Heterocyclic NLRP3 inhibitors

Abstract

The present invention relates to compounds of the general formula Ib TIFF2024540445000032.tif52161 (In the formula, R 1 , R 1b , R 2 , R 3 and Z is as described herein. The present invention relates to novel compounds having the formula:

Description

[Technical field]

[0001] FIELD OF THEINVENTION 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 1 is H, haloalkyl or OH; R 1b is H, halo, or alkyl; R 2 is halo, haloalkyl, haloalkoxy, nitrile or alkyl; R 3 is H; Or, R 2 and R 3 and the atoms to which they are attached, joined together, to form either a 5-membered heterocycle or a 4-membered cycloalkyl ring containing one O heteroatom; Z is a ring system [ka] Selected from; A 1 ,S,NR X1 or O and R X1 is H, alkyl or cyclopropyl; A 2 CR Y1 or N and R Y1 is H or alkyl; A 3 CR Z1 or N and R Z1 is H or alkyl; A 1 If is S or O, then A 2 and A 3cannot both be N; A 4 CR Z2 or N and R Z2 is H or alkyl; A 5 CR Y2 or N and CR Y2 is H or alkyl; A 6 ,S,NR X2 or O and R X2 is H or alkyl; A 6 If is S or O, then A 4 and A 5 cannot both be N; A 7 , A 8 and A 9 is an independent CR W1 or N and CR W1 is H or alkyl; A 7 , A 8 and A 9 cannot all be N; A 10 , A 11 and A 12 is an independent CR W2 or N and CR W2 is H or alkyl; A 10 , A 11 and A 12 cannot all be N; W is a substituted 4-membered cycloalkyl, a substituted 6-membered cycloalkyl, a substituted 6-membered heterocycle containing a single N heteroatom, or 1,2,3,5,6,7,8,8a-octahydroindolizin-7-yl, where the substituted 4-membered cycloalkyl is substituted with hydroxyl and methyl, the substituted 6-membered cycloalkyl is substituted with OH, and the substituted 6-membered heterocycle containing a single N heteroatom is substituted with one or two substituents independently selected from alkyl, 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] 2. Background of the Invention 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 attractant 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 attract and activate caspase-8, which can process pro-IL-1β and pro-IL-18 to cause apoptotic cell death.

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

[0007] NLRP3-dependent ASC specks are released into the extracellular milieu where they can activate caspase-1, induce 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 is also involved in the pathogenesis of several complex diseases, including metabolic disorders such as type 2 diabetes, atherosclerosis, obesity, and gout, among others.

[0010] The role of NLRP3 in 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 suggested to have a role in several central nervous system conditions, including Parkinson's disease (PD), Alzheimer's disease (AD), dementia, Huntington's disease, cerebral malaria, and brain damage from 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 play a role in several lung diseases, including chronic obstructive pulmonary disorder (COPD), asthma (including steroid-resistant asthma), asbestosis and silicosis (De Nardo et al., Am. J. Pathol., 184:42-54, 2014 and Kim et al. Am J Respir Crit Care Med. 2017 196(3):283-97). In addition, NLRP3 plays a role in the development of liver disease, kidney disease and aging. Many of these associations are related to the role 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 activation of NLRP3, but not NLRC4 or NLRP1. 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-associated 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-associated diseases.

[0013] There is a need to provide compounds which have improved pharmacological and / or physiological and / or physicochemical properties and / or which represent useful alternatives to known compounds. [Brief description of the drawings]

[0014] [Figure 1] FIG. 1 shows voltage patterns (pulse patterns used to elicit outward K+ currents at 35-37°C). Summary of the Invention

[0015] The present invention relates to novel compounds of formula Ib [ka] (In the formula, R 1 is H, haloalkyl is OH; R 1b is H, halo, or alkyl; R 2is halo, haloalkyl, haloalkoxy, nitrile or alkyl; R 3 is H; Or, R 2 and R 3 and the atoms to which they are attached, joined together, to form either a 5-membered heterocycle or a 4-membered cycloalkyl ring containing one O heteroatom; Z is a ring system [ka] Selected from; A 1 ,S,NR X1 or O and R X1 is H, alkyl or cyclopropyl; A 2 CR Y1 or N and R Y1 is H or alkyl; A 3 CR Z1 or N and R Z1 is H or alkyl; A 1 If is S or O, then A 2 and A 3 cannot both be N; A 4 CR Z2 or N and R Z2 is H or alkyl; A 5 CR Y2 or N and CR Y2 is H or alkyl; A 6 ,S,NR X2 or O and R X2 is H or alkyl; A 6 If is S or O, then A 4 and A 5 cannot both be N; A 7 , A 8 and A9 is an independent CR W1 or N and CR W1 is H or alkyl; A 7 , A 8 and A 9 cannot all be N; A 10 , A 11 and A 12 is an independent CR W2 or N and CR W2 is H or alkyl; A 10 , A 11 and A 12 cannot all be N; W is a substituted 4-membered cycloalkyl, a substituted 6-membered cycloalkyl, a substituted 6-membered heterocycle containing a single N heteroatom, or 1,2,3,5,6,7,8,8a-octahydroindolizin-7-yl, where the substituted 4-membered cycloalkyl is substituted with hydroxyl and methyl, the substituted 6-membered cycloalkyl is substituted with OH, and the substituted 6-membered heterocycle containing a single N heteroatom is substituted with one or two substituents independently selected from alkyl, OH, or halo. and pharma- ceutically acceptable salts thereof.

[0016] The term "alkyl" refers to a monovalent linear or branched saturated hydrocarbon group of 1 to 6 carbon atoms. In some embodiments, unless otherwise specified, alkyl refers to a group having 1 to 6 carbon atoms (C 1~6 -alkyl) or 1 to 4 carbon atoms (C 1~4 -alkyl). 1~6 Examples of -alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl and pentyl. Particular alkyl groups include methyl and ethyl.

[0017] 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. 1~6Examples of -alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and tert-butoxy.

[0018] The term "amino" means -NH 2 Represents a group.

[0019] 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. Particular examples include cyclopropyl, cyclobutyl, and cyclohexyl.

[0020] The terms "halogen", "halide" and "halo" are used interchangeably herein and refer to fluoro, chloro, bromo or iodo. Particular halogens are fluoro and chloro. A preferred halogen is fluoro.

[0021] 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. Examples of haloalkyl include fluoromethyl, difluoromethyl and trifluoromethyl. A particular example is trifluoromethyl.

[0022] The term "haloalkoxy" means 1~6 - at least one hydrogen atom of an alkoxy group is replaced by the same or different halogen atom 1~6-represents an alkoxy group. Examples of haloalkoxy are difluoromethoxy, trifluoromethoxy, difluoroethoxy and trifluoroethoxy. A particular example is trifluoromethoxy.

[0023] The term "heterocycle" refers to a monovalent saturated or partially unsaturated monocyclic or bicyclic ring system of 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 azetidinyl, diazepanyl, pyrrolidinyl, tetrahydrofuranyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, and piperazinyl. Examples of polycyclic saturated heterocycles are azaspiroheptanyl, diazaspiroheptanyl, azaspirooctanyl, diazospirooctanyl, diazaspirononanyl, oxaazaspirooctanyl, and oxadiazaspirononanyl. Particular examples of heterocyclic rings are azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, tetrahydropyranyl and piperazinyl.More particular examples of heterocyclic rings are pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl.A preferred example of heterocyclic ring is piperidinyl.Another preferred example of heterocyclic ring is oxolanyl ring.

[0024] The term "hydroxy" refers to an --OH group.

[0025] The term "nitrile" refers to the group -C≡N.

[0026] 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. In addition, these salts can be prepared from the addition of inorganic or organic bases to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, 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 resin salts.The compound of formula I may also exist in the form of a zwitterion.Particularly preferred pharma- ceutically acceptable salts of the compound of formula I are salts formed with formic acid and with hydrochloric acid to produce hydrochloride, dihydrochloride, or trihydrochloride salts.

[0027] The abbreviation uM means micromolar and is equivalent to the symbol μM.

[0028] The abbreviation uL means microliter and is equivalent to the symbol μL.

[0029] The abbreviation ug means microgram and is equivalent to the symbol μg.

[0030] The compounds of formula Ib may contain several asymmetric centers and may exist in the form of optically pure enantiomers, mixtures of enantiomers, such as racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereomeric racemates or mixtures of diastereomeric racemates.

[0031] The compounds of formula I may contain several asymmetric centers and may exist in the form of optically pure enantiomers, mixtures of enantiomers, such as racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereomeric racemates or mixtures of diastereomeric racemates.

[0032] According to the Cahn–Ingold–Prelog rules, the asymmetric carbon atom can be of the "R" or "S" configuration.

[0033] One embodiment of the present invention also provides 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.

[0034] One embodiment of the present invention also provides 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.

[0035] One embodiment of the present invention is where Z is A 1 But, S,NR X1 Or O and R X1 is H or alkyl; A 2 But, CR Y1 Or N and R Y1 is H; A 3 But, CR Z1 Or N and R Z1is H or alkyl; A 1 If is S or O, then A 2 Also A 3 cannot also be N, Ring system A; or A 4 CR Z2 and R Z2 is H; A 5 But, CR Y2 Or N and CR Y2 is H; A 6 But S or NR X2 and R X2 is alkyl; A 6 If S, then A 4 Also A 5 cannot also be N, Ring system B The present invention provides a compound according to formula Ib as described herein, selected from:

[0036] One embodiment of the present invention comprises: A 1 But, S,NR X1 or O and R X1 is H or alkyl; A 2 But, CR Y1 or N and R Y1 is H; A 3 But, CR Z1 or N and R Z1 is H or alkyl; A 1 If is S or O, then A 2 Also A 3 cannot also be N, Provided herein are compounds according to formula Ib.

[0037] One embodiment of the present invention provides a compound according to formula Ib as described herein, wherein Z is ring system A, which ring system A contains two N heteroatoms.

[0038] One embodiment of the present invention is where Z is A 1 NR X1 and R X1 is alkyl; A 2 is N; A 3 CR Z1 and R Z1 is H, The compound according to formula Ib described herein is provided, wherein the ring system A is

[0039] One embodiment of the present invention is 1 is H or OH.

[0040] One embodiment of the present invention is 1 is OH.

[0041] One embodiment of the present invention is 1b is H.

[0042] One embodiment of the present invention is 2 is halo, haloalkyl or haloalkoxy; R 3 is H; or R 2 and R 3 and the atoms to which they are attached are joined together to form either a heterocycle or a cycloalkyl ring containing one O heteroatom.

[0043] One embodiment of the present invention is 2 and R 3 and the atoms to which they are attached are joined together to form either a heterocycle containing one O heteroatom or a cycloalkyl ring.

[0044] One embodiment of the present invention is 2and R 3 and the atoms to which they are attached are joined together to form either a 5-membered heterocycle containing one O heteroatom or a 4-membered cycloalkyl ring.

[0045] One embodiment of the present invention is 2 and R 3 and the atom to which they are attached, are joined together to form a cycloalkyl ring.

[0046] One embodiment of the present invention is 2 and R 3 and the atom to which they are attached, joined together, to form a 4-membered cycloalkyl ring.

[0047] One embodiment of the present invention is 2 and R 3 and the atoms to which they are attached, taken together, form either a heterocycle or a cycloalkyl ring containing one O heteroatom, and Z is ring system A, which ring system A contains two N heteroatoms, according to formula Ib described herein.

[0048] One embodiment of the present invention is 2 and R 3 and the atoms to which they are attached, taken together, form a cycloalkyl ring, and Z is ring system A, which ring system A contains two N heteroatoms.

[0049] One embodiment of the present invention provides a compound according to formula Ib described herein, wherein W is a substituted 4-membered cycloalkyl, a substituted 6-membered cycloalkyl, or a substituted 6-membered heterocycle containing a single N heteroatom, wherein the substituted 4-membered cycloalkyl is substituted with hydroxyl and methyl, the substituted 6-membered cycloalkyl is substituted with OH, and the substituted 6-membered heterocycle containing a single N heteroatom is substituted with one or two substituents independently selected from alkyl and OH.

[0050] One embodiment of the present invention provides a compound according to formula Ib described herein, wherein W is ethyl piperidyl or 1-ethyl-piperidin-3-ol.

[0051] One embodiment of the present invention provides a compound according to formula Ib described herein, wherein W is ethyl piperidyl.

[0052] One embodiment of the present invention comprises: R 1 is H or OH; R 1b is H, halo, or alkyl; R 2 is halo, haloalkyl, or haloalkoxy; R 3 is H; Or, R 2 and R 3 and the atoms to which they are attached, joined together, to form either a 5-membered heterocycle or a 4-membered cycloalkyl ring containing one O heteroatom; Z, A 1 But, S,NR X1 Or O and R X1 is H or alkyl; A 2 CR Y1 Or N and R Y1 is H; A 3 CR Z1 Or N and R Z1 is H or alkyl; A1 If is S or O, then A 2 Also A 3 cannot also be N, Ring system A; or A 4 CR Z2 and R Z2 is H; A 5 But, CR Y2 Or N and CR Y2 is H; A 6 But S or NR X2 and R X2 is alkyl; A 6 If S, then A 4 Also A 5 cannot also be N, Ring system B Selected from; Provided herein are compounds according to formula Ib as described herein, and pharma- ceutically acceptable salts thereof, wherein W is a substituted 4-membered cycloalkyl, a substituted 6-membered cycloalkyl, or a substituted 6-membered heterocycle containing a single N heteroatom, wherein the substituted 4-membered cycloalkyl is substituted with hydroxyl and methyl, the substituted 6-membered cycloalkyl is substituted with OH, and the substituted 6-membered heterocycle containing a single N heteroatom is substituted with one or two substituents independently selected from alkyl and OH.

[0053] One embodiment of the present invention comprises: R 1 is H or OH; R 1b is H, halo, or alkyl; R 2 is halo, haloalkyl, or haloalkoxy; R 3 is H; Or, R 2 and R 3 and the atoms to which they are attached, joined together, to form either a 5-membered heterocycle or a 4-membered cycloalkyl ring containing one O heteroatom; Z, A1 But, S,NR X1 or O and R X1 is H or alkyl; A 2 But, CR Y1 or N and R Y1 is H; A 3 But, CR Z1 or N and R Z1 is H or alkyl; A 1 If is S or O, then A 2 Also A 3 cannot also be N, Ring system A; Provided herein are compounds according to formula Ib as described herein, and pharma- ceutically acceptable salts thereof, wherein W is a substituted 4-membered cycloalkyl, a substituted 6-membered cycloalkyl, or a substituted 6-membered heterocycle containing a single N heteroatom, wherein the substituted 4-membered cycloalkyl is substituted with hydroxyl and methyl, the substituted 6-membered cycloalkyl is substituted with OH, and the substituted 6-membered heterocycle containing a single N heteroatom is substituted with one or two substituents independently selected from alkyl and OH.

[0054] One embodiment of the present invention comprises: R 1 is OH; R 1b is H; R 2 and R 3 and the atoms to which they are attached, joined together, to form either a 5-membered heterocycle or a 4-membered cycloalkyl ring containing one O heteroatom; Z, A 1 NR X1 and R X1 is alkyl; A 2 is N; A 3 CR Z1 and R Z1 is H, Ring system A; Provided herein are compounds according to formula Ib as described herein, and pharma- ceutically acceptable salts thereof, wherein W is ethyl piperidyl or 1-ethyl-piperidin-3-ol.

[0055] One embodiment of the present invention comprises: R 1 is OH; R 1b is H; R 2 and R 3 and the atom to which they are attached, joined together, to form any of four-membered cycloalkyl rings; Z, A 1 NR X1 and R X1 is alkyl; A 2 is N; A 3 CR Z1 and R Z1 is H, Ring system A; Provided herein are compounds according to formula Ib as described herein, and pharma- ceutically acceptable salts thereof, wherein W is ethyl piperidyl.

[0056] Particular examples of compounds of formula Ib described herein are (rac)-2-[7-[(1-ethyl-3-piperidyl)amino]thieno[2,3-d]pyridazin-4-yl]-5-(trifluoromethyl)phenol;Formic acid; (rac)-2-[7-[(1-ethyl-3-piperidyl)amino]thieno[2,3-d]pyridazin-4-yl]-5-(trifluoromethyl)phenol; (rac)-2-[4-[(1-ethyl-3-piperidyl)amino]thieno[2,3-d]pyridazin-7-yl]-5-(trifluoromethyl)phenol;Formic acid; (rac)-2-[4-[(1-ethyl-3-piperidyl)amino]thieno[2,3-d]pyridazin-7-yl]-5-(trifluoromethyl)phenol; (rac)-N-(1-ethyl-3-piperidyl)-4-[4-(trifluoromethyl)phenyl]thieno[2,3-d]pyridazin-7-amine; (rac)-N-(1-ethyl-3-piperidyl)-7-[4-(trifluoromethyl)phenyl]thieno[2,3-d]pyridazin-4-amine; 2-[4-[[(3R)-1-Ethyl-3-piperidyl]amino]-1-methyl-pyrrolo[2,3-d]pyridazin-7-yl]-5-(trifluoromethyl)phenol; hydrochloride; 2-[4-[[(3R)-1-ethyl-3-piperidyl]amino]-1-methyl-pyrrolo[2,3-d]pyridazin-7-yl]-5-(trifluoromethyl)phenol;2,2,2-trifluoroacetic acid; 2-[4-[[(3R)-1-ethyl-3-piperidyl]amino]-1-methyl-pyrrolo[2,3-d]pyridazin-7-yl]-5-(trifluoromethyl)phenol; 2-[4-[[(3R)-1-ethyl-3-piperidyl]amino]-1-methyl-pyrazolo[3,4-d]pyridazin-7-yl]-5-(trifluoromethyl)phenol;2,2,2-trifluoroacetic acid; 2-[4-[[(3R)-1-ethyl-3-piperidyl]amino]-1-methyl-pyrazolo[3,4-d]pyridazin-7-yl]-5-(trifluoromethyl)phenol; and 2-[4-[[(3R)-1-ethyl-3-piperidyl]amino]furo[2,3-d]pyridazin-7-yl]-5-(trifluoromethyl)phenol and pharma- ceutically acceptable salts thereof.

[0057] Also specific examples of compounds of formula Ib described herein are 2-[4-[[(3R)-1-ethyl-3-piperidyl]amino]-1-methyl-imidazo[4,5-d]pyridazin-7-yl]-5-(trifluoromethyl)phenol; 2-[7-[[(3R)-1-ethyl-3-piperidyl]amino]-1-methyl-pyrazolo[3,4-d]pyridazin-4-yl]-5-(trifluoromethyl)phenol; 2-[4-[[(3R)-1-ethyl-3-piperidyl]amino]-1-methyl-pyrazolo[3,4-d]pyridazin-7-yl]-5-(trifluoromethoxy)phenol; 2-[4-[[(1R,2R)-2-hydroxycyclohexyl]amino]-1-methyl-pyrazolo[3,4-d]pyridazin-7-yl]-5-(trifluoromethyl)phenol; 5-Chloro-2-[1-methyl-4-[[(3R)-1-ethyl-3-piperidyl]amino]pyrazolo[3,4-d]pyridazin-7-yl]phenol; 2-[4-[[(3R)-1-ethyl-3-piperidyl]amino]-3-methyl-isoxazolo[4,5-d]pyridazin-7-yl]-5-(trifluoromethyl)phenol; 2-[4-[[(3R)-1-ethyl-3-piperidyl]amino]-1H-pyrazolo[3,4-d]pyridazin-7-yl]-3-methyl-5-(trifluoromethyl)phenol; 2-[4-[[(3R)-1-ethyl-3-piperidyl]amino]-1-methyl-pyrazolo[3,4-d]pyridazin-7-yl]-3-fluoro-5-(trifluoromethyl)phenol; 2-[4-[(3-hydroxy-3-methyl-cyclobutyl)amino]-1-methyl-pyrazolo[3,4-d]pyridazin-7-yl]-5-(trifluoromethyl)phenol; 5-[4-[[(3R)-1-ethyl-3-piperidyl]amino]-1-methyl-pyrazolo[3,4-d]pyridazin-7-yl]-2,3-dihydrobenzofuran-4-ol; 3-[4-[[(3R)-1-ethyl-3-piperidyl]amino]-1-methyl-pyrazolo[3,4-d]pyridazin-7-yl]bicyclo[4.2.0]octa-1(6),2,4-trien-2-ol; (3S,5R)-1-Ethyl-5-[[7-(4-hydroxy-2,3-dihydrobenzofuran-5-yl)-1-methyl-pyrazolo[3,4-d]pyridazin-4-yl]amino]piperidin-3-ol and pharma- ceutically acceptable salts thereof.

[0058] Preferred examples of compounds of formula Ib described herein are 5-[4-[[(3R)-1-ethyl-3-piperidyl]amino]-1-methyl-pyrazolo[3,4-d]pyridazin-7-yl]-2,3-dihydrobenzofuran-4-ol; 3-[4-[[(3R)-1-ethyl-3-piperidyl]amino]-1-methyl-pyrazolo[3,4-d]pyridazin-7-yl]bicyclo[4.2.0]octa-1(6),2,4-trien-2-ol; (3S,5R)-1-Ethyl-5-[[7-(4-hydroxy-2,3-dihydrobenzofuran-5-yl)-1-methyl-pyrazolo[3,4-d]pyridazin-4-yl]amino]piperidin-3-ol and pharma- ceutically acceptable salts thereof.

[0059] The most preferred example of the compound of formula Ib described herein is 3-[4-[[(3R)-1-ethyl-3-piperidyl]amino]-1-methyl-pyrazolo[3,4-d]pyridazin-7-yl]bicyclo[4.2.0]octa-1(6),2,4-trien-2-ol and pharma-ceutically acceptable salts thereof.

[0060] One embodiment of the present invention is a compound of formula I, which is a compound of formula Ib: [ka] (In the formula, R 1 is H, haloalkyl or OH; R 2 is halo, haloalkyl, haloalkoxy, nitrile, or alkyl; Z is a ring system [ka] Selected from; A 1 ,S,NR X1 or O and R X1 is H, alkyl or cyclopropyl; A 2 CR Y1 or N and R Y1 is H or alkyl; A 3 CR Z1 or N and R Z1 is H or alkyl; A 1 If is S or O, then A 2 and A 3 cannot both be N; A 4 CR Z2 or N and R Z2 is H or alkyl; A 5 CR Y2 or N and CR Y2 is H or alkyl; A 6 ,S,NR X2 or O and R X2 is H or alkyl; A 6 If is S or O, then A 4 and A 5 cannot both be N; A 7 , A 8 and A 9 is an independent CR W1 or N and CR W1 is H or alkyl; A 7 , A 8 and A 9 cannot all be N; A 10 , A 11 and A 12 is an independent CRW2 or N and CR W2 is H or alkyl; A 10 , A 11 and A 12 cannot all be N; W is a substituted 4-membered cycloalkyl, a substituted 6-membered cycloalkyl, a substituted 6-membered heterocycle containing a single N heteroatom, or 1,2,3,5,6,7,8,8a-octahydroindolizin-7-yl, where the substituted 4-membered cycloalkyl is substituted with hydroxyl and methyl, the substituted 6-membered cycloalkyl is substituted with OH, and the substituted 6-membered heterocycle containing a single N heteroatom is substituted with alkyl, OH, or halo. and pharma- ceutically acceptable salts thereof.

[0061] One embodiment of the present invention is 1 is H or OH.

[0062] One embodiment of the present invention is 1 is OH.

[0063] One embodiment of the present invention is 2 is halo, haloalkyl or haloalkoxy.

[0064] One embodiment of the present invention is 2 is halo or haloalkyl.

[0065] One embodiment of the present invention is 2 is haloalkyl.

[0066] One embodiment of the present invention is where Z is A 1 But, S,NR X1 or O and R X1 is alkyl; A2 But, CR Y1 or N and R Y1 is H; A 3 But, CR Z1 or N and R Z1 is H; A 1 If is S or O, then A 2 Also A 3 cannot also be N, Ring system A; A 4 But, CR Z2 or N and R Z2 There is H; A 5 But, CR Y2 or N and CR Y2 is H; A 6 But, S,NR X2 or O and R X2 is alkyl; A 6 If is S or O, then A 4 Also A 5 cannot also be N, Ring system B; A 7 is N and A 8 and A 9 and C are both CH; A 10 and A 11 Both are CH, and A 12 is N, ring system D Selected from; Provided herein are compounds according to formula I, wherein W is 1-ethyl-3-piperidyl or 1-methyl-3-piperidyl.

[0067] One embodiment of the present invention is where Z is A 1 NR X1 and R X1 is alkyl; A 2 But, CR Y1 or N and R Y1 is H; A3 CR Z1 and R Z1 is H, Ring system A; Provided herein are compounds according to formula I, wherein W is 1-ethyl-3-piperidyl or 1-methyl-3-piperidyl.

[0068] One embodiment of the present invention is where Z is A 1 NR X1 and R X1 is methyl; A 2 But, CR Y1 or N and R Y1 is H; A 3 CR Z1 and R Z1 is H, Ring system A; Provided herein is a compound according to formula I, wherein W is 1-ethyl-3-piperidyl.

[0069] One embodiment of the present invention is where Z is A 1 NR X1 and R X1 is methyl; A 2 is N; A 3 CR Z1 and R Z1 is H, Ring system A; Provided herein is a compound according to formula I, wherein W is 1-ethyl-3-piperidyl.

[0070] One embodiment of the present invention comprises: R 1 is H or OH; R 2 is halo, haloalkyl, or haloalkoxy; Z, A 1 But, S,NR X1 or O and R X1is alkyl; A 2 But, CR Y1 or N and R Y1 is H; A 3 But, CR Z1 or N and R Z1 is H; A 1 If is S or O, then A 2 Also A 3 cannot also be N, Ring system A; A 4 But, CR Z2 or N and R Z2 There is H; A 5 But, CR Y2 or N and CR Y2 is H; A 6 But, S,NR X2 or O and R X2 is alkyl; A 6 If is S or O, then A 4 Also A 5 cannot also be N, Ring system B; A 7 is N and A 8 and A 9 and C, ring system C, both of which are CH; A 10 and A 11 is CH and A 12 is N, ring system D Selected from; Provided herein are compounds according to formula I as described herein, and pharma- ceutically acceptable salts thereof, wherein W is 1-ethyl-3-piperidyl or 1-methyl-3-piperidyl.

[0071] One embodiment of the present invention comprises: R 1 is H or OH; R 2 is haloalkyl; Z, A 1 NRX1 and R X1 is alkyl; A 2 CR Y1 or N and R Y1 is H; A 3 CR Z1 and R Z1 is H, Selected from ring system A; Provided herein are compounds according to formula I as described herein, and pharma- ceutically acceptable salts thereof, wherein W is 1-ethyl-3-piperidyl or 1-methyl-3-piperidyl.

[0072] One embodiment of the present invention comprises: R 1 is H or OH; R 2 is haloalkyl; Z, A 1 NR X1 and R X1 is methyl; A 2 But, CR Y1 or N and R Y1 is H; A 3 CR Z1 and R Z1 is H, Selected from ring system A; Provided herein are compounds according to formula I as described herein, and pharma- ceutically acceptable salts thereof, wherein W is 1-ethyl-3-piperidyl.

[0073] One embodiment of the present invention comprises: R 1 is H or OH; R 2 is haloalkyl; Z, A 1 NR X1 and R X1 is methyl; A 2 is N; A 3CR Z1 and R Z1 is H, Selected from ring system A; Provided herein are compounds according to formula I as described herein, and pharma- ceutically acceptable salts thereof, wherein W is 1-ethyl-3-piperidyl.

[0074] One embodiment of the present invention comprises: R 1 is OH; R 2 is haloalkyl; Z, A 1 NR X1 and R X1 is methyl; A 2 is N; A 3 CR Z1 and R Z1 is H, Selected from ring system A; Provided herein are compounds according to formula I as described herein, and pharma- ceutically acceptable salts thereof, wherein W is 1-ethyl-3-piperidyl.

[0075] Specific examples of compounds of formula I described herein are (rac)-2-[7-[(1-ethyl-3-piperidyl)amino]thieno[2,3-d]pyridazin-4-yl]-5-(trifluoromethyl)phenol;Formic acid; (rac)-2-[7-[(1-ethyl-3-piperidyl)amino]thieno[2,3-d]pyridazin-4-yl]-5-(trifluoromethyl)phenol; (rac)-2-[4-[(1-ethyl-3-piperidyl)amino]thieno[2,3-d]pyridazin-7-yl]-5-(trifluoromethyl)phenol;Formic acid; (rac)-2-[4-[(1-ethyl-3-piperidyl)amino]thieno[2,3-d]pyridazin-7-yl]-5-(trifluoromethyl)phenol; (rac)-N-(1-ethyl-3-piperidyl)-4-[4-(trifluoromethyl)phenyl]thieno[2,3-d]pyridazin-7-amine; (rac)-N-(1-ethyl-3-piperidyl)-7-[4-(trifluoromethyl)phenyl]thieno[2,3-d]pyridazin-4-amine; 2-[4-[[(3R)-1-Ethyl-3-piperidyl]amino]-1-methyl-pyrrolo[2,3-d]pyridazin-7-yl]-5-(trifluoromethyl)phenol; hydrochloride; 2-[4-[[(3R)-1-ethyl-3-piperidyl]amino]-1-methyl-pyrrolo[2,3-d]pyridazin-7-yl]-5-(trifluoromethyl)phenol;2,2,2-trifluoroacetic acid; 2-[4-[[(3R)-1-ethyl-3-piperidyl]amino]-1-methyl-pyrrolo[2,3-d]pyridazin-7-yl]-5-(trifluoromethyl)phenol; 2-[4-[[(3R)-1-ethyl-3-piperidyl]amino]-1-methyl-pyrazolo[3,4-d]pyridazin-7-yl]-5-(trifluoromethyl)phenol;2,2,2-trifluoroacetic acid; 2-[4-[[(3R)-1-ethyl-3-piperidyl]amino]-1-methyl-pyrazolo[3,4-d]pyridazin-7-yl]-5-(trifluoromethyl)phenol; and 2-[4-[[(3R)-1-ethyl-3-piperidyl]amino]furo[2,3-d]pyridazin-7-yl]-5-(trifluoromethyl)phenol and pharma- ceutically acceptable salts thereof.

[0076] Preferred examples of compounds of formula I described herein are (rac)-2-[7-[(1-ethyl-3-piperidyl)amino]thieno[2,3-d]pyridazin-4-yl]-5-(trifluoromethyl)phenol;Formic acid; (rac)-2-[7-[(1-ethyl-3-piperidyl)amino]thieno[2,3-d]pyridazin-4-yl]-5-(trifluoromethyl)phenol; (rac)-N-(1-ethyl-3-piperidyl)-4-[4-(trifluoromethyl)phenyl]thieno[2,3-d]pyridazin-7-amine; 2-[4-[[(3R)-1-ethyl-3-piperidyl]amino]-1-methyl-pyrrolo[2,3-d]pyridazin-7-yl]-5-(trifluoromethyl)phenol;2,2,2-trifluoroacetic acid; 2-[4-[[(3R)-1-Ethyl-3-piperidyl]amino]-1-methyl-pyrrolo[2,3-d]pyridazin-7-yl]-5-(trifluoromethyl)phenol; hydrochloride; 2-[4-[[(3R)-1-ethyl-3-piperidyl]amino]-1-methyl-pyrrolo[2,3-d]pyridazin-7-yl]-5-(trifluoromethyl)phenol; 2-[4-[[(3R)-1-ethyl-3-piperidyl]amino]-1-methyl-pyrazolo[3,4-d]pyridazin-7-yl]-5-(trifluoromethyl)phenol;2,2,2-trifluoroacetic acid; 2-[4-[[(3R)-1-ethyl-3-piperidyl]amino]-1-methyl-pyrazolo[3,4-d]pyridazin-7-yl]-5-(trifluoromethyl)phenol; and 2-[4-[[(3R)-1-ethyl-3-piperidyl]amino]furo[2,3-d]pyridazin-7-yl]-5-(trifluoromethyl)phenol and pharma- ceutically acceptable salts thereof.

[0077] More preferred examples of compounds of formula I described herein are 2-[4-[[(3R)-1-ethyl-3-piperidyl]amino]-1-methyl-pyrazolo[3,4-d]pyridazin-7-yl]-5-(trifluoromethyl)phenol; 2,2,2-trifluoroacetic acid or 2-[4-[[(3R)-1-ethyl-3-piperidyl]amino]-1-methyl-pyrazolo[3,4-d]pyridazin-7-yl]-5-(trifluoromethyl)phenol; and pharma-ceutically acceptable salts thereof.

[0078] The most preferred examples of compounds of formula I described herein are 2-[4-[[(3R)-1-ethyl-3-piperidyl]amino]-1-methyl-pyrazolo[3,4-d]pyridazin-7-yl]-5-(trifluoromethyl)phenol; 2,2,2-trifluoroacetic acid or and pharma-ceutically acceptable salts thereof.

[0079] Another embodiment of the present invention provides pharmaceutical compositions or medicaments containing the compounds of the present invention and therapeutically inert carriers, diluents or excipients, as well as methods of using the compounds of the present invention to prepare such compositions and medicaments. In one example, the compounds of formula I can be formulated into galenic dosage forms by mixing at ambient temperature, at an appropriate pH, and to the desired degree of purity with a physiologically acceptable carrier, i.e., a carrier that is non-toxic to the recipient at the dosage and concentration used. The pH of the formulation will depend primarily on the particular application and the concentration of the compound, but is preferably anywhere in the range of about 3 to about 8. In one example, the compounds of formula I are formulated in acetate buffer at pH 5. In another embodiment, the compounds of formula I are sterile. The compounds can be stored, for example, as solid or amorphous compositions, as lyophilized formulations, or as aqueous solutions.

[0080] The compositions are formulated, dosed, and administered in a manner consistent with good medical practice. Factors to consider in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the administration schedule, and other factors known to the medical profession.

[0081] The compounds of the present invention may be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal and epidural and intranasal, and, where localized treatment is desired, intralesional administration. Parenteral administration includes intramuscular, intravenous, intraarterial, intraperitoneal or subcutaneous administration.

[0082] The compounds of the present invention may be administered in any convenient dosage form, such as tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain conventional components of pharmaceutical preparations, such as diluents, carriers, pH adjusters, sweeteners, fillers, and additional active agents.

[0083] Typical preparation is prepared by mixing the compound of the present invention and carrier or excipient.Suitable carrier and excipient are well known to those skilled in the art, and are described in detail in, for example, Ansel, Howard C. et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems.Philadelphia: Lippincott, Williams&Wilkins, 2004;Gennaro, Alfonso R. et al., Remington: The Science and Practice of Pharmacy.Philadelphia: Lippincott, Williams&Wilkins, 2000;and Rowe, Raymond C.Handbook of Pharmaceutical Excipients.Chicago, Pharmaceutical Press, 2005. The formulation may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, sweeteners, fragrances, flavorings, diluents, and other known additives to provide for superior presentation of the drug (i.e., the compound of the present invention or a pharmaceutical composition thereof) or to aid in the manufacture of a pharmaceutical product (i.e., a medicament).

[0084] The compounds of formula I and their pharmaceutically acceptable salts can be processed with pharmaceutically inert, inorganic or organic adjuvants for the manufacture of tablets, coated tablets, sugar-coated tablets, hard gelatin capsules, injections 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.

[0085] Suitable adjuvants for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semisolid substances and liquid polyols etc.

[0086] Suitable adjuvants for the production of solutions and syrups are, for example, water, polyols, saccharose, invert sugar, glucose etc.

[0087] Suitable adjuvants for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, etc.

[0088] Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semisolid or liquid polyols etc.

[0089] Suitable adjuvants for topical ophthalmic formulations are, for example, cyclodextrin, mannitol or many other carriers and excipients known in the art.

[0090] 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, which may also contain further therapeutically valuable substances.

[0091] The dosage can vary within a wide range and will of course be adapted to the individual requirements in 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 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, where this is indicated.

[0092] One embodiment of the present invention is a compound according to formula Ib as described herein for use as a therapeutically active substance.

[0093] One embodiment of the present invention is a compound according to formula Ib as described herein for use in the treatment or prevention of a disease, disorder or condition, wherein said disease, disorder or condition is responsive to NLRP3 inhibition.

[0094] 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, wherein said disorder or condition is responsive to NLRP3 inhibition.

[0095] One embodiment of the present invention is a compound according to formula I as described herein for use as a therapeutically active substance.

[0096] One embodiment of the present invention is a compound according to formula I as described herein for use in the treatment or prevention of a disease, disorder or condition, wherein said disease, disorder or condition is responsive to NLRP3 inhibition.

[0097] One embodiment of the present invention is a compound according to formula I as described herein for the treatment or prevention of a disease, disorder or condition, wherein said disorder or condition is responsive to NLRP3 inhibition.

[0098] 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.

[0099] There is evidence for a role for NLRP3-induced IL-1 and IL-18 in the 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).

[0100] 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 conditions; and (xviii) Any disease in which an individual is determined to have a germline or somatic non-silent mutation in NLRP3.

[0101] 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.

[0102] In a further exemplary embodiment of the present invention, the disease, disorder or condition is inflammation. Examples of inflammation that can be treated or prevented include inflammatory responses associated with or 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) joint conditions such as osteoarthritis, systemic juvenile idiopathic arthritis, adult-onset Still's disease, relapsing polychondritis, rheumatoid arthritis, juvenile chronic arthritis, gout, or seronegative spondyloarthropathy (e.g., ankylosing spondylitis, psoriatic arthritis, or Reiter's disease); (iii) muscle conditions such as polymyositis or myasthenia gravis; (iv) gastrointestinal conditions such as inflammatory bowel disease (including Crohn's disease and ulcerative colitis), colitis, gastric ulcer, celiac disease, proctitis, pancreatitis, eosinophilic gastroenteritis, mastocytosis, antiphospholipid syndrome, or food-related allergies that may have effects remote from the gut (e.g. migraine, rhinitis or eczema); (v) respiratory conditions such as chronic obstructive pulmonary disease (COPD), asthma (including eosinophilic, bronchial, allergic, intrinsic, extrinsic or dust-induced asthma, especially chronic or refractory asthma, e.g. late stage asthma and airway hyperresponsiveness), bronchitis, rhinitis (including acute rhinitis, allergic rhinitis, atrophic rhinitis, chronic rhinitis, caseous rhinitis, hypertrophic rhinitis, panlentic rhinitis, dry rhinitis, rhinitis medicamentosa, membranous rhinitis, seasonal rhinitis, e.g. hay fever and vasomotor rhinitis), sinusitis, idiopathic pulmonary fibrosis (IPF), sarcoidosis, farmer's lung, silicosis, asbestosis, volcanic ash-induced inflammation, adult respiratory distress syndrome, hypersensitivity pneumonitis, or idiopathic interstitial pneumonia; (vi) vascular conditions such as atherosclerosis, Behçet's disease, vasculitis, or Wegener's granulomatosis; (vii) autoimmune conditions such as systemic lupus erythematosus, Sjögren's syndrome, systemic sclerosis, Hashimoto's thyroiditis, type I diabetes 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, renal 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 mentioned above; (xvi) burns, wounds, trauma, hemorrhage or stroke; (xvii) radiation exposure; (xviii) metabolic diseases such as type 2 diabetes (T2D), atherosclerosis, obesity, gout or pseudogout; and / or (xix) Pain such as inflammatory hyperalgesia, pelvic pain, allodynia, neuropathic pain, or cancer-induced bone pain.

[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: (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 conditions; and (xviii) Any disease in which an individual is determined to have a germline or somatic non-silent mutation in NLRP3.

[0104] 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, wherein said disease, disorder or condition is responsive to NLRP3 inhibition.

[0105] 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.

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

[0107] 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.

[0108] 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.

[0109] 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.

[0110] One embodiment of the present invention is the use of a compound according to formula Ib as described herein for the preparation of a medicament for the treatment or prevention of a disease, disorder or condition selected from asthma or COPD.

[0111] One embodiment of the present invention is a method for the treatment or prevention of a disease, disorder or condition selected from Alzheimer's disease and Parkinson's disease, comprising administering an effective amount of a compound according to formula Ib as described herein.

[0112] 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 Ib as described herein.

[0113] One embodiment of the present invention relates to a method of inhibiting NLRP3 comprising administering an effective amount of a compound according to formula Ib described herein.

[0114] A compound of formula Ib as described herein when prepared according to any one of the processes described is also an embodiment of the present invention.

[0115] One embodiment of the present invention is a pharmaceutical composition comprising a compound according to formula Ib described herein and a therapeutically inert carrier.

[0116] One embodiment of the present invention is the use of a compound according to formula I as described herein in the treatment or prevention of a disease, disorder or condition, wherein said disease, disorder or condition is responsive to NLRP3 inhibition.

[0117] 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.

[0118] One embodiment of the present invention is a compound according to formula I as described herein for use in the treatment or prevention of a disease, disorder or condition selected from asthma or COPD.

[0119] 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.

[0120] 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.

[0121] One embodiment of the present invention is the use of a compound according to formula I as described herein for the preparation of a medicament for the treatment or prevention of a disease, disorder or condition selected from Alzheimer's disease and Parkinson's disease.

[0122] One embodiment of the present invention is the use of a compound according to formula I as described herein for the preparation of a medicament for the treatment or prevention of a disease, disorder or condition selected from asthma or COPD.

[0123] One embodiment of the present invention is a method for the treatment or prevention of a disease, disorder or condition selected from Alzheimer's disease and Parkinson's disease, comprising administering an effective amount of a compound according to formula I as described herein.

[0124] 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.

[0125] One embodiment of the present invention relates to a method of inhibiting NLRP3, comprising administering an effective amount of a compound according to formula I described herein.

[0126] A compound of formula I as described herein when prepared according to any one of the processes described is also an embodiment of the present invention.

[0127] One embodiment of the present invention is a pharmaceutical composition comprising a compound according to Formula I described herein and a therapeutically inert carrier.

[0128] Assay procedure NLRP3 and pyroptosis It is well established that activation of NLRP3 leads to cell pyroptosis, a hallmark 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). Thus, inhibitors of NLRP3 are expected to block pyroptosis as well as the release of proinflammatory cytokines (e.g., IL-1β) from cells.

[0129] 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 100,000 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.

[0130] 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 poly-D-lysine (VWR #734-0317) coated black-walled clear-bottom cell culture plates. 2. Add 5 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. 37℃, 5% CO 2 Incubate for 3 hours at 4°C. 4. Add 5 μl of Nigericin (Sigma No. N7143) (FAC 5 μM) to all wells 5. 37℃, 5% CO 2 Incubate for 1 hour at 4°C. 6. At the end of the incubation period, spin the plate at 300 x g for 3 minutes and remove the supernatant. 7. 50 μl of Resazurin (Sigma #R7017) (FAC 100 μM Resazurin in RPMI medium without FBS) is then added and the plate is incubated at 37° C. and 5% CO 2 Incubate for another 1-2 hours. 8. Plates were read on an Envision reader at excitation 560 nm and emission 590 nm. 9. IC 50Fit the data to a nonlinear regression equation (4-parameter log inhibitor vs. response variable slope)

[0131] The results of the pyroptosis assay were analyzed using THP IC 50 These are summarized in Table 1 below.

[0132] 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. For this reason, we investigated the NLRP3 inhibitory activity of a number of compounds in human whole blood according to the following protocol.

[0133] 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 flat-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. 37℃, 5% CO 2 Incubate for 3 hours at 4°C. 4. Add 10 μl of Nigericin (Sigma #N7143) (10 μM FAC) to all wells 5. 37℃, 5% CO 2 Incubate for 1 hour at 4°C. 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)

[0134] Human whole blood assay results HWB IC 50 These are summarized in Table 1 below.

[0135] hERG Screening Assay In the small molecule drug development process, one of the most frequent adverse side effects that leads to drug failure is cardiac arrhythmia. Such failure is often related to the drug's ability to inhibit the human delayed rectifier potassium ion channel gene (hERG) cardiac potassium channel. Therefore, it would be beneficial to have no or low inhibition of the hERG cardiac potassium channel.

[0136] 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.

[0137] Experimental solution The extracellular solution contained (in mM): NaCl 150; KCl 4; CaCl 2 1;MgCl 2 The internal solution contains (in mM): KCl, 10; KF, 100; NaCl, 10; HEPES, 10; EGTA, 20; pH=7.0-7.4 with KOH, osmolality 260-300 mOsm.

[0138] Electrophysiology The effects of compounds on hERG K+-current parameters will be evaluated at two concentrations in at least quadruplicate cells.

[0139] 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.

[0140] Hold the cells at a resting voltage of -80 mV and follow the voltage pattern shown in Figure 1 (at 35-37 °C, outward K + The cells were stimulated with a pulse pattern (used to elicit the current) at a stimulation frequency of 0.1 Hz (6 bpm) to activate the hERG channels and conduct outward IKhERG currents.

[0141] Data analysis The amplitude of IKhERG was recorded at each drug concentration and compared to vehicle control values ​​(taken as 100%) to define fractional blocks. Concentration-response data were fitted with the following relationship. [Table 1]

[0142] 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).

[0143] Intracellular P-gp assay: A typical assay uses transfected LLC-PK1 cells (porcine kidney epithelial cells) overexpressing human P-gp or mouse P-gp cultured on 96-well semi-permeable filter membrane plates, where these cells form a polarized monolayer with tight junctions that act as a barrier between the apical and basolateral compartments.

[0144] P-gp is expressed in the apical membrane of the monolayer.

[0145] The tightness 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.

[0146] 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 transcellular 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 to predict intestinal absorption.

[0147] The donor concentration is measured at t-start (reference) and compared to the donor and acceptor concentrations after a certain time period (t-end) to calculate the extent to which the compound crosses the membrane.

[0148] Microsomal Stability: Incubations of test compounds at 1 μM in microsomes (0.5 mg / mL) and cofactor NADPH are carried out in 96-well plates at 37° C. in a TECAN (Tecan Group Ltd, Switzerland) automated liquid handling system. After a 10 min pre-incubation step of the test compounds with the microsomes, the enzymatic reaction is started by the addition of the cofactor. At 1, 3, 6, 9, 15, 25, 35 and 45 min, aliquots of the incubations are removed and quenched with 1:3 (v / v) acetonitrile containing an internal standard. The samples are then cooled and centrifuged before analyzing the supernatants by LC-MS / MS 2.

[0149] Metabolic stability in hepatocytes: Assay Description: Biological material. Obtain cryopreserved hepatocytes [mouse, rat, rabbit, monkey and human (male and female; mixed)]. 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 (n=5 for human males, n=5 for human females)] with stromal mouse fibroblasts (negative control; pooled), including plates for incubation, application medium and maintenance medium.

[0150] Metabolism by Suspension Hepatocytes. Primary pooled cryopreserved hepatocytes are reconstituted to a final suspension density of 1 × 106 cells / mL in pre-warmed William's E medium containing 10% FCS, 0.05 mg / mL streptomycin and 50 U / mL penicillin and 0.4 mM L-glutamine and 0.01 mg / mL gentamicin, 0.048 mg / mL hydrocortisone and 0.004 mg / mL insulin. Incubation was performed fully automatically using a liquid handling system (Tecan) equipped with a CO2 incubator equipped with an orbital shaker. After adding test compounds (1 × 105 cells / well) at e.g. 1 μM to the wells, the 96-well hepatocyte suspension culture plates are incubated at 37 °C in 5% CO2. Samples are quenched by adding acetonitrile (containing the internal standard) to the incubation wells at the specified time points up to 2 h.

[0151] Metabolism with HepatoPac®. Incubation of test articles (e.g., 1 μM, 0.1% v / v DMSO) performed in suspension assays is performed in 96-well plates containing either co-cultures of adherent hepatocytes and mouse fibroblast control cells or control cells alone (5% CO2 atmosphere and 37°C). The incubation medium in human HepatoPac® is identical to that of suspension hepatocytes. At defined time points (2, 18, 26, 48, 72 and 96 hours), the entire well is quenched with ice-cold acetonitrile containing an internal standard.

[0152] The samples are then appropriately centrifuged and the supernatants are analyzed by LC-MS / MS. Incubations are performed at n=1 or 2. [Table 2]

[0153] The invention will now be illustrated by the following examples, which have no limiting character.

[0154] Where preparations are obtained as mixtures of enantiomers or diastereomers, the pure enantiomers or diastereomers may be obtained by methods described herein or by methods known to those skilled in the art, such as, for example, chiral chromatography or crystallization.

[0155] Experimental Method Abbreviation: [Table 3]

[0156] Analysis method NMR spectra were run on a Bruker 400 MHz spectrometer using an ICON-NMR under TopSpin program control. Spectra were measured at 298 K and referenced to the solvent resonance unless otherwise stated.

[0157] LC-MS method: SHIMADZU LCMS-2020, Agilent 1200 LC / G1956A MSD and Agilent 1200\G6110A, Agilent 1200 LC&Agilent 6110 MSD were used. Mobile phase: A: 0.025% NH 3 H 2 O (v / v); B: acetonitrile. Column: Kinetex EVO C 18 2.1X30mm, 5μm.

[0158] system Waters Acquity UPLC - Binary Pump - Autosampler Waters 2777C (also known as CTC Pal HT) - Column Manager (4 columns) - Photodiode Array Detector (PDA) - Single quadrupole mass spectrometers (SQD1 and SQD2)

[0159] Eluent Channel A: Water 0.1% formic acid Channel B: Acetonitrile 0.07% formic acid

[0160] Built-in column (50℃): Column 1 Agilent Zorbax Eclipse Plus C18, Rapid Resolution HT, 2.1x30mm, 1.8μm, part number 959731-902 Column 2: (MS1+5+7 only): Waters Acquity UPLC BEH C18, 2.1 x 50 mm, 1.7 μm, part number 186002350 Column 3: None Column 4: None (flow injection)

[0161] method: Fast gradient (2 min, column 1, mass range m / z 150-900) [Table 4] EXAMPLES

[0162] Working Example Unless otherwise stated, all examples and intermediates were prepared under a nitrogen atmosphere.

[0163] Examples 1 and 2: (rac)-2-[7-[(1-ethyl-3-piperidyl)amino]thieno[2,3-d]pyridazin-4-yl]-5-(trifluoromethyl)phenol;Formic acid and (rac)-2-[4-[(1-ethyl-3-piperidyl)amino]thieno[2,3-d]pyridazin-7-yl]-5-(trifluoromethyl)phenol; Formic acid [ka]

[0164] Step A: (rac)-7-chloro-N-(1-ethyl-3-piperidyl)thieno[2,3-d]pyridazin-4-amine and (rac)-4-chloro-N-(1-ethyl-3-piperidyl)thieno[2,3-d]pyridazin-7-amine

[0165] To a mixture of 4,7-dichlorothieno[2,3-d]pyridazine (CAS no. 699-89-8, 50 mg, 0.244 mmol, 1.0 equiv.) and (rac)-1-ethylpiperidin-3-amine (CAS no. 6789-94-2, 41.8 μL, 0.293 mmol, 1.2 equiv.) in DMSO (0.2 mL) was added DIPEA (128 μL, 0.731 mmol, 3.0 equiv.). The reaction mixture was heated to 120° C. for 16 h. The yellow reaction mixture was extracted with ethyl acetate and water. The organic layer was washed with brine. The aqueous layer was back-extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product (brown oil, 110.9 mg) was combined with another crude mixture (50 mg in NMP) from a different experiment performed on the same scale in a different solvent to give a new crude residue (orange oil, 169 mg) which was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 4 g, CH with a MeOH gradient). 2 Cl 2 ) to give the title compound (82.5 mg) as a dark yellow solid containing a mixture of regioisomers. LCMS: m / z 297.1 [M+H] + ,ESI pos.

[0166] Step B: (rac)-2-[7-[(1-ethyl-3-piperidyl)amino]thieno[2,3-d]pyridazin-4-yl]-5-(trifluoromethyl)phenol; formic acid and (rac)-2-[4-[(1-ethyl-3-piperidyl)amino]thieno[2,3-d]pyridazin-7-yl]-5-(trifluoromethyl)phenol; formic acid

[0167] The above-mentioned regioisomers (rac)-7-chloro-N-(1-ethyl-3-piperidyl)thieno[2,3-d]pyridazin-4-amine and (rac)-4-chloro-N-(1-ethyl-3-piperidyl)thieno[2,3-d]pyridazin-7-amine (82.5 mg, 0.278 mmol, 1.0 equiv.), [2-hydroxy-4-(trifluoromethyl)pyridazin-4-amine], [2-hydroxy-4-(trifluoromethyl)pyridazin-7 ... A mixture of 1,1'-bis(diphenylphosphino)ferrocene-palladium(ii) dichloride dichloromethane complex (26.2 mg, 0.032 mmol, 0.116 equiv.) was flushed with argon and stirred at 90 °C for 2 h. The reaction mixture was cooled to room temperature, MeOH was added (2 mL) and concentrated in vacuo. The crude product was purified by RP preparative HPLC (column: YMC-Triart C 18 , 12 nm, 5 μm, 100×30 mm; conditions: ACN / water+0.1% HCOOH, run time 11 min, gradient 10-98-100 ACN in water) to give the title compound 1 (14.8 mg, 11% yield) as a yellow solid and its regioisomer 2 (29.5 mg, 23% yield), both as formate salts, in molar ratios (molar ratio by NMR, product:formate) of 53:47 and 52:48, respectively. LCMS: m / z 423.1 [M+H] + ,ESI pos.

[0168] Examples 3 and 4: (rac)-N-(1-ethyl-3-piperidyl)-4-[4-(trifluoromethyl)phenyl]thieno[2,3-d]pyridazin-7-amine and (rac)-N-(1-ethyl-3-piperidyl)-7-[4-(trifluoromethyl)phenyl]thieno[2,3-d]pyridazin-4-amine [ka]

[0169] The above regioisomers (rac)-7-chloro-N-(1-ethyl-3-piperidyl)thieno[2,3-d]pyridazin-4-amine and (rac)-4-chloro-N-(1-ethyl-3-piperidyl)thieno[2,3-d]pyridazin-7-amine (80 mg, 0.270 mmol, 1.0 equiv.), [4-(trifluoromethyl)pyridazin-4-amine], and [4-(trifluoromethyl)pyridazin-7-amine] in 1,4-dioxane (1.6 mL) and water (0.8 mL) were reacted in the same manner as in Examples 1 and 2, Step B above. A mixture of [fluoromethyl]phenyl]boronic acid (CAS no. 128796-39-4, 86.8 mg, 0.457 mmol, 1.7 equiv.), potassium carbonate (178 mg, 1.29 mmol, 4.8 equiv.) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (25.4 mg, 0.031 mmol, 0.116 equiv.) was flushed with argon and stirred at 90° C. for 2 h. The reaction mixture was cooled to room temperature and then extracted with ethyl acetate and water. The organic layer was washed with brine. The aqueous layer was back-extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by RP preparative HPLC (column: YMC-Triart C 18 , 12 nm, 5 μm, 100×30 mm; Conditions: ACN / water+0.1% triethylamine) to give the title compound 3 (28.1 mg, 24% yield) and its regioisomer 4 (47.9 mg, 42% yield) as a yellow solid. LCMS: m / z 407.2 [M+H] + ,ESI pos.

[0170] Example 5 - HCl: 2-[4-[[(3R)-1-Ethyl-3-piperidyl]amino]-1-methyl-pyrrolo[2,3-d]pyridazin-7-yl]-5-(trifluoromethyl)phenol; hydrochloride [ka]

[0171] Step A: Methyl 1-(2-trimethylsilylethoxymethyl)pyrrole-3-carboxylate

[0172] To a mixture of methyl 1H-pyrrole-3-carboxylate (CAS no. 2703-17-5, 10.0 g, 79.9 mmol, 1.0 equiv.) in DMF (100 mL), NaH (3.52 g, 87.9 mmol, 1.1 equiv., 60% purity) was added 2 The mixture was stirred for 15 min, then 2-(trimethylsilyl)ethoxymethyl chloride (18.4 mL, 104 mmol, 1.3 equiv) was added and stirred at 25° C. for 45 min. TLC (PE / EtOAc=2:1) ​​showed the reaction was complete, with one new spot detected. The mixture was poured into water (20 mL) and extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column silica gel using PE / EtOAc=2 / 1 to give the title compound (20 g, 98% yield) as a colorless oil. LCMS: m / z 255.9 [M+H] + ,ESI.

[0173] Step B: Methyl 2-[hydroxy-[2-methoxy-4-(trifluoromethyl)phenyl]methyl]-1-(2-trimethylsilylethoxymethyl)pyrrole-3-carboxylate

[0174] To a mixture of the above methyl 1-(2-trimethylsilylethoxymethyl)pyrrole-3-carboxylate (5.0 g, 19.6 mmol, 1.0 equiv.) in diisopropyl ether (100 mL), lithium diisopropylamide (24.5 mL, 48.9 mmol, 2.5 equiv.) was added in N 2The mixture was added dropwise under -60°C and stirred for 10 min. Then, 2-methoxy-4-(trifluoromethyl)benzaldehyde (4.40 g, 21.5 mmol, 1.1 equiv) was added and the mixture was stirred for 50 min at -60°C. After the reaction was completed (TLC: PE / EtOAc = 10:1), the mixture was diluted with saturated NH 4 The mixture was quenched with Cl (10 mL). The aqueous layer was extracted with EtOAc (100 mL×2). The combined organic layers were washed with water (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography eluted with PE / EtOAc=10:1 to give the title compound (4.50 g, 50% yield) as a colorless oil. 1 H NMR (400 MHz, METHANOL-d 4 )δ=7.49(d,1H),7.25(d,1H),7.20(d,1H),6.79(d,1H),6.73(s,1H),6.57(d,1H),5.31-5.21(m,2H),3.83,3.81(2 s,3H each),3.26-3.10,0.64-0.55,0.50-0.41(3 m,2H,1H,1H),-0.10(s,9H).

[0175] Step C: Methyl 2-[2-methoxy-4-(trifluoromethyl)benzoyl]-1-(2-trimethylsilylethoxymethyl)pyrrole-3-carboxylate

[0176] CH 2 Cl 2 A mixture of the above methyl 2-[hydroxy-[2-methoxy-4-(trifluoromethyl)phenyl]methyl]-1-(2-trimethylsilylethoxymethyl)pyrrole-3-carboxylate (4.50 g, 9.79 mmol, 1.0 equiv.) and 2,2-dimethoxypropane (6.23 g, 14.7 mmol, 1.5 equiv.) in (50 mL) was stirred at 25° C. for 1 h. After the reaction was complete (TLC: PE / EtOAc=10:1), the mixture was diluted with saturated Na 2 SO 3 (50 mL) and the aqueous layer was separated into CH 2 Cl 2(100 mL x 2). The combined organic layers were washed with water (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography eluted with PE / EtOAc = 10:1 to give the title compound (2.0 g, 44% yield) as a colorless oil. LCMS: m / z 458.0 [M+H] + ,ESI.

[0177] Step D: 7-[2-Methoxy-4-(trifluoromethyl)phenyl]-1-(2-trimethylsilylethoxymethyl)-5H-pyrrolo[2,3-d]pyridazin-4-one

[0178] A mixture of the above methyl 2-[2-methoxy-4-(trifluoromethyl)benzoyl]-1-(2-trimethylsilylethoxymethyl)pyrrole-3-carboxylate (1.50 g, 3.28 mmol, 1.0 equiv.) and hydrazine hydrate (820 mg, 16.4 mmol, 5.0 equiv.) in ethanol (10 mL) was stirred at 70° C. for 16 h. After completion of the reaction, the mixture was poured into water (20 mL) and extracted with EtOAc (100 mL×3). The combined organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column silica gel using PE / EtOAc=2 / 1 to give the title compound (1.0 g, 68% yield) as a white solid. LCMS: m / z 440.4 [M+H] + ,ESI.

[0179] Step E: 4-chloro-7-[2-methoxy-4-(trifluoromethyl)phenyl]-1H-pyrrolo[2,3-d]pyridazine

[0180] A solution of 7-[2-methoxy-4-(trifluoromethyl)phenyl]-1-(2-trimethylsilylethoxymethyl)-5H-pyrrolo[2,3-d]pyridazin-4-one (1.0 g, 2.28 mmol, 1.0 equiv.) and POCl in toluene (10 mL). 3A mixture of (3.49 g, 22.8 mmol, 10 equiv) was stirred at 110° C. for 2 h. After completion of the reaction, the mixture was concentrated under reduced pressure. The crude product was purified by reverse phase flash (CombiFlash 0.1% TFA aqueous-MeCN conditions) and subsequently lyophilized to give the title compound (340 mg, 46% yield) as a white solid. LCMS: m / z 327.9 [M+H] + ,ESI.

[0181] Step F: 4-Chloro-7-[2-methoxy-4-(trifluoromethyl)phenyl]-1-methyl-pyrrolo[2,3-d]pyridazine

[0182] To a mixture of the above 4-chloro-7-[2-methoxy-4-(trifluoromethyl)phenyl]-1H-pyrrolo[2,3-d]pyridazine (340 mg, 1.04 mmol, 1.0 equiv.) in DMF (4 mL), NaH (62.3 mg, 1.56 mmol, 1.5 equiv., 60% purity) was added 2 The mixture was added at 0° C. under reduced pressure and stirred for 5 min. Methyl iodide (221 mg, 1.56 mmol, 1.5 equiv.) was then added to the mixture and stirred at 25° C. for 55 min. Upon completion of the reaction, the mixture was washed with saturated NH 4 Poured into Cl solution (20 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column silica gel using PE / EtOAc = 4 / 1 to give the title compound (260 mg, 67% yield) as a white solid. LCMS: m / z 341.8 [M+H] + ,ESI.

[0183] Step G: N-[(3R)-1-Ethyl-3-piperidyl]-7-[2-methoxy-4-(trifluoromethyl)phenyl]-1-methyl-pyrrolo[2,3-d]pyridazin-4-amine

[0184] To a solution of the above 4-chloro-7-[2-methoxy-4-(trifluoromethyl)phenyl]-1-methyl-pyrrolo[2,3-d]pyridazine (100 mg, 0.29 mmol, 1.0 equiv.) in 1,4-dioxane (4 mL), BinapPdG 3 (20.0 mg, 0.060 mmol, 0.20 equiv.), cesium carbonate (190.7 mg, 0.590 mmol, 2.0 equiv.) and 4-chloro-7-[2-methoxy-4-(trifluoromethyl)phenyl]-1-methyl-pyrrolo[2,3-d]pyridazine (100 mg, 0.29 mmol, 1.0 equiv.) were added to N 2 The mixture was stirred at 100° C. for 4 h. After completion of the reaction, the reaction mixture was quenched with water (2 mL) and concentrated under reduced pressure. The residue was purified by reverse phase flash (CombiFlash 0.1% TFA aqueous-ACN condition) followed by lyophilization to give the title compound (100 mg, 79% yield) as a pale yellow solid. LCMS: m / z 434.2 [M+H] + ,ESI.

[0185] Step H: 2-[4-[[(3R)-1-ethyl-3-piperidyl]amino]-1-methyl-pyrrolo[2,3-d]pyridazin-7-yl]-5-(trifluoromethyl)phenol; hydrochloride

[0186] CH 2 Cl 2 N-[(3R)-1-ethyl-3-piperidyl]-7-[2-methoxy-4-(trifluoromethyl)phenyl]-1-methyl-pyrrolo[2,3-d]pyridazin-4-amine (130 mg, 0.30 mmol, 1.0 equiv.) and BBr 3A mixture of (1.13 g, 4.50 mmol, 15 equiv) was stirred at -60°C for 10 min and then at 25°C for 50 min. After completion of the reaction, the pH was adjusted to about pH 7 by adding ammonia, then the mixture was filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase flash (CombiFlash 0.1% HCl aqueous-ACN) and subsequently lyophilized to give the title compound (92.7 mg, 66% yield) as a pale yellow solid. LCMS: m / z 420.0 [M+H] + ,ESI.

[0187] As above, Example 5 was also prepared as the TFA salt.

[0188] Example 5 - TFA: 2-[4-[[(3R)-1-ethyl-3-piperidyl]amino]-1-methyl-pyrrolo[2,3-d]pyridazin-7-yl]-5-(trifluoromethyl)phenol;2,2,2-trifluoroacetic acid; [ka]

[0189] CH 2 Cl 2 N-[(3R)-1-ethyl-3-piperidyl]-7-[2-methoxy-4-(trifluoromethyl)phenyl]-1-methyl-pyrrolo[2,3-d]pyridazin-4-amine (30.0 mg, 0.070 mmol, 1 equiv.) and BBr 3 A mixture of (173 mg, 0.69 mmol, 10 equiv) was stirred at -60°C for 10 min and then at 25°C for 50 min. After completion of the reaction, the mixture was adjusted to about pH 7 by addition of ammonia, then filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by RP flash (CombiFlash 0.1% TFA aqueous-ACN) and subsequently lyophilized to give the title compound (15.0 mg, 37% yield) as a pale yellow solid. LCMS: m / z 420.1 [M+H] + ,ESI.

[0190] Example 6: 2-[4-[[(3R)-1-ethyl-3-piperidyl]amino]-1-methyl-pyrazolo[3,4-d]pyridazin-7-yl]-5-(trifluoromethyl)phenol;2,2,2-trifluoroacetic acid [ka]

[0191] Step A: Diethyl 2-methylpyrazole-3,4-dicarboxylate

[0192] To a solution of diethyl 1H-pyrazole-4,5-dicarboxylate (4.00 g, 18.9 mmol, 1.0 equiv) in ACN (60 mL) was added potassium carbonate (5.21 g, 37.7 mmol, 2.0 equiv). The reaction mixture was stirred at 20° C. for 0.5 h, then iodomethane (4.01 g, 28.3 mmol, 1.5 equiv) was added to the mixture. The mixture was stirred at 20° C. for 12 h. Upon completion of the reaction (TLC: PE:EtOAc=3:1), the mixture was diluted with H 2 The mixture was quenched with O (100 mL) and extracted with EtOAc (100 mL x 3). The organic phase was washed with brine (100 mL x 2) and anhydrous Na 2 SO 4 The mixture was dried over 1000 ml of water, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO 2 , petroleum ether:ethyl acetate, 5:1 to 2:1) to give the title compound (1.35 g, 32% yield) as a colorless oil. 1 H NMR (400 MHz, DMSO-d 6 )δ=7.88(s,1H),4.37,4.21(q,2H each),3.94(s,3H),1.34-1.21(m,6H).

[0193] Step B: 1-Methylpyrazolo[3,4-d]pyridazine-4,7-diol

[0194] To a solution of diethyl 2-methylpyrazole-3,4-dicarboxylate (1.1 g, 4.86 mmol, 1.0 equiv.) in methanol (20 mL) was added hydrazine monohydrate (0.71 mL, 14.6 mmol, 3.0 equiv.). The mixture was stirred at 20° C. for 24 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by RP Flash (CombiFlash 0.1% NH 3 .H 2 Purification by 0H20 (aqueous-ACN conditions) followed by lyophilization afforded the title compound (100 mg, 12% yield) as a white solid. LCMS: m / z 167.1 [M+H] + ,ESI pos.

[0195] Step C: 4,7-Dichloro-1-methyl-pyrazolo[3,4-d]pyridazine

[0196] POCl 3 A mixture of the above 1-methylpyrazolo[3,4-d]pyridazine-4,7-diol (200 mg, 1.20 mmol, 1.0 equiv) in 1,2-dichloro-2,4-diphenyl-3,5-diol (2.0 mL) was stirred at 60° C. for 12 h. Upon completion of the reaction, the mixture was concentrated under reduced pressure to give the title compound (220 mg, 90% yield) as a yellow solid. LCMS: m / z 202.8 [M+H]+, ESI pos.

[0197] Step D: 7-Chloro-N-[(3R)-1-ethyl-3-piperidyl]-1-methyl-pyrazolo[3,4-d]pyridazin-4-amine

[0198] To a solution of the above 4,7-dichloro-1-methyl-pyrazolo[3,4-d]pyridazine (200 mg, 0.99 mmol, 1.0 equiv.) and (3R)-1-ethylpiperidin-3-amine (CAS number 1020396-26-2, 152 mg, 1.18 mmol, 1.20 equiv.) in NMP (1 mL) was added potassium carbonate (272 mg, 1.97 mmol, 2.0 equiv.). The mixture was heated to 85° C. and N 2The mixture was stirred under reduced pressure for 16 h. Upon completion of the reaction, the reaction mixture was cooled to 20° C. and purified by reverse phase flash (CombiFlash 0.1% TFA aqueous-ACN conditions) followed by lyophilization to give the title compound (70 mg, 24% yield) as a yellow solid. LCMS: m / z 295.0 [M+H] + ,ESI pos.

[0199] Step E: 2-[4-[[(3R)-1-ethyl-3-piperidyl]amino]-1-methyl-pyrazolo[3,4-d]pyridazin-7-yl]-5-(trifluoromethyl)phenol; 2,2,2-trifluoroacetic acid

[0200] To a solution of the above 7-chloro-N-[(3R)-1-ethyl-3-piperidyl]-1-methyl-pyrazolo[3,4-d]pyridazin-4-amine (60.0 mg, 0.20 mmol, 1.0 equiv.) and [2-hydroxy-4-(trifluoromethyl)phenyl]boronic acid (CAS no. 1072951-50-8, 83.8 mg, 0.410 mmol, 2.0 equiv.) in 1,4-dioxane (2 mL) and water (0.400 mL) was added CsF (92.8 mg, 0.610 mmol, 3.0 equiv.) and Pd(dppf)Cl 2 (29.8 mg, 0.040 mmol, 0.20 equiv) was added. The reaction mixture was stirred at 130° C. for 1.5 h under microwave. Upon completion of the reaction, the mixture was concentrated under reduced pressure and purified by reverse phase flash (CombiFlash 0.1% TFA aqueous-ACN condition) followed by lyophilization to give the crude product. The crude product was purified by preparative HPLC (Method Column 3_Phenomenex Luna C 18 Purification by chromatography (75 mm x 30 mm x 3 μm; conditions water (TFA)-ACN; start B: 10; end B: 40; gradient time (min): 7; 100% B hold time (min): 2; flow rate (mL / min): 25) followed by lyophilization afforded the title compound (34.4 mg, 30% yield) as a white solid. LCMS: m / z 421.1 [M+H] + ,ESI pos.

[0201] Purification method: Automated reverse-phase column chromatography was performed using a Gilson GX-281 system driven by a Gilson-322 pump module, a Gilson-156 UV photometer detection unit and a Gilson-281 fraction collector.

[0202] Phenomenex Luna C 18 : 75mm x 30mm x 3μm pH (water (10mM TFA)-ACN): 5~6 Average particle size: 3μm Prior to use, the column was conditioned with 100% ACN (2 min) followed by 1% ACN (0.8 min). Flow rate = 25 mL / min.

[0203] Separation operation: [Table 5]

[0204] Detection wavelengths: 220 and 254 nm.

[0205] Before each new run, the cartridge was cleaned using the conditioning method.

[0206] Example 7: 2-[4-[[(3R)-1-ethyl-3-piperidyl]amino]furo[2,3-d]pyridazin-7-yl]-5-(trifluoromethyl)phenol [ka]

[0207] Step A: Furo[2,3-d]pyridazine-4,7-diol

[0208] To a mixture of dimethylfuran-2,3-dicarboxylate (4.50 g, 24.4 mmol, 1.0 equiv) in ethanol (45 mL) was added hydrazine hydrate (1.22 g, 244 mmol, 10 equiv). The mixture was stirred at 70° C. for 2 h. The mixture was then filtered and the filter cake was added to a solution of HCl (3.05 mL, 36.7 mmol, 1.5 equiv) in water (30 mL). Upon completion of the reaction (TLC (PE: EtOAc = 1:1)), the mixture was filtered to obtain a white filter cake. The filter cake was triturated with water to give the title compound (2.70 g, 73% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 )δ=11.77(br.s,2H),8.20(d,1H),7.03(d,1H).

[0209] Step B: 4,7-Dichlorofuro[2,3-d]pyridazine

[0210] POCl 3 A mixture of the above furo[2,3-d]pyridazine-4,7-diol (1.00 g, 6.57 mmol, 1.0 equiv.) in 10 mL of hexane was degassed and cooled with N 2 The mixture was purged with 3× and pyridine (1.0 mL, 12.4 mmol, 1.88 equiv) was added to the mixture. The mixture was stirred at 110° C. for 3 h. LCMS showed the desired mass was detected. The mixture was poured into ice water (100 mL) and extracted with methylene dichloride (20 mL×3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (1.10 g, 88% yield) as a yellow solid. LCMS: m / z 188.9 [M+H] + ,ESI pos.

[0211] Step C: 2-(4-chlorofuro[2,3-d]pyridazin-7-yl)-5-(trifluoromethyl)phenol

[0212] 4,7-dichlorofuro[2,3-d]pyridazine (3.00 g, 1.59 mmol, 1.0 equiv.) as described above in 1,4-dioxane (50 mL) and water (10 mL), K 2 CO 3 (4.38 g, 3.17 mmol, 2.0 equiv.) and Pd(dppf)Cl 2 A mixture of (116 mg, 0.160 mmol, 0.10 equiv.) was degassed and diluted with N 2 The mixture was purged three times with 500 rpm. Then, [2-hydroxy-4-(trifluoromethyl)phenyl]boronic acid (CAS number 1072951-50-8, 262 mg, 1.27 mmol, 0.80 equiv.) was added to the mixture. The mixture was stirred at 100° C. for 12 h. The mixture was concentrated under reduced pressure and purified by reverse phase flash (CombiFlash 0.1% TFA aqueous / ACN conditions) and preparative HPLC (column Waters Xbridge 150×25 mm×5 μm; conditions water (ammonia hydroxide v / v)-ACN; start B: 35, end B: 65; gradient time (min): 9; 100% B retention time (min): 2; flow rate (mL / min): 25). After lyophilization, the title compound (110 mg, 22% yield) was obtained as a yellow oil. LCMS: m / z 315.0 [M+H] + ,ESI pos.

[0213] Step D: 2-[4-[[(3R)-1-ethyl-3-piperidyl]amino]furo[2,3-d]pyridazin-7-yl]-5-(trifluoromethyl)phenol

[0214] A solution of 2-(4-chlorofuro[2,3-d]pyridazin-7-yl)-5-(trifluoromethyl)phenol (28.0 mg, 0.09 mmol, 1.0 equiv.) and (3R)-1-ethylpiperidin-3-amine (CAS no. 1020396-26-2, 57.1 mg, 0.44 mmol, 5.0 equiv.) in 1,4-dioxane (1 mL) was diluted with Cs 2 CO 3 (72.5 mg, 0.220 mmol, 2.5 equiv.) and BinapPdG 3 (5.0 mg, 0.020 mmol, 0.20 equiv.) was added. The mixture was diluted with N 2The mixture was stirred at 110° C. for 12 h under reduced pressure. The mixture was concentrated under reduced pressure and purified by reverse phase flash (CombiFlash 0.1% NH 3 H 2 Purification by HCl (aqueous / ACN conditions) followed by lyophilization afforded the title compound (4 mg, 10% yield) as a yellow solid. LCMS: m / z 407.1 [M+H] + ,ESI pos.

[0215] Example 9: 2-[7-[[(3R)-1-ethyl-3-piperidyl]amino]-1-methyl-pyrazolo[3,4-d]pyridazin-4-yl]-5-(trifluoromethyl)phenol [ka]

[0216] Step A: 4-Chloro-N-[(3R)-1-ethyl-3-piperidyl]-1-methyl-pyrazolo[3,4-d]pyridazin-7-amine

[0217] To a solution of 4,7-dichloro-1-methyl-pyrazolo[3,4-d]pyridazine (Example 6, Step C; 200 mg, 0.99 mmol, 1.0 equiv.) and (3R)-1-ethylpiperidin-3-amine (CAS number 1020396-26-2, 151.57 mg, 1.18 mmol, 1.2 equiv.) in NMP (1 mL) was added potassium carbonate (272 mg, 1.97 mmol, 2.0 equiv.). The mixture was diluted with N 2 The mixture was stirred at 85° C. for 16 h under 100° C. Upon completion of the reaction, the reaction mixture was cooled to 20° C. and purified by reverse phase flash (CombiFlash, 0.1% TFA aqueous-ACN conditions) to give both regioisomers (70.0 mg, 24% yield; INT Example 6, Step D) as yellow solids and the title compound (20.0 mg, 7% yield) as yellow solids. LCMS: m / z 295.0 [M+H] + ,ESI pos.

[0218] Step B: 2-[7-[[(3R)-1-ethyl-3-piperidyl]amino]-1-methyl-pyrazolo[3,4-d]pyridazin-4-yl]-5-(trifluoromethyl)phenol

[0219] A solution of 4-chloro-N-[(3R)-1-ethyl-3-piperidyl]-1-methyl-pyrazolo[3,4-d]pyridazin-7-amine (20 mg, 0.07 mmol, 1.0 equiv.) and [2-hydroxy-4-(trifluoromethyl)phenyl]boronic acid (CAS no. 1072951-50-8, 27.94 mg, 0.14 mmol, 2.0 equiv.) in 1,4-dioxane (2 mL) and water (0.40 mL) was treated with CsF (30.92 mg, 0.2 mmol, 3.0 equiv.) and Pd(dppf)Cl 2 (9.93 mg, 0.01 mmol, 0.2 equiv.) was added. The above reaction mixture was stirred at 130° C. for 1.5 h under microwave conditions. Upon completion of the reaction, the mixture was concentrated under reduced pressure and purified by reverse phase flash (CombiFlash 0.1% TFA aqueous-ACN conditions) to give the crude product. The crude product was purified by preparative HPLC (Column: Phenomenex Synergi Polar-RP 100 mm×25 mm×4 μm; Conditions: Water (TFA)-MeCN Start B: 23; End B: 43; Gradient time (min): 7; 100% B Retention time (min): 2; Flow rate (ml / min): 25) to give a yellow solid, which was then purified by preparative HPLC (Column: Waters Xbridge 150×25 mm×5 μm; Conditions: Water (NH 4 HCO 3 )-MeCN, start B: 55; end B: 85; gradient time (min): 10; 100% B hold time (min): 2; flow rate (ml / min): 25) to give the title compound (6.48 mg, 22% yield) as a yellow solid. LCMS: m / z 421.1 [M+H] + ,ESI pos.

[0220] Example 10: 2-[4-[[(3R)-1-ethyl-3-piperidyl]amino]-1-methyl-pyrazolo[3,4-d]pyridazin-7-yl]-5-(trifluoromethoxy)phenol;2,2,2-trifluoroacetic acid [ka]

[0221] Step A: N-[(3R)-1-Ethyl-3-piperidyl]-7-[2-methoxy-4-(trifluoromethoxy)phenyl]-1-methyl-pyrazolo[3,4-d]pyridazin-4-amine

[0222] In a microwave tube, 7-chloro-N-[(3R)-1-ethyl-3-piperidyl]-1-methyl-pyrazolo[3,4-d]pyridazin-4-amine (Example 6, Step D, 150.0 mg, 0.51 mmol, 1.0 equiv.), CsF (386.47 mg, 2.54 mmol, 5.0 equiv.) and 2-methoxy-4-(trifluoromethoxy)phenylboronic acid (144.08 mg, 0.61 mmol, 1.2 equiv.; CAS: 355836-10-1) were dissolved in 1,4-dioxane (2 mL) and water (0.4 mL), the mixture was purged with nitrogen three times, and then Pd(dppf)Cl was added. 2 (74.39 mg, 0.1 mmol, 0.2 equiv) was added to give a red solution. The reaction mixture was stirred at 130 °C under microwave conditions for 3 h to give a black solution. The reaction mixture was quenched with water (10 mL) to give a brown solution, which was then extracted with EtOAc (3 x 20 mL), washed with brine (2 x 30 mL) and diluted with anhydrous Na 2 SO 4 The mixture was dried over 100 ml, filtered, and the filtrate was concentrated under reduced pressure to give a yellow solid. The crude product was purified by reverse phase flash (CombiFlash, 0.1% TFA aqueous-ACN conditions) to give the title compound (60.0 mg, 26% yield) as a yellow solid. LCMS: m / z 451.2 [M+H]+, ESI pos.

[0223] Step B: 2-[4-[[(3R)-1-ethyl-3-piperidyl]amino]-1-methyl-pyrazolo[3,4-d]pyridazin-7-yl]-5-(trifluoromethoxy)phenol; 2,2,2-trifluoroacetic acid

[0224] To a mixture of N-[(3R)-1-ethyl-3-piperidyl]-7-[2-methoxy-4-(trifluoromethoxy)phenyl]-1-methyl-pyrazolo[3,4-d]pyridazin-4-amine (40.0 mg, 0.09 mmol, 1.0 equiv) in DCM (0.5 mL) was added BBr 3 (222.46 mg, 0.89 mmol, 10.0 equiv.) 2 The mixture was added under reduced pressure and stirred at -60°C for 10 min, then at 25°C for 1 h. The reaction mixture was quenched by the addition of ice water (2 mL) and NH 3 -H 2 The mixture was neutralized with O solution, filtered, and the filtrate was concentrated under reduced pressure to give a yellow solid. The crude product was purified by reverse phase flash (CombiFlash, 0.1% TFA aqueous-ACN conditions) to give the title compound (29.7 mg, 58% yield) as a white solid. LCMS: m / z 437.2 [M+H] + ,ESI pos.

[0225] Example 11: 2-[4-[[(1R,2R)-2-hydroxycyclohexyl]amino]-1-methyl-pyrazolo[3,4-d]pyridazin-7-yl]-5-(trifluoromethyl)phenol;2,2,2-trifluoroacetic acid [ka]

[0226] Step A: (1R,2R)-2-((7-chloro-1-methyl-1H-pyrazolo[3,4-d]pyridazin-4-yl)amino)cyclohexan-1-ol and (1R,2R)-2-((4-chloro-1-methyl-1H-pyrazolo[3,4-d]pyridazin-7-yl)amino)cyclohexan-1-ol

[0227] A solution of (1R,2R)-2-aminocyclohexanol hydrochloride (CAS: 13374-31-7, 896.2 mg, 5.91 mmol, 8.0 equiv.) in NMP (5 mL) was added with K 2 CO 3 (815.64 mg, 5.91 mmol, 8.0 equiv.) and 4,7-dichloro-1-methyl-pyrazolo[3,4-d]pyridazine (Example 6, Step C; 150.0 mg, 0.74 mmol, 1.0 equiv.) 2 and the mixture was stirred at 115° C. for 16 h. The reaction mixture was quenched with water (2 mL) and then concentrated in vacuo. The residue was purified by reverse phase flash (CombiFlash, 0.1% TFA aqueous-ACN conditions) to give the desired product (1R,2R)-2-[(7-chloro-1-methyl-pyrazolo[3,4-d]pyridazin-4-yl)amino]cyclohexanol (45.0 mg, 14% yield) as a pale yellow solid, LCMS: m / z 282.2 [M+H] + ,ESI pos. As a by-product, (1R,2R)-2-[(4-chloro-1-methyl-pyrazolo[3,4-d]pyridazin-7-yl)amino]cyclohexanol (40.0 mg, 19% yield) was obtained as a pale yellow solid, LCMS: m / z 282.2 [M+H] + , isolated as ESI pos.

[0228] Step B: 2-[4-[[(1R,2R)-2-hydroxycyclohexyl]amino]-1-methyl-pyrazolo[3,4-d]pyridazin-7-yl]-5-(trifluoromethyl)phenol; 2,2,2-trifluoroacetic acid

[0229] To a solution of [2-hydroxy-4-(trifluoromethyl)phenyl]boronic acid (CAS no. 1072951-50-8, 43.86 mg, 0.210 mmol, 1.5 equiv.), (1R,2R)-2-[(7-chloro-1-methyl-pyrazolo[3,4-d]pyridazin-4-yl)amino]cyclohexanol (40.0 mg, 0.140 mmol, 1 equiv.), and CsF (86.26 mg, 0.570 mmol, 4 equiv.) in 1,4-dioxane (1 mL) / water (0.2 mL) was added Pd(dppf)Cl 2 (5.19 mg, 0.01 mmol, 0.05 equiv.) 2 The mixture was added under microwave irradiation at 25° C. for 2 h. Upon completion of the reaction, the mixture was concentrated under reduced pressure and purified by reverse phase flash (CombiFlash, 0.1% TFA aqueous-ACN condition) to give the title compound (29.0 mg, 38% yield) as a white solid. LCMS: m / z 408.0 [M+H] + ,ESI pos.

[0230] Example 12: 5-Chloro-2-[1-methyl-4-[[(3R)-1-ethyl-3-piperidyl]amino]pyrazolo[3,4-d]pyridazin-7-yl]phenol; 2,2,2-trifluoroacetic acid [ka]

[0231] Step A: 4-Chloro-N-[(3R)-1-ethyl-3-piperidyl]-1-methyl-pyrazolo[3,4-d]pyridazin-7-amine

[0232] A mixture of 7-chloro-N-[(3R)-1-ethyl-3-piperidyl]-1-methyl-pyrazolo[3,4-d]pyridazin-4-amine (Example 6, Step D; 80.0 mg, 0.27 mmol, 1.0 equiv.), 4-chloro-2-hydroxyphenylboronic acid (CAS: 1238196-66-1, 93.6 mg, 0.54 mmol, 2.0 equiv.) and Cs in 1,4-dioxane (1.5 mL) and water (0.3 mL). 2CO 3 (265.26 mg, 0.81 mmol, 3.0 equiv.) was added to a mixture of XPhos Pd G 3 (34.5 mg, 0.04 mmol, 0.15 equiv) was added at 25 °C and the mixture was cooled to 5 °C with N 2 The mixture was stirred at 100° C. for 4 h under reduced pressure to give a brown solution. The reaction mixture was quenched with 2 mL of water, then 2 mL of 1N HCl solution was added to adjust the pH to <5, then diluted with 2 mL of MeOH to give a brown solution, which was purified by reverse phase flash (CombiFlash 0.1% TFA aqueous-ACN condition) and subsequently lyophilized to give the title compound (22.0 mg, 15% yield) as a white solid. LCMS: m / z 387.2 [M+H] + ,ESI pos.

[0233] Example 13: 2-[4-[[(3R)-1-ethyl-3-piperidyl]amino]-3-methyl-isoxazolo[4,5-d]pyridazin-7-yl]-5-(trifluoromethyl)phenol [ka]

[0234] Step A: 7-Chloro-N-[(3R)-1-ethyl-3-piperidyl]-3-methyl-isoxazolo[4,5-d]pyridazin-4-amine

[0235] 4,7-Dichloro-3-methyl-isoxazolo[4,5-d]pyridazine (124.0 mg, 0.61 mmol, 1.0 equiv., CAS no. 106584-70-7), DIPEA (0.53 mL, 3.04 mmol, 5.0 equiv.) and [(3R)-1-ethylpiperidin-1-ium-3-yl]ammonium; dichloride (128.37 mg, 0.64 mmol, 1.05 equiv.) were dissolved in NMP (5 mL) and stirred at 110° C. for 16 h. The reaction mixture was diluted with MeOH (20 mL) and stirred with SCX (6 g) for 30 min. The mixture was filtered and the resin was washed with MeOH (20 mL). The crude product was then purified by 0.7 N NH3 The crude product was purified by silica gel chromatography (0-10% (0.7N NH 3 ) / DCM) to afford the title compound (83.0 mg, 42% yield) as a yellow oil. 1 H NMR (500 MHz, DMSO-d 6 )δ [ppm]:6.48(d,1H),4.39-4.26(m,1H),2.96-2.84(m,1H),2.74-2.53(m,4H),2.37(q,2H) ,2.22-2.13(m,2H),1.89-1.81(m,1H),1.77-1.68(m,1H),1.65-1.47(m,2H),1.01(t,3H).

[0236] Step B: 2-[4-[[(3R)-1-ethyl-3-piperidyl]amino]-3-methyl-isoxazolo[4,5-d]pyridazin-7-yl]-5-(trifluoromethyl)phenol

[0237] The above 7-chloro-N-[(3R)-1-ethyl-3-piperidyl]-3-methyl-isoxazolo[4,5-d]pyridazin-4-amine (90.0 mg, 0.3 mmol, 1.0 equiv.), cesium fluoride (596.41 mg, 1.22 mmol, 4.0 equiv.), XPhosPd G3 (25.79 mg, 0.03 mmol, 0.1 equiv.; CAS no. 1445085-55-1) and 2-methoxy-4-(trifluoromethyl)-phenylboronic acid (93.7 mg, 0.43 mmol, 1.4 equiv.; CAS no. 312936-89-3) were suspended in DMF (2 mL), the vessel was evacuated and agitated with N 2 (3 times). The reaction mixture was stirred at 110° C. for 24 h. The reaction mixture was cooled, diluted with EtOAc (20 mL), washed with brine (20 mL) and 10 wt % aqueous LiCl (20 mL), then dried using a phase separator and concentrated in vacuo. The resulting residue was dissolved in DCM (3 mL) and washed with BBr 3(1.0 M in DCM, 0.91 mL, 0.91 mmol, 3.0 equiv.) was added. The reaction mixture was stirred at room temperature for 1 h and then concentrated in vacuo. The resulting residue was dissolved in DCM (10 mL) and NaHCO 3 (1g) was added. The reaction mixture was stirred for 20 min, then filtered and the filtrate was concentrated in vacuo. The resulting residue was dissolved in a mixture of DMSO / MeOH / DCM, filtered and purified by reversed-phase preparative HPLC (Waters 2767 Sample Manager, Waters 2545 Binary Gradient Module, Waters Systems Fluidics Organiser, Waters 515 ACD pump, Waters 515 Makeup pump, Waters 2998 Photodiode Array Detector, Waters QDa) on a Waters XBridge BEH C18 ODB preparative column, 130 Å, 5 μm, 30 mm×100 mm, flow rate 40 mL min−1, eluting with 0.3% ammonia in water-MeCN gradient over 12.5 min using UV across all wavelengths with PDA as well as QDA and ELS detectors. The at-column dilution pump provided 2 mL min−1 of methanol throughout the method, which is included in the MeCN percentages below. Gradient information: 0.0-0.5 min, 55% MeCN; 0.5-10.5 min, ramp from 55% MeCN to 85% MeCN; 10.5-10.6 min, ramp from 85% MeCN to 100% MeCN; 10.6-12.5 min, hold at 100% MeCN. This gave the title compound (4.3 mg, 3% yield) as a light brown solid. LCMS (m / z): 421.8 (M+H). + ,ESI pos.

[0238] Example 14 2-[4-[[(3R)-1-Ethyl-3-piperidyl]amino]-1H-pyrazolo[3,4-d]pyridazin-7-yl]-3-methyl-5-(trifluoromethyl)phenol;2,2,2-Trifluoroacetic acid [ka]

[0239] Step A: 1H-Pyrazole-4,5-dicarbohydrazide

[0240] To a solution of diethyl 1H-pyrazole-4,5-dicarboxylate (CAS: 37687-26-6, 1.0 g, 4.71 mmol, 1.0 equiv) in ethanol (20 mL) was added hydrazine monohydrate (1.6 mL, 33 mmol, 7.0 equiv) at 20° C. The mixture was slowly heated to 70° C. and stirring was continued at 70° C. for 5 h. The mixture was then cooled to 20° C., the suspension was filtered, and the filter cake was washed with EtOH (3×20 mL) and dried under vacuum to give the title compound (800.0 mg, 92% yield) as a white solid.

[0241] Step B: 1H-Pyrazolo[3,4-d]pyridazine-4,7-diol

[0242] To a solution of 2-methylpyrazole-3,4-dicarbohydrazide (0.8 g, 4.04 mmol, 1.0 equiv) in water (4 mL) was added HCl (2.29 mL, 27.43 mmol, 6.79 equiv) dropwise at 20° C. The mixture was stirred at 100° C. for 2 h. After cooling to ambient temperature, the suspension was diluted with water (20 mL) and filtered. The filter cake was washed with EtOH (3×10 mL) and dried in vacuum to afford the title compound (570.0 mg, 85% yield) as a white solid.

[0243] Step C: 4,7-Dichloro-1H-pyrazolo[3,4-d]pyridazine

[0244] A mixture of 1H-pyrazolo[3,4-d]pyridazine-4,7-diol (0.92 g, 6.02 mmol, 1.0 equiv.) in POCl 3 (10.0 mL). The mixture was stirred at 60° C. for 12 h. The mixture was then concentrated under vacuum to remove excess POCl. 3 Removal of was carried out to give the crude title compound (600.0 mg, 53% yield), which was used directly in the next step.

[0245] Step D: 4,7-Dichloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyridazine

[0246] To a solution of 4,7-dichloro-1H-pyrazolo[3,4-d]pyridazine (0.22 g, 1.14 mmol, 1.0 equiv) in THF (5 mL) was added NaH (68.57 mg, 1.71 mmol, 1.5 equiv) in portions at 0° C., then stirred at 0° C. for 0.25 h, followed by addition of SEMCl (286.29 mg, 1.71 mmol, 1.5 equiv) at 0° C. for 2 h. Upon completion of the reaction, the mixture was immersed in H 2 The mixture was quenched with 20 mL of O (30 mL) and extracted with EtOAc (30 mL x 3). The organic phase was washed with brine (30 mL x 2) and anhydrous Na 2 SO 4 The mixture was dried over 100 ml, filtered and concentrated in vacuo. The residue was purified by column chromatography (Hexanes / EtOAc, 5:1) to give the title compound (85.0 mg, 23% yield) as a pale yellow oil. LCMS: m / z 319.2 [M+H] + ,ESI pos.

[0247] Step E: (R)-7-chloro-N-(1-ethylpiperidin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyridazin-4-amine

[0248] To a solution of 4,7-dichloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyridazine (65.0 mg, 0.2 mmol, 1.0 equiv.) and (3R)-1-ethylpiperidin-3-amine (33.94 mg, 0.26 mmol, 1.3 equiv.) in NMP (2 mL) was added DIEA (78.91 mg, 0.61 mmol, 3.0 equiv.). The mixture was diluted with N 2The mixture was stirred at 85° C. for 16 h under reduced pressure. Upon completion of the reaction, the mixture was concentrated under reduced pressure and purified by reverse phase flash (CombiFlash, 0.1% TFA aqueous-ACN conditions) to give the title compound (10.0 mg, 12% yield) as a yellow oil. LCMS: m / z 411.2 [M+H] + ,ESI pos.

[0249] Step F: 2-(4-(((R)-1-ethylpiperidin-3-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyridazin-7-yl)-3-methyl-5-(trifluoromethyl)phenol

[0250] A solution of (R)-7-chloro-N-(1-ethylpiperidin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyridazin-4-amine (15.0 mg, 0.04 mmol, 1.0 equiv.) and [2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]boronic acid (32.11 mg, 0.15 mmol, 4.0 equiv.) in 1,4-dioxane (1 mL) and water (0.2 mL) was diluted with CsF (22.17 mg, 0.15 mmol, 4.0 equiv.) and Xphos Pd G 3 (3.09 mg, 0.1 equiv.) 2 The mixture was stirred at 95° C. for 5 h. Upon completion of the reaction, the mixture was concentrated under reduced pressure and the residue was purified by preparative TLC (DCM / MeOH 10:1) to give the title compound (9.0 mg, 67% yield) as a yellow oil. LCMS: m / z 551.3 [M+H] + ,ESI pos.

[0251] Step G: 2-[4-[[(3R)-1-ethyl-3-piperidyl]amino]-1H-pyrazolo[3,4-d]pyridazin-7-yl]-3-methyl-5-(trifluoromethyl)phenol; 2,2,2-trifluoroacetic acid

[0252] To a solution of 2-[4-[[(3R)-1-ethyl-3-piperidyl]amino]-1-(2-tri-methylsilylethoxymethyl)-pyrazolo[3,4-d]pyridazin-7-yl]-3-methyl-5-(trifluoromethyl)phenol (9.0 mg, 0.02 mmol, 1.0 equiv.) in DCM (0.5 mL) was added TFA (0.5 mL). The mixture was stirred at 25° C. for 2 h. Upon completion of the reaction, the mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC (column: Phenomenex Synergi Polar-RP 100×25 mm×4 μm; condition: water (TFA)-ACN; start B: 12; end B: 32; gradient time (min): 7; flow rate (ml / min): 25) to give the desired product (1.58 mg, 18% yield) as a yellow solid. LCMS: m / z 421.2 [M+H] + ,ESI pos.

[0253] Example 15 2-[4-[[(3R)-1-ethyl-3-piperidyl]amino]-1-methyl-pyrazolo[3,4-d]pyridazin-7-yl]-3-fluoro-5-(trifluoromethyl)phenol [ka]

[0254] Step A: 2-Bromo-6-fluoro-4-(trifluoromethyl)aniline

[0255] To a solution of commercially available 2-fluoro-4-(trifluoromethyl)aniline (25.0 g, 140 mmol, 1.00 equiv.) in DMF (300 mL) was added NBS (26.1 g, 147 mmol, 1.05 equiv.) at -10°C. The mixture was stirred at 25°C for 12 h. The reaction mixture was diluted with EtOAc (500 mL) and extracted. The organic phase was washed with brine (500 mL x 3) and diluted with Na 2 SO 4 The mixture was dried over ice, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO 2, petroleum ether / ethyl acetate=1 / 0-10 / 1) to give the title compound (36.0 g, 99.9% yield) as a yellow oil. LCMS: m / z 257.9 [M+H] + ,ESI pos.

[0256] Step B: 2-Fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline

[0257] A solution of the compound 2-bromo-6-fluoro-4-(trifluoromethyl)aniline (30.0 g, 116 mmol, 1.00 equiv.) in dioxane (500 mL) was treated with 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (59.1 g, 233 mmol, 2.00 equiv.), KOAc (28.5 g, 291 mmol, 2.50 equiv.) and Pd(dppf)Cl 2 .CH 2 Cl 2 (9.50 g, 11.6 mmol, 0.10 equiv.) was dissolved in N 2 The mixture was stirred at 100° C. for 3 h. The reaction was concentrated in vacuo. The residue was diluted with EtOAc (1000 mL) and extracted. The organic phase was washed with brine (1000 mL) and diluted with Na 2 SO 4 Drying on, filtering and concentrating in vacuo gave the title compound (45.0 g) as a black oil which was used directly in the next step. LCMS: m / z 306.1 [M+H] + ,ESI pos.

[0258] Step C: 2-Amino-3-fluoro-5-(trifluoromethyl)phenol

[0259] To a solution of the above 2-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline (45.0 g, 148 mmol, 1.00 equiv.) in THF (600 mL) was added NaOH (2 M, 221 mL, 3.00 equiv.) and H2 O 2 (100 g, 885 mmol, 85.0 mL, 30.0% purity, 6.00 equiv) was added at 0° C. and the reaction was stirred at 25° C. for 3 h. The reaction was diluted with EtOAc (1500 mL) and extracted. The organic phase was washed with Na 2 SO 3 Wash with aqueous solution (1500 mL x 3) and add Na 2 SO 4 The mixture was dried over 100 ml, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reverse phase HPLC (0.1% formic acid) to give the title compound (11.0 g, 38% yield) as a brown solid. LCMS: m / z 196.0 [M+H]+, ESI pos.

[0260] Step D: 3-Fluoro-2-iodo-5-(trifluoromethyl)phenol

[0261] The compound 2-amino-3-fluoro-5-(trifluoromethyl)phenol (11.0 g, 56.4 mmol, 1.00 equiv.) and H 2 SO 4 (40.5 g, 404 mmol, 22.0 mL, 7.17 equiv.) of H 2 To a solution of NaNO in 20O (200 mL) and acetone (50.0 mL), 2 (7.78 g, 113 mmol, 2.00 equiv) was added at 0° C. and the reaction was stirred at 0° C. for 30 min. Then CuI (26.8 g, 141 mmol, 2.50 equiv) and NaI (21.1 g, 141 mmol, 2.50 equiv) were added to the reaction at 0° C. and the reaction was stirred at 0° C. for 1.5 h. After completion of the reaction, water (500 mL) was added to the reaction mixture. The aqueous phase was washed with EtOAc (300 mL×2). The combined organic layer was washed with brine (300 mL×2) and Na 2 SO 4 The mixture was dried over ice, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=1 / 0-10 / 1) to give the title compound (20.0 g) as a brown oil. 1 H NMR (400 MHz, CDCl3 )δ=7.04(s,1H),6.89(dd,1H),6.76(s,1H).

[0262] Step E: 1-(ethoxymethoxy)-3-fluoro-2-iodo-5-(trifluoromethyl)benzene

[0263] To a solution of the compound 3-fluoro-2-iodo-5-(trifluoromethyl)phenol (20.0 g, 65.4 mmol, 1.00 equiv.) and chloromethoxyethane (9.27 g, 98.0 mmol, 9.09 mL, 1.50 equiv.) in DMF (200 mL) was added Cs 2 CO 3 (31.9 g, 98.0 mmol, 1.50 equiv) was added and the mixture was stirred at 25° C. for 2 h. After completion of the reaction, EtOAc (500 mL) was added, the phases were separated and extracted. The organic phase was washed with brine (500 mL×3) and added with Na 2 SO 4 The mixture was dried over hexane, filtered, and concentrated under reduced pressure to give a residue which was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=1 / 0-10 / 1) to give the title compound (10.0 g, yield 42%) as a colorless oil. 1 H NMR (400 MHz, CDCl 3 ):δ=7.15(s,1H),7.00(dd,1H),5.36(s,2H),3.78(q,2H),1.24(t,3H).

[0264] Step F: 2-[2-(ethoxymethoxy)-6-fluoro-4-(trifluoromethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0265] To a solution of 1-(ethoxymethoxy)-3-fluoro-2-iodo-5-(trifluoromethyl)benzene (10.0 g, 27.5 mmol, 1.00 equiv) and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (15.3 g, 82.4 mmol, 16.8 mL, 3.00 equiv) in THF (100 mL) was added n-BuLi (2.50 M, 27.5 mL, 2.50 equiv) at -70°C and the reaction was stirred at -70°C for 1 h. After completion of the reaction, NH 4 Aqueous Cl (300 mL) was added, the mixture was stirred for 10 min, and extracted with EtOAc (200 mL×2). The combined organic layers were washed with brine (300 mL) and Na 2 SO 4 The mixture was dried over ice, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Welch Ultimate XB-CN 250×50×10 μm; mobile phase: [hexane-EtOH]; B%: 0%-0%, 7 min) to give the title compound (7.00 g, yield 60%, purity 86.3%) as a white solid. 1 H NMR (400 MHz, CDCl 3 ):δ=7.10(s,1H),6.94(d,1H),5.24(s,2H),3.73(q,2H),1.39(s,12H),1.22(t,3H).

[0266] Step G: 7-[2-(ethoxymethoxy)-6-fluoro-4-(trifluoromethyl)phenyl]-1-methyl-N-[(3R)-1-ethyl-3-piperidyl]pyrazolo[3,4-d]pyridazin-4-amine

[0267] A mixture of 7-chloro-N-[(3R)-1-ethyl-3-piperidyl]-1-methyl-pyrazolo[3,4-d]pyridazin-4-amine (70 mg, 0.24 mmol, 1.0 equiv; Example 6, Step D), 2-[2-(ethoxymethoxy)-6-fluoro-4-(trifluoromethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (201.5 mg, 0.48 mmol, 2.0 equiv), potassium carbonate (131.3 mg, 0.95 mmol, 4.0 equiv) and SPhosPd G3 (25.1 mg, 0.03 mmol, 0.14 equiv) in 1,4-dioxane (2.81 mL) and water (0.7 mL) was flushed with argon and stirred at 110° C. for 3 h. An additional equivalent of boronic acid and 0.1 equivalent of SPhos Pd G3 were added and the reaction was stirred overnight at 90° C. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (approximately 30 mL) and half-saturated NH 4 Extracted with aqueous Cl (ca. 0.5 mL). 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 used in the next step without further purification. LCMS m / z: 439.3; 497.3 [M+H] + ,ESI pos.

[0268] Step H: 2-[4-[[(3R)-1-ethyl-3-piperidyl]amino]-1-methyl-pyrazolo[3,4-d]pyridazin-7-yl]-3-fluoro-5-(trifluoromethyl)phenol

[0269] To a solution of 7-[2-(ethoxymethoxy)-6-fluoro-4-(trifluoromethyl)phenyl]-1-methyl-N-[(3R)-1-ethyl-3-piperidyl]pyrazolo[3,4-d]pyridazin-4-amine (100 mg, 0.20 mmol, 1.0 equiv.) and dichloromethane (4.1 mL) was added TFA (689 mg, 466 μL, 6.0 mmol, 30 equiv.) dropwise under ice cooling. The reaction mixture was stirred at 0° C. and then allowed to reach room temperature with continued stirring for 2 h. The mixture was then concentrated under reduced pressure and the crude product was dissolved in DCM and saturated NaHCO 3The organic phase was separated and washed once more with water and brine. The aqueous phase was back-extracted with DCM. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (gradient 0% to 100% (dichloromethane:methanol:NH in dichloromethane). 4 OH;110:10:1)) to give the title compound (50 mg, 57% yield). LCMS m / z: 439.2 [M+H] + ,ESI pos.

[0270] Example 16 2-[4-[(3-hydroxy-3-methyl-cyclobutyl)amino]-1-methyl-pyrazolo[3,4-d]pyridazin-7-yl]-5-(trifluoromethyl)phenol [ka]

[0271] Step A: 3-[(7-chloro-1-methyl-pyrazolo[3,4-d]pyridazin-4-yl)amino]-1-methyl-cyclobutanol

[0272] To a mixture of 4,7-dichloro-1-methyl-pyrazolo[3,4-d]pyridazine (Example 6, step C) (130 mg, 0.61 mmol, 1.00 equiv.) in 1,4-dioxane (1.0 mL) and water (0.10 mL) was added N,N-diisopropylethylamine (337 mg, 0.455 mL, 2.61 mmol, 4.28 equiv.) and cis-3-amino-1-methylcyclobutan-1-ol hydrochloride (CAS number 1523606-23-6, 125 mg, 0.91 mmol, 1.49 equiv.). The mixture was stirred at 100° C. for 16 hours. The reaction mixture was cooled to room temperature and then extracted with ethyl acetate and water. The aqueous layer was back-extracted with ethyl acetate. The organic layer was washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient 0% to 5% methanol in dichloromethane). All fractions containing the product were combined and concentrated to give the title compound (57 mg, 33% yield) as an off-white solid. LCMS: m / z 268.1 [M+H] + ,ESI pos.

[0273] Step B: 2-[4-[(3-hydroxy-3-methyl-cyclobutyl)amino]-1-methyl-pyrazolo[3,4-d]pyridazin-7-yl]-5-(trifluoromethyl)phenol

[0274] A mixture of 3-[(7-chloro-1-methyl-pyrazolo[3,4-d]pyridazin-4-yl)amino]-1-methyl-cyclobutanol (Example 16, Step A) (54 mg, 0.19 mmol, 1.00 equiv.), [2-hydroxy-4-(trifluoromethyl)phenyl]boronic acid (CAS number 1072951-50-8, 80 mg, 0.39 mmol, 2.03 equiv.), potassium carbonate (130 mg, 0.94 mmol, 4.91 equiv.) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (20 mg, 0.02 mmol, 0.13 equiv.) in 1,4-dioxane (1.1 mL) and water (0.55 mL) was flushed with argon and stirred at 100° C. for 16 h. The reaction mixture was cooled to room temperature and then diluted with ethyl acetate and half-saturated NH 4 Cl aq. The aqueous layer was back extracted with ethyl acetate. The organic layer was washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient 0% to 20% methanol in dichloromethane). All fractions containing product were combined and concentrated in vacuo. The residue was triturated with ethyl acetate to give the title compound (25 mg, 32% yield) as a dark brown powder. LCMS: m / z 394.3 [M+H] + ,ESI pos.

[0275] Example 17: 5-[4-[[(3R)-1-Ethyl-3-piperidyl]amino]-1-methyl-pyrazolo[3,4-d]pyridazin-7-yl]-2,3-dihydrobenzofuran-4-ol [ka]

[0276] Step A: 4-benzyloxy-5-bromo-2,3-dihydrobenzofuran

[0277] To a solution of 5-bromocoumaran-4-ol (CAS no. 2279149-27-6, 4.59 g, 20.26 mmol, 1.00 equiv) in acetonitrile (40 mL) was added potassium carbonate (5.6 g, 40.51 mmol, 2.00 equiv), followed by benzyl bromide (4.89 g, 3.4 mL, 28.57 mmol, 1.41 equiv). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was 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, 220 g, gradient 0% to 10% ethyl acetate in heptane) to give the title compound (6.17 g, 95% yield) as a colorless oil. LCMS: m / z 305.1 / 307.0 [M+H] + ,ESI pos.

[0278] Step B: 2-(4-benzyloxy-2,3-dihydrobenzofuran-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0279] To a solution of 4-benzyloxy-5-bromo-2,3-dihydrobenzofuran (Example 17, Step A) (6.16 g, 19.18 mmol, 1.00 equiv.) and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (CAS number 61676-62-8, 5.47 g, 6.0 mL, 29.41 mmol, 1.53 equiv.) in tetrahydrofuran (80 mL) was added n-butyllithium, 1.6 M solution in hexanes (19 mL, 30.4 mmol, 1.59 equiv.) dropwise within 40 min at -76°C. Stirring was allowed to take place at -76°C for 2.5 h. The reaction mixture was warmed to -60°C and saturated NH 4 Quench with aqueous Cl at -60 °C, warm to room temperature, then add ethyl acetate and saturated NH 4Cl(aq). The aqueous layer was back extracted with ethyl acetate. The organic layer was washed 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, 120 g, gradient 0% to 10% ethyl acetate in heptane) to afford the title compound (5.78 g, 81% yield) as a colorless oil. LCMS: m / z 353.1 [M+H] + ,ESI pos.

[0280] Step C: 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-4-ol

[0281] A solution of 2-(4-benzoxycoumaran-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Example 17, Step B) (5.77 g, 15.56 mmol, 1.00 equiv) in ethyl acetate (70 mL) was alternately evacuated and flushed with argon three times. Palladium on activated carbon, 10% Pd basis (577 mg, 0.54 mmol, 0.03 equiv) was added. The reaction flask was evacuated, flushed with argon, evacuated, and flushed with hydrogen. The reaction mixture was stirred under a hydrogen atmosphere (balloon) at room temperature for 3 hours. Methanol (10 mL) was added. The reaction flask was alternately evacuated, flushed with argon, evacuated, and flushed with hydrogen three times. The reaction mixture was stirred under a hydrogen atmosphere (balloon) at room temperature for 1 hour. The reaction mixture was filtered and rinsed thoroughly with ethyl acetate / methanol. The filtrate was concentrated in vacuo to give the title compound (4.22 g, 98% yield) as an off-white solid which was used without further purification. LCMS: m / z 263.2 [M+H] + ,ESI pos.

[0282] Step D: 5-[4-[[(3R)-1-ethyl-3-piperidyl]amino]-1-methyl-pyrazolo[3,4-d]pyridazin-7-yl]-2,3-dihydrobenzofuran-4-ol

[0283] A solution of 7-chloro-N-[(3R)-1-ethyl-3-piperidyl]-1-methyl-pyrazolo[3,4-d]pyridazin-4-amine (Example 6, Step D) (300 mg, 1.02 mmol, 1.00 equiv.), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran in 1,4-dioxane (6.0 mL) and water (3.0 mL) was added. A mixture of ran-4-ol (Example 17, Step C) (570 mg, 1.87 mmol, 1.84 equiv), potassium carbonate (675 mg, 4.88 mmol, 4.80 equiv) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (126 mg, 0.15 mmol, 0.15 equiv) was flushed with argon and stirred at 95° C. for 16 h. The reaction mixture was cooled to room temperature and then diluted with ethyl acetate and half-saturated NH 4 Extracted with aqueous Cl. The aqueous layer was back extracted twice 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.

[0284] The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 25 g, gradient 0% to 100% (dichloromethane:methanol:NH 4 OH 9:1:0.05). All fractions containing the product were combined and concentrated in vacuo. The residue was adsorbed onto ISOLUTE HM-N and repurified by flash chromatography (Si-amine, 25 g, gradient 0% to 10% methanol in ethyl acetate). All fractions containing the product were combined and concentrated in vacuo. The residue was adsorbed onto ISOLUTE HM-N and repurified by flash chromatography (silica gel, 25 g, gradient 0% to 20% methanol in dichloromethane). All fractions containing the product were combined and concentrated in vacuo to give the title compound (234 mg, 57% yield) as a yellow foam. LCMS: m / z 395.3 [M+H] + ,ESI pos.

[0285] Example 18: 3-[4-[[(3R)-1-Ethyl-3-piperidyl]amino]-1-methyl-pyrazolo[3,4-d]pyridazin-7-yl]bicyclo[4.2.0]octa-1(6),2,4-trien-2-ol [ka]

[0286] Step A: 2-[(3-bromo-2-bicyclo[4.2.0]octa-1,3,5-trienyl)oxymethoxy]ethyl-trimethyl-silane

[0287] To a solution of 3-bromobicyclo[4.2.0]octa-1,3,5trien-2-ol (WO2021150574, 195 mg, 0.98 mmol, 1.0 equiv.) in DMF (5 mL) was added potassium carbonate (302 mg, 2.19 mmol, 2.20 equiv.) at room temperature. The resulting mixture was sonicated, then 2-(trimethylsilyl)ethoxymethyl chloride (200 μL, 1.13 mmol, 1.15 equiv.) was added and the reaction mixture was stirred at room temperature for 16 h. Potassium carbonate (140 mg, 1.01 mmol, 1.03 equiv.) was then added, followed by 2-(trimethylsilyl)ethoxymethyl chloride (0.1 mL, 0.570 mmol, 0.58 equiv.) and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with EtOAc (50 mL) and 50 v% brine (100 mL) and the separated aqueous layer was further extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with 50 v% brine (100 mL), dried (MgSO4), filtered and concentrated. The crude reaction mixture was purified by silica gel column chromatography (40 g, 0-20% MTBE:isohexane) to afford the title compound (345.0 mg, 100% yield) as a colorless oil. 1 H NMR(500 MHz,DMSO)δ 7.39(d,1H),6.67(d,1H),5.27(s,2H),3.72(dd,2H),3.28(dd,2H),3.05(dd,2H),0.91-0.85(m,2H),-0.05(s,9H).LCMS No ionization.

[0288] Step B: Trimethyl-[2-[[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-bicyclo[4.2.0]octa-1,3,5-trienyl]oxymethoxy]ethyl]silane

[0289] 2-[(3-Bromo-2-bicyclo[4.2.0]octa-1,3,5-trienyl)oxymethoxy]ethyl-trimethyl-silane (103.0 mg, 0.270 mmol, 1 equiv.), bis(pinacolato)diboron (81.0 mg, 0.320 mmol, 1.2 equiv.) and potassium acetate (111.0 mg, 1.13 mmol, 4.25 equiv.) in isopropyl acetate (8 mL) were sparged (nitrogen was bubbled through for 10 min while sonicating). XPhos Pd G3 (46.0 mg, 0.05 mmol, 0.05 equiv.) and XPhos (11.0 mg, 0.02 mmol, 0.02 equiv.) were added and the reaction mixture was stirred at 90 °C for 16 h. The reaction mixture was concentrated and the resulting residue was purified by silica gel chromatography (40 g, 0-20% MTBE:isohexane) to afford the title compound (199 mg, 41% yield) as a pale yellow oil. 1 H NMR (500 MHz, CDCl 3 ) δ 7.57(d,1H), 6.71(d,1H), 5.25(s,2H), 3.81-3.71(m,2H), 3.30(dd,2H), 3.18-3.05(m,2H), 1.33(s,12H), 0.97-0.92(m,2H), -0.03(s,9H). LCMS no ionization.

[0290] Step C: N-[(3R)-1-ethyl-3-piperidyl]-1-methyl-7-[2-(2-trimethylsilylethoxymethoxy)-3-bicyclo[4.2.0]octa-1(6),2,4-trienyl]pyrazolo[3,4-d]pyridazin-4-amine

[0291] 7-Chloro-N-[(3R)-1-ethyl-3-piperidyl]-1-methyl-pyrazolo[3,4-d]pyridazin-4-amine (Example 6, Step D) (48 mg, 0.16 mmol, 1.00 equiv.) in 1,4-dioxane (1.4 mL) and water (0.70 mL), trimethyl-[2-[[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-bicyclo[4.2. A mixture of 0-octa-1,3,5-trienyloxymethoxyethylsilane (93 mg, 0.22 mmol, 1.37 equiv), potassium carbonate (108 mg, 0.78 mmol, 4.80 equiv) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (20 mg, 0.02 mmol, 0.150 equiv) was flushed with argon and stirred at 95 °C for 16 h. The reaction mixture was extracted with ethyl acetate and water. The aqueous layer was back-extracted with ethyl acetate. The organic layer was washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient 0% to 100% (dichloromethane:methanol:NH in dichloromethane). 4 OH 9:1:0.05). All fractions containing the product were combined and concentrated in vacuo to give the title compound (33 mg, 38% yield) as a dark green oil. LCMS: m / z 509.4 [M+H] + ,ESI pos.

[0292] Step D: 3-[4-[[(3R)-1-ethyl-3-piperidyl]amino]-1-methyl-pyrazolo[3,4-d]pyridazin-7-yl]bicyclo[4.2.0]octa-1(6),2,4-trien-2-ol

[0293] To a solution of N-[(3R)-1-ethyl-3-piperidyl]-1-methyl-7-[2-(2-trimethylsilylethoxymethoxy)-3-bicyclo[4.2.0]octa-1(6),2,4-trienyl]pyrazolo[3,4-d]pyridazin-4-amine (Example 18, Step A) (33 mg, 0.06 mmol, 1.00 equiv.) in dichloromethane (1.6 mL) and methanol (0.40 mL) was added dropwise 4M HCl in dioxane (192 mg, 0.160 mL, 0.64 mmol, 10.39 equiv.). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with dichloromethane / methanol (19:1) and washed with 1 mL of ice-cold water and 4 mL of saturated NaHCO. 3 The aqueous mixture was carefully added and then extracted with dichloromethane / methanol (19:1). The organic layer was washed with brine. The aqueous layer was back-extracted twice with dichloromethane / methanol (19:1). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound (25 mg, 96% yield, 90% purity) as a brown foam. LCMS: m / z 379.3 [M+H] + ,ESI pos.

[0294] Example 19: (3S,5R)-1-Ethyl-5-[[7-(4-hydroxy-2,3-dihydrobenzofuran-5-yl)-1-methyl-pyrazolo[3,4-d]pyridazin-4-yl]amino]piperidin-3-ol [ka]

[0295] Step A: tert-Butyl (3R,5S)-3-[(7-chloro-1-methyl-pyrazolo[3,4-d]pyridazin-4-yl)amino]-5-hydroxy-piperidine-1-carboxylate

[0296] To a mixture of 4,7-dichloro-1-methyl-pyrazolo[3,4-d]pyridazine (Example 6, step C) (200 mg, 0.94 mmol, 1.00 equiv.) and tert-butyl (3R,5S)-3-amino-5-hydroxy-piperidine-1-carboxylate (CAS number 1932513-59-1, 306 mg, 1.41 mmol, 1.51 equiv.) in 1,4-dioxane (1.2 mL) was added N,N-diisopropylethylamine (366 mg, 0.494 mL, 2.83 mmol, 3.02 equiv.). The reaction mixture was stirred at 100° C. for 2 days and then left at room temperature for 3 days. The reaction mixture was 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 residue was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 25 g, gradient 0% to 5% methanol in dichloromethane) to give the title compound (210 mg, 56% yield) as an off-white solid. LCMS: m / z 383.2 [M+H] + ,ESI pos.

[0297] Step B: (3S,5R)-5-[(7-chloro-1-methyl-pyrazolo[3,4-d]pyridazin-4-yl)amino]piperidin-3-ol hydrochloride

[0298] To a solution of tert-butyl (3R,5S)-3-[(7-chloro-1-methyl-pyrazolo[3,4-d]pyridazin-4-yl)amino]-5-hydroxy-piperidine-1-carboxylate (Example 19, Step A) (205 mg, 0.51 mmol, 1.00 equiv.) in dichloromethane (1.0 mL) and methanol (0.50 mL) was added dropwise 4M HCl in dioxane (1.2 mL, 4.8 mmol, 9.44 equiv.). The reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated in vacuo to give the title compound (162 mg, 95% yield) as an off-white solid. LCMS: m / z 283.2 [M+H] + ,ESI pos.

[0299] Step C: (3S,5R)-5-[(7-chloro-1-methyl-pyrazolo[3,4-d]pyridazin-4-yl)amino]-1-ethyl-piperidin-3-ol

[0300] To a suspension of (3S,5R)-5-[(7-chloro-1-methyl-pyrazolo[3,4-d]pyridazin-4-yl)amino]piperidin-3-ol hydrochloride (Example 19, Step B) (160 mg, 0.48 mmol, 1.00 equiv.) in dichloromethane (3.0 mL), acetaldehyde (47 mg, 0.06 mL, 1.06 mmol, 2.23 equiv.) was added followed by sodium acetate (79 mg, 0.96 mmol, 2.02 equiv.) under ice bath cooling. Sodium triacetoxyborohydride (152 mg, 0.72 mmol, 1.51 equiv.) was added in three portions at 0° C. After the addition was complete, the ice bath was removed and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with saturated NaHCO 3 It was carefully quenched with aqueous solution and extracted three times with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient 0% to 10% methanol in dichloromethane) to give the title compound (102 mg, 65% yield) as a pale yellow foam. LCMS: m / z 311.2 [M+H] + ,ESI pos.

[0301] Step D: (3S,5R)-1-Ethyl-5-[[7-(4-hydroxy-2,3-dihydrobenzofuran-5-yl)-1-methyl-pyrazolo[3,4-d]pyridazin-4-yl]amino]piperidin-3-ol

[0302] (3S,5R)-5-[(7-chloro-1-methyl-pyrazolo[3,4-d]pyridazin-4-yl)amino]-1-ethyl-piperidin-3-ol (Example 19, Step C) (90 mg, 0.28 mmol, 1.00 equiv), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro- A mixture of dorobenzofuran-4-ol (Example 17, Step C) (140 mg, 0.51 mmol, 1.84 equiv), potassium carbonate (170 mg, 1.23 mmol, 4.47 equiv) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (34 mg, 0.04 mmol, 0.15 equiv) was flushed with argon and stirred at 95° C. for 16 h. The reaction mixture was diluted with ethyl acetate and half-saturated NH 4 The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient 0% to 100% (dichloromethane:methanol:NH in dichloromethane). The aqueous layer was back-extracted with ethyl acetate. The organic layer was washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient 0% to 100% (dichloromethane:methanol:NH in dichloromethane). 4 OH 9:1:0.05). All fractions containing the product were combined and concentrated in vacuo to give the title compound (58 mg, 49% yield) as a brown foam. LCMS: m / z 411.3 [M+H] + ,ESI pos.

[0303] 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: Per tablet Active ingredient: 200mg Microcrystalline cellulose 155mg Cornstarch 25mg Talc 25mg Hydroxypropyl methylcellulose 20mg 425mg

[0304] 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: Per capsule Active ingredient 100.0mg Cornstarch 20.0mg Lactose 95.0mg Talc 4.5mg Magnesium stearate 0.5mg 220.0mg

[0305] 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: Per tablet Active ingredient: 200mg Microcrystalline cellulose 155mg Cornstarch 25mg Talc 25mg Hydroxypropyl methylcellulose 20mg 425mg

[0306] 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: Per capsule Active ingredient 100.0mg Cornstarch 20.0mg Lactose 95.0mg Talc 4.5mg Magnesium stearate 0.5mg 220.0mg

Claims

1. Compounds of Formula I 【Chemical 1】 (In the formula, R １ is H, alkoxy, haloalkyl or OH; R １ｂ is H, halo, or alkyl; R ２ is halo, haloalkyl, haloalkoxy, nitrile, or alkyl; R ３ is H; Or, R ２ and R ３ and the atom to which they are attached, joined together to form either a heterocycle containing one O heteroatom or a cycloalkyl ring; Z is a ring system 【Chemistry 2】 Selected from: A １ is S, NR Ｘ１ or O, and R Ｘ１ is H, alkyl or cyclopropyl; A ２ is CR Ｙ１ or N, and R Ｙ１ is H or alkyl; A ３ is CR Ｚ１ or N, and R Ｚ１ is H or alkyl; A １ is S or O, then A ２ and A ３ cannot both be N; A ４ is CR Ｚ２ or N, and R Ｚ２ is H or alkyl; A ５ is CR Ｙ２ or N, CR Ｙ２ is H or alkyl; A ６ is S, NR Ｘ２ or O, and R Ｘ２ is H or alkyl; A ６ is S or O, then A ４ and A ５ cannot both be N; A ７ , A ８ and A ９ is an independent CR Ｗ１ or N, CR Ｗ１ is H or alkyl; A ７ , A ８ and A ９ cannot all be N; A １０ , A １１ and A １２ is an independent CR Ｗ２ or N, CR Ｗ２ is H or alkyl; A １０ , A １１ and A １２ cannot all be N; W is a substituted 4-membered cycloalkyl, a substituted 6-membered cycloalkyl, a substituted 6-membered heterocycle containing a single N heteroatom, or 1,2,3,5,6,7,8,8a-octahydroindolizin-7-yl, wherein the substituted 4-membered cycloalkyl is substituted with hydroxyl and methyl, the substituted 6-membered cycloalkyl is substituted with OH, and the substituted 6-membered heterocycle containing a single N heteroatom is substituted with one or two substituents independently selected from alkyl, OH, or halo. or a pharmaceutically acceptable salt thereof.

2. Z is, A １ But S, NR Ｘ１ Or O, R Ｘ１ is H or alkyl; A ２ But, CR Ｙ１ Or N and R Ｙ１ is H; A ３ But, CR Ｚ１ Or N and R Ｚ１ is H or alkyl; A １ is S or O, then A ２ Also A ３ cannot also be N, Ring system A; or A ４ is CR Ｚ２ and R Ｚ２ is H; A ５ But, CR Ｙ２ Or N and CR Ｙ２ is H; A ６ But S or NR Ｘ２ and R Ｘ２ is alkyl; A ６ If S, then A ４ Also A ５ cannot also be N, Ring system B 2. The compound of claim 1 selected from:

3. Z is, A １ But S, NR Ｘ１ or O, and R Ｘ１ is H or alkyl; A ２ But, CR Ｙ１ or N, and R Ｙ１ is H; A ３ But, CR Ｚ１ or N, and R Ｚ１ is H or alkyl; A １ is S or O, then A ２ Also A ３ cannot also be N, 3. The compound of claim 1 or 2, which is ring system A.

4. 3. The compound of claim 1 or 2, wherein ring system A contains two N heteroatoms.

5. Z is, A １ NR Ｘ１ and R Ｘ１ is alkyl; A ２ is N; A ３ is CR Ｚ１ and R Ｚ１ is H, 3. The compound of claim 1 or 2, which is ring system A.

6. R １ The compound according to claim 1 or 2, wherein is H or OH.

7. R １ 3. The compound of claim 1 or 2, wherein is OH.

8. R １ｂ 3. The compound of claim 1 or 2, wherein is H.

9. R ２ is halo, haloalkyl, or haloalkoxy; R ３ is H; or R ２ and R ３ and the atom to which they are attached are joined together to form either a heterocycle containing one O heteroatom or a 4-membered cycloalkyl ring.

10. R ２ and R ３ and the atom to which they are attached are joined together to form either a heterocycle or a cycloalkyl ring containing one O heteroatom.

11. R ２ and R ３ 3. The compound of claim 1 or 2, wherein and the atoms to which they are attached are joined together to form a cycloalkyl ring.

12. R ２ and R ３ and the atoms to which they are attached are joined together to form either a 5-membered heterocycle containing one O heteroatom or a 4-membered cycloalkyl ring.

13. R ２ and R ３ 3. The compound of claim 1 or 2, wherein and the atoms to which they are attached are joined together to form a 4-membered cycloalkyl ring.

14. 3. The compound of claim 1 or 2, wherein W is a substituted 4-membered cycloalkyl, a substituted 6-membered cycloalkyl, or a substituted 6-membered heterocycle containing a single N heteroatom, wherein the substituted 4-membered cycloalkyl is substituted with hydroxyl and methyl, the substituted 6-membered cycloalkyl is substituted with OH, and the substituted 6-membered heterocycle containing a single N heteroatom is substituted with one or two substituents independently selected from alkyl and OH.

15. The compound of claim 1 or 2, wherein W is ethylpiperidyl or 1-ethyl-piperidin-3-ol.

16. 3. The compound of claim 1 or 2, wherein W is ethylpiperidyl.

17. R １ is H or OH; R １ｂ is H, halo, or alkyl; R ２ is halo, haloalkyl, or haloalkoxy; R ３ is H; Or, R ２ and R ３ and the atom to which they are attached, joined together to form either a 5-membered heterocycle or a 4-membered cycloalkyl ring containing one O heteroatom; Z is, A １ But S, NR Ｘ１ Or O, R Ｘ１ is H or alkyl; A ２ But, CR Ｙ１ Or N and R Ｙ１ is H; A ３ But, CR Ｚ１ Or N and R Ｚ１ is H or alkyl; A １ is S or O, then A ２ Also A ３ cannot also be N, Ring system A; or A ４ is CR Ｚ２ and R Ｚ２ is H; A ５ But, CR Ｙ２ Or N and CR Ｙ２ is H; A ６ But S or NR Ｘ２ and R Ｘ２ is alkyl; A ６ If S, then A ４ Also A ５ cannot also be N, Ring system B Selected from: W is a substituted 4-membered cycloalkyl, a substituted 6-membered cycloalkyl, or a substituted 6-membered heterocycle containing a single N heteroatom, wherein the substituted 4-membered cycloalkyl is substituted with hydroxyl and methyl, the substituted 6-membered cycloalkyl is substituted with OH, and the substituted 6-membered heterocycle containing a single N heteroatom is substituted with one or two substituents independently selected from alkyl and OH; The compound of claim 1 or a pharmaceutically acceptable salt thereof.

18. R １ is H or OH; R １ｂ is H, halo, or alkyl; R ２ is halo, haloalkyl, or haloalkoxy; R ３ is H; Or, R ２ and R ３ and the atom to which they are attached, joined together to form either a 5-membered heterocycle or a 4-membered cycloalkyl ring containing one O heteroatom; Z is, A １ But S, NR Ｘ１ or O, and R Ｘ１ is H or alkyl; A ２ But, CR Ｙ１ or N, and R Ｙ１ is H; A ３ But, CR Ｚ１ or N, and R Ｚ１ is H or alkyl; A １ is S or O, then A ２ Also A ３ cannot also be N, is ring system A; W is a substituted 4-membered cycloalkyl, a substituted 6-membered cycloalkyl, or a substituted 6-membered heterocycle containing a single N heteroatom, wherein the substituted 4-membered cycloalkyl is substituted with hydroxyl and methyl, the substituted 6-membered cycloalkyl is substituted with OH, and the substituted 6-membered heterocycle containing a single N heteroatom is substituted with one or two substituents independently selected from alkyl and OH; A compound according to claim 1 or 17 or a pharmaceutically acceptable salt thereof.

19. R １ is OH; R １ｂ is H; R ２ and R ３ and the atom to which they are attached, joined together to form either a 5-membered heterocycle containing one O heteroatom or a 4-membered cycloalkyl ring; Z is, A １ NR Ｘ１ and R Ｘ１ is alkyl; A ２ is N; A ３ is CR Ｚ１ and R Ｚ１ is H, is ring system A; W is ethylpiperidyl or 1-ethyl-piperidin-3-ol; A compound according to claim 1 or 17 or a pharmaceutically acceptable salt thereof.

20. R １ is OH; R １ｂ is H; R ２ and R ３ and the atom to which they are attached, joined together to form any of the four-membered cycloalkyl rings; Z is, A １ NR Ｘ１ and R Ｘ１ is alkyl; A ２ is N; A ３ is CR Ｚ１ and R Ｚ１ is H, is ring system A; W is ethylpiperidyl; A compound according to claim 1 or 17 or a pharmaceutically acceptable salt thereof.

21. (rac)-2-[7-[(1-ethyl-3-piperidyl)amino]thieno[2,3-d]pyridazin-4-yl]-5-(trifluoromethyl)phenol; formic acid; (rac)-2-[7-[(1-ethyl-3-piperidyl)amino]thieno[2,3-d]pyridazin-4-yl]-5-(trifluoromethyl)phenol; (rac)-2-[4-[(1-ethyl-3-piperidyl)amino]thieno[2,3-d]pyridazin-7-yl]-5-(trifluoromethyl)phenol; formic acid; (rac)-2-[4-[(1-ethyl-3-piperidyl)amino]thieno[2,3-d]pyridazin-7-yl]-5-(trifluoromethyl)phenol; (rac)-N-(1-ethyl-3-piperidyl)-4-[4-(trifluoromethyl)phenyl]thieno[2,3-d]pyridazin-7-amine; (rac)-N-(1-ethyl-3-piperidyl)-7-[4-(trifluoromethyl)phenyl]thieno[2,3-d]pyridazin-4-amine; 2-[4-[[(3R)-1-ethyl-3-piperidyl]amino]-1-methyl-pyrrolo[2,3-d]pyridazin-7-yl]-5-(trifluoromethyl)phenol; hydrochloride salt; 2-[4-[[(3R)-1-ethyl-3-piperidyl]amino]-1-methyl-pyrrolo[2,3-d]pyridazin-7-yl]-5-(trifluoromethyl)phenol; 2,2,2-trifluoroacetic acid; 2-[4-[[(3R)-1-ethyl-3-piperidyl]amino]-1-methyl-pyrrolo[2,3-d]pyridazin-7-yl]-5-(trifluoromethyl)phenol; 2-[4-[[(3R)-1-ethyl-3-piperidyl]amino]-1-methyl-pyrazolo[3,4-d]pyridazin-7-yl]-5-(trifluoromethyl)phenol; 2,2,2-trifluoroacetic acid; 2-[4-[[(3R)-1-ethyl-3-piperidyl]amino]-1-methyl-pyrazolo[3,4-d]pyridazin-7-yl]-5-(trifluoromethyl)phenol; and 2-[4-[[(3R)-1-ethyl-3-piperidyl]amino]furo[2,3-d]pyridazin-7-yl]-5-(trifluoromethyl)phenol 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, selected from:

22. 2-[4-[[(3R)-1-ethyl-3-piperidyl]amino]-1-methyl-imidazo[4,5-d]pyridazin-7-yl]-5-(trifluoromethyl)phenol; 2-[7-[[(3R)-1-ethyl-3-piperidyl]amino]-1-methyl-pyrazolo[3,4-d]pyridazin-4-yl]-5-(trifluoromethyl)phenol; 2-[4-[[(3R)-1-ethyl-3-piperidyl]amino]-1-methyl-pyrazolo[3,4-d]pyridazin-7-yl]-5-(trifluoromethoxy)phenol; 2-[4-[[(1R,2R)-2-hydroxycyclohexyl]amino]-1-methyl-pyrazolo[3,4-d]pyridazin-7-yl]-5-(trifluoromethyl)phenol; 5-chloro-2-[1-methyl-4-[[(3R)-1-ethyl-3-piperidyl]amino]pyrazolo[3,4-d]pyridazin-7-yl]phenol; 2-[4-[[(3R)-1-ethyl-3-piperidyl]amino]-3-methyl-isoxazolo[4,5-d]pyridazin-7-yl]-5-(trifluoromethyl)phenol; 2-[4-[[(3R)-1-ethyl-3-piperidyl]amino]-1H-pyrazolo[3,4-d]pyridazin-7-yl]-3-methyl-5-(trifluoromethyl)phenol; 2-[4-[[(3R)-1-ethyl-3-piperidyl]amino]-1-methyl-pyrazolo[3,4-d]pyridazin-7-yl]-3-fluoro-5-(trifluoromethyl)phenol; 2-[4-[(3-hydroxy-3-methyl-cyclobutyl)amino]-1-methyl-pyrazolo[3,4-d]pyridazin-7-yl]-5-(trifluoromethyl)phenol; 5-[4-[[(3R)-1-ethyl-3-piperidyl]amino]-1-methyl-pyrazolo[3,4-d]pyridazin-7-yl]-2,3-dihydrobenzofuran-4-ol; 3-[4-[[(3R)-1-ethyl-3-piperidyl]amino]-1-methyl-pyrazolo[3,4-d]pyridazin-7-yl]bicyclo[4.2.0]octa-1(6),2,4-trien-2-ol; (3S,5R)-1-ethyl-5-[[7-(4-hydroxy-2,3-dihydrobenzofuran-5-yl)-1-methyl-pyrazolo[3,4-d]pyridazin-4-yl]amino]piperidin-3-ol 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, selected from:

23. 5-[4-[[(3R)-1-ethyl-3-piperidyl]amino]-1-methyl-pyrazolo[3,4-d]pyridazin-7-yl]-2,3-dihydrobenzofuran-4-ol; 3-[4-[[(3R)-1-ethyl-3-piperidyl]amino]-1-methyl-pyrazolo[3,4-d]pyridazin-7-yl]bicyclo[4.2.0]octa-1(6),2,4-trien-2-ol; (3S,5R)-1-ethyl-5-[[7-(4-hydroxy-2,3-dihydrobenzofuran-5-yl)-1-methyl-pyrazolo[3,4-d]pyridazin-4-yl]amino]piperidin-3-ol 3. The compound of claim 1 or 2, wherein:

24. 3. The compound according to claim 1 or 2, which is 3-[4-[[(3R)-1-ethyl-3-piperidyl]amino]-1-methyl-pyrazolo[3,4-d]pyridazin-7-yl]bicyclo[4.2.0]octa-1(6),2,4-trien-2-ol, or a pharmaceutically acceptable salt thereof.

25. 3. A compound according to claim 1 or 2 for use as a therapeutically active substance.

26. 3. A compound according to claim 1 or 2 for use in the treatment or prevention of a disease, disorder or condition, wherein the disease, disorder or condition is responsive to NLRP3 inhibition.

27. 10. A pharmaceutical composition comprising a compound of claim 1 or 2 and a therapeutically inert carrier.

28. 28. The pharmaceutical composition of claim 27 for use in the treatment or prevention of a disease, disorder or condition, wherein the disease, disorder or condition is responsive to NLRP3 inhibition.

29. 3. A compound according to claim 1 or 2 for use in the treatment or prevention of a disease, disorder or condition selected from asthma or COPD.

30. 3. A compound according to claim 1 or 2 for use in the treatment or prevention of a disease, disorder or condition selected from Parkinson's disease or Alzheimer's disease.

31. 10. Use of a compound according to claim 1 or 2 for the preparation of a medicament for the treatment or prevention of a disease, disorder or condition selected from asthma or COPD.

32. 10. Use of a compound according to claim 1 or 2 for the preparation of a medicament for the treatment or prevention of a disease, disorder or condition selected from Parkinson's disease or Alzheimer's disease.

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