 and R 2 form a five-membered ring together with the atoms to which they are attached; R 3 is H, Provided are compounds according to formula I described herein.

[0058] One embodiment of the invention is wherein W is the ring system A, wherein R 1 is H; R 2 is ethyl; R 3is H, Provided are compounds according to formula I described herein.

[0059] One embodiment of the present invention provides a compound according to formula I described herein, wherein W is selected from: i. Methylcyclobutanol ii. Cyclohexanol iii. 1-Ethylpiperdine iv. 1-Methylpiperdine v. 1-Methyl-3-fluoro-piperidine vi. 1-Methylpiperidin-3-ol vii. 1,2,3,5,6,7,8,8a-Octahydroindolizine.

[0060] One embodiment of the present invention comprises: 4-[6-[[(3R)-1-ethyl-3-piperidyl]amino]-4-methyl-pyridazin-3-yl]-3-hydroxy-benzonitrile; formic acid; and 4-[6-[[(3R)-1-ethyl-3-piperidyl]amino]-4-methyl-pyridazin-3-yl]-3-hydroxy-benzonitrile; and pharma- ceutically acceptable salts thereof.

[0061] Illustrative of the compounds of formula I described herein is 4-[6-[[(3R)-1-ethyl-3-piperidyl]amino]-4-methyl-pyridazin-3-yl]-3-hydroxy-benzonitrile and pharma- ceutically acceptable salts thereof.

[0062] Specific examples of compounds of formula I described herein are 4-[6-[[(3R)-1-ethyl-3-piperidyl]amino]-4-methyl-pyridazin-3-yl]-3-hydroxy-benzonitrile; formic acid and pharma-ceutically acceptable salts thereof.

[0063] Another embodiment of the present invention provides pharmaceutical compositions or medicaments containing the compound of the present invention and therapeutically inert carriers, diluents or excipients, and methods of using the compound of the present invention to prepare such compositions and medicaments.In one example, the compound of formula Ib can be formulated into galenic dosage forms by mixing with a physiologically acceptable carrier, i.e., a carrier that is non-toxic to recipients at the dosage and concentration used, at ambient temperature, at an appropriate pH, and at the desired degree of purity. The pH of the formulation depends mainly on the specific application and the 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 formulation, or as an aqueous solution.

[0064] The compositions are formulated, dosed, and administered in a manner consistent with good medical practice. Factors to consider in this regard include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of drug delivery, the method of administration, the administration schedule, and other factors known to medical practitioners.

[0065] The compounds of the present invention may be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal, as well as epidural and intranasal, and, where desired for localized treatment, intralesional administration. Parenteral administration includes intramuscular, intravenous, intraarterial, intraperitoneal or subcutaneous administration.

[0066] The compounds of the present invention may be administered in any convenient dosage form, such as tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions can contain ingredients that are conventional in pharmaceutical preparations, such as diluents, carriers, pH modifiers, sweeteners, fillers, and additional active agents.

[0067] Typical formulations are prepared by mixing the compound of the present invention with carrier or additive.Suitable carrier and additive are well known to those skilled in the art and are described in detail in, for example, Ansel, Howard C., et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. The formulation may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricating agents, emulsifying agents, suspending agents, preservatives, antioxidants, opacifying agents, glidants, processing aids, colorants, sweeteners, flavors, flavorings, diluents, and other known additives to present the drug (i.e., a compound of the invention or a pharmaceutical composition thereof) in an attractive manner or to aid in the manufacture of a pharmaceutical product (i.e., a medicament).

[0068] The compound of formula Ib and its pharma- ceutically acceptable salts can be processed with pharma- ceutically inert, inorganic or organic adjuvants for the production of tablets, coated tablets, sugar-coated tablets, hard gelatin capsules, injectable solutions, or topical preparations.Lactose, corn starch or its derivatives, talc, stearic acid or its salts, etc., can be used as such adjuvants for tablets, sugar-coated tablets, and hard gelatin capsules, for example.

[0069] Suitable adjuvants for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semisolid substances, and liquid polyols.

[0070] Suitable adjuvants for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose etc.

[0071] Suitable adjuvants for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, and the like.

[0072] Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semisolid or liquid polyols etc.

[0073] Suitable adjuvants for topical ophthalmic formulations are, for example, cyclodextrin, mannitol or many other carriers and additives known in the art.

[0074] In addition, pharmaceutical preparations may contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorings, salts for varying the osmotic pressure, buffers, masking agents, or antioxidants. Pharmaceutical preparations may also contain other therapeutically valuable substances.

[0075] The dosage may vary within a wide range and will of course be adapted to the individual requirements of each particular case. In general, for oral administration, a daily dosage of about 0.1 mg to 20 mg per kg of body weight, preferably about 0.5 mg to 4 mg per kg of body weight (e.g. about 300 mg per person), preferably divided into 1 to 3 individual administrations, which may, if appropriate, consist of, for example, equal amounts. For topical administration, the preparation may contain 0.001% to 15% by weight of medicament, and the required dose, which may be between 0.1 mg and 25 mg, may be administered either by a single administration per day or per week, or by multiple administrations (2 to 4 times) per day, or by multiple administrations per week. However, it will be clear that the upper or lower limits given herein may be exceeded in the cases indicated.

[0076] One embodiment of the present invention is a compound according to formula Ib as described herein for use as a therapeutically active substance.

[0077] One embodiment of the invention is a compound according to formula Ib as described herein for use in the treatment or prevention of a disease, disorder or condition, wherein the disease, disorder or condition is responsive to NLRP3 inhibition.

[0078] One embodiment of the invention is a compound according to formula Ib as described herein for the treatment or prevention of a disease, disorder or condition, wherein the disorder or condition is responsive to NLRP3 inhibition.

[0079] One embodiment of the present invention is a compound according to formula I as described herein for use as a therapeutically active substance.

[0080] One embodiment of the invention is a compound according to formula I as described herein for use in the treatment or prevention of a disease, disorder or condition, wherein the disease, disorder or condition is responsive to NLRP3 inhibition.

[0081] One embodiment of the invention is a compound according to formula I as described herein for the treatment or prevention of a disease, disorder or condition, wherein the disorder or condition is responsive to NLRP3 inhibition.

[0082] As used herein, the term "NLRP3 inhibition" refers to a complete or partial reduction in the activity level of NLRP3, including, for example, inhibition of active NLRP3 and / or inhibition of activation of NLRP3.

[0083] There is evidence for a role for NLRP3-induced IL-1 and IL-18 in inflammatory responses associated with or resulting from a number of different disorders (Menu et al., Clinical and Experimental Immunology, 166:1-15, 2011; Strowig et al., Nature, 481:278-286, 2012).

[0084] In one embodiment, the disease, disorder or condition is selected from the following: (i) Inflammation; (ii) autoimmune diseases; (iii) cancer; (iv) infectious diseases; (v) central nervous system disorders; (vi) metabolic diseases; (vii) cardiovascular disease; (viii) respiratory diseases; (ix) liver disease; (x) Kidney disease; (xi) eye diseases; (xii) skin diseases; (xiii) Lymphatic symptoms; (xiv) psychological disorders; (xv) graft-versus-host disease; (xvi) allodynia; (xvii) diabetes-related symptoms; and (xviii) Any disease in which an individual is determined to have a germline or somatic non-silent mutation in NLRP3.

[0085] In another embodiment, the disease, disorder or condition is selected from the following: (i) Cancer; (ii) infectious diseases; (iii) central nervous system disorders; (iv) cardiovascular disease; (v) liver disease; (vi) eye disease; or (vii) Skin diseases.

[0086] In a further exemplary embodiment of the invention, the disease, disorder or condition is inflammation. Examples of inflammation that may be treated or prevented include inflammatory responses associated with or resulting from: (i) skin conditions such as contact sensitivity, bullous pemphigoid, sunburn, psoriasis, atopic dermatitis, contact dermatitis, allergic contact dermatitis, seborrheic dermatitis, lichen planus, scleroderma, pemphigus, epidermolysis bullosa, urticaria, erythema, or alopecia; (ii) articular conditions such as osteoarthritis, systemic juvenile idiopathic arthritis, adult-onset Still's disease, relapsing polychondritis, rheumatoid arthritis, juvenile chronic arthritis, gout, or seronegative spondyloarthropathy (e.g. ankylosing spondylitis, psoriatic arthritis or Reiter's disease); (iii) muscle conditions such as polymyositis or myasthenia gravis; (iv) gastrointestinal conditions such as inflammatory bowel disease (including Crohn's disease and ulcerative colitis), colitis, gastric ulcer, celiac disease, proctitis, pancreatitis, eosinophilic gastroenteritis, mastocytosis, antiphospholipid syndrome, or food-related allergies that may have effects remote from the gut (e.g. migraine, rhinitis or eczema); (v) respiratory conditions such as chronic obstructive pulmonary disease (COPD), asthma (including eosinophilic asthma, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma or dust asthma, in particular chronic or refractory asthma, such as late-onset asthma and airway hyperresponsiveness), bronchitis, rhinitis (including acute rhinitis, allergic rhinitis, atrophic rhinitis, chronic rhinitis, caseous rhinitis, hypertrophic rhinitis, purulent rhinitis (rhinitis pumlenta), dry rhinitis, rhinitis medicamentosa, membranous rhinitis, seasonal rhinitis, such as hay fever and vasomotor rhinitis), sinusitis, idiopathic pulmonary fibrosis (IPF), sarcoidosis, farmer's lung, silicosis, asbestosis, volcanic ash-induced inflammation, adult respiratory distress syndrome, hypersensitivity pneumonitis, or idiopathic interstitial pneumonia; (vi) vascular diseases such as atherosclerosis, Behcet's disease, vasculitis, or Wegener's granulomatosis; (vii) autoimmune diseases such as systemic lupus erythematosus, Sjogren's syndrome, systemic sclerosis, Hashimoto's thyroiditis, type I diabetes mellitus, idiopathic thrombocytopenic purpura, or Graves' disease; (viii) ocular conditions such as uveitis, allergic conjunctivitis, or vernal conjunctivitis; (ix) neurological conditions such as multiple sclerosis or encephalomyelitis; (x) an infection or infection-related condition such as acquired immune deficiency syndrome (AIDS), acute or chronic bacterial infection, acute or chronic parasitic infection, acute or chronic viral infection, acute or chronic fungal infection, meningitis, hepatitis (A, B or C, or other viral hepatitis), peritonitis, pneumonia, epiglottitis, malaria, hemorrhagic dengue fever, leishmaniasis, streptococcal myositis, Mycobacterium avium intracellulare, Pneumocystis carinii pneumonia, orchitis / epidimitis, Legionnaires' disease, Lyme disease, influenza A, Epstein-Barr virus infection, viral encephalitis / aseptic meningitis, or pelvic inflammatory disease; (xi) renal conditions such as mesangial proliferative glomerulonephritis, nephrotic syndrome, nephritis, glomerulonephritis, obesity-related glomerulopathy, acute renal failure, acute kidney injury, uremia, nephritic syndrome, renal fibrosis including chronic crystal nephropathy, or renal hypertension; (xii) Lymphatic conditions such as Castleman's disease; (xiii) conditions of or involving the immune system, such as hyper-IgE syndrome, hepatoblastomatous leprosy, familial hemophagocytic lymphohistiocytosis, or graft-versus-host disease; (xiv) hepatic conditions such as chronic active hepatitis, nonalcoholic steatohepatitis (NASH), alcohol-induced hepatitis, nonalcoholic fatty liver disease (NAFLD), alcoholic fatty liver disease (AFLD), alcoholic steatohepatitis (ASH), primary biliary cirrhosis, fulminant hepatitis, hepatic fibrosis, or liver failure; (xv) Cancer, including those listed above; (xvi) Burns, wounds, trauma, hemorrhage or stroke; (xvii) radiation exposure; (xviii) metabolic diseases such as type 2 diabetes (T2D), atherosclerosis, obesity, gout or pseudogout; and / or (xix) Pain such as inflammatory hyperalgesia, pelvic pain, allodynia, neuropathic pain, or cancer-induced bone pain.

[0087] One embodiment of the present invention is a compound according to formula Ib as described herein for the treatment or prevention of a disease, disorder or condition selected from: (i) Inflammation; (ii) autoimmune diseases; (iii) cancer; (iv) infectious diseases; (v) central nervous system disorders; (vi) metabolic diseases; (vii) cardiovascular disease; (viii) respiratory diseases; (ix) liver disease; (x) Kidney disease; (xi) eye diseases; (xii) skin diseases; (xiii) Lymphatic symptoms; (xiv) psychological disorders; (xv) graft-versus-host disease; (xvi) allodynia; (xvii) diabetes-related symptoms; and (xviii) Any disease in which an individual is determined to have a germline or somatic non-silent mutation in NLRP3.

[0088] One embodiment of the 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, which disease, disorder or condition is responsive to NLRP3 inhibition.

[0089] 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.

[0090] 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 asthma or COPD.

[0091] One embodiment of the present invention is a compound according to formula Ib as described herein for the treatment or prevention of a disease, disorder or condition selected from Alzheimer's disease and Parkinson's disease.

[0092] One embodiment of the present invention is a compound according to formula Ib as described herein for the treatment or prevention of a disease, disorder or condition selected from asthma or COPD.

[0093] 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.

[0094] One embodiment of the 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.

[0095] One embodiment of the invention is a method for the treatment or prevention of a disease, disorder or condition selected from Alzheimer's disease and Parkinson's disease, comprising administering an effective amount of a compound according to formula Ib as described herein.

[0096] One embodiment of the invention is a method for the treatment or prevention of a disease, disorder or condition selected from asthma or COPD, comprising administering an effective amount of a compound according to formula Ib as described herein.

[0097] One embodiment of the invention relates to a method of inhibiting NLRP3, comprising administering an effective amount of a compound according to formula Ib described herein.

[0098] A compound of formula Ib as described herein, when prepared according to any one of the processes described, is also an embodiment of the invention.

[0099] One embodiment of the invention is a pharmaceutical composition comprising a compound according to Formula Ib described herein and a therapeutically inert carrier.

[0100] One embodiment of the invention is the use of a compound according to formula I as described herein in the treatment or prevention of a disease, disorder or condition, which disease, disorder or condition is responsive to NLRP3 inhibition.

[0101] One embodiment of the present invention is the use of a compound according to formula I as described herein in the treatment or prevention of a disease, disorder or condition selected from Alzheimer's disease and Parkinson's disease.

[0102] One embodiment of the present invention is the use of a compound according to formula I as described herein for use in the treatment or prevention of a disease, disorder or condition selected from asthma or COPD.

[0103] One embodiment of the present invention is a compound according to formula I as described herein for the treatment or prevention of a disease, disorder or condition selected from Alzheimer's disease and Parkinson's disease.

[0104] One embodiment of the present invention is a compound according to formula I as described herein for the treatment or prevention of a disease, disorder or condition selected from asthma or COPD.

[0105] One embodiment of the present invention is the use of a compound according to formula I as described herein for the preparation of a medicament for the treatment or prevention of a disease, disorder or therapy selected from Alzheimer's disease and Parkinson's disease.

[0106] One embodiment of the invention is the use of a compound according to formula I as described herein for the preparation of a medicament for the treatment or prevention of a disease, disorder or condition selected from asthma or COPD.

[0107] One embodiment of the invention is a method for the treatment or prevention of a disease, disorder or condition selected from Alzheimer's disease and Parkinson's disease, comprising administering an effective amount of a compound according to formula I as described herein.

[0108] One embodiment of the present invention is a method for the treatment or prevention of a disease, disorder or condition selected from asthma or COPD, comprising administering an effective amount of a compound according to formula I as described herein.

[0109] One embodiment of the invention relates to a method of inhibiting NLRP3, comprising administering an effective amount of a compound according to formula I described herein.

[0110] A compound of formula I as described herein when prepared according to any one of the processes described is also an embodiment of the invention.

[0111] One embodiment of the invention is a pharmaceutical composition comprising a compound according to Formula I described herein and a therapeutically inert carrier. [Brief description of the drawings]

[0112] [Figure 1] Voltage Pattern DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0113] Assay procedure NLRP3 and pyroptosis It is well established that activation of NLRP3 leads to cell pyroptosis, a feature that plays a key role in the manifestation of clinical disease (Yan-gang Liu et al., Cell Death & Disease, 2017, 8 (2), e2579; Alexander Wree et al., Hepatology, 2014, 59 (3), 898-910; Alex Baldwin et al., Journal of Medicinal Chemistry, 2016, 59 (5), 1691-1710; Ema Ozaki et al., Journal of Inflammation Research, 2015, 8, 15-27; Zhen Xie & Gang Zhao, Neuroimmunology Neuroinflammation, 2014, 1 (2), 60-65; Mattia Cocco et al., Journal of Medicinal Chemistry, 2014, 57(24), 10366-10382; T. Satoh et al., Cell Death & Disease, 2013, 4, e644). Therefore, inhibitors of NLRP3 are expected to block pyroptosis and the release of proinflammatory cytokines (e.g., IL-1β) from cells.

[0114] THP-1 cells: culture and preparation THP-1 cells (ATCC no. TIB-202) were grown in RPMI containing L-glutamine (Gibco no. 11835) supplemented with 1 mM sodium pyruvate (Sigma no. S8636) and penicillin (100 units / ml) / streptomycin (0.1 mg / ml) (Sigma no. P4333) in 10% fetal bovine serum (FBS) (Sigma no. F0804). Cells were passaged periodically and cultured until confluent (approximately 10 6The THP-1 cells were grown to a concentration of 625,000 cells / ml. On the day of the experiment, the THP-1 cells were harvested and resuspended in RPMI medium (without FBS). The cells were then counted and viability (>90%) was confirmed by trypan blue (Sigma #T8154). Appropriate dilutions were made to obtain a concentration of 625,000 cells / ml. LPS (Sigma #L4524) was added to this diluted cell solution to obtain a final assay concentration (FAC) of 1 μg / ml. 40 μl of the final preparation was dispensed into each well of a 96-well plate. The plates thus prepared were used for compound screening.

[0115] THP-1 cell pyroptosis assay For compound screening, the following method stepwise assay was followed. 1. Seed THP-1 cells (25,000 cells / well) in 40 μl of RPMI medium (without FBS) containing 1.0 μg / ml LPS in 96-well black-walled, clear-bottom cell culture plates coated with poly-D-lysine (VWR no. 734-0317). Add 2.5 μl of compound (8-point half-log dilutions with the highest dose at 10 μM) or vehicle (DMSO 0.1% FAC) to appropriate wells. 3. Incubate at 37℃, 5% CO2 for 3 hours. Add 4.5 μl of Nigericin (Sigma No. N7143) (FAC 5 μM) to all wells. 5. Incubate at 37℃, 5% CO2 for 1 hour. 6. At the end of the incubation period, spin the plate at 300 x g for 3 minutes and remove the supernatant. 7. Then, 50 μl of resazurin (Sigma #R7017) (FAC 100 μM resazurin in RPMI medium without FBS) is added and the plate is incubated at 37° C. and 5% CO2 for a further 1-2 hours. 8. Plates were read on an Envision reader at Ex 560nm and Em 590nm. 9. IC 50 Fit the data to a nonlinear regression equation (4-parameter log inhibitor vs. response variable slope) The results of the pyroptosis assay were analyzed using THP IC 50 These are summarized in Table 1 below.

[0116] Human whole blood IL-1β release assay For systemic delivery, the ability of a compound to inhibit NLRP3 when present in the bloodstream is of great importance. Therefore, we investigated the NLRP3 inhibitory activity of a number of compounds in human whole blood according to the following protocol.

[0117] Human whole blood in Li-heparin tubes was obtained from healthy donors from a volunteer donor pool. 1. Plate out 80 μl of whole blood containing 1 μg / ml LPS into a 96-well clear bottom cell culture plate (Corning #3585). 2. Add 10 μl of compound (8-point half log dilutions at the highest dose of 10 μM) or vehicle (DMSO 0.1% FAC) to appropriate wells. 3. Incubate at 37℃, 5% CO2 for 3 hours. 4. Add 10 μl of Nigericin (Sigma #N7143) (10 μM FAC) to all wells 5. Incubate at 37℃, 5% CO2 for 1 hour. 6. At the end of the incubation period, spin the plates at 300 x g for 5 minutes to pellet the cells and remove 20 μl of the supernatant and add to a 96-well v-bottom plate for IL-1β analysis (Note: these plates containing supernatants can be stored at -80°C for analysis at a later date) 7. IL-1β was measured according to the manufacturer's protocol (Perkin Elmer-AlphaLisa IL-1 Kit AL220F-5000). 8. IC 50 Fit the data to a nonlinear regression equation (4-parameter log inhibitor vs. response variable slope) Human whole blood assay results HWB IC 50 These are summarized in Table 1 below.

[0118] hERG screening assay cell CHO-crelox hERG cell line (ATCC reference number PTA-6812, female Chinese hamster cells) was generated and validated at Roche. Ready-to-use frozen instant CHO-hERG cells were cryopreserved at Evotec (Germany) and used directly in the experiments.

[0119] Experimental solution The extracellular solution contained (in mM): NaCl 150; KCl 4; CaCl2 1; MgCl2 1; HEPES 10, pH 7.2-7.4 with NaOH, osmolarity 290-330 mOsm. The internal solution contained (in mM): KCl, 10; KF, 100; NaCl, 10; HEPES, 10; EGTA, 20, pH 7.0-7.4 with KOH, osmolarity 260-300 mOsm.

[0120] Electrophysiology The effects of compounds on hERG K+-current parameters will be evaluated at two concentrations in at least quadruplicate cells.

[0121] hERG studies are performed using the automated patch clamp system SynchroPatch® 384 (Nanion Technologies GmbH, Germany). K+ currents are measured using the patch voltage clamp technique in the whole-cell configuration at 35-37°C.

[0122] Cells were held at a resting voltage of -80 mV and stimulated with the voltage pattern shown in Figure 1 (outward K at 35–37 °C). + (pulse pattern used to elicit currents), a stimulation frequency of 0.1 Hz (6 bpm) activated hERG channels and conducted outward IKhERG currents.

[0123] Data analysis The IKhERG amplitude was recorded at each drug concentration and compared to vehicle control values ​​(set at 100%) to define fractional blocks. Concentration-response data were fitted with the following relationship: [Table 1]

[0124] Concentration-response curves were fitted by nonlinear regression analysis using the EworkBook suite (ID Business Solutions Ltd, UK). Data fitting was performed using a four-parameter logistic model (fit=(A+(B / (1+((x / C)^D)))), where A=0 and B=100).

[0125] Brain penetration : Brain penetration in rats was studied by measuring drug concentrations in plasma, brain, and cerebrospinal fluid (CSF) samples after oral drug administration. Unbound brain concentrations were estimated through kinetic lipid membrane binding assays and ex vivo partitioning experiments. Unbound partition coefficients (kp, u, u) from brain or CSF to plasma were determined by correlating unbound brain or CSF concentrations with plasma exposure corrected for plasma protein binding.

[0126] Intracellular P-gp assay: A typical assay uses transfected LLC-PK1 cells (porcine kidney epithelial cells) overexpressing human or mouse P-gp and cultured on 96-well semi-permeable filter membrane plates. These cells form a tightly junctioned polarized monolayer that acts as a barrier between the apical and basolateral compartments.

[0127] P-gp is expressed in the apical membrane of the monolayer.

[0128] The adhesion of the cell monolayer and the functional activity of P-gp are confirmed by the addition of the cell impermeable marker Lucifer Yellow and the reference P-gp substrate Edoxaban, respectively.

[0129] PAMPA : PAMPA (Parallel Artificial Membrane Permeability Assay) is a first-choice permeability screen for drug candidates. The PAMPA assay uses artificial phospholipid membranes to mimic intracellular absorption conditions. The assay determines permeability values ​​that can be used for compound optimization and ranking purposes as well as input parameters for in silico models predicting intestinal absorption.

[0130] The donor concentration is measured at t-start (baseline) and compared to the donor and acceptor concentrations after a period of time (t-end) and the extent of compound crossing the membrane is calculated.

[0131] Microsomal Stability : Incubations with 1 μM test compound in microsomes (0.5 mg / mL) and the cofactor NADPH are carried out in 96-well plates at 37° C. on a TECAN (Tecan Group Ltd, Switzerland) automated liquid handling system. After a 10 min pre-incubation step of microsomes with test compound, the enzymatic reaction is initiated by addition of the cofactor. At 1, 3, 6, 9, 15, 25, 35 and 45 min, aliquots of the incubation are removed and quenched with 1:3 (v / v) acetonitrile containing an internal standard. Samples are then cooled and centrifuged before analyzing the supernatant by LC-MS / MS2.

[0132] Metabolic stability in hepatocytes : Assay Description: Biological materials. Obtain cryopreserved hepatocytes [mouse, rat, rabbit, monkey, human (mixed sex)]. Hepatocyte viability after reconstitution is at least 80% throughout the study. Obtain ready-to-use rat / human HepatoPac® cultures [long-term hepatocyte co-cultures; pooled (human male n=5, female n=5)], stromal mouse fibroblasts (negative control; pooled), culture plates, application medium, and maintenance medium.

[0133] Metabolism by Suspension Hepatocytes. The first pooled cryopreserved hepatocytes are reconstituted with pre-warmed William's E medium containing 10% FCS, 0.05 mg / mL streptomycin, 50 U / mL penicillin, and 0.4 mM L-glutamine, as well as 0.01 mg / mL gentamicin, 0.048 mg / mL hydrocortisone, and 0.004 mg / mL insulin to a final suspension density of 1×106 cells / mL. Incubations were performed fully automated using a Liquid Handling System (Tecan) equipped with a CO2 incubator with an orbital shaker. After addition of test compounds to the wells (1×105 cells / well), for example at 1 μM, the 96-well hepatocyte suspension culture plate is incubated at 5% CO2 and 37°C. Samples are quenched by adding acetonitrile (containing internal standard) to the incubation wells at the designated time points up to 2 hours.

[0134] Incubations of test substances (e.g., 1 μM, 0.1% v / v DMSO) performed in metabolic suspension assays with HepatoPac® are performed in 96-well plates containing either co-cultures of adherent hepatocytes and mouse fibroblast control cells or control cells alone (5% CO2 atmosphere, 37°C). The incubation medium in human HepatoPac® is the same as that in suspension stem cells. At the designated time points (2, 18, 26, 48, 72, and 96 hours), the entire well is quenched with ice-cold acetonitrile containing the internal standard.

[0135] The samples are then appropriately centrifuged and the supernatants are analyzed by LC-MS / MS. n=1 or 2 incubations are performed. [Table 2]

[0136] In the small molecule drug development process, one of the most frequent side effects leading to drug failure is cardiac arrhythmias. Such failures are often related to the drug's ability to inhibit the human ether-a-go-go-related gene (hERG) cardiac potassium channel. Therefore, no or low inhibition of the hERG cardiac potassium channel would be beneficial. [Table 3]

[0137] The invention will now be illustrated by the following examples, which have no limiting character.

[0138] If obtained as a mixture of enantiomers or diastereoisomers, the pure enantiomers or diastereoisomers may be obtained by the methods described herein or by methods known to those skilled in the art, e.g., chiral chromatography or crystallization.

[0139] Experimental Method Abbreviation: [Table 4] EXAMPLES

[0140] Unless otherwise stated, all examples and intermediates were prepared under a nitrogen atmosphere.

[0141] Preparative HPLC conditions: The sample was dissolved in 10 mL with DMSO, filtered, and purified by reversed-phase preparative HPLC (Gilson) using a Phenomenex Gemini NC-C18 preparative column (110 Å, 5 μm, 30 mm × 150 mm, eluted with a gradient of 0.1% formic acid in water-MeCN over 6 min at a flow rate of 40 mL min−1). An at-column dilution pump delivered 5 mL min−1 MeCN for 1.2 min. Gradient information: 0.0–1 min, 5% MeCN; 1–7.5 min, ramp from 5% MeCN to 15.8% MeCN; 7.5–7.6 min, ramp from 15.8% MeCN to 100% MeCN; 7.6–10.9 min, hold at 100% MeCN. Clean fractions were evaporated by lyophilization.

[0142] Example 1: 4-[6-[[(3R)-1-Ethyl-3-piperidyl]amino]-4-methyl-pyridazin-3-yl]-3-hydroxy-benzonitrile;Formic acid [ka]

[0143] Intermediate A1: 6-chloro-N-[(3R)-1-ethyl-3-piperidyl]-5-methyl-pyridazin-3-amine [ka] 3,6-Dichloro-4-methylpyridazine (CAS number 19064-64-3, 3.0 g, 18.4 mmol, 1.0 equiv.) and DIPEA (8.02 mL, 46.01 mmol, 2.5 equiv.) and (3R)-1-ethylpiperidin-3-amine (CAS number 1020396-26-2, 2.95 g, 23.01 mmol, 1.25 equiv.) were dissolved in NMP (30 mL) and the reaction mixture was stirred for 6 days at 120° C. The reaction mixture was diluted with EtOAc (200 mL), washed with brine (2×150 mL) and 10 wt % aqueous LiCl (2×150 mL), dried using a phase separator and concentrated in vacuo. The resulting residue was purified by chromatography on silica gel (24 g column, 0-10% (0.7N NH3 in MeOH) / CH2Cl2) to give the title compound (1.21 g, 4.75 mmol, 17% yield) as an orange solid (approximately 3:1 mixture of the desired product and its regioisomer 6-chloro-N-[(3R)-1-ethyl-3-piperidyl]-4-methyl-pyridazin-3-amine). LCMS m / z 255.3 (M+H). + (ES+).

[0144] Intermediate B1: 4-[6-[[(3R)-1-ethyl-3-piperidyl]amino]-4-methyl-pyridazin-3-yl]-3-methoxy-benzonitrile [ka] 6-Chloro-N-[(3R)-1-ethyl-3-piperidyl]-5-methyl-pyridazin-3-amine (Intermediate A1, 200.0 mg, 0.390 mmol, 1.0 equiv), 4-cyano-2-methoxyphenylboronic acid (CAS no. 1256345-67-1, 196 mg, 1.11 mmol, 2.2 equiv) and saturated aqueous sodium carbonate (0.5 mL, 0.390 mmol, 1 equiv) were suspended in 1,4-dioxane (3 mL) and the reaction mixture was sparged with N2, then evacuated and backfilled with N2 (3 times). XPhos Pd G3 (40.0 mg, 0.050 mmol, 0.09 equiv) was added and the reaction mixture was placed under N2 and then stirred at 80 °C for 18 h. The reaction mixture was cooled to room temperature and dry loaded onto silica gel (5 g). The crude product was purified by column chromatography (SiO2, 40 g cartridge, 0-10% (0.7 N NH3 in MeOH) / CH2Cl2) to give the title compound (184 mg, 0.52 mmol, 93% yield) (approximately 3:1 mixture with its regioisomer 4-[6-[[(3R)-1-ethyl-3-piperidyl]amino]-5-methyl-pyridazin-3-yl]-3-methoxy-benzonitrile) as a yellow solid. LCMS m / z 352.1 (M+H). + (ES+).

[0145] Example 1: 4-[6-[[(3R)-1-ethyl-3-piperidyl]amino]-4-methyl-pyridazin-3-yl]-3-hydroxy-benzonitrile; formic acid [ka] A solution of 4-[6-[[(3R)-1-ethyl-3-piperidyl]amino]-4-methyl-pyridazin-3-yl]-3-methoxy-benzonitrile (Intermediate B1) (172.0 mg, 0.49 mmol, 1.0 equiv) (Note: starting material is approximately a 3:1 mixture of methylpyridazine regioisomers) in CHCl (8 mL) was treated dropwise with boron tribromide 1 M in CHCl (1.7 mL, 1.70 mmol, 3.47 equiv) at 0 °C. After 30 min, the mixture was warmed and stirred at room temperature for 2 h. The reaction mixture was cooled to 0 °C and boron tribromide 1 M in CHCl (1.35 mL, 1.35 mmol, 3.94 equiv) was added, after which the reaction mixture was warmed to room temperature and stirred for 1.5 h. The reaction mixture was quenched with 0.7M NH3 MeOH (ca. 15 mL), left stirring for 30 min and concentrated under reduced pressure to give the crude product, which was subjected to preparative HPLC separation to give the title compound (50 mg, 0.13 mmol, 25% yield) as a light brown solid. LCMS: m / z 338.3 (M+H). + (ES+);336.4(MH)-(ES-).

[0146] Example 2: 4-[6-[[(3R)-1-ethyl-3-piperidyl]amino]pyridazin-3-yl]-3-hydroxy-5-methyl-benzonitrile [ka]

[0147] Intermediate 2A: 6-chloro-N-[(3R)-1-ethyl-3-piperidyl]pyridazin-3-amine To a yellow solution of commercially available 3,6-dichloropyridazine (CAS no. 141-30-0, 500 mg, 3.36 mmol, 1.0 equiv.) and commercially available [(3R)-1-ethyl-3-piperidyl]amine (CAS no. 1020396-26-2, 516.7 mg, 4.03 mmol, 1.2 equiv.) in N-methyl-2-pyrrolidinone (2.83 mL) was added N,N-diisopropylethylamine (1.5 mL, 8.59 mmol, 2.56 equiv.) with stirring at room temperature in a sealed tube. The yellow reaction mixture was stirred at 120° C. overnight (16 h). The reaction mixture was cooled to room temperature and extracted with approximately 70 mL of ethyl acetate and approximately 10 mL of 5% aqueous LiCl. The aqueous layer was back extracted with approximately 70 mL of ethyl acetate. The organic layer was washed twice with ca. 10 mL of 5% aqueous LiCl, once with ca. 10 mL of water, and once with ca. 10 mL of brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, gradient 0% to 100% in dichloromethane (dichloromethane:methanol:NH4OH 9:1:0.05)) to afford the title compound (542 mg, 66% yield) as an off-white solid. LCMS: m / z 241.1 [M+H] + ,ESI pos.

[0148] Intermediate 2B: 4-amino-3-methoxy-5-methyl-benzonitrile [ka] Two batches were run in parallel.

[0149] To a solution of commercially available 4-bromo-2-methoxy-6-methylbenzenamine (CAS number 348169-39-1, 25.0 g, 115 mmol, 1.00 equiv.) in DMF (250 mL) was added Zn(CN)2 (13.5 g, 115 mmol, 7.34 mL, 1.00 equiv.) and Pd(PPh3)4 (66.8 g, 57.8 mmol, 0.50 equiv.). The reaction mixture was stirred at 100° C. for 12 h. The reaction mixture was poured into water (1.50 L) and extracted with ethyl acetate (1 L×3). The organic phase was washed with brine (1 L×3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue which was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=100 / 1 to 0 / 1) to give the title compound (28.0 g, 75% yield) as a yellow solid. 1 H NMR(DMSO-d6)δ 7.05(s,2H),5.47(bs,2H),3.81(s,3H),2.09(s,3H).

[0150] Intermediate 2C: 4-Bromo-3-methoxy-5-methyl-benzonitrile [ka] To a solution of CuBr (46.4 g, 323 mmol, 9.86 mL, 1.50 equiv) in MeCN (180 mL) was added t-BuONO (33.3 g, 323 mmol, 38.5 mL, 1.50 equiv) and stirred at 65 °C. Then, a solution of intermediate 2B 4-bromo-3-methoxy-5-methyl-benzonitrile (35.0 g, 215 mmol, 1.00 equiv) in MeCN (180 mL) was added at 65 °C. The mixture was stirred at 65 °C for 3.5 h. After completion, saturated aqueous Na2SO3 (400 mL) and saturated aqueous NH4Cl (200 mL) were added to the mixture and extracted with ethyl acetate (500 mL x 3). The organic phase was washed with brine (50 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1, Rf = 0.75) to give the title compound (20.7 g, 42% yield) as a white solid. 1H NMR(DMSO-d6)δ 7.43,7.40(2s,1H each),3.90(s,3H),2.37(s,3H).

[0151] Intermediate 2D: 3-Methoxy-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile [ka] To a solution of the above 4-bromo-3-methoxy-5-methyl-benzonitrile (18.0 g, 79.6 mmol, 1.00 equiv.) in DMF (180 mL) was added B2Pin2 (30.3 g, 119 mmol, 1.50 equiv.) and AcOK (35.1 g, 358 mmol, 4.50 equiv.). The mixture was stirred at 20° C. for 0.5 h and Pd(dppf)Cl 2· CH2Cl2 (13.0 g, 15.9 mmol, 0.20 equiv) was added. The mixture was stirred at 100 °C for 12 h. The mixture was filtered through diatomaceous earth, diluted with H2O (500 mL), and extracted with ethyl acetate (800 mL x 3). The organic phase was washed with brine (800 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 1 / 1, Rf = 0.30) to give the title compound (18.0 g, 83% yield) as a white solid. 1 H NMR(DMSO-d6)δ 7.22,7.21(2s,1H each),3.75(s,3H),2.27(s,3H),1.30(s,12H).

[0152] Intermediate 2E: (4-cyano-2-hydroxy-6-methyl-phenyl)boronic acid [ka] A solution of the above 3-methoxy-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (17.0 g, 96.0 mmol, 1.00 equiv) in dichloromethane (170 mL) was cooled at 0 °C and BBr3 (38.9 g, 155 mmol, 2.50 equiv) was added dropwise at 0 °C. The mixture was stirred at 0 °C for 0.5 h. The mixture was poured into H2O (200 mL), filtered, and the cake was collected and triturated with EtOAc (20 mL) to give the title compound (4.67 g, 42% yield) as a grey solid. LCMS: m / z 178.1 [M+H] + ,ESI pos.

[0153] Example 2: 4-[6-[[(3R)-1-ethyl-3-piperidyl]amino]pyridazin-3-yl]-3-hydroxy-5-methyl-benzonitrile To a mixture of Intermediate A2 6-chloro-N-[(3R)-1-ethyl-3-piperidyl]pyridazin-3-amine (80 mg, 0.332 mmol, 1.00 equiv) from above and Intermediate 2E (4-cyano-2-hydroxy-6-methyl-phenyl)boronic acid (128 mg, 0.665 mmol, 2.00 equiv) in excess dry 1,4-dioxane (2 mL) and water (1 mL) in a sealed tube was added potassium carbonate (206.7 mg, 1.50 mmol, 4.50 equiv) with stirring at room temperature (23° C.). The orange reaction mixture was sparged with argon for 3 min, after which 1,1'-bis(diphenylphosphino)ferrocene-palladium(ii) dichloride dichloromethane complex (40.7 mg, 0.05 mmol, 0.150 equiv.) was added with stirring at room temperature (23 °C). The orange reaction mixture was sealed and stirred at 95 °C (oil bath) for 16 h (overnight). After completion of the reaction, the mixture was cooled to room temperature and extracted twice with dichloromethane (2 x ca. 20 mL) and saturated NH4Cl solution (ca. 20 mL). The organic layer was washed with water (ca. 10 mL) and brine (ca. 10 mL). The aqueous phase was back extracted with dichloromethane (ca. 20 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE HN-M and purified by flash chromatography (SiO2; gradient 0% to 20% dichloromethane:methanol:NH4OH (v / v) 110:10:1 in dichloromethane) followed by further purification by preparative HPLC to give the title compound (51.7 mg, 46%) as a white powder. LCMS: m / z 338.2 [M+H] + ,ESI pos.

[0154] Example 3: 4-[6-[[(3R)-1-ethyl-3-piperidyl]amino]-4-(trifluoromethyl)pyridazin-3-yl]-3-hydroxy-benzonitrile [ka] Intermediate 3A: tert-butyl (3R)-3-[[6-chloro-5-(trifluoromethyl)pyridazin-3-yl]amino]piperidine-1-carboxylate and tert-butyl (3R)-3-[[6-chloro-4-(trifluoromethyl)pyridazin-3-yl]amino]piperidine-1-carboxylate A neat mixture of commercially available 3,6-dichloro-4-(trifluoromethyl)pyridazine (CAS no. 1057672-68-0, 1.72 g, 7.93 mmol, 1.0 equiv.) and commercially available (3R)-3-aminopiperidine-1-carboxylic acid tert-butyl ester (CAS no. 188111-79-7, 3.18 g, 15.9 mmol, 2.0 equiv.) in N,N-diisopropylethylamine (3.46 mL, 19.8 mmol, 2.5 equiv.) was stirred at 130° C. in a sealed tube for 24 hours. The warm mixture (approximately 50° C.) was poured into an Erlenmeyer containing ethyl acetate (100 mL), which was used to transfer the oily mixture, and water (100 mL) was added. This was stirred at room temperature for 20 minutes to dissolve all components. Extractions were performed with ethyl acetate / water and finally with brine. The residue was purified by flash chromatography (SiO2; 0-50% ethyl acetate in heptane) to give the title compound (first regioisomer) (1.67 g, 55%) as a pale yellow foam and the second regioisomer (1.07 g, 35% yield) as a pale yellow oil. LCMS: m / z 381.1 ([{35Cl}M+H]+), 383.1 ([{37Cl}M+H]+), ESI pos.

[0155] Intermediate 3B: 6-chloro-N-[(3R)-3-piperidyl]-5-(trifluoromethyl)pyridazin-3-amine; hydrochloride [ka] To a solution of the above tert-butyl (3R)-3-[[6-chloro-5-(trifluoromethyl)pyridazin-3-yl]amino]piperidine-1-carboxylate intermediate 3A (first regioisomer) (1.67 g, 4.39 mmol, 1.00 equiv.) in dichloromethane (20 mL) and methanol (10 mL) was added 4 M HCl in dioxane (13.2 g, 10.9 mL, 43.9 mmol, 10.0 equiv.) via syringe. The clear yellow reaction solution was stirred at room temperature for 16 h. After complete conversion, the reaction mixture was concentrated in vacuo to afford the title compound (1.51 g, 98% yield) as a pale yellow foam. This compound was used in the next step without further purification. LCMS:m / z 281.1([{35Cl}M+H]+),283.1([{37Cl}M+H]+),ESI pos.

[0156] Intermediate 3C: 6-chloro-N-[(3R)-1-ethyl-3-piperidyl]-5-(trifluoromethyl)pyridazin-3-amine [ka] To a suspension of the above 6-chloro-N-[(3R)-3-piperidyl]-5-(trifluoromethyl)pyridazin-3-amine; hydrochloride intermediate 3B (1.51 g, 4.29 mmol, 1.00 equiv.) in dry dichloromethane (30 mL) was added acetaldehyde (472 mg, 597 μL, 10.7 mmol, 2.5 equiv.), followed by sodium acetate (879 mg, 10.7 mmol, 2.5 equiv.) with ice bath cooling. Sodium triacetoxyborohydride (1.63 g, 7.71 mmol, 1.8 equiv.) was then added at 0° C. The reaction mixture was stirred at 0° C. for 15 min and at room temperature for 2 h (light yellow suspension). After complete conversion, the reaction mixture was carefully basified with aqueous NaHCO3 (50 mL) and then extracted with dichloromethane (3×80 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product (1.4 g) was adsorbed onto ISOLUTE HM-N and purified by flash chromatography [silica gel, gradient 0% to 100% in dichloromethane (dichloromethane:methanol:NH4OH 110:10:1)] to afford the title compound (1.03 g, 76% yield) as a light brown oil. LCMS: m / z 309.1 ([{35Cl}M+H] + ), 311.0([{37Cl}M+H] + ),ESI pos.

[0157] Example 3: 4-[6-[[(3R)-1-ethyl-3-piperidyl]amino]-4-(trifluoromethyl)pyridazin-3-yl]-3-hydroxy-benzonitrile In a sealed tube, the above 6-chloro-N-[(3R)-1-ethyl-3-piperidyl]-5-(trifluoromethyl)pyridazin-3-amine intermediate 3C (143 mg, 454 μmol, 1.0 equiv.) and commercially available (4-cyano-2-hydroxy-phenyl)boronic acid (no CAS number, 130.9 mg, 771.7 μmol, 1.70 equiv.) were dissolved in 1,4-dioxane (5 mL) and water (2.5 mL). Potassium carbonate (282.3 mg, 2.04 mmol, 4.5 equiv.) was added with stirring at room temperature, followed by 1,1'-bis(diphenylphosphino)ferrocene palladium(ii) dichloride dichloromethane complex (55.6 mg, 68.09 μmol, 0.15 equiv.) under argon atmosphere. The mixture was then stirred at 95° C. overnight. The dark brown mixture was cooled to room temperature and extracted with water, ethyl acetate, brine, and ammonium chloride. The aqueous layer was back-extracted twice with ethyl acetate. The combined organic layers were washed with brine, then dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by RP-HPLC (C 18 , column: YMC-triart, 12 nm, 5 μm, 100×30 mm, ELSD, acetonitrile / water+0.1% triethylamine) to give the title compound (24 mg, 13% yield) as a white powder. LCMS: m / z 392.2 [M+H] + ,ESI pos.

[0158] Example 4: 3-Hydroxy-4-[6-[(3-hydroxy-3-methyl-cyclobutyl)amino]-4-methyl-pyridazin-3-yl]benzonitrile [ka] A mixture of 3-[(6-chloro-5-methyl-pyridazin-3-yl)amino]-1-methyl-cyclobutanol (CAS number 2557359-89-2, 70.0 mg, 0.28 mmol, 1.00 equiv, 90% purity), commercially available (no CAS number, 4-cyano-2-hydroxy-phenyl)boronic acid (95 mg, 0.58 mmol, 2.11 equiv), potassium carbonate (195 mg, 1.41 mmol, 5.10 equiv) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (45 mg, 0.06 mmol, 0.20 equiv) in 1,4-dioxane (2.2 mL) and water (1.1 mL) was flushed with argon and stirred at 95° C. for 16 h. The reaction mixture was cooled to room temperature and extracted with ethyl acetate and water. The aqueous layer was back extracted with ethyl acetate. The organic layer was washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, gradient 0% to 10% methanol in dichloromethane). All fractions containing the product were combined and concentrated in vacuo. The residue was adsorbed onto ISOLUTE HM-N and purified a second time by flash chromatography (SI-amine, gradient 0% to 10% methanol in ethyl acetate). All fractions containing the product were combined and concentrated in vacuo to give the title compound (25 mg, 28% yield) as an off-white solid. LCMS: m / z 311.2 [M+H] + ,ESI pos.

[0159] Examples 5A and 5B: 4-[6-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-hydroxy-5-methyl-benzonitrile and 4-[6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-hydroxy-5-methyl-benzonitrile [ka]

[0160] Intermediate 5A: t ert-Butyl 1-(6-chloropyridazin-3-yl)-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridine-6-carboxylate [ka] To a mixture of commercially available 3,6-dichloropyridazine (CAS number 141-30-0, 413 mg, 2.69 mmol, 1.00 equiv.) and commercially available 6-boc-octahydropyrrolo[2,3-c]pyridine (CAS number 1286755-20-1, 752.9 mg, 3.23 mmol, 1.20 equiv.) in N-methyl-2-pyrrolidinone (3 mL) was added N-ethyldiisopropylamine (1.14 mL, 6.72 mmol, 2.50 equiv.). The reaction mixture was stirred at 120° C. overnight. After complete conversion, the brown reaction mixture was cooled to room temperature, poured into ice water and brine, and extracted with ethyl acetate:tBME (v / v) 1:1 (3×80 mL). The organic layer was washed with water (80 mL) and brine (80 ml). The aqueous layer was re-extracted with ethyl acetate:tBME (v / v) 1:1 (80 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (SiO2; 0-90% ethyl acetate in heptane) to give the title compound (865 mg, 95%) as a pale yellow oil. LCMS: m / z 339.2 ([{35Cl}M+H]+), 341.1 ([{37Cl}M+H]+), ESI pos.

[0161] Intermediate 5B: 1-(6-chloropyridazin-3-yl)-2,3,3a,4,5,6,7,7a-octahydropyrrolo[2,3-c]pyridine; hydrochloride [ka] To a solution of intermediate 5A from above (865 mg, 2.55 mmol, 1.00 equiv) in excess dry dichloromethane (20 mL) was added 4M HCl (6.38 mL, 25.5 mmol, 10.0 equiv) dropwise at room temperature. The reaction mixture was stirred at 23° C. for 5 h. After complete conversion, the mixture was concentrated in vacuo to give the crude title compound as a pale yellow foam hydrogen chloride (733 mg), which was used in the next step without further purification. LCMS: m / z 239.2 ([{35Cl}M+H]+), 241.1 ([{37Cl}M+H]+), ESI pos.

[0162] Intermediate 5C: 1-(6-chloropyridazin-3-yl)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridine [ka] To a suspension of intermediate 5B from above (733 mg, 2.66 mmol, 1.00 equiv) in 1,2-dichloroethane (20 mL) was added triethylamine (577 μL, 4.13 mmol, 1.552 equiv). Stirring was allowed for 5 min at room temperature. Formaldehyde, 37% aqueous solution (448.5 mg, 411 μL, 5.53 mmol, 2.08 equiv) was added followed by sodium triacetoxyborohydride (2.26 g, 10.7 mmol, 4.00 equiv) in portions. The reaction mixture was stirred at room temperature for 1.5 h. The reaction mixture was carefully quenched with saturated aqueous NaHCO3 and extracted four times with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give the crude title compound (680 mg) as an off-white solid, which was used in the next step without further purification. LCMS:m / z 253.2([{35Cl}M+H]+),255.2([{37Cl}M+H]+),ESI pos.

[0163] Examples 5A and 5B: 4-[6-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-hydroxy-5-methyl-benzonitrile and 4-[6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-hydroxy-5-methyl-benzonitrile To a stirred yellow solution of intermediate 5C from above (300 mg, 1.19 mmol, 1.00 equiv) and (4-cyano-2-hydroxy-6-methyl-phenyl)boronic acid intermediate 2E from above (420.1 mg, 2.37 mmol, 2.00 equiv) in 1,4-dioxane (10 mL) and water (2.5 mL) in a sealed tube was added cesium carbonate (1.16 g, 3.56 mmol, 3.00 equiv) at room temperature (23° C.). The yellow reaction solution was flushed with argon (balloon) for 3 minutes, followed by the addition of XPhos Pd G3 (201 mg, 237 μmol, 0.20 equiv) at room temperature. The yellow reaction mixture was flushed with argon (balloon) for 2 minutes and stirred at 100° C. (preheated oil bath) for 3 hours. After complete conversion, the orange-yellow reaction mixture was cooled to room temperature, transferred to a separatory funnel and extracted with dichloromethane (50 mL) and saturated NH4Cl solution (40 mL). The organic phase was washed with water (20 mL) and brine (20 mL). The aqueous phase was back-extracted twice with dichloromethane (2 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE-HN-M and purified by flash chromatography (SiO2; 0%-70% dichloromethane:methanol:NH4OH (v / v) 110:10:1 in CH2Cl2) to give the title compound (383 mg, 91%) as an orange foam, which was directly purified by chiral HPLC (column: Chiral IK 5 μm, 250×20 mm; SFC, flow rate: 80 mL / min, 80 bar, 220 nm, 38% MeOH, 0.2% DEA). The first enantiomer (Example 5A) (rt=4.599 min, 103 mg, 27%) and the second enantiomer (Example 5B) (rt=4.990 min, 157 mg, 41%) were both obtained as a light brown foam. LCMS: m / z 350.2 [M+H] + ,ESI pos.

[0164] Reference example RE-A 2-[6-[(1-ethyl-3-piperidyl)amino]-4-methyl-pyridazin-3-yl]-5-(trifluoromethyl)phenol RE-A was synthesized similarly to WO20200234715.

[0165] Reference example RE-B 3-Methyl-2-[6-[[(3R)-1-ethyl-3-piperidyl]amino]pyridazin-3-yl]-5-(trifluoromethyl)phenol RE-B was synthesized as described in WO20200234715.

[0166] Examples 6A and 6B: 4-[6-[(3aS,7aR)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-hydroxy-5-methyl-benzonitrile and 4-[6-[(3aR,7aS)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-hydroxy-5-methyl-benzonitrile [ka]

[0167] Step A: tert-Butyl 1-(6-chloropyridazin-3-yl)-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridine-6-carboxylate To a mixture of 3,6-dichloropyridazine (CAS number 141-30-0, 300 mg, 2.01 mmol, 1.00 equiv.) and 1,2,3,3a,4,5,7,7a-octahydropyrrolo[2,3-c]pyridine-6-carboxylic acid tert-butyl ester (CAS number 1196147-27-9, 548 mg, 2.42 mmol, 1.20 equiv.) in N-methyl-2-pyrrolidinone (2.0 mL) was added N,N-diisopropylethylamine (666 mg, 0.90 mL, 5.15 mmol, 2.56 equiv.). The reaction mixture was stirred at 120° C. for 16 h. The reaction mixture was cooled to room temperature and extracted with ethyl acetate and 5% aqueous LiCl. The aqueous layer was back-extracted with ethyl acetate. The organic layer was washed three times with 5% aqueous LiCl, once with water, and once with brine. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 25 g, gradient 0% to 50% ethyl acetate in heptane) to give the title compound (603 mg, 84% yield) as a pale yellow oil. LCMS: m / z 339.2 [M+H] + ,ESI pos.

[0168] Step B: 1-(6-chloropyridazin-3-yl)-2,3,3a,4,5,6,7,7a-octahydropyrrolo[2,3-c]pyridine hydrochloride To a solution of tert-butyl 1-(6-chloropyridazin-3-yl)-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridine-6-carboxylate (Example 6, Step A) (596 mg, 1.67 mmol, 1.00 equiv) in dichloromethane (8.0 mL) was added 4M HCl in dioxane (5.04 g, 4.2 mL, 16.8 mmol, 10.05 equiv) dropwise. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo to give the title compound (665 mg, 94% yield, 65% purity) as a pale yellow foam which was used without further purification. LCMS: m / z 239.1 [M+H] + ,ESI pos.

[0169] Step C: 1-(6-chloropyridazin-3-yl)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridine To a suspension of 1-(6-chloropyridazin-3-yl)-2,3,3a,4,5,6,7,7a-octahydropyrrolo[2,3-c]pyridine hydrochloride (Example 6, Step B) (665 mg, 1.57 mmol, 1.00 equiv., 65% purity) in dichloromethane (10 mL) was added acetaldehyde (172 mg, 0.22 mL, 3.90 mmol, 2.48 equiv.), followed by sodium acetate (26 mg, 3.17 mmol, 2.02 equiv.) under ice bath cooling. Sodium triacetoxyborohydride (502 mg, 2.37 mmol, 1.51 equiv.) was added in three portions at 0° C. The reaction mixture was stirred at 0° C. for 30 min and at room temperature for 1 h. The reaction mixture was carefully quenched with saturated aqueous NaHCO3 and extracted three times with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 25 g, gradient 0% to 10% methanol in dichloromethane) to give the title compound (262 mg, 59% yield) as a brown solid. LCMS: m / z 267.2 [M+H] + ,ESI pos.

[0170] Step D: 4-[6-(6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl)pyridazin-3-yl]-3-hydroxy-5-methyl-benzonitrile A mixture of 1-(6-chloropyridazin-3-yl)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridine (Example 6, Step C) (160 mg, 0.57 mmol, 1.00 equiv), (4-cyano-2-hydroxy-6-methyl-phenyl)boronic acid (172 mg, 0.97 mmol, 1.71 equiv, Intermediate 2E), cesium carbonate (557 mg, 1.71 mmol, 3.00 equiv), and XPhos Pd G3 (72 mg, 0.09 mmol, 0.15 equiv) in 1,4-dioxane (3.6 mL) and water (0.90 mL) was flushed with argon and stirred at 100° C. for 4 h and at room temperature for 16 h. The reaction mixture was extracted with ethyl acetate and half-saturated aqueous NH4Cl solution. The aqueous layer was back-extracted with ethyl acetate. The organic layer was washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (Si-amine, 12 g, gradient 0% to 10% methanol in ethyl acetate). All fractions containing product were combined and concentrated in vacuo. The residue was repurified by flash chromatography (silica gel, 12 g, gradient 0% to 50% in dichloromethane (dichloromethane:methanol:NH4OH 9:1:0.05)) to give the title compound (167 mg, 77% yield) as a pale yellow foam. LCMS: m / z 364.3 [M+H] + ,ESI pos.

[0171] Step E: 4-[6-[(3aS,7aR)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-hydroxy-5-methyl-benzonitrile and 4-[6-[(3aR,7aS)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-hydroxy-5-methyl-benzonitrile Chiral separation of 4-[6-(6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl)pyridazin-3-yl]-3-hydroxy-5-methyl-benzonitrile (Example 6, step D) (164 mg, 0.43 mmol, 1.00 equiv.) by SFC (column Chiral IK, eluent B: 40% methanol + 0.2% diethylamine) gave the two enantiomers Example 6A (first elution, R t = 1.98 min) (76 mg, 46% yield) as a light brown foam (LCMS: m / z 364.2 [M+H] +, ESI pos), and Example 6B (second elution, R t = 2.55 min) (78 mg, 48% yield) as a light brown foam (LCMS: m / z 364.3 [M+H] + ,ESI pos) was obtained.

[0172] Examples 7, 7A, and 7B 3-Hydroxy-4-[4-methyl-6-(6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl)pyridazin-3-yl]benzonitrile, 4-[6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-4-methyl-pyridazin-3-yl]-3-hydroxy-benzonitrile and 4-[6-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-4-methyl-pyridazin-3-yl]-3-hydroxy-benzonitrile [ka]

[0173] Step A: tert-Butyl 1-(6-chloro-5-methyl-pyridazin-3-yl)-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridine-6-carboxylate 3,6-Dichloro-4-methyl-pyridazine (200 mg, 1.23 mmol, 1.0 equiv) was dissolved in NMP (2.0 mL), and 1,2,3,3a,4,5,7,7a-octahydropyrrolo[2,3-c]pyridine-6-carboxylic acid tert-butyl ester (277.69 mg, 1.23 mmol, 1.0 equiv, CAS number 1196147-27-9) and N,N-diisopropylethylamine (641.3 mg, 867 μL, 4.96 mmol, 4.0 equiv) were added to the reaction mixture, which was stirred for 5 h at 130° C. After cooling to room temperature, the reaction mixture was extracted with ethyl acetate (10 mL) and aqueous LiCl (10%, 2.0 mL). The organic layer was washed twice with aqueous LiCl (10%, 2.0 mL), once with water (5.0 mL), and once with brine (5.0 mL). The aqueous layer was back-extracted with ethyl acetate (10 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (gradient 0% to 50% EtOAc in heptane) and repurified by SFC (column: achiral Torus2Pic, 12 nm, 5 μm, 250×20 mm, 10% MeOH) to give the title compound (197.4 mg, 41% yield) as a pale yellow solid and tert-butyl 1-(6-chloro-4-methyl-pyridazin-3-yl)-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridine-6-carboxylate (58 mg, 13%) as a pale yellow solid. LCMS m / z: 353.2 [M+H] + ,ESI pos.

[0174] Step B: 1-(6-chloro-5-methyl-pyridazin-3-yl)-2,3,3a,4,5,6,7,7a-octahydropyrrolo[2,3-c]pyridine; Hydrogen chloride The above tert-butyl 1-(6-chloro-5-methyl-pyridazin-3-yl)-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridine-6-carboxylate (197 mg, 0.5 mmol, 1.0 equiv.) was dissolved in dichloromethane (1.6 mL) and methanol (0.8 mL). Then, 4M HCl in dioxane (1.2 mL, 4.78 mmol, 9.0 equiv.) was added dropwise to the reaction mixture, which was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo to give the title compound (180 mg, 88% yield) as a pale yellow solid. LCMS m / z: 253.2 [M+H] + ,ESI pos.

[0175] Step C: 1-(6-chloro-5-methyl-pyridazin-3-yl)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridine The above 1-(6-chloro-5-methyl-pyridazin-3-yl)-2,3,3a,4,5,6,7,7a-octahydropyrrolo[2,3-c]pyridine; hydrogen chloride (200 mg, 691.6 μmol, 1.0 equiv.) was dissolved in 1,2-dichloroethane (6.6 mL) and triethylamine (107.8 mg, 148 μL, 1.06 mmol, 1.54 equiv.). After stirring for 5 min, formaldehyde (37% aqueous solution, 125.8 mg, 115.4 μL, 1.6 mmol, 2.2 equiv.) was added, followed by sodium triacetoxyborohydride (586.3 mg, 2.77 mmol, 4.0 equiv.) in portions. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was carefully quenched with saturated aqueous NaHCO3 and extracted 5 times with DCM (+2% MeOH). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (gradient 0% to 5% methanol in dichloromethane) to give the title compound (123 mg, 63% yield) as a light brown solid. LCMS m / z: 267.2 [M+H] + ,ESI pos.

[0176] Step D: 3-Hydroxy-4-[4-methyl-6-(6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl)pyridazin-3-yl]benzonitrile 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 (50 mg, 187 μmol, 1.0 equiv.), commercially available (4-cyano-2-hydroxy-phenyl)boronic acid (49.5 mg, 304 μmol, 1.6 equiv.; no CAS number), potassium carbonate (119 mg, 860 μmol, 4.6 equiv.) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(ii) dichloride dichloromethane complex (23.1 mg, 28.3 μmol, 0.15 equiv.) in 1,4-dioxane (1.19 mL) and water (0.59 mL) was flushed with argon and stirred at 95° C. overnight. Then, (4-cyano-2-hydroxy-phenyl)boronic acid (49.53 mg, 304 μmol, 1.6 equiv.) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(ii) dichloride dichloromethane complex (23.1 mg, 28.3 μmol, 0.15 equiv.) were added to the reaction mixture and stirring was continued at 95° C. for 5 h. The reaction mixture was cooled to room temperature and then extracted with ethyl acetate and half-saturated NH4Cl solution. 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 purified by flash chromatography on silica gel (gradient 0% to 10% methanol in dichloromethane) and repurified by preparative HPLC (column: Gemini NX, 12 nm, 5 μm, 100×300 mm; gradient MeCN / water+0.1% TEA) to give the title compound (8 mg, 12% yield) as a white solid. LCMS m / z: 348.2 [MH] - ,ESI neg.

[0177] Step E: 4-[6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-4-methyl-pyridazin-3-yl]-3-hydroxy-benzonitrile and 4-[6-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-4-methyl-pyridazin-3-yl]-3-hydroxy-benzonitrile The above 3-hydroxy-4-[4-methyl-6-(6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl)pyridazin-3-yl]benzonitrile (60 mg) was prepared as described above. After chiral separation via SFC (column: Chiral AD-H, 5 μm, 250×20 mm, 20% MeOH+0.2% DEA), compound 7A (first elution, R t = 2.16 min; 20.6 mg, 8% yield) as a pale yellow solid, and compound 7B (second elution, R t = 2.16 min; 11.4 mg, 4% yield) was isolated as a pale yellow solid. LCMS m / z: 348.2 [MH] - ,ESI neg.

[0178] Example 8: 4-[4-ethyl-6-[[(3R)-1-ethyl-3-piperidyl]amino]pyridazin-3-yl]-3-hydroxy-benzonitrile [ka]

[0179] Step A: tert-Butyl (3R)-3-[(6-chloro-5-ethyl-pyridazin-3-yl)amino]piperidine-1-carboxylate A neat mixture of (3R)-3-aminopiperidine-1-carboxylic acid tert-butyl ester (4.53 g, 22.6 mmol, 2.0 equiv., CAS no. 188111-79-7) and 3,6-dichloro-4-ethyl-pyridazine (2 g, 11.3 mmol, 1.0 equiv., CAS no. 10728-54-6) in N,N'-diisopropylethylamine (3.65 g, 4.93 mL, 28.2 mmol, 2.5 equiv.) was sealed in a sealed tube and stirred overnight at 130°C (preheated oil bath). The viscous brown reaction mixture was poured into warm water (~50°C, ~100 mL) and ethyl acetate (~50 ml) was used to decant the oily mixture. The brown reaction solution was stirred for 10 min, transferred to a separatory funnel, and extracted twice with ethyl acetate (2 x ~100 mL). The organic layer was washed with water (ca. 50 mL) and brine (ca. 50 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. The brown crude product was purified by flash chromatography on silica gel (0% to 40% ethyl acetate in heptane) to afford the title compound (1.32 g, 34% yield) as a yellow foam. LCMS m / z: 341.1 ([{35Cl}M+H] + ), 341.1([{37Cl}M+H] + ),ESI pos.

[0180] The second peak, (3R)-3-[(6-chloro-4-ethyl-pyridazin-3-yl)amino]piperidine-1-carboxylic acid tert-butyl ester (545 mg, 13% yield) was isolated as a pale yellow foam. LCMS: m / z 341.1 ([{35Cl}M+H] + ), 341.1([{37Cl}M+H] + ),ESI pos.

[0181] Step B: 6-chloro-5-ethyl-N-[(3R)-3-piperidyl]pyridazin-3-amine; hydrogen chloride To a solution of the above tert-butyl (3R)-3-[(6-chloro-5-ethyl-pyridazin-3-yl)amino]piperidine-1-carboxylate (943 mg, 2.77 mmol, 1.0 equiv.) in dichloromethane (10 mL) and methanol (5 mL) was added 4M HCl in 1,4-dioxane (8.3 g, 6.92 mL, 27.67 mmol, 10 equiv.) dropwise at ambient temperature. The reaction mixture was stirred at 23° C. for 16 h. After removal of the solvent under reduced pressure, the title compound was obtained as a pale yellow solid (786 mg, 97% yield). LCMS: m / z 241.1 ([{35Cl}M+H] + ), 243.1([{37Cl}M+H] + ),ESI pos.

[0182] Step C: 6-chloro-5-ethyl-N-[(3R)-1-ethyl-3-piperidyl]pyridazin-3-amine To a suspension of the above 6-chloro-5-ethyl-N-[(3R)-3-piperidyl]pyridazin-3-amine;hydrogen chloride (400 mg, 1.44 mmol, 1.0 equiv) in excess dry dichloromethane (15 mL) was added acetaldehyde (158.9 mg, 204 μL, 3.6 mmol, 2.5 equiv), followed by sodium acetate (296 mg, 3.61 mmol, 2.5 equiv) with ice bath cooling. Sodium triacetoxyborohydride (562.6 mg, 2.65 mmol, 1.8 equiv) was then added at 0° C. and stirring was continued for 5 min and then at room temperature for 3 h. The reaction mixture was carefully basified with NaHCO3 solution (25 mL) and then extracted with dichloromethane dichloromethane (3×60 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (gradient 0% to 100% in dichloromethane; dichloromethane:methanol:NH4OH 110:10:1) to give the title compound (204 mg, 53% yield) as a light brown oil. MS: m / z 269.1 ([{35Cl}M+H] + ), 271.1([{37Cl}M+H] + ),ESI pos.

[0183] Step D: 4-[4-ethyl-6-[[(3R)-1-ethyl-3-piperidyl]amino]pyridazin-3-yl]-3-hydroxy-benzonitrile To a mixture of the above (6-chloro-5-ethyl-pyridazin-3-yl)-[(3R)-1-ethyl-3-piperidyl]amine (134 mg, 499 μmol, 1.0 equiv.), commercially available (4-cyano-2-hydroxy-phenyl)boronic acid (118.5 mg, 698 μmol, 1.4 equiv., no CAS number) and cesium carbonate (487.3 mg, 1.5 mmol, 3.0 equiv.) in 1,4-dioxane (4 mL) and water (1 mL) was added XPhos Pd G3 (63.3 mg, 74.78 umol, 0.15 equiv., CAS number 1445085-55-1) under argon. The reaction mixture was stirred at 100° C. for 4 h in a sealed tube. The reaction mixture was extracted with ethyl acetate (2×40 mL) and half-saturated NH4Cl solution (40 mL). The organic layer was washed with water (40 mL) and brine (40 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (gradient 0% to 100% in dichloromethane (dichloromethane:methanol:NH4OH 110:10:1)) followed by preparative HPLC to afford the title compound (44 mg, 25% yield) as a white amorph lyophilized solid. LCMS m / z: 352.3 [M+H] + ,ESI pos.

[0184] Example A' The compound of formula Ib can be used in a manner known per se as active ingredient to produce tablets of the following composition: [Table 5]

[0185] Example B' The compound of formula Ib can be used in a manner known per se as active ingredient to produce capsules of the following composition: [Table 6]

[0186] Example A The compounds of formula I can be used in a manner known per se as active ingredient to produce tablets of the following composition: [Table 7]

[0187] Example B The compounds of formula I can be used in a manner known per se as active ingredient to produce capsules of the following composition: [Table 8]

Claims

1. Compound of Formula Ib 【Chemistry 1】 [In the formula, R Ｘ is selected from H, alkyl and haloalkyl; R Ｙ is selected from H, alkyl, alkoxyalkyl, and halo, with the proviso that R Ｘ If is H, then R Ｙ is not H; Z is the system R, S, and T 【Chemistry 2】 wherein the systems S and T may be further substituted with OH, halo, alkyl or cyano; R ６ is H or alkyl; Y is CH ２ , O or NR ７ and R ７ is H or alkyl; W is a substituted 4-6 membered cycloalkyl ring or a substituted heterocycle of ring system A, where the substituted cycloalkyl is substituted with 1 or 2 substituents selected from OH, halo, and alkyl, and ring system A is 【Transformation 3】 and R １ is H and R ２ is alkyl, or R １ and R ２ and the atoms to which they are attached together form a 5-membered ring which may be substituted with OH or halo; R ３ is H, OH or halo] or a pharmaceutically acceptable salt thereof.

2. R Ｘ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein is H, alkyl, or haloalkyl.

3. R Ｘ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein is H or alkyl.

4. R Ｙ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein is H or alkyl.

5. 2. The compound of claim 1, wherein Z is the system R or the system S, or a pharmaceutically acceptable salt thereof.

6. 2. The compound of claim 1, wherein Z is the system S, or a pharmaceutically acceptable salt thereof.

7. R ６ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein is alkyl.

8. W is a 4-membered cycloalkyl ring substituted with alkyl and OH, or W is a substituted heterocycle of ring system A, where R １ is H and R ２ is alkyl, and R ３ or a pharmaceutically acceptable salt thereof.

9. R Ｘ is selected from H, alkyl and haloalkyl; R Ｙ is selected from H and alkyl, with the proviso that R Ｘ If is H, then R Ｙ is not H; Z is the system R and S 【Chemistry 4】 Selected from: R ６ is alkyl; W is a substituted 4-membered cycloalkyl ring substituted with alkyl and OH, or W is a ring system A 【Transformation 5】 is a substituted heterocycle of the formula: R １ is H and R ２ is alkyl; R ３ is H; 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

10. R Ｘ is selected from H and alkyl, and R Ｙ is selected from H and alkyl, with the proviso that R Ｘ If is H, then R Ｙ is not H; Z is the system S 【Transformation 6】 and R ６ is alkyl, 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

11. 4-[6-[[(3R)-1-ethyl-3-piperidyl]amino]-4-methyl-pyridazin-3-yl]-3-hydroxy-benzonitrile formic acid; and 4-[6-[[(3R)-1-ethyl-3-piperidyl]amino]-4-methyl-pyridazin-3-yl]-3-hydroxy-benzonitrile; 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from:

12. 4-[6-[[(3R)-1-ethyl-3-piperidyl]amino]pyridazin-3-yl]-3-hydroxy-5-methyl-benzonitrile; 4-[6-[[(3R)-1-ethyl-3-piperidyl]amino]-4-(trifluoromethyl)pyridazin-3-yl]-3-hydroxy-benzonitrile; 3-hydroxy-4-[6-[(3-hydroxy-3-methyl-cyclobutyl)amino]-4-methyl-pyridazin-3-yl]benzonitrile; 4-[6-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-hydroxy-5-methyl-benzonitrile; 4-[6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-hydroxy-5-methyl-benzonitrile; 4-[6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-hydroxy-5-methyl-benzonitrile; and 4-[6-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-hydroxy-5-methyl-benzonitrile; 2. The compound of claim 1 selected from: or a pharmaceutically acceptable salt thereof.

13. 4-[6-[(3aS,7aR)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-hydroxy-5-methyl-benzonitrile; 4-[6-[(3aR,7aS)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-hydroxy-5-methyl-benzonitrile; 4-[6-[(3aR,7aS)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-hydroxy-5-methyl-benzonitrile; 4-[6-[(3aS,7aR)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-hydroxy-5-methyl-benzonitrile; 3-hydroxy-4-[4-methyl-6-(6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl)pyridazin-3-yl]benzonitrile; 4-[6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-4-methyl-pyridazin-3-yl]-3-hydroxy-benzonitrile; 4-[6-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-4-methyl-pyridazin-3-yl]-3-hydroxy-benzonitrile; 4-[6-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-4-methyl-pyridazin-3-yl]-3-hydroxy-benzonitrile; 4-[6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-4-methyl-pyridazin-3-yl]-3-hydroxy-benzonitrile; and 4-[4-ethyl-6-[[(3R)-1-ethyl-3-piperidyl]amino]pyridazin-3-yl]-3-hydroxy-benzonitrile; 2. The compound of claim 1 selected from: or a pharmaceutically acceptable salt thereof.

14. 4-[6-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-hydroxy-5-methyl-benzonitrile; 4-[6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-hydroxy-5-methyl-benzonitrile; 4-[6-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-hydroxy-5-methyl-benzonitrile; and 4-[6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-hydroxy-5-methyl-benzonitrile; 2. The compound of claim 1 selected from: or a pharmaceutically acceptable salt thereof.

15. 4-[6-[(3aS,7aR)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-hydroxy-5-methyl-benzonitrile; 4-[6-[(3aR,7aS)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-hydroxy-5-methyl-benzonitrile; 4-[6-[(3aR,7aS)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-hydroxy-5-methyl-benzonitrile; 4-[6-[(3aS,7aR)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]pyridazin-3-yl]-3-hydroxy-5-methyl-benzonitrile; 3-hydroxy-4-[4-methyl-6-(6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl)pyridazin-3-yl]benzonitrile; 4-[6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-4-methyl-pyridazin-3-yl]-3-hydroxy-benzonitrile; 4-[6-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-4-methyl-pyridazin-3-yl]-3-hydroxy-benzonitrile; 4-[6-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-4-methyl-pyridazin-3-yl]-3-hydroxy-benzonitrile; and 4-[6-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-4-methyl-pyridazin-3-yl]-3-hydroxy-benzonitrile; 2. The compound of claim 1 selected from: or a pharmaceutically acceptable salt thereof.

16. 16. A compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, for use as a therapeutically active substance.

17. A compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, for treating or preventing a disease, disorder or condition responsive to NLRP3 inhibition.

18. 16. A compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, for treating or preventing a disease, disorder or condition selected from asthma or COPD.

19. 16. A compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, for treating or preventing a disease, disorder or condition selected from Parkinson's disease or Alzheimer's disease.

20. 16. A pharmaceutical composition comprising a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof.

21. The pharmaceutical composition of claim 20 for treating or preventing a disease, disorder or condition responsive to NLRP3 inhibition.

22. The pharmaceutical composition of claim 20 for treating or preventing a disease, disorder or condition selected from asthma or COPD.

23. A pharmaceutical composition according to claim 20 for treating or preventing a disease, disorder or condition selected from Parkinson's disease or Alzheimer's disease.

24. 20. Use of a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for treating or preventing a disease, disorder or condition responsive to NLRP3 inhibition.

25. 20. Use of a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for treating or preventing a disease, disorder or condition selected from asthma or COPD.

26. 20. Use of a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for treating or preventing a disease, disorder or condition selected from Parkinson's disease or Alzheimer's disease.

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