A useful 5,6-unsaturated bicyclic heterocycle as an inhibitor of NOD-like receptor protein 3.

Abstract

The novel compound represented by structural formula (I), and its pharmaceutically acceptable salts, hydrates, and solvates, are NLRP3 inhibitors and may be useful in the treatment, prevention, management, improvement, control, and suppression of NLRP3-mediated diseases. The compound represented by structural formula I may be useful in the treatment, prevention, or management of NLRP3-mediated diseases, disorders, and symptoms (e.g., but not limited to, gout, pseudogout, CAPS, NASH, fibrosis, heart failure, idiopathic pericarditis, atopic dermatitis, inflammatory bowel disease, Alzheimer's disease, Parkinson's disease, and traumatic brain injury). [Formula 1] TIFF2026509042000061.tif33130

Description

[Technical Field]

[0001] Cross-reference with related applications This application claims the interests of U.S. Provisional Patent Application No. 63 / 505,807, filed on 2 June 2023, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] Inflammasomes function as a central signaling hub of the innate immune system. They are multiprotein complexes assembled after intracellular pattern recognition receptors (PRRs) are activated by various pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs). It has been shown that inflammasomes can be formed by nucleotide-binding oligomeric domain (NOD)-like receptors (NLRs) and pyrin and HIN200-domain-containing proteins (Van Opdenbosch N and Lamkanfi M. Immunity, 2019 Jun 18;50(6):1352-1364). Activation of inflammasomes triggers a cascade of events that release inflammatory cytokines and events that promote a form of inflammatory cell death called pyroptosis, which is induced by gasdermin activation. Pyroptosis is a unique form of inflammatory cell death that not only results in the release of cytokines but also the release of other intracellular components that promote a broad immune response in both the innate and adaptive immune systems. Thus, inflammasome activation is a major regulator of the inflammatory cascade.

[0003] The (NOD)-like receptor protein 3 (NLRP3) inflammasome is the most well-studied of all inflammasomes. NLRP3 can be activated by a number of stimuli, including environmental crystals, pollutants, host-derived DAMPs, and protein aggregates (Tartey S and Kanneganti TD. Immunology, 2019 Apr;156(4):329-338). Risk-associated molecular patterns involving NLRP3 include uric acid and cholesterol crystals that cause gout and atherosclerosis, amyloid-P fibrils that exhibit neurotoxicity in Alzheimer's disease, and asbestos particles that cause mesothelioma (Kelley et al., Int J Mol Sci, 2019 Jul 6;20(13)). Furthermore, NLRP3 is activated by infectious pathogens such as Vibrio cholerae, fungal pathogens such as Aspergillus jumigatus and Candida albicans, adenoviruses, influenza A virus, and SARS-CoV-2 (Tartey and Kanneganti, 2019 (see above); Fung et al. Emerg Microbes Infect, 2020 Mar 14;9(1):558-570).

[0004] The activation mechanism of NLRP3 in humans remains unclear. The NLRP3 inflammasome is suggested to require regulation at both the transcriptional and post-transcriptional levels (Yang Yet al., Cell Death Dis, 2019 Feb 12;10(2): 128). NOD-like receptor protein 3 (NLRP3) is a protein-coding gene that encodes a protein consisting of an N-terminal pyrin domain, a nucleotide-binding site domain (NBD), and a leucine-rich repeat (LRR) motif at the C-terminus (Inoue et al., Immunology, 2013, 139, 11-18; Sharif et al., Nature, 2019 Jun;570(7761):338-343).

[0005] In response to sterile inflammatory risk signals PAMPs or DAMPs, NLRP3 interacts with an adapter protein, an apoptosis-associated plaque-like protein containing a caspase recruitment domain (ASC), and the protease caspase-1 to form the NLRP3 inflammasome. Upon activation, procaspase-1 undergoes autoproteolysis, cleaving gasdermin D (Gsdmd) to produce an N-terminal Gsdmd molecule, thereby creating a pore in the cell membrane and inducing lytic cell death known as pyroptosis. Alternatively, caspase-1 cleaves the inflammatory cytokines pro-IL-Iβ and pro-IL-18, releasing their biologically active forms (see Kelley et al., above). Activation of the NLRP3 inflammasome releases the inflammatory cytokines IL-Iβ (interleukin-Iβ) and IL-18 (interleukin-18), and dysregulation of these cytokines can lead to a wide range of diseases.

[0006] Dysregulation of the NLRP3 inflammasome or its downstream mediators is associated with many immune disorders, inflammatory diseases, autoimmune diseases, and autoinflammatory diseases. Activation of the NLRP3 inflammasome is associated with the following diseases and disorders: cryopyrin-associated periodic syndromes; sickle cell disease; systemic lupus erythematosus; allodynia; graft-versus-host disease; liver disorders, e.g., non-alcoholic steatohepatitis (NASH), chronic liver disease, viral hepatitis, alcoholic steatohepatitis, and alcoholic liver disease; inflammatory bowel diseases, e.g., Crohn's disease and ulcerative colitis; inflammatory joint diseases, e.g., gout, pseudogout, arthritis, osteoarthritis, rheumatoid arthritis; further rheumatic diseases, e.g., dermatomyositis, Still's disease, and juvenile idiopathic arthritis; kidney-related diseases, e.g., hyperoxaluria, lupus nephritis, hypertensive nephropathy, hemodialysis-associated inflammation, diabetic nephropathy, and diabetic kidney disease; and other inflammatory diseases (Miyamae T. Paediatr Drugs, 2012 Apr 1, 14(2)): 109-17;Szabo G and Petrasek J. Nat Rev Gastroenterol Hepatol, 2015 Jul;12(7):387-400;Zhen Y and Zhang H. Front Immunol, 2019 Feb 28;10:276;Vande Walle Let al., Nature, 2014 Aug 7;512(7512):69-73;Knauf et al., Kidney Int, 2013 Nov;84(5):895-901;Krishnan et al., Br J Pharmacol, 2016 Feb;l 73(4):752-65);Shahzad et al., Kidney Int, 2015 Jan;87(1):74-84;Jankovic, et al. J Exp Med. 2013 Sep (23;210(10):1899-910). Neuroinflammation-related diseases such as cerebral infections, acute injuries, multiple sclerosis, and amyotrophic lateral sclerosis, as well as the onset and progression of neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease, are also associated with NLRP3 inflammasome activation (Sarkar et al., NPJ Parkinsons Dis, 2017 Oct 17;3:30).

[0007] Cardiovascular and metabolic diseases such as atherosclerosis, type 1 and type 2 diabetes, and diabetic complications such as nephropathy and retinopathy, peripheral artery disease, acute heart failure, and hypertension are associated with NLRP3 (Ridker et al., CANTOS Trial Group. N Engl J Med, 2017 Sep 21;377(12):1119-1131; and Toldo S and Abbate A Nat Rev Cardiol, 2018 Apr;15(4):203-214). NLRP3-related skin diseases include: wound healing and scar formation; inflammatory skin diseases such as acne, atopic dermatitis, hidradenitis suppurativa, and psoriasis (Kelly et al., Br J Dermatol, 2015 Dec;1 73(6)). NLRP3 inflammasome activity is also associated with: respiratory diseases, e.g., asthma, sarcoidosis, acute respiratory distress syndrome, severe acute respiratory syndrome (SARS) (Nieto-Torres et al., Virology, 2015 Nov;485:330-9); and eye diseases, e.g., age-related macular degeneration (AMD) and diabetic retinopathy (Doyle et al., Nat Med, 2012 May;18(5):791-8). Cancers associated with NLRP3 include myeloproliferative neoplasms, leukemia, myelodysplastic syndrome, myelofibrosis, lung cancer, and colorectal cancer (Ridker et al., Lancet, 2017 Oct 21;390(10105): 1833-1842; Derangere et al., Cell Death Differ. 2014 Dec;21(12): 1914-24; Basiorka et al., Lancet Haematol, 2018 Sep;5(9): e393-e402, Zhang et al., Hum Immunol, 2018 Jan;79(1):57-62).

[0008] Immune and inflammatory diseases are typically difficult to diagnose and treat efficiently and effectively. Most treatments include symptomatic treatment, slowing disease progression, lifestyle modifications, and surgery.

[0009] NLRP3 inhibitors remain in demand to provide new therapies for diseases and disorders associated with NLRP3 inflammasome activation and dysregulation. The compound shown in structural formula I is useful for treating and preventing diseases, disorders, and symptoms mediated by NLRP3 inflammasome formation and proliferation.

[0010] NLRP3 inhibitors are disclosed in the following publications: Nat. 2022, 1; Cell. 2021, 184, 1; J. Mol. Biol. 2021, 433, 167308; J. Med. Chem. 2021, 64, 101; Nat. Chem. Biol. 2019, 15, 556; Nat. 2019, 570, 338; Nat. Chem. Biol. 2019, 15, 560; PLOS Biol. 2019, 1; Nat. Med. 2015, 21, 248; Cell. 2014, 156, 1193; Nat. Immunol. 2014, 15, 738; PNAS. 2007, 104, 8041; Nat. 2006, 440, 9; Immunity. 2006, 24, 317.Several patent applications, including the following, describe NLRP3 inhibitors: WO 2021 / 239885, WO 2021 / 209552, WO 2021 / 209539, WO 2021 / 193897, WO 2020 / 018975, WO 2020 / 037116, WO 2020 / 021447, WO 2020 / 010143, WO 2019 / 079119, WO 2019 / 0166621, WO 2019 / 121691, WO 2019 / 034696, WO 2019 / 034697, WO 2019 / 034693, WO 2019 / 034692, WO 2019 / 034690, WO 2019 / 034688, WO 2019 / 034686, WO 2019 / 008025, WO 2019 / 008029, WO 2019 / 023145, WO 2019 / 023147, WO 2019 / 025467, WO 2018 / 167468, WO 2018 / 015445, WO 2017 / 184746, WO 2017 / 184735, WO 2017 / 184623, WO 2017 / 184604, WO 2017 / 184624, WO 2017 / 140778, WO 2016 / 131098, US 11,319,319, US 2020 / 0361898, WO 2023 / 032987, WO 2023 / 032987, WO 2022 / 230912, WO 2023 / 275366, WO 2022 / 237781, WO 2022 / 036204, WO 2023 / 288039, WO 2022 / 204227, WO 2022 / 229315, WO 2022 / 184843, WO 2022 / 184842, WO 2022 / 063896, WO 2022 / 063876, WO 2021 / 219784, WO 2023 / 032987, WO 2022 / 166890, WO 2023 / 028534, WO 2023 / 028536, WO 2022 / 238347, WO 2022 / 253936, WO 2022 / 253326, WO 2022 / 135567, WO 2023 / 278438, and US 11,618,751. [Prior art documents] [Patent Documents]

[0011] [Patent Document 1] WO 2021 / 239885 [Patent Document 2] WO 2021 / 209552 [Patent Document 3] WO 2021 / 209539 [Patent Document 4] WO 2021 / 193897 [Patent Document 5] WO 2020 / 018975 [Patent Document 6] WO 2020 / 037116 [Patent Document 7] WO 2020 / 021447 [Patent Document 8] WO 2020 / 010143 [Patent Document 9] WO 2019 / 079119 [Patent Document 10] WO 2019 / 0166621 [Patent Document 11] WO 2019 / 121691 [Patent Document 12] WO 2019 / 034696 [Patent Document 13] WO 2019 / 034697 [Patent Document 14] WO 2019 / 034693 [Patent Document 15] WO 2019 / 034692 [Patent Document 16] WO 2019 / 034690 [Patent Document 17] WO 2019 / 034688 [Patent Document 18] WO 2019 / 034686 [Patent Document 19] WO 2019 / 008025 [Patent Document 20] WO 2019 / 008029 [Patent Document 21] WO 2019 / 023145 [Patent Document 22] WO 2019 / 023147 [Patent Document 23] WO 2019 / 025467 [Patent Document 24] WO 2018 / 167468 [Patent Document 25] WO 2018 / 015445 [Patent Document 26] WO 2017 / 184746 [Patent Document 27] WO 2017 / 184735 [Patent Document 28] WO 2017 / 184623 [Patent Document 29] WO 2017 / 184604 [Patent Document 30] WO 2017 / 184624 [Patent Document 31] WO 2017 / 140778 [Patent Document 32] WO 2016 / 131098 [Patent Document 33] US 11,319,319 [Patent Document 34] US 2020 / 0361898 [Patent Document 35] WO 2023 / 032987 [Patent Document 36] WO 2023 / 032987 [Patent Document 37] WO 2022 / 230912 [Patent Document 38] WO 2023 / 275366 [Patent Document 39] WO 2022 / 237781 [Patent Document 40] WO 2022 / 036204 [Patent Document 41] WO 2023 / 288039

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[0013] This disclosure is based on structural formula I: [ka] This invention relates to a novel compound represented by [formula], as well as its pharmaceutically acceptable salts, hydrates, and solvates.

[0014] The compound represented by structural formula I and its embodiments are inhibitors of NOD-like receptor protein 3 (NLRP3) and may be useful in the treatment and prevention of NLRP3-mediated diseases, disorders and symptoms (e.g., but not limited to, gout, pseudogout (chondrocalcinosis), cryopyrin-associated periodic syndromes (CAPS), NASH, fibrosis, heart failure, idiopathic pericarditis, atopic dermatitis, inflammatory bowel disease, Alzheimer's disease, Parkinson's disease, and traumatic brain injury). The disclosure further relates to pharmaceutical compositions comprising the compound represented by structural formula I or pharmaceutically acceptable salts, hydrates or solvates thereof and pharmaceutically acceptable carriers.

[0015] Also disclosed are methods for treating, managing, preventing, alleviating, improving, suppressing or controlling disorders, diseases and symptoms in subjects requiring treatment, management, prevention, alleviation, improvement, suppression or control of disorders, diseases and symptoms that respond to inhibition of the NLRP3 receptor, wherein the method involves administering the compounds and pharmaceutical compositions of the Disclosure.

[0016] This disclosure also relates to the use of the compound represented by structural formula I for the manufacture of pharmaceuticals useful in the treatment of diseases, disorders and symptoms that may respond to inhibition of the NLRP3 receptor.

[0017] This disclosure also relates to methods for treating or preventing these diseases, disorders and symptoms by administering the compound represented by structural formula I in combination with another agent that may be useful in treating these diseases, disorders and symptoms. This disclosure also relates to processes for preparing the compound represented by structural formula I.

Mode for Carrying Out the Invention

[0018] The present disclosure relates to Structural Formula I:

Chemical Formula

[0019] This disclosure has many embodiments, which are summarized below. This disclosure encompasses the compounds shown, and further encompasses the individual diastereoisomers, enantiomers and epimers of said compounds, and also encompasses mixtures of said diastereoisomers and / or enantiomers (this includes racemic mixtures).

[0020] In another embodiment of the present invention, X is = C(R 4 )- and =N- are independently selected. In one class of this embodiment, X is =C(R 4 )-. In another class of this embodiment, X is = N-.

[0021] In one embodiment, R 1 is -C 3-12 Cycloalkyl, -C 3-12 Cycloalkenyl, -C 2-11 Cycloheteroalkyl, -C 2-11 Cycloheteralkenyl, aryl, heteroaryl, -C 1-6 Alkyl, -C 1-6 alkyl-OH, -C 1-6 Alkyl-C 3-12 Cycloalkyl, -C 1-6 Alkyl-C 3-12 Cycloalkenyl, -C 1-6 Alkyl-C2-11 Cycloheteroalkyl, -C 1-6 Alkyl-C 2-11 Cycloheteralkenyl, -C 1-6 Alkyl-aryl and -C 1-6 Selected from the group of alkyl-heteroaryls, where R 1 is either not substituted, or R a It is substituted with 1 to 6 substituents selected from the following.

[0022] In another embodiment, R 1 is -C 3-12 Cycloalkyl, -C 2-11 Cycloheteroalkyl, aryl, heteroaryl, -C 1-6 Alkyl, -C 1-6 alkyl-OH, -C 1-6 Alkyl-C 3-12 Cycloalkyl, -C 1-6 Alkyl-C 2-11 Cycloheteroalkyl, -C 1-6 Alkyl-aryl and -C 1-6 Selected from the group of alkyl-heteroaryls, where R 1 is either not substituted, or R a It is substituted with 1 to 6 substituents selected from the following.

[0023] In another embodiment, R 1 is -C 3-12 Cycloalkyl, -C 2-11 Cycloheteroalkyl, aryl, heteroaryl, -C 1-6 Alkyl, -C 1-6 alkyl-OH, -C 1-6 Alkyl-C 3-12 Cycloalkyl and -C 1-6 Alkyl-C 2-11 Selected from the group of cycloheteralkyls, where R 1 is either not substituted, or R a It is substituted with 1 to 6 substituents selected from the following.

[0024] In another embodiment, R 1 is -C3-12 Cycloalkyl, -C 2-11 Cycloheteroalkyl, heteroaryl, -C 1-6 Alkyl, -C 1-6 alkyl-OH, -C 1-6 Alkyl-C 3-12 Cycloalkyl and -C 1-6 Alkyl-C 2-11 Selected from the group of cycloheteralkyls, where R 1 is either not substituted, or R a It is substituted with 1 to 6 substituents selected from the following.

[0025] In another embodiment, R 1 is -C 3-12 Cycloalkyl, -C 2-11 Cycloheteroalkyl, heteroaryl, -C 1-6 alkyl-OH, -C 1-6 Alkyl-C 3-12 Cycloalkyl and -C 1-6 Alkyl-C 2-11 Selected from the group of cycloheteralkyls, where R 1 is either not substituted, or R a It is substituted with 1 to 6 substituents selected from the following.

[0026] In another embodiment, R 1 is -C 3-12 Cycloalkyl, -C 2-11 Cycloheteroalkyl, -C 1-6 Alkyl-C 3-12 Cycloalkyl and -C 1-6 Alkyl-C 2-11 Selected from the group of cycloheteralkyls, where R 1 is either not substituted, or R a It is substituted with 1 to 6 substituents selected from the following.

[0027] In another embodiment, R 1 is -C 3-12 Cycloalkyl and -C 2-11 Selected from the group of cycloheteralkyls, where R 1is either not substituted, or R a It is substituted with 1 to 6 substituents selected from. In one class of this embodiment, R 1 R is selected from the group of bicyclo[3.1.1]heptane, piperidine, 8-azabicyclo[3.2.1]octane and octahydroindolidine, where R 1 is either not substituted, or R a It is substituted with 1 to 6 substituents selected from the following.

[0028] In another embodiment, R 1 is -C 3-12 It is a cycloalkyl, where R 1 is either not substituted, or R a It is substituted with 1 to 6 substituents selected from. In one class of this embodiment, R 1 is bicyclo[3.1.1]heptane, where bicyclo[3.1.1]heptane is either unsubstituted or R a It is substituted with 1 to 6 substituents selected from the following.

[0029] In another embodiment, R 1 C 2-11 It is a cycloheteroalkyl, where the cycloheteroalkyl is either unsubstituted or R a It is substituted with 1 to 6 substituents selected from. In one class of this embodiment, R 1 is piperidine, where piperidine is either unsubstituted or R a It is substituted with 1 to 6 substituents selected from. In another class of this embodiment, R 1 R is selected from the group of piperidine, 8-azabicyclo[3.2.1]octane and octahydroindolidine, where R 1 is either not substituted, or R a It is substituted with 1 to 6 substituents selected from the following.

[0030] In another embodiment, R 2 These are hydrogen, CN, -CF3, -CHF2, -C1-6 Selected from the group of alkyls and halogens, where R 2 is either not substituted, or R b It is substituted with 1 to 5 substituents selected from. In one class of this embodiment, R 2 is hydrogen and -C 1-6 Selected from the group of alkyls, where alkyl is either unsubstituted or R b It is substituted with 1 to 5 substituents selected from. In one subclass of this class, R 2 is hydrogen or -CH3, where -CH3 is unsubstituted or R b It is substituted with 1 to 3 substituents selected from. In another class of this embodiment, R 2 is -C 1-6 It is alkyl, and here, R 2 is either not substituted, or R b It is substituted with 1 to 5 substituents selected from. In one subclass of this class, R 2 is -CH3, where R 2 is either not substituted, or R b It is substituted with 1 to 3 substituents selected from. In another class of this embodiment, R 2 It is hydrogen.

[0031] In another embodiment of the present invention, R 3 R is selected from the group of aryl and heteroaryl, where R 3 is either not substituted, or R c It is substituted with 1 to 5 substituents selected from. In one class of this embodiment, R 3 R is selected from the group consisting of phenyl, benzothiophene, and indan, where R 3 is either not substituted, or R c It is substituted with 1 to 5 substituents selected from the following.

[0032] In another embodiment, R 3 is a heteroaryl compound, where the heteroaryl compound is either unsubstituted or R cIt is substituted with 1 to 5 substituents selected from. In one class of this embodiment, R 3 is benzothiophene, and here, R 3 is either not substituted, or R c It is substituted with 1 to 5 substituents selected from the following.

[0033] In another embodiment, R 3 is an aryl, where the aryl is either unsubstituted or R c It is substituted with 1 to 5 substituents selected from. In one class of this embodiment, R 3 R is phenyl or indan, where R 3 is either not substituted, or R c It is substituted with 1 to 5 substituents selected from. In another class of this embodiment, R 3 is phenyl, where phenyl is either unsubstituted or R c It is substituted with 1 to 5 substituents selected from. In another class of this embodiment, R 3 is indane, where indane is either unsubstituted or R c It is substituted with 1 to 5 substituents selected from the following.

[0034] In another embodiment of the present invention, R 4 is hydrogen, CN, -C 1-6 Alkyl, -OC 1-6 Selected from the group of alkyls and halogens, where each alkyl is either unsubstituted or R d It is substituted with 1 to 5 substituents selected from the following.

[0035] In another embodiment of the present invention, R 4 is hydrogen or -C 1-6 It is an alkyl group, where each alkyl group is either unsubstituted or R d It is substituted with 1 to 5 substituents selected from the following.

[0036] In another embodiment of the present invention, R 4is -C 1-6 It is an alkyl group, where each alkyl group is either unsubstituted or R d It is substituted with 1 to 5 substituents selected from the following.

[0037] In another embodiment of the present invention, R 4 It is hydrogen.

[0038] In another embodiment of the present invention, R 5 is hydrogen, CN, -C 1-6 Alkyl, -OC 1-6 Selected from the group of alkyls and halogens, where each alkyl is either unsubstituted or R e It is substituted with 1 to 5 substituents selected from the following.

[0039] In another embodiment of the present invention, R 5 is hydrogen, CN, -C 1-6 Alkyl, -OC 1-6 Selected from the group of alkyls and halogens, where each alkyl is either unsubstituted or R e It is substituted with 1 to 5 substituents selected from the following.

[0040] In another embodiment of the present invention, R 5 is hydrogen or -C 1-6 It is an alkyl group, where each alkyl group is either unsubstituted or R e It is substituted with 1 to 5 substituents selected from. In one class of this embodiment, R 5 It is either hydrogen or -CH3.

[0041] In another embodiment of the present invention, R 5 is -C 1-6 It is an alkyl group, where each alkyl group is either unsubstituted or R e It is substituted with 1 to 5 substituents selected from. In one class of this embodiment, R 5 It is -CH3.

[0042] In another embodiment of the present invention, R 5It is hydrogen.

[0043] In another embodiment, each R a CN, oxo, -OH, halogen, -C 1-6 Alkyl, -C 1-6 alkyl-OH, -OC 1-6 Alkyl, -C 3-6 Cycloalkyl, -C 2-6 Cycloheteroalkyl, aryl, heteroaryl, -C(O)C 1-6 Alkyl, -C(O)C 3-6 Cycloalkyl, -C 1-6 Alkyl-aryl, -C 1-6 Alkyl-heteroaryl, -C 1-6 Alkyl-C 3-6 Cycloalkyl, -C 1-6 Alkyl-C 2-6 Cycloheteroalkyl, -(CH2) p -OC 1-6 Alkyl, -(CH2) p -OC 3-6 Cycloalkyl, -(CH2) p -OC 2-6 Cycloheteroalkyl, -(CH2) p -O-aryl, -(CH2) p -O-heteroaryl, -(CH2) p -S(O) r R f and -N(R g )Independently selected from group 2, where each R a It is either not substituted, or contains halogen, CF3, OH, C 1-6 Alkyl and -OC 1-6 It is substituted with 1 to 6 substituents selected from alkyl groups.

[0044] In another embodiment, each R a CN, oxo, -OH, halogen, -C 1-6 Alkyl, -C 1-6 alkyl-OH, -OC 1-6 Alkyl, -C 3-6 Cycloalkyl, -C 2-6 Cycloheteroalkyl, aryl, heteroaryl, -C1-6 Alkyl-aryl, -C 1-6 Alkyl-heteroaryl, -C 1-6 Alkyl-C 3-6 Cycloalkyl, -C 1-6 Alkyl-C 2-6 Cycloheteroalkyl, -(CH2) p -S(O) r R f and -N(R g )Independently selected from group 2, where each R a It is either not substituted, or contains halogen, CF3, OH, C 1-6 Alkyl and -OC 1-6 It is substituted with 1 to 6 substituents selected from alkyl groups.

[0045] In another embodiment, each R a CN, oxo, -OH, halogen, -C 1-6 Alkyl, -C 1-6 alkyl-OH, -OC 1-6 Alkyl, -C 3-6 Cycloalkyl, -C 2-6 Cycloheteroalkyl, -C 1-6 Alkyl-C 3-6 Cycloalkyl, -C 1-6 Alkyl-C 2-6 Cycloheteroalkyl, -(CH2) p -S(O) r R f and -N(R g ) Independently selected from group 2, where each CH2, alkyl, cycloalkyl and cycloheteroalkyl is independently unsubstituted or halogen, CF3, OH, C 1-6 Alkyl and -OC 1-6 It is substituted with 1 to 6 substituents selected from alkyl groups.

[0046] In another embodiment, each R a CN, oxo, -OH, halogen, -C 1-6 Alkyl, -C 1-6 alkyl-OH, -OC 1-6 Alkyl, -C 3-6 Cycloalkyl, -C2-6 Cycloheteroalkyl, aryl, heteroaryl, -C 1-6 Alkyl-C 3-6 Cycloalkyl, -C 1-6 Alkyl-C 2-6 Cycloheteroalkyl, -(CH2) p -S(O) r R f and -N(R g ) Independently selected from group 2, where each CH2, alkyl, cycloalkyl and cycloheteroalkyl is independently unsubstituted or halogen, CF3, OH, C 1-6 Alkyl and -OC 1-6 It is substituted with 1 to 6 substituents selected from alkyl groups.

[0047] In another embodiment, each R a CN, oxo, -OH, halogen, -C 1-6 Alkyl, -C 1-6 alkyl-OH, -OC 1-6 Alkyl, -C 3-6 Cycloalkyl, -C 2-6 Cycloheteroalkyl, aryl, heteroaryl, -C 1-6 Alkyl-C 3-6 Cycloalkyl and -C 1-6 Alkyl-C 2-6 A group of cycloheteralkyls is independently selected, where each CH2, alkyl, cycloalkyl, and cycloheteralkyl is independently unsubstituted or substituted with a halogen, CF3, OH, C 1-6 Alkyl and -OC 1-6 It is substituted with 1 to 6 substituents selected from alkyl groups.

[0048] In another embodiment, each R a CN, oxo, -OH, halogen, -C 1-6 Alkyl, -C 1-6 alkyl-OH, -OC 1-6 Alkyl, -C 3-6 Cycloalkyl, -C 1-6 Alkyl-C 3-6 Cycloalkyl, -(CH2) p-S(O) r R f and -N(R g ) Independently selected from group 2, where each CH2, alkyl and cycloalkyl is independently unsubstituted or halogen, CF3, OH, C 1-6 Alkyl and -OC 1-6 It is substituted with 1 to 6 substituents selected from alkyl groups.

[0049] In another embodiment, each R a CN, oxo, -OH, halogen, -C 1-6 Alkyl, -C 1-6 alkyl-OH, -OC 1-6 Alkyl, -C 3-6 Cycloalkyl and -C 1-6 Alkyl-C 3-6 Independently selected from the group of cycloalkyl groups, where each CH2, alkyl, and cycloalkyl is independently unsubstituted or substituted with a halogen, CF3, OH, C 1-6 Alkyl and -OC 1-6 It is substituted with 1 to 6 substituents selected from alkyl groups.

[0050] In another embodiment, each R a is -OH, -C 1-6 Alkyl and -C 3-6 A group of cycloalkyls is independently selected, where each alkyl and cycloalkyl is independently unsubstituted or substituted with a halogen, CF3, OH, C 1-6 Alkyl and -OC 1-6 It is substituted with 1 to 6 substituents selected from alkyl groups. In one class of this embodiment, each R a R is independently selected from the group consisting of -OH, -CH3, -CD3, -CH2CH3, -CH(CH3)2 and cyclobutyl. In another class of this embodiment, each R a R is independently selected from the group consisting of -OH, -CH3, -CH2CH3, -CH(CH3)2 and cyclobutyl. In another class of this embodiment, each R aR is independently selected from the group -OH, -CH3, -CD3, -CH2CH3 and -CH(CH3)2. In another class of this embodiment, each R a The group is independently selected from the groups -OH, -CH3, -CH2CH3, and -CH(CH3)2.

[0051] In another embodiment, each R a is -OH or -C 1-6 It is an alkyl group, where each alkyl group is either unsubstituted or a halogen, CF3, OH, C 1-6 Alkyl and -OC 1-6 It is substituted with 1 to 6 substituents selected from alkyl groups. In one class of this embodiment, each R a The group is independently selected from the groups -OH, -CH3, and -CH2CH3.

[0052] In another embodiment, each R a It is -OH.

[0053] In another embodiment, each R a is -C 1-6 It is an alkyl group, where each alkyl group is either unsubstituted or a halogen, CF3, OH, C 1-6 Alkyl and -OC 1-6 It is substituted with 1 to 6 substituents selected from alkyl groups. In one class of this embodiment, each R a This is either -CH3 or -CH2CH3.

[0054] In another embodiment of the present invention, each R b CF3, halogen, -C 1-6 Alkyl and -C 3-6 It is independently selected from the group of cycloalkyls. In one class of this embodiment, each R b This includes CF3, halogen and -C 1-6 It is independently selected from the group of alkyls. In another class of this embodiment, each R b This is CF3. In another class of this embodiment, each R b is a halogen. In another class of this embodiment, each R bis -C 1-6 It is alkyl.

[0055] In another embodiment of the present invention, each R c CN, -OH, oxo, halogen, -C 1-6 Alkyl, -OC 1-6 Alkyl, -C 3-6 Cycloalkyl, -C 2-6 Cycloheteroalkyl, aryl, heteroaryl, -C 1-6 Alkyl-aryl, -C 1-6 Alkyl-heteroaryl, -C 1-6 Alkyl-C 3-6 Cycloalkyl, -C 1-6 Alkyl-C 2-6 Cycloheteroaryl, -(CH2) q -OC 1-6 Alkyl, -(CH2) q -OC 3-6 Cycloalkyl, -(CH2) q -OC 2-6 Cycloheteroaryl, -(CH2) q -O-aryl, -(CH2) q -O-heteroaryl, -OC 1-6 Alkyl-C 3-6 Cycloalkyl, -OC 1-6 Alkyl-C 2-6 Cycloheteroalkyl, -OC 1-6 Alkyl-aryl, -OC 1-6 Alkyl-heteroaryl, -(CH2) q -S(O) r R h , -N(R i )2, -C(O)R j and -C(O)NR i Independently selected from the group, where each R c These are either not substituted, or halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 It is substituted with 1 to 6 substituents selected from alkyl groups.

[0056] In another embodiment, each Rc CN, -OH, oxo, halogen, -C 1-6 Alkyl, -OC 1-6 Alkyl, -C 3-6 Cycloalkyl, -C 2-6 Cycloheteroalkyl, aryl, heteroaryl, -(CH2) q -S(O) r R h , -N(R i )2, -C(O)R j and -C(O)NR i Independently selected from the group, where each R c These are either not substituted, or halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 It is substituted with 1 to 6 substituents selected from alkyl groups.

[0057] In another embodiment, each R c CN, -OH, oxo, halogen, -C 1-6 Alkyl, -OC 1-6 Alkyl, -(CH2) q -S(O) r R h , -N(R i )2, -C(O)R j and -C(O)NR i Independently selected from the group, where each alkyl is either unsubstituted or halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 It is substituted with 1 to 6 substituents selected from alkyl groups.

[0058] In another embodiment, each R c CN, -OH, oxo, halogen, -C 1-6 Alkyl, -OC 1-6 Alkyl, -C 3-6 Cycloalkyl and -N(R i )Independently selected from group 2, where each R cThese are either not substituted, or halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 It is substituted with 1 to 6 substituents selected from alkyl groups. In one class of this embodiment, each R c R is independently selected from the group consisting of -OH, Cl, F, -CH3, -CF3, -OCHF2, cyclopropyl, and NH2. In another class of this embodiment, each R c The group is independently selected from -OH, Cl, -CH3, -CF3, and -OCHF2.

[0059] In another embodiment, each R c -OH, halogen, -C 1-6 Alkyl, -C 3-6 Cycloalkyl and -N(R i )Independently selected from group 2, where each R c These are either not substituted, or halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 It is substituted with 1 to 6 substituents selected from alkyl groups. In one class of this embodiment, each R c R is independently selected from the group consisting of -OH, Cl, F, -CH3, -CF3, -OCHF2, cyclopropyl, and NH2. In another class of this embodiment, each R c The group is independently selected from -OH, Cl, -CH3, -CF3, and -OCHF2.

[0060] In another embodiment, each R c -OH, halogen, -C 1-6 Alkyl and -OC 1-6 A alkyl group is independently selected from the alkyl group, where each alkyl is either unsubstituted or halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 It is substituted with 1 to 6 substituents selected from alkyl groups. In one class of this embodiment, each R cR is independently selected from the group -OH, Cl, F, -CH3, -CF3 and -OCHF2. In another class of this embodiment, each R c The group is independently selected from -OH, Cl, -CH3, -CF3, and -OCHF2.

[0061] In another embodiment, each R c These are -OH and -C 1-6 A alkyl group is independently selected from the alkyl group, where each alkyl is either unsubstituted or halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 It is substituted with 1 to 6 substituents selected from alkyl groups. In one class of this embodiment, each R c The group is independently selected from the -OH, -CH3, and -CF3 groups.

[0062] In another embodiment, each R c It is selected independently from the -OH group.

[0063] In another embodiment, each R c is -C 1-6 A alkyl group is independently selected from the alkyl group, where each alkyl is either unsubstituted or halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 It is substituted with 1 to 6 substituents selected from alkyl groups. In one class of this embodiment, each R c The group is independently selected from the -OH, -CH3, and -CF3 groups.

[0064] In another embodiment of the present invention, each R d These are hydrogen, OH, halogens and -C 1-6 Selected independently from the group of alkyls. In another embodiment of the present invention, each R d This includes hydrogen, halogens, and -C 1-6 Selected independently from the group of alkyls. In another embodiment of the present invention, each R d is hydrogen and -C 1-6It is independently selected from the group of alkyls. In one class of this embodiment, each R d is -C 1-6 It is alkyl. In another class of this embodiment, each R d It is hydrogen.

[0065] In another embodiment of the present invention, each R e These are hydrogen, OH, halogens and -C 1-6 Selected independently from the group of alkyls. In another embodiment of the present invention, each R e This includes hydrogen, halogens, and -C 1-6 Selected independently from the group of alkyls. In another embodiment of the present invention, each R e is hydrogen and -C 1-6 It is independently selected from the group of alkyls. In one class of this embodiment, each R e is -C 1-6 It is alkyl. In another class of this embodiment, each R e It is hydrogen.

[0066] In another embodiment, each R f is hydrogen, -C 1-6 Alkyl, -C 3-6 Cycloalkyl and -C 2-6 Selected independently from the group of cycloheteralkyls. In another embodiment, each R f is hydrogen and -C 1-6 It is independently selected from the group of alkyls. In one class of this embodiment, each R f R is independently selected from the group consisting of hydrogen and CH3. In another embodiment, each R f is -C 1-6 It is alkyl. In one class of this embodiment, each R f This is CH3. In another embodiment, each R f It is hydrogen.

[0067] In another embodiment of the present invention, each R g is hydrogen, -C 1-6 Alkyl, -C 3-6 Cycloalkyl, -C 2-6 Cycloheteroalkyl, aryl, heteroaryl, -C(O)C1-6 Alkyl and -S(O) r R f Independently selected from the group, where alkyl, cycloalkyl, cycloheteroalkyl, aryl, and heteroaryl are either unsubstituted or CF3, halogen, OH, and -OC 1-6 It can be substituted with 1 to 3 substituents selected from alkyl groups. In one class of this embodiment, each R g is hydrogen, -C 1-6 Alkyl, -C 3-6 Cycloalkyl, -C 2-6 Cycloheteroalkyl, -C(O)C 1-6 Alkyl and -S(O) r R f Independently selected from the group, where alkyl, cycloalkyl and cycloheteroalkyl are unsubstituted or CF3, halogen, OH and -OC 1-6 It can be substituted with 1 to 3 substituents selected from alkyl groups.

[0068] In another embodiment, each R g is hydrogen, -C 1-6 Alkyl, -C(O)C 1-6 Alkyl and -S(O) r R f Independently selected from the group, where alkyl is unsubstituted or CF3, halogen, OH and -OC 1-6 It can be substituted with 1 to 3 substituents selected from alkyl groups. In another embodiment, each R g is hydrogen or -C 1-6 It is an alkyl group, where the alkyl is either unsubstituted or contains CF3, halogen, OH, and -OC. 1-6 It can be substituted with 1 to 3 substituents selected from alkyl groups. In one class of this embodiment, each R g is -C 1-6 It is an alkyl group, where the alkyl is either unsubstituted or contains CF3, halogen, OH, and -OC. 1-6 It can be substituted with 1 to 3 substituents selected from alkyl groups. In another class of this embodiment, each R g It is hydrogen.

[0069] In another embodiment of the present invention, each R h is hydrogen, -C 1-6 Alkyl, -C 3-6 Cycloalkyl and -C 2-6 Selected independently from the group of cycloheteralkyls. In another embodiment, each R h is hydrogen and -C 1-6 It is independently selected from the group of alkyls. In one class of this embodiment, each R h R is independently selected from the group consisting of hydrogen and CH3. In another embodiment, each R h is -C 1-6 It is alkyl. In one class of this embodiment, each R h This is CH3. In another embodiment, each R h It is hydrogen.

[0070] In another embodiment of the present invention, each R i is hydrogen, -C 1-6 Alkyl, -C 3-6 Cycloalkyl and -C 2-6 Selected independently from the group of cycloheteralkyls. In another embodiment, each R i is hydrogen and -C 1-6 It is independently selected from the group of alkyls. In one class of this embodiment, each R i R is independently selected from the group consisting of hydrogen and CH3. In another embodiment, each R i is -C 1-6 It is alkyl. In one class of this embodiment, each R i This is CH3. In another embodiment, each R i It is hydrogen.

[0071] In another embodiment of the present invention, each R j is OH, -C 1-6 Alkyl, -C 3-6 Cycloalkyl and -C 2-6 Independently selected from the group of cycloheteralkyls, where alkyl, cycloalkyl, and cycloheteralkyl are unsubstituted or CF3, halogen, OH, and -OC. 1-6It can be substituted with 1 to 3 substituents selected from alkyl groups. In another embodiment of the present invention, each R j is OH, -C 1-6 Alkyl, -C 3-6 Cycloalkyl and -C 2-6 Selected independently from the group of cycloheteralkyls. In another embodiment, each R j OH and -C 1-6 It is independently selected from the group of alkyls. In one class of this embodiment, each R j is independently selected from the group of OH and CH3. In another embodiment, each R j is -C 1-6 It is alkyl. In one class of this embodiment, each R j This is CH3. In another embodiment, each R j It is OH.

[0072] In another embodiment, p is 0, 1, 2, 3, 4, 5, or 6. In another embodiment, p is 0, 1, 2, 3, 4, or 5. In another embodiment, p is 1, 2, 3, 4, 5, or 6. In another embodiment, p is 1, 2, 3, 4, or 5. In another embodiment, p is 0, 1, 2, 3, or 4. In another embodiment, p is 1, 2, 3, or 4. In another embodiment, p is 0, 1, 2, or 3. In another embodiment, p is 1, 2, or 3. In another embodiment, p is 0, 1, or 2. In another embodiment, p is 1 or 2. In another embodiment, p is 0. In another embodiment, p is 1. In another embodiment, p is 2. In another embodiment, p is 3. In another embodiment, p is 4. In another embodiment, p is 5. In another embodiment, p is 6.

[0073] In another embodiment, q is 0, 1, 2, 3, 4, 5, or 6. In another embodiment, q is 0, 1, 2, 3, 4, or 5. In another embodiment, q is 1, 2, 3, 4, 5, or 6. In another embodiment, q is 1, 2, 3, 4, or 5. In another embodiment, q is 0, 1, 2, 3, or 4. In another embodiment, q is 1, 2, 3, or 4. In another embodiment, q is 0, 1, 2, or 3. In another embodiment, q is 1, 2, or 3. In another embodiment, q is 0, 1, or 2. In another embodiment, q is 1 or 2. In another embodiment, q is 0. In another embodiment, q is 1. In another embodiment, q is 2. In another embodiment, q is 3. In another embodiment, q is 4. In another embodiment, q is 5. In another embodiment, q is 6.

[0074] In another embodiment, r is 1 or 2. In another embodiment, r is 1. In another embodiment, r is 2.

[0075] In another embodiment, the present disclosure relates to structural formula Ia: [ka] This relates to a compound represented by or its pharmaceutically acceptable salt, hydrate, or solvate.

[0076] In another embodiment, the present disclosure relates to structural formula Ib: [ka] This relates to a compound represented by or its pharmaceutically acceptable salt, hydrate, or solvate.

[0077] In another embodiment, the present disclosure relates to structural formula Ic: [ka] This relates to a compound represented by or its pharmaceutically acceptable salt, hydrate, or solvate.

[0078] In another embodiment, the present disclosure relates to structural formula Id: [ka] This relates to a compound represented by or its pharmaceutically acceptable salt, hydrate, or solvate.

[0079] In another embodiment, the present disclosure relates to structural formula Ie: [ka] This relates to a compound represented by or its pharmaceutically acceptable salt, hydrate, or solvate.

[0080] Compounds represented by structural formula I include compounds represented by structural formulas Ia, Ib, Ic, Id, and Ie, as well as their pharmaceutically acceptable salts, hydrates, and solvates.

[0081] In another embodiment, the present disclosure relates to structural formula I [where, X is =C(R 4 )- or = N-; R 1 teeth, (1)-C 3-12 Cycloalkyl, (2)-C 2-11 Cycloheteroalkyl, (3) Heteroaryl, (4)-C 1-6 alkyl-OH, (5)-C 1-6 Alkyl-C 3-12 Cycloalkyl, and, (6) New C 1-6 Alkyl-C 2-11 Cycloheteroalkyl Selected from the group, where R 1 is either not substituted, or R a It is substituted with 1-6 substituents selected from; R 2 is hydrogen and -C 1-6 Selected from the group of alkyls, where alkyl is either unsubstituted or Rb It is substituted with 1 to 5 substituents selected from; R 3 is a heteroaryl compound, where the heteroaryl compound is either unsubstituted or R c It is substituted with 1 to 5 substituents selected from; R 4 is hydrogen or -C 1-6 It is an alkyl group, where each alkyl group is either unsubstituted or R d It is substituted with 1 to 5 substituents selected from; and, R 5 is hydrogen or -C 1-6 It is an alkyl group, where each alkyl group is either unsubstituted or R e It is substituted with 1 to 5 substituents selected from; And the remaining substituents are as defined above. This relates to the compound represented by or its pharmaceutically acceptable salts, hydrates, and solvates.

[0082] In another embodiment, the present disclosure relates to structural formula I [where, X is =C(R 4 )- or = N-; R 1 C 2-11 It is a cycloheteroalkyl, where the cycloheteroalkyl is either unsubstituted or R a It is substituted with 1 to 6 substituents selected from; R 2 is hydrogen and -C 1-6 Selected from the group of alkyls, where alkyl is either unsubstituted or R b It is substituted with 1 to 5 substituents selected from; R 3 is an aryl, where the aryl is either unsubstituted or R c It is substituted with 1 to 5 substituents selected from; R 4 is hydrogen; and, R 5 is hydrogen; And the remaining substituents are as defined above. This relates to the compound represented by or its pharmaceutically acceptable salts, hydrates, and solvates.

[0083] In another embodiment, the present disclosure relates to structural formula I [where, X is = N-; R 1 C 2-11 It is a cycloheteroalkyl, where the cycloheteroalkyl is either unsubstituted or R a It is substituted with 1 to 6 substituents selected from; R 2 is hydrogen and -C 1-6 Selected from the group of alkyls, where alkyl is either unsubstituted or R b It is substituted with 1 to 5 substituents selected from; R 3 is an aryl, where the aryl is either unsubstituted or R c It is substituted with 1 to 5 substituents selected from; R 4 is hydrogen; and, R 5 is hydrogen; And the remaining substituents are as defined above. This relates to the compound represented by or its pharmaceutically acceptable salts, hydrates, and solvates.

[0084] Exemplary, but non-limiting, examples of compounds of this disclosure that are useful as NLRP3 inhibitors include the following compounds: (1) (R)-2-(7-(1-ethylpiperidine-3-yl)-7H-pyrrolo[2,3-c]pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; (2) (R)-2-(7-(1-ethylpiperidine-3-yl)-4-methyl-7H-pyrrolo[2,3-c]pyridazin-3-yl)-5-(trifluoromethyl)phenol; (3) (R)-2-(7-(1-ethylpiperidine-3-yl)-7H-imidazo[4,5-c]pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; (4) (R)-3-methyl-2-(7-(1-methylpiperidine-3-yl)-7H-imidazo[4,5-c]pyridazin-3-yl)-5-(trifluoromethyl)phenol; (5) (S)-3-methyl-2-(7-(1-methylpiperidine-3-yl)-7H-imidazo[4,5-c]pyridazin-3-yl)-5-(trifluoromethyl)phenol; (6) (R)-2-(4-methyl-7-(piperidine-3-yl)-7H-imidazo[4,5-c]pyridazin-3-yl)-5-(trifluoromethyl)phenol; (7) (3S,4R)-3-(3-(2-hydroxy-4-(trifluoromethyl)phenyl)-4-methyl-7H-imidazo[4,5-c]pyridazin-7-yl)piperidine-4-ol; (8) (R)-2-(7-(1-ethylpiperidine-3-yl)-4-methyl-7H-imidazo[4,5-c]pyridazin-3-yl)-5-(trifluoromethyl)phenol; (9) (R)-2-(7-(1-methylpiperidine-3-yl)-7H-imidazo[4,5-c]pyridazin-3-yl)-5-(trifluoromethyl)phenol; (10) (S)-2-(7-(1-methylpiperidine-3-yl)-7H-imidazo[4,5-c]pyridazin-3-yl)-5-(trifluoromethyl)phenol; (11) (R)-3-(2-(difluoromethoxy)-4-(trifluoromethyl)phenyl)-7-(1-ethylpiperidine-3-yl)-4-methyl-7H-imidazo[4,5-c]pyridazine; (12) (R)-2-(4-methyl-7-(1-methylpiperidine-3-yl)-7H-imidazo[4,5-c]pyridazin-3-yl)-5-(trifluoromethyl)phenol; (13) (3S,4R)-3-(3-(2-hydroxy-4-(trifluoromethyl)phenyl)-4-methyl-7H-imidazo[4,5-c]pyridazin-7-yl)-1-methylpiperidine-4-ol; and, (14) (3S,4R)-1-ethyl-3-(3-(2-hydroxy-4-(trifluoromethyl)phenyl)-4-methyl-7H-imidazo[4,5-c]pyridazin-7-yl)piperidine-4-ol; (15) (R)-5-chloro-2-(4-methyl-7-(piperidine-3-yl)-7H-imidazo[4,5-c]pyridazine-3-yl)phenol; (16) (R)-2-(4,6-dimethyl-7-(1-methylpiperidine-3-yl)-7H-imidazo[4,5-c]pyridazin-3-yl)-5-(trifluoromethyl)phenol; (17) (R)-5-(4-methyl-7-(1-methylpiperidine-3-yl)-7H-imidazo[4,5-c]pyridazine-3-yl)benzo[b]thiophene-4-ol; (18) (R)-5-(4-methyl-7-(1-methylpiperidine-3-yl)-7H-imidazo[4,5-c]pyridazin-3-yl)-2,3-dihydro-1H-inden-4-ol; (19) (R)-5-chloro-2-(4-methyl-7-(1-methylpiperidine-3-yl)-7H-imidazo[4,5-c]pyridazine-3-yl)phenol; and, (20) (R)-5-chloro-2-(7-(1-ethylpiperidine-3-yl)-4-methyl-7H-imidazo[4,5-c]pyridazin-3-yl)phenol; Alternatively, a pharmaceutically acceptable salt of the above compound.

[0085] Exemplary, but non-limiting, further examples of the compounds of this disclosure that are useful as NLRP3 inhibitors are the following compounds: (1) (R)-2-(7-(1-ethylpiperidine-3-yl)-7H-imidazo[4,5-c]pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; (2) (R)-2-(4-methyl-7-(piperidine-3-yl)-7H-imidazo[4,5-c]pyridazin-3-yl)-5-(trifluoromethyl)phenol; (3) (R)-2-(7-(1-ethylpiperidine-3-yl)-4-methyl-7H-imidazo[4,5-c]pyridazin-3-yl)-5-(trifluoromethyl)phenol; and, (4) (R)-2-(4-methyl-7-(1-methylpiperidine-3-yl)-7H-imidazo[4,5-c]pyridazin-3-yl)-5-(trifluoromethyl)phenol; Alternatively, a pharmaceutically acceptable salt of the above compound.

[0086] While the specific stereochemistry described above is preferred, other stereoisomers, including diastereoisomers, enantiomers, epimers, and mixtures thereof, may also be useful in the treatment of NLRP3-mediated diseases.

[0087] A synthetic method for producing the aforementioned compounds is disclosed in the following examples. Where the details of the synthesis are not described in the examples, the compounds can be readily produced by those skilled in the art of medicinal chemistry or synthetic organic chemistry by applying the synthetic information provided herein. Where a stereochemical center is not defined, the structure represents a mixture of stereoisomers at that center. For such compounds, individual stereoisomers, including enantiomers and diastereoisomers, and mixtures thereof are also compounds of this disclosure.

[0088] definition "Ac" stands for acetyl, which is CH3C(=O)-.

[0089] "Alkyl" refers to a saturated carbon chain that can be linear, branched, or a combination thereof, unless otherwise defined regarding the carbon chain. Other groups with the prefix "alk," such as alkoxy and alkanoyl, can also be linear, branched, or a combination thereof, unless otherwise defined regarding the carbon chain. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and tert-butyl, pentyl, hexyl, heptyl, octyl, and nonyl. In one embodiment, the alkyl is methyl or ethyl. In another embodiment, the alkyl is methyl. In yet another embodiment, the alkyl is ethyl.

[0090] Unless otherwise defined, "alkenyl" refers to a carbon chain that contains at least one carbon-carbon double bond and can be linear, branched, or a combination thereof. Examples of alkenyls include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl, and 2-methyl-2-butenyl.

[0091] Unless otherwise defined, "alkynyl" refers to a carbon chain containing at least one carbon-carbon triple bond, which can be linear, branched, or a combination thereof. Examples of alkynyls include ethynyl, propargyl, 3-methyl-1-pentynyl, and 2-heptynyl.

[0092] "Cycloalkyl" refers to a saturated monocyclic, bicyclic, spirocyclic, fused, or bridged carbon ring having a specified number of carbon atoms. Examples of cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. In one embodiment, the cycloalkyl is -C 3-12 It is a cycloalkyl group.

[0093] A "cycloalkenyl" refers to a monocyclic, bicyclic, spirocyclic, fused, or bridged carbon ring having at least one double bond and a specified number of carbon atoms. Examples of cycloalkenyls include cyclopropene, cyclobutane, cyclopentene, cyclohexene, and cycloheptene.

[0094] "Cycloheteroalkyl" means a monocyclic, bicyclic, spirocyclic, fused or bridged ring or ring system having a specified number of carbon atoms and containing at least one saturated ring (where at least one ring heteroatom is selected from N, NH, S (including SO and SO2) and O) or at least one partially unsaturated ring (where at least one ring heteroatom is selected from N, NH, S (including SO and SO2) and O). The cycloheteroalkyl ring may be substituted at the ring carbon and / or at the ring nitrogen or ring sulfur. The cycloheteroalkyl ring may be fused to an aryl ring or a heteroaryl ring. Examples of cycloheteroalkyls include tetrahydrofuranyl, pyrrolidinyl, tetrahydrothiophenyl, azetidinyl, piperazinyl, piperidinyl, morpholinyl, oxetanyl and tetrahydropyranyl. In one embodiment, the cycloheteroalkyl is C 2-11 It is a cycloheteralkyl. In another embodiment, C 2-11 Cycloheteroalkyl groups are piperidines.

[0095] A "cycloheteralkenyl" refers to a monocyclic, bicyclic, spirocyclic, fused, or bridged ring or ring system having a specified number of carbon atoms, at least one double bond, and at least one heteroatom selected from N, NH, S (including SO and SO2), and O. Examples of cycloheteralkenyls include dihydropyran and dihydrofuran.

[0096] "Aryl" refers to a monocyclic, bicyclic, or tricyclic carbocyclic aromatic ring or aromatic ring system containing 6 to 14 carbon atoms, where at least one of the rings is aromatic. Examples of aryls include phenyl, indan, and naphthalene. In one embodiment, the aryl is phenyl. In another embodiment, the aryl is indan.

[0097] A "heteroaryl" refers to a monocyclic, bicyclic, or tricyclic ring or ring system containing 5 to 14 ring atoms, and at least one ring heteroatom selected from N, NH, S (including SO and SO2), and O, where at least one of the rings containing the heteroatom is aromatic. Examples of heteroaryls include pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, pyrimidyl, pyridadinyl, pyrazinyl, benzoisoxazolyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, quinolyl, indolyl, isoquinolyl, quinazolinyl, and dibenzofuranyl.

[0098] "Halogen" includes fluorine, chlorine, bromine, and iodine. In one embodiment, halogen is fluorine, chlorine, or bromine. In another embodiment, halogen is fluorine or chlorine. In another embodiment, halogen is chlorine or bromine. In another embodiment, halogen is fluorine. In another embodiment, halogen is chlorine. In another embodiment, halogen is bromine.

[0099] "Me" stands for methyl.

[0100] "Okiso" represents =O.

[0101] "Saturated" means containing only single bonds.

[0102] "Unsaturated" means containing at least one double or triple bond. In one embodiment, "unsaturated" means containing at least one double bond. In another embodiment, "unsaturated" means containing at least one triple bond.

[0103] Variable part (for example, R 1 , R a If a compound (such as ) appears two or more times in any of its constituent elements or structural formula I, its definition in each instance is independent of its definition in all other instances. Furthermore, combinations of substituents and / or variable parts are only permitted if such combinations result in a stable compound. A wavy line crossing a bond in a substituent variable part represents a bond point.

[0104] Under the nomenclature used throughout this disclosure, the bond point is described first, followed by the terminal portion of the specified side chain. For example, C 1-5 Alkylcarbonylamino C 1-6 Alkyl substituents are equivalent to the following: [ka]

[0105] In selecting the compounds disclosed herein, those skilled in the art can choose from a variety of substituents (i.e., R 1 , R 2 It should be recognized that compounds such as these should be selected according to well-known principles regarding the bonding and stability of chemical structures.

[0106] The term "substituted" should be understood to encompass multiple substitutions by the specified substituents. If multiple substituent parts are disclosed or requested, the substituted compound may be independently substituted, once or multiple times, by one or more of the disclosed or requested substituent parts. Independent substitution means that the substituents may be identical or different.

[0107] The expression “pharmaceutically acceptable” is used herein to indicate a compound, material, composition, salt and / or dosage form that is safe and suitable for administration to human or animal, using sound medical judgment and in accordance with all applicable government regulations.

[0108] Compounds represented by structural formula I may contain one or more chiral centers. Therefore, compounds represented by structural formula I may exist as racemic compounds and racemic mixtures, single enantiomers, diastereomer mixtures, and individual diastereomers. The present invention is intended to encompass all such isomeric forms of compounds represented by structural formula I.

[0109] The independent synthesis of optical isomers and diastereoisomers, or their chromatographic separation, can be achieved as known in the Art by appropriately modifying the methodologies disclosed herein. Their absolute stereochemistry can be determined by X-ray crystallography of crystalline products or crystalline intermediates (which are, if necessary, derivatized with reagents containing chiral centers of known absolute configuration or reagents containing atoms heavy enough to perform absolute assignment).

[0110] If necessary, the racemic mixture of the compound can be separated so that the individual enantiomers are isolated. This separation can be carried out by methods well known in the art, such as coupling the racemic mixture of the compound to an enantiomerically pure compound to form a diastereoisomer mixture, and then separating the individual diastereoisomers by standard methods such as fractional crystallization or chromatography. The coupling reaction is often the formation of a salt using an enantiomerically pure acid or base. The diastereomeric derivative can then be converted back to the pure enantiomer by cleavage of an added chiral residue. The racemic mixture of the compound can also be separated directly by chromatography using a chiral stationary phase, a method well known in the art.

[0111] Alternatively, any enantiomer of a compound can be obtained by stereoselective synthesis using optically pure starting materials or reagents with known configurations in methods well known in the art.

[0112] Some of the compounds described herein contain olefinic double bonds and, unless otherwise specified, are intended to encompass both E and Z geometric isomers.

[0113] A tautomer is defined as a compound that undergoes a rapid proton shift from one atom to another. Some of the compounds described herein may exist as tautomers with different hydrogen bonding sites. Such examples may be ketones and their enol forms, known as keto-enol tautomers. Individual tautomers and mixtures thereof are encompassed by the compound represented by structural formula I.

[0114] In compounds represented by structural formula I, atoms may exhibit their natural isotopic abundance, or one or more of these atoms may be artificially enriched in specific isotopes having the same atomic number but with atomic masses or mass numbers different from those predominantly found in nature. This disclosure is intended to encompass all appropriate isotopic variants of compounds represented by structural formula I. For example, different isotopic forms of hydrogen (H) include protium ( 1 H), deuterium ( 2 H or D) and tritium ( 3H) is included. Protium is the primary hydrogen isotope found in nature. Enriching deuterium may provide certain therapeutic benefits, such as extending the half-life in vivo or reducing the required dosage, or it may provide compounds that are useful as standards for characterizing biological samples. Tritium is radioactive and therefore can provide radiolabeled compounds that are useful as tracers in metabolic or kinetic studies. Isotopically enriched compounds within the range of structural formula I can be prepared without excessive experimentation by conventional techniques well known to those skilled in the art, or by preparation methods similar to those described herein in the schemes and examples, using appropriate isotope-enriched reagents and / or intermediates.

[0115] Furthermore, some of the crystalline forms of the compounds of this disclosure may exist as polymorphs and are themselves intended to be included in this disclosure. Additionally, some of the compounds of this disclosure may form solvates with water or common organic solvents. Such solvates are included within the scope of the present invention.

[0116] It is generally preferred that the compounds of this disclosure be administered as enantiomerically pure formulations. Racemic mixtures can be separated into their individual enantiomers by any of many conventional methods. These methods include chiral chromatography, derivatization with chiral auxiliaries followed by separation by chromatography or crystallization, and fractional crystallization of diastereomer salts.

[0117] salt Where used herein, references to the compounds in this disclosure are intended to include pharmaceutically acceptable salts, and also to include pharmaceutically acceptable salts when used as precursors to the free compounds or their pharmaceutically acceptable salts, or in other synthetic operations.

[0118] The compounds of this disclosure may be administered in the form of pharmaceutically acceptable salts. The term “pharmaceutically acceptable salt” refers to a salt prepared from a pharmaceutically acceptable, non-toxic base or acid, including inorganic or organic bases and inorganic or organic acids. Salts of basic compounds included in the term “pharmaceutically acceptable salt” generally refer to non-toxic salts of the compounds of this disclosure prepared by reacting the free base with a suitable organic or inorganic acid. Representative salts of the basic compounds of this disclosure include, but are not limited to, the following: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, tartrate, borate, bromide, camusylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estrate, esylate, formate, fumarate, gluceptate, gluconate, glutamate, glycolyl arsanilate, hexylresorcinate, hydravamin, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, iso Thionates, lactates, lactobionates, laurates, malates, maleates, mandelates, mesylates, methyl bromides, methylnitrates, methyl sulfates, mucinates, napsylates, nitrates, N-methylglucamine ammonium salts, oleates, oxalates, pamoates (embonates), palmitates, pantothenates, phosphates / diphosphates, polygalacturonates, salicylates, stearates, sulfates, acetates, succinates, tannates, tartrates, theoclates, tosylates, triethioides, trifluoroacetates, and valersates. If the compounds of this disclosure have an acidic moiety, suitable pharmaceutically acceptable salts include, but are not limited to, salts derived from inorganic bases such as aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganese, manganese, potassium, sodium, and zinc. Particularly preferred are ammonium salts, calcium salts, magnesium salts, potassium salts, and sodium salts.Examples of salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary amines, secondary and tertiary amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydravamin, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc.

[0119] Furthermore, if a carboxylic acid (-COOH) group or an alcohol group is present in the compounds of this disclosure, pharmaceutically acceptable esters of carboxylic acid derivatives such as methyl, ethyl, or pivaloyloxymethyl, or acyl derivatives of alcohols such as O-acetyl, O-pivaloyl, O-benzoyl, and O-aminoacyl may also be used. This includes esters and acyl groups known in the art for modifying solubility or hydrolysis properties for use as sustained-release formulations or prodrug formulations.

[0120] The term “prodrug” means a compound that is rapidly converted in vivo to a parent compound, for example, by hydrolysis in the blood (e.g., conversion from a prodrug of structural formula I to a compound of structural formula I or a salt thereof); a full discussion is provided in “T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACS Symposium Series” and “Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987” (both incorporated herein by reference). This disclosure encompasses prodrugs of compounds represented by structural formula I. Solvates, in particular hydrates of compounds represented by structural formula I, are also likewise included in this disclosure.

[0121] usefulness The compound represented by structural formula I is a potent inhibitor of Nod-like receptor protein 3 (NLPR3). The compound represented by structural formula I, as well as its pharmaceutically acceptable salts, hydrates, and solvates, may be effective in treating diseases, disorders, and symptoms mediated by inhibition of Nod-like receptor protein 3 (NLPR3).

[0122] This disclosure relates to the treatment or prevention of NLRP3-mediated diseases, disorders or conditions, such as inflammation, autoimmune diseases, cancer, infections, central nervous system diseases or disorders, metabolic diseases, cardiovascular diseases, fibrotic diseases or fibrosis, respiratory diseases, kidney diseases, liver diseases, eye or ocular diseases, skin diseases, lymphatic system diseases, rheumatic diseases, graft-versus-host diseases, allodynia, or NLRP3-related diseases in subjects determined to have germline mutations or somatic nonsilent mutations in NLRP3.

[0123] Diseases, disorders, or symptoms mediated by NLRP3 include, but are not limited to, the following: gout, pseudogout, osteoarthritis, familial cold autoinflammatory syndrome, Macklewells syndrome, neonatal-onset multi-system inflammatory disease, diabetes mellitus, NASH, sepsis, age-related macular degeneration, diabetic retinopathy, hepatic fibrosis, renal fibrosis, atherosclerosis, heart failure, peripheral artery disease, myeloproliferative neoplasms, leukemia, myelodysplastic syndrome, myelofibrosis, lung cancer, colorectal cancer, Parkinson's disease, Alzheimer's disease, traumatic brain injury, spinal cord injury, amyotrophic lateral sclerosis, multiple sclerosis, atopic dermatitis, hidradenitis suppurativa, pericarditis, myocarditis, pre-eclampsia, dermatomyositis, Still's disease, juvenile idiopathic arthritis, age-related macular degeneration, diabetic retinopathy, acute kidney disease, chronic kidney disease, or rare kidney disease. Diseases, disorders, or symptoms mediated by Nod-like receptor protein 3 (NLPR3) also include gout, pseudogout, CAPS, NASH, fibrosis, osteoarthritis, atherosclerosis, heart failure, idiopathic pericarditis, myocarditis, atopic dermatitis, hidradenitis suppurativa, inflammatory bowel disease, cancer, Alzheimer's disease, Parkinson's disease, and traumatic brain injury.

[0124] In one embodiment, the symptom, disease, or disorder is an inflammatory joint disease such as gout, pseudogout, or osteoarthritis.

[0125] In another embodiment, the cryopyrin-associated periodic syndrome is familial cold autoinflammatory syndrome, Macklewells syndrome, or neonatal-onset multi-system inflammatory disease.

[0126] In another embodiment, the metabolic disease is diabetes mellitus.

[0127] In another embodiment, the liver disease is NASH.

[0128] In another embodiment, the infection is sepsis.

[0129] In another embodiment, the eye or eye disease is age-related macular degeneration or diabetic retinopathy.

[0130] In another embodiment, the fibrous disease is hepatic fibrosis or renal fibrosis.

[0131] In some embodiments, the cardiovascular disease is atherosclerosis, heart failure, or peripheral artery disease.

[0132] In another embodiment, the cancer is myeloproliferative neoplasm, leukemia, myelodysplastic syndrome, myelofibrosis, lung cancer, or colorectal cancer.

[0133] In another embodiment, the central nervous system symptoms, diseases, or disorders are Parkinson's disease, Alzheimer's disease, traumatic brain injury, spinal cord injury, amyotrophic lateral sclerosis, or multiple sclerosis.

[0134] In another embodiment, the skin condition is atopic dermatitis or hidradenitis suppurativa (HS).

[0135] In another embodiment, the inflammatory disease is pericarditis or myocarditis.

[0136] In another embodiment, the inflammatory disease is pre-eclampsia.

[0137] In another embodiment, the rheumatic disease is dermatomyositis, Still's disease, or juvenile idiopathic arthritis.

[0138] In another embodiment, the eye disease is age-related macular degeneration or diabetic retinopathy.

[0139] In another embodiment, the kidney disease is an acute kidney disease, a chronic kidney disease, or a rare kidney disease.

[0140] One or more of these symptoms or diseases can be treated, managed, prevented, reduced, alleviated, improved, or controlled by administering a therapeutically effective amount of the compound represented by structural formula I or a pharmaceutically acceptable salt thereof to a patient in need of treatment.

[0141] The compound represented by structural formula I also contains compounds that can cause these symptoms, diseases, or disorders (for example, but are not limited to, gout, pseudogout, osteoarthritis, familial cold autoinflammatory syndrome, Macklewells syndrome, neonatal onset multi-system inflammatory disease, diabetes mellitus, NASH, sepsis, age-related macular degeneration, diabetic retinopathy, hepatic fibrosis, renal fibrosis, atherosclerosis, heart failure, peripheral artery disease, myeloproliferative neoplasms, leukemia, myelodysplastic syndrome, myelofibrosis, and lung cancer). It may also be used to manufacture pharmaceuticals that may be useful in treating, preventing, managing, alleviating, improving or controlling one or more of the following conditions: colorectal cancer, Parkinson's disease, Alzheimer's disease, traumatic brain injury, spinal cord injury, amyotrophic lateral sclerosis, multiple sclerosis, atopic dermatitis, hidradenitis suppurativa, pericarditis, myocarditis, pre-eclampsia, dermatomyositis, Still's disease, juvenile idiopathic arthritis, age-related macular degeneration, diabetic retinopathy, acute kidney disease, chronic kidney disease, or rare kidney disease. The compound represented by structural formula I may also be used to manufacture pharmaceuticals that may be useful in treating, preventing, managing, alleviating, improving or controlling one or more of these symptoms, diseases, or disorders (for example, but not limited to, gout, pseudogout, CAPS, NASH, fibrosis, osteoarthritis, atherosclerosis, heart failure, idiopathic pericarditis, myocarditis, atopic dermatitis, hidradenitis suppurativa, inflammatory bowel disease, cancer, Alzheimer's disease, Parkinson's disease, and traumatic brain injury).

[0142] A preferred use of the compound may be for the treatment of one or more of the following diseases by administering a therapeutically effective amount to a patient in need of treatment. The compound can be used to manufacture pharmaceuticals for the treatment of one or more of these diseases: (1) Gout; (2) Pseudogout, (3) Cryopyrin-associated periodic syndromes, (4) Non-alcoholic steatohepatitis, (5) Fibrosis, (6) Osteoarthritis, (7) Atherosclerosis, (8) Atopic dermatitis, (9) Hidradenitis suppurativa, (10) Alzheimer's disease, and (11) Parkinson's disease.

[0143] Treatment of diseases, disorders, or symptoms mediated by NLPR3 or the NLPR3 inflammasome pathway means administering a compound represented by structural formula I to a subject having said disease, disorder, or symptom.

[0144] One possible outcome of treatment is the reduction of disease, disorder, or symptoms mediated by NLPR3 or the NLPR3 inflammasome pathway. Another possible outcome of treatment is the alleviation of disease, disorder, or symptoms mediated by NLPR3 or the NLPR3 inflammasome pathway. Another possible outcome of treatment is the improvement of disease, disorder, or symptoms mediated by NLPR3 or the NLPR3 inflammasome pathway. Another possible outcome of treatment is the suppression of disease, disorder, or symptoms mediated by NLPR3 or the NLPR3 inflammasome pathway. Another possible outcome of treatment is the management of disease, disorder, or symptoms mediated by NLPR3 or the NLPR3 inflammasome pathway. Another possible outcome of treatment is the prevention of disease, disorder, or symptoms mediated by NLPR3 or the NLPR3 inflammasome pathway.

[0145] Prevention of diseases, disorders, or symptoms mediated by NLPR3 or the NLPR3 inflammasome pathway means administering the compound represented by structural formula I to subjects at risk of such diseases, disorders, or symptoms. One outcome of prevention may be the reduction of diseases, disorders, or symptoms mediated by NLPR3 or the NLPR3 inflammasome pathway in subjects at risk of such diseases, disorders, or symptoms. Another outcome of prevention may be the suppression of diseases, disorders, or symptoms mediated by NLPR3 or the NLPR3 inflammasome pathway in subjects at risk of such diseases, disorders, or symptoms. Another outcome of prevention may be the improvement of diseases, disorders, or symptoms mediated by NLPR3 or the NLPR3 inflammasome pathway in subjects at risk of such diseases, disorders, or symptoms. Another outcome of prevention may be the alleviation of diseases, disorders, or symptoms mediated by NLPR3 or the NLPR3 inflammasome pathway in subjects at risk of such diseases, disorders, or symptoms. Another outcome of prevention may be the management of diseases, disorders, or symptoms mediated by NLPR3 or the NLPR3 inflammasome pathway in individuals at risk of the disease, disorder, or symptom.

[0146] The terms “administering” and / or “giving” a compound should be understood to mean providing the compound represented by structural formula I or a prodrug of the compound represented by structural formula I to an individual or mammal in need of treatment.

[0147] The administration of the compound represented by structural formula I for this therapeutic method is carried out by administering an effective amount of the compound represented by structural formula I to a mammal requiring such treatment or prophylaxis. The need for prophylactic administration by the method disclosed herein is determined by using well-known risk factors. The effective amount of each compound is determined in the final analysis by the physician or veterinarian in charge of the case, however, the effective amount depends on various factors, such as the exact disease being treated, the severity of the disease and any other diseases or conditions the patient is suffering from, the chosen route of administration, any other drugs and treatments the patient may require simultaneously, and other factors at the physician's discretion.

[0148] The usefulness of this compound in these diseases or disorders can be demonstrated in animal disease models reported in the literature.

[0149] Dosage and dosage range To provide an effective dose of the compound represented by structural formula I to mammals (especially humans), any suitable route of administration can be used. For example, oral, intravenous, infusion, subcutaneous, transcutaneous, intramuscular, intradermal, transmucosal, intramucosal, rectal, topical, parenteral, ocular, lung, and nasal administration can be used. Dosage forms include tablets, lozenges, dispersions, suspensions, solutions, capsules, creams, ointments, and aerosols. Preferably, the compound represented by structural formula I is administered orally.

[0150] In the treatment or prevention of disorders, diseases and / or symptoms requiring inhibition of NLRP3, appropriate dosage levels are generally about 0.0001 to 500 mg per kg of patient body weight per day, which can be administered as a single or multiple doses. In one embodiment, appropriate dosage levels may be about 0.001 to 500 mg per kg of patient body weight per day. In another embodiment, appropriate dosage levels may be about 0.001 to 250 mg / kg per day. In yet another embodiment, appropriate dosage levels may be about 0.01 to 250 mg / kg per day. In yet another embodiment, appropriate dosage levels may be about 0.1 to 100 mg / kg per day. In yet another embodiment, appropriate dosage levels may be about 0.05 to 100 mg / kg per day. In yet another embodiment, appropriate dosage levels may be about 0.1 to 50 mg / kg per day. In another embodiment, an appropriate dosage level may be about 0.05 to 0.5 mg / kg per day. In yet another embodiment, an appropriate dosage level may be about 0.5 to 5 mg / kg per day. In yet another embodiment, an appropriate dosage level may be about 5 to 50 mg / kg per day.For oral administration, the composition is preferably administered in amounts of 0.01 to 1000 mg of the active ingredient, particularly 0.01, 0.025, 0.05, 0.075, 0.1, 0.25, 0.5, 0.75, 1.0, 2.5, 5.0, 7.5, 10.0, 15.0, 20.0, 25.0, 30.0, 40.0, 50.0, 60.0, 70.0, 75.0, 80.0, 90.0, 100.0, 110.0, and 120 mg, in order to adjust the dosage for the patient being treated according to their symptoms. 0, 125, 130, 140, 150, 160, 170, 175, 180, 190, 200, 210, 220, 225, 230, 240, 250, 260, 270, 275, 280, 290, 300, 310, 320, 325, 330, 340, 350, 360, 370, 375, 380, 390. 0, 400.0, 410.0, 420.0, 425.0, 430.0, 440.0, 450.0, 460.0, 470.0, 475.0, 480.0, 490.0, 500.0, 510.0, 520.0, 525.0, 530.0, 540.0, 550.0, 560.0, 570.0, 575.0, 580.0, 590.0, 600.0, 610.0, 620.0, 625.0, 630.0, 640.0, 650.0, 660.0, 670. The compound is provided in the form of tablets containing 0, 675.0, 680.0, 690.0, 750.0, 800.0, 810.0, 820.0, 825.0, 830.0, 840.0, 850.0, 860.0, 870.0, 875.0, 880.0, 890.0, 900.0, 910.0, 920.0, 925.0, 930.0, 940.0, 950.0, 960.0, 970.0, 975.0, 980.0, 990.0, and 1000.0 mg of the active ingredient. The compound can be administered in a regimen of 1 to 8 times per day (preferably 1 to 4 times per day, more preferably 1 or 2 times per day, and even more preferably 1 time per day). This dosing regimen can be adjusted to provide the optimal therapeutic response.

[0151] However, it is understood that specific dosage levels and frequencies for any particular patient may be modified and depend on various factors including the activity of the specific compound used, its metabolic stability and duration of action, age, weight, general health, sex, diet, method and timing of administration, elimination rate, drug combinations, severity of specific symptoms, and the recipient being treated.

[0152] The compound represented by structural formula I can be used in a pharmaceutical composition comprising (a) the compound or a pharmaceutically acceptable salt thereof, and (b) a pharmaceutically acceptable carrier. The compound represented by structural formula I can be used in a pharmaceutical composition in which the compound represented by structural formula I or a pharmaceutically acceptable salt thereof is the sole active ingredient. The compound represented by structural formula I can also be used in a pharmaceutical composition comprising one or more other active pharmaceutical ingredients.

[0153] In pharmaceutical compositions, the term "composition" is intended to encompass products containing one or more active ingredients and one or more inactive ingredients that constitute the individual components, and further intended to encompass any products directly or indirectly arising from any combination, complexation, or aggregation of any two or more components, or from the dissociation of one or more components, or from another type of reaction or interaction of one or more components. Accordingly, the pharmaceutical compositions of this disclosure encompass any compositions prepared by mixing a compound represented by structural formula I or a pharmaceutically acceptable salt, hydrate, or solvate thereof with a pharmaceutically acceptable carrier.

[0154] The compound represented by structural formula I can be used in combination with another drug that may be equally useful in treating or improving a disease or symptom for which the compound represented by structural formula I is useful. Such another drug may be administered simultaneously with or sequentially with the compound represented by structural formula I, in the routes and amounts commonly used for that drug. In the treatment of patients suffering from chronic inflammatory symptoms, two or more drugs may be administered. The compound represented by structural formula I can generally be administered to patients who are already taking one or more other drugs for these symptoms. Often, the compound is administered to patients who are already being treated with one or more anti-pain compounds, when the patient's pain is not responding adequately to the treatment.

[0155] Combination therapy also includes therapies in which the compound represented by structural formula I and one or more other drugs are administered on different schedules that overlap. When used in combination with one or more other active ingredients, it is also intended that lower doses can be used than when the compound represented by structural formula I and the other active ingredients are used individually. Accordingly, the pharmaceutical compositions of this disclosure include pharmaceutical compositions comprising the compound represented by structural formula I in addition to one or more other active ingredients.

[0156] Other active ingredients that can be administered in combination with the compound represented by structural formula I, and that can be administered separately or in the same pharmaceutical composition, include, but are not limited to, the following: (i) Anti-steatotic agent; (ii) Anti-inflammatory drugs; (iii) Immunotherapy agents; (iv) Lipid-lowering drugs; (v) Cholesterol-lowering drugs; (vi) Glucose-lowering drugs (including SGLT2 inhibitors); (vii) Anti-angiogenic drugs; (viii) Nonsteroidal anti-inflammatory drugs ("NSAIDs"); (ix) Acetylsalicylic acid drugs (ASA) (including aspirin and paracetamol); (x) regenerative therapy treatment; (xi) Checkpoint inhibitors (including anti-PD1 inhibitors and anti-PDL1 inhibitors); (xii) chemotherapy; (xiii) Radiation therapy; (xiv) surgical procedures; (xv) uric acid-lowering therapy; (xvi) Anabolic drugs and cartilage regeneration therapies; (xvii) Antifibrotic drugs; (xviii) JAK inhibitors; (xix) TNF-α inhibitors; (xx) Antihypertensive drugs; and, (xxi) STING / cGAS antagonist Furthermore, the above-mentioned pharmaceutically acceptable salts.

[0157] In another embodiment, the pharmaceutical composition includes: (1) The compound described in claim 1 or a pharmaceutically acceptable salt thereof; (2) One or more compounds selected from the following group or pharmaceutically acceptable salts thereof: (i) Anti-steatotic agent; (ii) Anti-inflammatory drugs; (iii) Immunotherapy agents; (iv) Lipid-lowering drugs; (v) Cholesterol-lowering drugs; (vi) Glucose-lowering drugs (including SGLT2 inhibitors); (vii) Anti-angiogenic drugs; (viii) Nonsteroidal anti-inflammatory drugs ("NSAIDs"); (ix) Acetylsalicylic acid drugs (ASA) (including aspirin and paracetamol); (x) regenerative therapy treatment; (xi) Checkpoint inhibitors (including anti-PD1 inhibitors and anti-PDL1 inhibitors); (xii) chemotherapy; (xiii) Radiation therapy; (xiv) surgical procedures; (xv) uric acid-lowering therapy; (xvi) Anabolic drugs and cartilage regeneration therapies; (xvii) Antifibrotic drugs; (xviii) JAK inhibitors; (xix) TNF-α inhibitors; (xx) Antihypertensive drugs; and, (xxi) STING / cGAS antagonists; and pharmaceutically acceptable salts thereof; and (3) A pharmaceutically acceptable carrier.

[0158] Specific compounds that can be used in combination with the compound represented by structural formula I include anti-steatotic agents, such as, but are not limited to, DGAT2 inhibitors.

[0159] Appropriate anti-inflammatory drugs, though not limited to them, include TNFα inhibitors, JAK inhibitors, and NSAIDs.

[0160] Appropriate lipid-lowering drugs include, but are not limited to, statins and PCSK9.

[0161] Appropriate immunotherapy agents for cancer include, but are not limited to, PD-L1 inhibitors, PD-1 inhibitors, and STING antagonists.

[0162] Appropriate glucose-lowering drugs, though not limited to them, include insulin, SGLT2 inhibitors, metformin, and GLP-1 antagonists.

[0163] Appropriate anti-angiogenic drugs, though not limited to them, include anti-VEGF therapy.

[0164] Appropriate NSAIDs or nonsteroidal anti-inflammatory drugs include, but are not limited to, aspirin, diclofenac, diflunisal, etodolac, fenoprofin, flurbiprofen, ibuprofen, indomethacin, ketoprofen, meclofenamic acid, mefenamic acid, meloxicam, naproxen, naproxen sodium, oxaprozin, piroxicam, sulindac, and tolmetine.

[0165] Appropriate analgesics include, but are not limited to, acetaminophen and duloxetine.

[0166] The above combinations include not only combinations of the compound represented by structural formula I with one other active compound, but also combinations with two or more other active compounds. Non-limiting examples include combinations of compounds with two or more active compounds selected from the following: anti-steatotic agents, anti-inflammatory agents, lipid-lowering agents, anti-fibrotic agents, immunotherapy agents, glucose-lowering agents, and anti-angiogenic agents, NSAIDs (non-steroidal anti-inflammatory drugs), and analgesics.

[0167] The disclosure further provides a method for treating or preventing NLRP3-mediated diseases, disorders, or symptoms, the method comprising administering a therapeutically effective dose of an NLRP3 inhibitor and a specific dose of one or more active ingredients to a patient in need of such treatment or a patient at risk of developing an NLRP3-mediated disease, thereby providing effective relief together.

[0168] In a further aspect of this disclosure, a pharmaceutical composition is provided comprising an NLRP3 inhibitor and one or more active ingredients together with at least one pharmaceutically acceptable carrier or excipient.

[0169] Accordingly, further aspects of this disclosure provide the use of an NLRP3 inhibitor and one or more active ingredients for manufacturing a medicament for treating or preventing a disease, disorder, or symptom mediated by NLRP3. Accordingly, further aspects of this disclosure or alternative aspects provide a product comprising an NLRP3 inhibitor and one or more active ingredients as a combined preparation for simultaneous, separate, or sequential use in the treatment or prevention of a disease, disorder, or symptom mediated by NLRP3. Such a combined preparation may be, for example, in the form of a twin pack.

[0170] It is understood that compounds represented by structural formula I may be used in combination with other pharmaceuticals effective in treating or preventing cardio-metabolic diseases, neurodegenerative diseases, inflammatory joint diseases, fibrosis, and cancer.

[0171] The disclosure also provides a method for treating or preventing chronic inflammatory symptoms, the method comprising administering to a patient in need of such treatment a specific amount of a compound represented by structural formula I and a specific amount of another agent that is effective in treating (threat) the disorder, disease or symptom, thereby resulting in effective relief when they are combined.

[0172] The disclosure also provides a method for treating or preventing chronic inflammatory symptoms, wherein the method involves administering to a patient in need of such treatment a specific amount of a compound represented by structural formula I and a specific amount of another agent useful in treating the specific symptoms, disorder or disease thereafter, so that they together produce effective relief.

[0173] The term “therapeutic dose” means the amount of a compound represented by structural formula I that elicits a biological or medical response in a cell, tissue, system, animal, or human (which includes alleviation of symptoms of the disorder being treated) as determined by a researcher, veterinarian, physician, or other clinician. The novel therapeutic methods described herein are for disorders known to those skilled in the art. The term “mammalian” includes humans and companion animals (e.g., dogs and cats).

[0174] The weight ratio of the compound represented by structural formula I to the second active ingredient can be varied and depends on the effective dose of each ingredient. Generally, the effective dose of each is used. For example, when the compound represented by structural formula I is combined with an anti-steatotic agent, the weight ratio of the compound represented by structural formula I is generally in the range of about 1000:1 to about 1:1000, preferably in the range of about 200:1 to about 1:200. The combination of the compound represented by structural formula I with another active ingredient is also generally within the aforementioned range, but in any case, the effective dose of each active ingredient should be used.

[0175] Synthesis method The following reaction schemes and examples illustrate methods that may be used to synthesize the compounds represented by structural formula I as described herein. These reaction schemes and examples are provided for illustrative purposes and should not be construed as limiting the disclosure in any way. All substituents are as defined above unless otherwise indicated. Several strategies based on synthetic transformations known in the organic synthesis literature can be used to prepare the compounds represented by structural formula I. The scope of this disclosure is defined by the attached "Claims". Compound names were created using Chemdraw Version 21.0.0.28.

[0176] device Reverse-phase chromatography was performed on a Waters 150 with columns selected from the following: Phenomenex Synergi C18 (250 mm × 30 mm × 4 microns), Phenomenex Luna C18 (250 mm × 21 mm × 5 microns), Agilent Zorbax Bonus-RP (150 mm × 21 mm × 5 microns), and Waters X-Select CSH C18 (150 mm × 19 mm × 5 microns). Conditions included either high pH (0-100% acetonitrile / water eluent containing 0.1% v / vNH4OH) or low pH (0-100% acetonitrile / water eluent containing 0.1% v / vTFA or formic acid), as noted in some examples. SFC chiral resolution was performed on a Waters Thar 80 SFC or a Berger MG II preparative SFC system.

[0177] LC / MS measurements were performed using a Waters ACQUITY UPLC equipped with DAD and QDa MS detectors under the following conditions: A Waters ACQUITY UPLC BEH C18 (1.7 mm 2.1 × 50 mm) column was used with a mobile phase containing A (0.1% TFA in water) and B (0.1% TFA in acetonitrile) (flow rate 0.5 mL / min, gradient from 10% B to 90% B over 2 minutes, retention at 90% B for 0.4 minutes). Proton NMR or 1 ¹H NMR spectra were acquired using a Bruker 500 MHz NEO NMR spectrometer equipped with a 5 mm iProbe, according to standard analytical techniques unless otherwise specified. The results of the spectral analysis are reported. Chemical shift (δ) values ​​are reported in delta (δ) units, parts per million (ppm). 1Chemical shifts in the 1H NMR spectrum are given relative to the signals of residual non-deuterated solvents (CDCl3 (referenced at δ 7.26 ppm), DMSO d-6 (referenced at δ 2.50 ppm), and CD3OD (referenced at δ 3.31 ppm)). Multiplets are reported using the following abbreviations: s = singlet, d = doublet, t = triplet, q = quadruplet, dd = doublet of doublets, dt = doublet of triplets, m = multiplet or overlap of non-equivalent resonances. Coupling constants (J) are reported in Hertz (Hz).

[0178] Chiral separation method: The general preparative conditions for separating diastereomer or enantiomer mixtures of compounds using chiral SFC are as follows: [Table 1]

[0179] Abbreviation In the molecule * " indicates the stereocenter; Ac is acetyl; Ad 2n-BuP Pd G2 is chloro[(di(1-adamantyl)-N-butylphosphine)-2-(2-aminobiphenyl)]-palladium(II); OAc is acetate; AcOH is acetic acid; aq. is aqueous solution; B2pin2 is bis(pinacolato)diborone; BPin ester is pinacol boronic acid ester; Boc or boc is tert-butoxycarbonyl; br is broad line; °C is Celsius; calc'd is calculated; cat. is catalyst; δ is chemical shift; d is double line; D is deuterium; DCM is dichloromethane; dd is double line of double line; DIPEA is N,N-diisopropylethylamine; DMA is dimethylacetamide; DMF is dimethylformamide; DMSO is dimethyl sulfoxide; DMSO-d6 is deuterated dimethyl sulfoxide; dppf is 1,1'-bis(diphenylphosphino)ferrocene; dtbpf is bis(di-tert-butylphosphino)ferrocene; ESI is electrospray ionization; Et is ethyl; Et3N is triethylamine; SiO is ethyl acetate; EtOH is ethanol; FA is formic acid; g is grams; h is hours; HPLC is high-performance liquid chromatography; Hz is Hertz; iPr is isopropyl; J is the binding constant; L is liter; LC is liquid chromatography; LCMS is liquid chromatography / mass spectrometry; m is multiline; M is mole; Me is methyl; MeCN is acetonitrile; MeOD-d4 is deuterated methanol; MeOH is methanol; mg is milligram; MHz is megahertz; min is minute; mL is milliliter; mM is millimole; mmol is millimole; μL is microliter; MPLC is medium-pressure liquid chromatography; MS is mass spectrometry; n-BuOH is n-butanol; nM is nanomoles; NMP is N-methylpyrrolidone; NMR is nuclear magnetic resonance; PdCl2(dppf) or Pd(dppf)Cl2 is [1,1'-bis-(diphenylphosphinno)-ferrocene]dichloropalladium(II); PG is a protecting group; Ph is phenyl; POCl3 is phosphorus oxychloride; q is a quadruplet; qd is a quadruplet of double lines; rac is a racemic mixture; s is a single line; sat. is saturated; SFC is supercritical fluid chromatography; S N Ar is a nucleophilic aromatic substitution; t is a triplet; t-AmOH is a tert-amyl alcohol; t-Bu or t Bu is tert-butyl; tert is tertiary; TFA is trifluoroacetic acid; THF is tetrahydrofuran; TLC is thin-layer chromatography; tt is triplet; XPhos Pd G3 is (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)methanesulfonate; UV is ultraviolet light; and wt% is weight percent.

[0180] General scheme Scheme A [ka]

[0181] Scheme A shows the synthetic sequence for preparing the biarylpyridazine derivative represented by formula A-4. Dihaloaminopyridazine A-1 is regioselectively synthesized using various primary amines. N By adding to Ar, a diamine like A-2 is obtained. Cycloforming diamine A-2 with a suitable orthoester yields imidazopyridazine represented by formula A-3. Cross-coupling with a suitable aryl nucleophile (e.g., arylboronic acid) and a palladium catalyst yields a biaryl product, which, if applicable, is deprotected in situ to obtain the compound represented by formula A-4.

[0182] Scheme B [ka]

[0183] Scheme B shows the synthetic sequence for preparing the biarylpyridazine derivative represented by formula B-7. Methyltrihalopyridazine B-1 is regioselectively reacted with sodium benzenesulfinate to produce sulfone B-2, which is then S N Under Ar conditions, various primary amines can be coupled to form aminopyrididines such as B-3. Substituting the sulfone with sodium azide yields aminoazidopyridazine B-4, which can then be treated with Zn in AcOH and reduced to diaminopyrazine B-5. Cycloforming diamine B-5 with a suitable orthoester yields imidazopyridazine represented by formula B-6. Cross-coupling with a suitable aryl nucleophile (e.g., arylboronic acid) and a palladium catalyst yields a biaryl product, which can be deprotected in situ (where applicable) to obtain the compound represented by formula B-7.

[0184] Scheme C [ka]

[0185] Scheme C shows a synthetic sequence for preparing the biarylpyrrolopyridazine derivative represented by formula C-5. Trihalopyridazine C-1 is subjected to a single-selective cross-coupling with a suitable vinylboron reagent to obtain a vinyl derivative such as C-2. The vinyl derivative C-2 is reacted with various primary amines in the presence of a base (e.g., DIPEA) to produce dihydropyrrolopyridazine represented by formula C-3. Oxidation with manganese oxide at high temperature in a suitable solvent (e.g., toluene) yields the pyrrolopyridazine core represented by C-4. Cross-coupling with a suitable aryl nucleophile (e.g., arylboronic acid) using a palladium catalyst yields the biaryl product, which, if applicable, is deprotected in situ to obtain the compound represented by formula C-5.

[0186] Scheme D [ka]

[0187] Scheme D shows the synthetic sequence for preparing biarylpyrrolopyridazine derivatives represented by formula D-5. Various primary amines are alkylated with bromopentine D-1 to produce aminoalkynes represented by formula D-2. The aminoalkyne D-2 is reacted with dichlorotetrazine at high temperature in the presence of a base (e.g., Et3N), and S NPyridazopyrrolidine represented by formula D-3 is directly obtained through a series of processes including Ar, hetero-Diels-Alder cycloaddition, and retro-Diels-Alder. The pyrrolopyridazine core represented by D-4 is obtained by oxidation of manganese oxide at high temperature in a suitable solvent (e.g., toluene). Cross-coupling with a suitable aryl nucleophile (e.g., arylboronic acid) and a palladium catalyst yields a biaryl product, which, if applicable, is deprotected in situ to obtain the compound represented by formula D-5.

[0188] Scheme E [ka]

[0189] Scheme E shows a synthetic sequence for preparing the biarylpyridazine derivative represented by formula E-3. The N-Boc cyclic amine E-1 can be deprotected with an acid (e.g., TFA or HCl) to obtain a secondary amine such as E-2. E-2 can then be subjected to reductive amination with a suitable aldehyde or ketone in the presence of a reducing agent (e.g., sodium borocyanohydride or sodium triacetoxyborohydride) to obtain the trialkylamine represented by formula E-3. [Examples]

[0190] Intermediate 1 (R)-6-chloro-N 3 -(1-ethylpiperidine-3-yl)pyridazine-3,4-diamine [ka] A suspension of 3,6-dichloropyridazine-4-amine (Ambeed, 800 mg, 4.88 mmol) and (R)-1-ethylpiperidine-3-amine (Enamine, 688 mg, 5.37 mmol) in n-BuOH (1.63 mL) was treated with DIPEA (1.19 mL, 6.83 mmol). The reaction mixture was heated at 150°C for 2 days. The reaction mixture was then cooled to room temperature, filtered, and purified by preparative reverse-phase HPLC (C18 stationary phase, MeCN / water + 0.1% TFA) to obtain the title compound.

[0191] LCMS [M+H] + = 256.2 (Calculated value: 256.2)

[0192] Table 1. The following intermediates were prepared using appropriate starting materials and the same procedure as described for intermediate 1. [Table 2]

[0193] Intermediate 3 (R)-6-chloro-N 3 -(1-ethylpiperidine-3-yl)-5-methylpyridazine-3,4-diamine [ka] Stage 1: 3,4,6-Trichloro-5-methylpyridazine: A solution of 4-bromo-5-methylpyridazine-3,6-diol (enamine, 1.20 g, 5.85 mmol) and POCl3 (10 mL, 107 mmol) was stirred at 100°C for 2 hours. The mixture was then cooled to room temperature and slowly added to water. The mixture was diluted with butyl, the layers were separated, and the aqueous layer was extracted with butyl (×2). The combined organic layers were concentrated, and the resulting crude residue was purified by silica gel chromatography (butyl: petroleum ether) to obtain the title compound.

[0194] LCMS [M+H] + = 197.1 (Calculated value 196.9)

[0195] Stage 2: Phenyl 3,6-dichloro-5-methylpyridazine-4-sulfinate: A solution of 3,4,6-trichloro-5-methylpyridazine (6.4 g, 32.4 mmol) in THF (50 mL) and DMSO (10 mL) was treated with sodium benzenesulfinate (5.6 g, 34.0 mmol). The resulting reaction mixture was heated at 40°C for 48 hours. The reaction mixture was then cooled to room temperature and diluted with water and phosphate. The layers were separated, and the aqueous layer was extracted with phosphate (×3). The combined organic layers were concentrated, and the resulting crude residue was purified by silica gel chromatography (phosphate: petroleum ether) to obtain the title compound.

[0196] LCMS [M+H] + = 303.1 (Calculated value: 303.0)

[0197] Stage 3: 6-Chloro-3-(((R)-1-ethylpiperidine-3-yl)amino)-5-methylpyridazine-4-ylbenzenesulfinate: A solution of phenyl 3,6-dichloro-5-methylpyridazine-4-sulfinate (1.5 g, 4.95 mmol) in 1,4-dioxane (30 mL) was treated with (R)-1-ethylpiperidine-3-amine (enamine, 952 mg, 7.42 mmol) and K2CO3 (3.08 g, 22.3 mmol). The resulting mixture was heated at 100°C for 12 hours. After cooling to room temperature, the reaction mixture was filtered and purified by preparative reverse-phase HPLC (C18 stationary phase, MeCN / water + 0.05% TFA) to obtain the title compound.

[0198] LCMS [M+H] + = 395.1 (Calculated value: 395.1)

[0199] Stage 4: (R)-4-azido-6-chloro-N-(1-ethylpiperidine-3-yl)-5-methylpyridazine-3-amine:A solution of 6-chloro-3-(((R)-1-ethylpiperidine-3-yl)amino)-5-methylpyridazine-4-ylbenzene sulfinate (500 mg, 1.27 mmol) in 1,4-dioxane (8 mL) and DMSO (2 mL) was treated with NaN3 (494 mg, 7.60 mmol). The resulting mixture was heated at 50°C for 12 hours. After cooling to room temperature, the reaction mixture was filtered and purified by preparative reverse-phase HPLC (C18 stationary phase, MeCN / water + 0.05% NH4OH + 10 mM NH4HCO3) to obtain the title compound.

[0200] LCMS [M+H] + = 296.2 (calculated value 296.1).

[0201] Stage 5: (R)-6-chloro-N 3 -(1-ethylpiperidine-3-yl)-5-methylpyridazine-3,4-diamine: A solution of (R)-4-azido-6-chloro-N-(1-ethylpiperidine-3-yl)-5-methylpyridazine-3-amine (300 mg, 1.01 mmol) in DCM (5 mL) and AcOH (1 mL) was cooled to 0°C and treated with zinc (133 mg, 2.03 mmol). The resulting mixture was stirred at 0°C for 2 hours, then filtered and concentrated to obtain the title compound.

[0202] LCMS [M+H] + = 270.1 (Calculated value: 270.1)

[0203] Table 2. The following intermediates were prepared using suitable commercially available amines, following the same procedure as described for intermediate 3. In step 4, a modified procedure was used, with pure DMSO as the solvent and a reaction temperature of 60°C. The compounds were purified at all component stages using silica gel chromatography instead of reversed-phase HPLC. [Table 3]

[0204] Intermediate 6 (R)-3-chloro-7-(1-ethylpiperidine-3-yl)-7H-imidazo[4,5-c]pyridazine [ka] (R)-6-chloro-N in trimethyl orthoformate (4.2 mL) 3 A suspension of (1-ethylpiperidine-3-yl)pyridazine-3,4-diamine (intermediate 1, 400 mg, 1.56 mmol) was treated with HCl (4 M in 1,4-dioxane, 380 μL, 1.52 mmol). The reaction mixture was heated at 100°C for 2 hours. The reaction mixture was then cooled to room temperature and concentrated. The resulting crude residue was purified by silica gel chromatography (MeOH:DCM) to obtain the title compound.

[0205] LCMS [M+H] + = 266.2 (calculated value 266.1).

[0206] Table 3. The following intermediates were prepared using appropriate starting materials and the same procedure as described for intermediate 6. [Table 4]

[0207] Intermediate 11 tert-butyl (R)-3-(3-chloro-7H-pyrrolo[2,3-c]pyridazine-7-yl)piperidine-1-carboxylate [ka] Stage 1: 3,6-Dichloro-4-vinylpyridazine:A suspension of 4-bromo-3,6-dichloropyridazine (Combi-Blocks, 3.00 g, 13.2 mmol), potassium vinyltrifluoroborate (1.85 g, 13.8 mmol), and Cs2CO3 (12.9 g, 39.5 mmol) in 1,4-dioxane (44 mL) and water (9 mL) was degassed with argon for 10 minutes. Then, Pd(dppf)Cl2 (482 mg, 0.658 mmol) was added, and the mixture was heated to 50°C for 1.5 hours with stirring under argon. The reaction mixture was then cooled to room temperature and diluted with H2O and DCM. The layers were separated, the organic phase was dehydrated with Na2SO4, filtered, and the solvent was removed. The resulting crude residue containing the title compound was used in the next step without further purification.

[0208] Step 2: tert-butyl (R)-3-(3-chloro-5,6-dihydro-7H-pyrrolo[2,3-c]pyridazine-7-yl)piperidine-1-carboxylate: 3,6-dichloro-4-vinylpyridazine (100 mg, 0.571 mmol) and 1,4-dioxane (2.5 mL) were placed in a sealed vial. Then, DIPEA (200 μL, 1.14 mmol) and tert-butyl (R)-3-aminopiperidine-1-carboxylate (Pharmablock, 122 μL, 0.686 mmol) were added. The vial was sealed, and the reaction mixture was heated at 150°C for 2 hours. The reaction mixture was then cooled to room temperature and concentrated. The resulting crude residue was purified by silica gel chromatography (siRNA:hexane) to obtain the title compound. LCMS [M+H] + = 339.3, (calculated value 339.2).

[0209] Stage 3: tert-butyl (R)-3-(3-chloro-7H-pyrrolo[2,3-c]pyridazin-7-yl)piperidine-1-carboxylate:A solution of tert-butyl (R)-3-(3-chloro-5,6-dihydro-7H-pyrrolo[2,3-c]pyridazin-7-yl)piperidine-1-carboxylate (135 mg, 0.398 mmol) in toluene (8 mL) was treated with MnO2 (225 mg, 2.59 mmol). The reaction mixture was heated at 125°C for 2.5 days. The reaction mixture was then cooled to room temperature, filtered through Celite®, and concentrated. The resulting crude residue was purified by silica gel chromatography (Â:hexane) to obtain the title compound.

[0210] LCMS [M+Na] + = 359.2 (calculated value 359.1).

[0211] Intermediate 12 tert-butyl (R)-3-(3-chloro-4-methyl-7H-pyrrolo[2,3-c]pyridazin-7-yl)piperidine-1-carboxylate [ka] Step 1: tert-butyl (R)-3-(penta-3-in-1-ylamino)piperidine-1-carboxylate: A suspension of tert-butyl (R)-3-aminopiperidine-1-carboxylate (Pharmablock, 1.50 g, 7.48 mmol) and K2CO3 (1.41 g, 10.2 mmol) in MeCN (27 mL) was treated with 5-bromopenta-2-yne (Enamine, 1.00 g, 6.80 mmol). The mixture was heated at 80°C for 12 hours with stirring. The reaction mixture was then cooled to room temperature, filtered, and concentrated. The resulting crude residue was purified by silica gel chromatography (siRNA:hexane) to obtain the title compound. LCMS [M+H] + = 267.2 (calculated value 267.2).

[0212] Step 2: tert-butyl (R)-3-(3-chloro-4-methyl-5,6-dihydro-7H-pyrrolo[2,3-c]pyridazin-7-yl)piperidine-1-carboxylate:A solution of 3,6-dichloro-1,2,4,5-tetrazine (Pharmablock, 75 mg, 0.500 mmol) in THF (2 mL) in a sealed tube was treated with Et3N (77 μL, 0.550 mmol) and tert-butyl (R)-3-(penta-3-in-1-ylamino)piperidine-1-carboxylate (133 mg, 0.5 mmol). The reaction mixture was heated at 110°C for 16 hours. The reaction mixture was then cooled to room temperature and diluted with water and ethyl acetate. The mixture was filtered through Celite®. The layers were separated, and the aqueous layer was extracted with ethyl acetate (×3). The combined organic layers were dehydrated with anhydrous MgSO4, filtered, and concentrated. The resulting crude residue was purified by silica gel chromatography (ethyl acetate:hexane) to obtain the title compound.

[0213] LCMS [M+H] + = 353.2 (calculated value 353.2).

[0214] Stage 3: tert-butyl (R)-3-(3-chloro-4-methyl-7H-pyrrolo[2,3-c]pyridazin-7-yl)piperidine-1-carboxylate: A solution of tert-butyl (R)-3-(3-chloro-4-methyl-5,6-dihydro-7H-pyrrolo[2,3-c]pyridazin-7-yl)piperidine-1-carboxylate (70 mg, 0.20 mmol) in toluene (4 mL) was treated with MnO2 (103 mg, 1.19 mmol). The reaction mixture was heated at 125°C for 2.5 days. The reaction mixture was then cooled to room temperature, filtered through Celite®, and concentrated. The resulting crude residue was purified by silica gel chromatography (siRNA:hexane) to obtain the title compound.

[0215] LCMS [M+Na] + = 373.3 (Calculated value: 373.1)

[0216] Intermediate 13 2-(2-(ethoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka] Stage 1: 3-Methyl-5-(trifluoromethyl)phenol:To a solution of 3-bromo-5-(trifluoromethyl)phenol (Carbosynth, 500 g, 2.07 mol), K2CO3 (859 g, 6.22 mol), and Pd(dppf)Cl2 (75.8 g, 103.7 mmol) in 1,4-dioxane (7.5 L), trimethyl-1,3,5,2,4,6-trioxatriborinane (Aldrich, 1.04 kg, 4.15 mol, 50 wt% in THF) was added in small amounts under an N2 atmosphere. The resulting mixture was stirred at 100°C for 12 hours, and then cooled to 25°C. The reaction product was quenched with ice water at 0°C and diluted with ethyl acetate. The organic layer was separated, washed with brine, dehydrated with anhydrous Na2SO4, and concentrated. The resulting crude residue was purified by silica gel chromatography (ethyl acetate: petroleum ether) to obtain the title compound.

[0217] LCMS [MH] - = 175.1 (calculated value 175.0).

[0218] Stage 2: 2-iodo-3-methyl-5-(trifluoromethyl)phenol: To a stirred solution of 3-methyl-5-(trifluoromethyl)phenol (283 g, 1.61 mol) in toluene (1.42 L), NaH (128.5 g, 3.21 mol, 60 wt%) was added at 0°C under an N2 atmosphere. The resulting mixture was stirred at 0°C for 30 minutes, and then a solution of I2 (306.1 g, 1.21 mmol) dissolved in toluene (5.66 L) was added in small amounts. The reaction mixture was stirred at 20°C for 3 hours, and then quenched by pouring into a water / ice bath. The mixture was diluted with phenylethylamine, and the layers were separated. The organic layer was washed with brine, dehydrated with anhydrous Na2SO4, and the solvent was removed under reduced pressure. The resulting crude residue containing the title compound was used in the next step without further purification.

[0219] Stage 3: 1-(ethoxymethoxy)-2-iodo-3-methyl-5-(trifluoromethyl)benzene:To a stirred solution of 2-iodo-3-methyl-5-(trifluoromethyl)phenol (463 g, 1.53 mol) and Cs2CO3 (999 g, 3.07 mmol) in DMF (4.6 L), chloromethyl ethyl ether (290 g, 3.07 mol) was added at 0°C under an N2 atmosphere. The resulting mixture was stirred at room temperature for 8 hours, then cooled to 0°C and quenched with ice water. The resulting mixture was diluted with SiO2, the organic layer was separated, washed with brine, and dehydrated with anhydrous Na2SO4. The solvent was removed under reduced pressure, and the resulting crude residue was purified by silica gel chromatography (SiO2: petroleum ether) to obtain the title compound.

[0220] 1 H NMR (300 MHz, DMSO-d6) δ 7.55 (s, 1H), 7.18 (s, 1H), 5.42 (s, 2H), 3.75 - 3.65 (m, 2H), 2.50 (s, 3H), 1.21 - 1.10 (m, 3H).

[0221] Stage 4: 2-(2-(ethoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane: A mixture of 1-(ethoxymethoxy)-2-iodo-3-methyl-5-(trifluoromethyl)benzene (330 g, 916.4 mmol), B2pin2 (469 g, 3.67 mol), Et3N (556 g, 5.50 mol), Pd(OAc)2 (10.3 g, 45.8 mmol), and biphenyl-2-yl-dichlorohexylphosphine (32.1 g, 91.6 mmol) in 1,4-dioxane (3.3 L) was placed under an N2 atmosphere. The resulting solution was stirred at 100°C for 6 hours, cooled to 25°C, and quenched with ice water. The resulting mixture was filtered, and the solid residue was washed with ethyl acetate. The organic filtrate layer was separated, washed with brine, dehydrated with anhydrous Na2SO4, and concentrated. The resulting crude residue was purified by silica gel chromatography (ethyl acetate: petroleum ether), and the desired fraction was concentrated. The obtained solid was dissolved in hexane and stirred at -30°C for 5 minutes. The precipitated solid was filtered and collected to obtain the title compound.

[0222] 1H NMR (300 MHz, CDCl3) δ 7.13-7.03 (m, 2H), 5.23 (s, 2H), 3.74 (q, J = 7.1 Hz, 2H), 2.41 (s, 3H), 1.41 (s, 12H), 1.24 (t, J = 7.1 Hz, 3H).

[0223] Intermediate 14 2-(2-(difluoromethoxy)-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka] A solution of 1-bromo-2-(difluoromethoxy)-4-(trifluoromethyl)benzene (enamine, 200 mg, 0.687 mmol) in toluene (5 mL) was treated with B2pin2 (0.262 g, 1.031 mmol), KOAc (0.202 g, 2.062 mmol), and PdCl2 (dppf) (Aldrich, 0.050 g, 0.069 mmol). After cooling to room temperature, the reaction mixture was concentrated, and the resulting crude residue was purified by silica gel chromatography (siRNA: petroleum ether) to obtain the title compound.

[0224] 1 H NMR (CDCl3, 400 MHz) δ 7.88 (d, J = 7.6 Hz, 1H), 7.51 (d, J = 7.7 Hz, 1H), 7.41 (s, 1H), 6.56 (t, J = 58.0 Hz, 1H), 1.37 (s, 12H).

[0225] Example 1 (R)-2-(7-(1-ethylpiperidine-3-yl)-7H-pyrrolo[2,3-c]pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol [ka] Step 1: tert-butyl (R)-3-(3-(2-(ethoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl)-7H-pyrrolo[2,3-c]pyridazin-7-yl)piperidine-1-carboxylate:The first vial was loaded with tert-butyl (R)-3-(3-chloro-7H-pyrrolo[2,3-c]pyridazin-7-yl)piperidine-1-carboxylate (intermediate 11, 78 mg, 0.232 mmol), 2-(2-(ethoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (intermediate 13, 125 mg, 0.347 mmol), XPhos Pd G3 (16.6 mg, 0.019 mmol), and potassium carbonate (160 mg, 1.16 mmol). The vial was then evacuated and filled with N2. In the second vial, a solvent mixture of 1,4-dioxane (1.2 mL) and water (0.3 mL) was spurged with N2 for 15 minutes and then added to the first vial. The reaction mixture was heated to 100°C for 3 hours, then cooled to room temperature and diluted with water and DCM. The layers were separated, and the aqueous layer was extracted with DCM (×3). The combined organic layers were dehydrated with anhydrous MgSO4, filtered, and concentrated. The resulting crude residue was purified by silica gel chromatography (RINKAN:hexane) to obtain the title compound.

[0226] [M+H] + = 535.2, (calculated value 535.3).

[0227] Stage 2: (R)-3-methyl-2-(7-(piperidine-3-yl)-7H-pyrrolo[2,3-c]pyridazin-3-yl)-5-(trifluoromethyl)phenol hydrochloride: A solution of tert-butyl (R)-3-(3-(2-(ethoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl)-7H-pyrrolo[2,3-c]pyridazin-7-yl)piperidine-1-carboxylate (121 mg, 0.226 mmol) in 1,4-dioxane (2.3 mL) was treated with HCl (4 M in 1,4-dioxane, 283 μL, 1.13 mmol). The reaction mixture was heated to 70°C and stirred for 3 hours. The reaction mixture was then cooled to room temperature, and the precipitated solid was collected by filtration to obtain the title compound.

[0228] LCMS [M+H] + = 377.2, (calculated value 377.2).

[0229] Stage 3: (R)-2-(7-(1-ethylpiperidine-3-yl)-7H-pyrrolo[2,3-c]pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol:A solution of (R)-3-methyl-2-(7-(piperidine-3-yl)-7H-pyrrolo[2,3-c]pyridazin-3-yl)-5-(trifluoromethyl)phenol hydrochloride (72 mg, 0.174 mmol) and acetaldehyde (20 μL, 0.35 mmol) in DCM (1.7 mL) was treated with sodium triacetoxyborohydride (74 mg, 0.35 mmol). The resulting reaction mixture was stirred at 25°C for 1 hour, then quenched with water and partitioned using 10% MeOH in DCM. The layers were separated, and the aqueous layer was extracted with 10% MeOH (×2) in DCM. The combined organic layers were dehydrated with anhydrous MgSO4, filtered, and concentrated. The resulting crude residue was placed in DMSO, filtered, and purified by preparative reverse-phase HPLC (C18 stationary phase, MeCN / water + 0.05% FA) to obtain the title compound.

[0230] LCMS [M+H] + = 405.2, (calculated value 405.2). 1 H NMR (500 MHz, DMSO-d6) 10.02 (s, 1H), 8.15 (d, J = 3.1 Hz, 1H), 7.80 (s, 1H), 7.15 (s, 1H), 7.09 (s, 1H), 6.60 (d, J = 3.3 Hz, 1H), 5.10 (br s, 1H), 3.29 - 3.26 (m, 1H), 3.13 (br s, 1H), 2.88 (br s, 1H), 2.61 - 2.54 (m, 2H), 2.21 (s, 1H), 2.09 - 2.02 (m, 2H), 2.05 (s, 3H), 1.86 - 1.81 (m, 1H), 1.72 (br s, 1H), 1.04 (t, J = 7.1 Hz, 3H).

[0231] Table 4. The following compounds were prepared using appropriate starting materials and the same procedure as described for Example 1. [Table 5]

[0232] Example 3 (R)-2-(7-(1-ethylpiperidine-3-yl)-7H-imidazo[4,5-c]pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol [ka] Step 1: (R)-3-(2-(ethoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl)-7-(1-ethylpiperidine-3-yl)-7H-imidazo[4,5-c]pyridazine: (R)-3-chloro-7-(1-ethylpiperidine-3-yl)-7H-imidazo[4,5-c]pyridazine (intermediate 6, 100 mg, 0.376 mmol), 2-(2-(ethoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (intermediate 13, 203 mg, 0.564 mmol), XPhos Pd G3 (26 mg, 0.030 mmol), and potassium carbonate (260 mg, 1.88 mmol) were charged into a vial. The vial was then evacuated and filled with nitrogen (3×). In a second vial, a solvent mixture of 1,4-dioxane (2 mL) and water (0.5 mL) was spurged with nitrogen for 15 minutes and then added to the first vial. The reaction mixture was heated to 100°C for 3 hours. The reaction mixture was then cooled to room temperature and diluted with water and DCM. The layers were separated, and the aqueous layer was extracted with DCM (×3). The combined organic layers were dehydrated with anhydrous MgSO4, filtered, and concentrated. The resulting crude residue was purified by silica gel chromatography (MeOH:DCM) to obtain the title compound.

[0233] LCMS [M+H] + = 464.4, (calculated value 464.2).

[0234] Stage 2: (R)-2-(7-(1-ethylpiperidine-3-yl)-7H-imidazo[4,5-c]pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol:A solution of (R)-3-(2-(ethoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl)-7-(1-ethylpiperidine-3-yl)-7H-imidazo[4,5-c]pyridazine (30 mg, 0.065 mmol) in 1,4-dioxane (0.65 mL) was treated with HCl (4 M in 1,4-dioxane, 81 μL, 0.324 mmol). The reaction mixture was heated to 70 °C and stirred for 3 hours. The reaction mixture was then cooled to room temperature and concentrated. The resulting crude residue was placed in DMSO, filtered, and purified by preparative reverse-phase HPLC (C18 stationary phase, MeCN / water + 0.05% FA) to obtain the title compound.

[0235] LCMS [M+H] + = 406.4, (calculated value 406.2). 1 H NMR (500 MHz, MeOD-d4) δ 8.94 (s, 1H), 7.92 (s, 1H), 7.09 (s, 1H), 7.05 (s, 1H), 5.07 - 4.97 (m, 1H), 3.30 - 3.22 (m, 1H), 2.89 - 2.75 (m, 2H), 2.56 - 2.47 (m, 2H), 2.38 - 2.15 (m, 3H), 2.09 (s, 3H), 1.93 - 1.72 (m, 2H), 1.10 (t, J = 7.2 Hz, 3H).

[0236] Table 5. The following compounds were prepared using appropriate starting materials and the same procedure as described in Example 3. [Table 6]

[0237] Example 7 (R)-2-(7-(1-ethylpiperidine-3-yl)-4-methyl-7H-imidazo[4,5-c]pyridazin-3-yl)-5-(trifluoromethyl)phenol [ka] A solution of (R)-3-chloro-7-(1-ethylpiperidine-3-yl)-4-methyl-7H-imidazo[4,5-c]pyridazine (intermediate 8, 40 mg, 0.143 mmol) in 1,4-dioxane (3 mL) and water (0.8 mL) was treated with (2-hydroxy-4-(trifluoromethyl)phenyl)boronic acid (Combi-Blocks, 35.3 mg, 0.172 mmol), K2CO3 (59.3 mg, 0.429 mmol), and PdCl2 (dppf) (10.5 mg, 0.014 mmol). The mixture was degassed with argon and then heated at 100°C for 12 hours. After cooling to room temperature, the reaction mixture was filtered and concentrated. The resulting crude residue was purified by preparative reverse-phase HPLC (C18 stationary phase, MeCN / water + 0.05% TFA) to obtain the title compound.

[0238] LCMS [M+H] + = 406.2, (calculated value 406.2). 1 H NMR (400 MHz, MeOD-d4) δ 8.82 (s, 1H), 7.51 (d, J = 7.9 Hz, 1H), 7.33 (d, J = 7.2 Hz, 1H), 7.27 (s, 1H), 5.17 (br s, 1H), 4.07 (br d, J = 10.8 Hz, 1H), 3.79 - 3.62 (m, 2H), 3.36 (br s, 2H), 3.14 (br t, J = 12.4 Hz, 1H), 2.61 (br s, 1H), 2.56 (s, 3H), 2.46 (br s, 1H), 2.32 (br d, J = 14.7 Hz, 1H), 2.16 - 2.00 (m, 1H), 1.41 (br t, J = 7.2 Hz, 3H).

[0239] Table 6. The following compounds were prepared using appropriate starting materials and the same procedure as described in Example 7. [Table 7]

[0240] Example 10 (R)-2-(4-methyl-7-(1-methylpiperidine-3-yl)-7H-imidazo[4,5-c]pyridazin-3-yl)-5-(trifluoromethyl)phenol [ka] A mixture of (R)-2-(4-methyl-7-(piperidine-3-yl)-7H-imidazo[4,5-c]pyridazin-3-yl)-5-(trifluoromethyl)phenol (Example 5, 20 mg, 0.053 mmol) in MeOH (0.27 mL) and THF (0.27 mL) was treated with formaldehyde (37% in water, 24 μL, 0.318 mmol) and sodium triacetoxyborohydride (34 mg, 0.159 mmol). The reaction mixture was stirred at 25°C for 1 hour. The reaction product was then quenched with 4 drops of AcOH and concentrated. The resulting crude residue was placed in DMSO, filtered, and purified by preparative reverse-phase HPLC (C18 stationary phase, MeCN / water + 0.1% TFA) to obtain the title compound.

[0241] LCMS [M+H] + = 392.3 (calculated value 392.2). 1 H NMR (500 MHz, MeOD-d4) δ 8.88 (s, 1H), 7.48 (d, J = 7.8 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.24 (s, 1H), 5.10 - 5.00 (m, 1H), 3.40 - 3.28 (m, 2H), 3.08 - 2.88 (m, 2H), 2.51 (s, 3H), 2.51 (s, 3H), 2.36 - 2.21 (m, 2H), 2.04 - 1.83 (m, 2H).

[0242] Example 10 (Alternative Synthesis) (R)-2-(4-methyl-7-(1-methylpiperidine-3-yl)-7H-imidazo[4,5-c]pyridazin-3-yl)-5-(trifluoromethyl)phenol [ka] Stage 1: 3,4,6-Trichloro-5-methylpyridazine:A solution of 4-bromo-5-methylpyridazine-3,6-diol (enamine, 1.20 g, 5.85 mmol) and POCl3 (10 mL, 107 mmol) was stirred at 100°C for 2 hours. The mixture was then cooled to room temperature, and water was slowly added. The mixture was diluted with butyl, the layers were separated, and the aqueous layer was extracted with butyl (×2). The combined organic layers were concentrated, and the resulting crude residue was purified by silica gel chromatography (butyl: petroleum ether) to obtain the title compound.

[0243] LCMS [M+H] + = 197.1 (calculated value 196.9).

[0244] Stage 2: Phenyl 3,6-dichloro-5-methylpyridazine-4-sulfinate: A solution of 3,4,6-trichloro-5-methylpyridazine (6.4 g, 32.4 mmol) in THF (50 mL) and DMSO (10 mL) was treated with sodium benzenesulfinate (5.6 g, 34.0 mmol). The resulting reaction mixture was heated at 40°C for 48 hours. The reaction mixture was then cooled to room temperature and diluted with water and phosphate. The layers were separated, and the aqueous layer was extracted with phosphate (×3). The combined organic layers were concentrated, and the resulting crude residue was purified by silica gel chromatography (phosphate: petroleum ether) to obtain the title compound.

[0245] LCMS [M+H] + = 303.1 (calculated value 303.0).

[0246] Step 3: tert-butyl (R)-3-((6-chloro-5-methyl-4-(phenylsulfonyl)pyridazin-3-yl)amino)piperidine-1-carboxylate:Two 40 mL scintillation vials were set up in two different configurations. In each vial, a solution of phenyl 3,6-dichloro-5-methylpyridazine-4-sulfinate (750 mg, 2.47 mmol) in 1,4-dioxane (15 mL) was treated with tert-butyl (R)-3-aminopiperidine-1-carboxylate (Aldrich, 743 mg, 3.71 mmol) and K2CO3 (1.54 g, 11.1 mmol). The resulting mixtures were heated at 100 °C for 5 hours. After cooling to room temperature, the reaction mixtures were combined, filtered, and concentrated under reduced pressure. The resulting crude residue was purified by silica gel chromatography ([25% EtOH in ethylethanol]:hexane) to obtain the title compound.

[0247] LCMS [M+Na] + = 489.4 (calculated value 489.1).

[0248] Stage 4: tert-butyl (R)-3-((4-azido-6-chloro-5-methylpyridazine-3-yl)amino)piperidine-1-carboxylate: A solution of tert-butyl (R)-3-((6-chloro-5-methyl-4-(phenylsulfonyl)pyridazin-3-yl)amino)piperidine-1-carboxylate (1.50 g, 3.21 mmol) in DMSO (23 mL) was treated with NaN3 (1.25 g, 19.3 mmol). The resulting mixture was heated at 60°C for 5 hours. After cooling to room temperature, the reaction mixture was quenched with water and extracted with ELISA (3×). The combined organic layers were washed with water (2×) and brine, dehydrated with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The resulting crude residue was purified by silica gel chromatography (MeOH:DCM) to obtain the title compound.

[0249] LCMS [M+H] + = 368.2 (calculated value 368.2).

[0250] Stage 5: tert-butyl (R)-3-((4-amino-6-chloro-5-methylpyridazine-3-yl)amino)piperidine-1-carboxylate:A solution of tert-butyl (R)-3-((4-azido-6-chloro-5-methylpyridazin-3-yl)amino)piperidine-1-carboxylate (686 mg, 1.87 mmol) in DCM (9.1 mL) and AcOH (1.8 mL) was cooled to 0°C and treated with zinc (244 mg, 3.73 mmol). The resulting mixture was stirred at 0°C for 2 hours, then filtered and concentrated under vacuum to obtain the title compound.

[0251] LCMS [M+H] + = 342.2 (calculated value 342.2).

[0252] Stage 6: tert-butyl (R)-3-(3-chloro-4-methyl-7H-imidazo[4,5-c]pyridazine-7-yl)piperidine-1-carboxylate: A solution of tert-butyl (R)-3-((4-amino-6-chloro-5-methylpyridazin-3-yl)amino)piperidine-1-carboxylate (1.10 g, 3.22 mmol) in trimethyl orthoformate (21.5 mL) was treated with HCl (4 M in 1,4-dioxane, 40 μL, 0.161 mmol). The reaction mixture was heated at 100 °C for 2 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The resulting crude residue was purified by silica gel chromatography (MeOH:DCM) to obtain the title compound.

[0253] LCMS [M+H] + = 352.4 (calculated value 352.2).

[0254] Step 7: tert-butyl (R)-3-(3-(2-hydroxy-4-(trifluoromethyl)phenyl)-4-methyl-7H-imidazo[4,5-c]pyridazin-7-yl)piperidine-1-carboxylate:A vial was loaded with tert-butyl (R)-3-(3-chloro-4-methyl-7H-imidazo[4,5-c]pyridazin-7-yl)piperidine-1-carboxylate (700 mg, 1.99 mmol), (2-hydroxy-4-(trifluoromethyl)phenyl)boronic acid (Combi-Blocks, 615 mg, 2.98 mmol), XPhos Pd G3 (135 mg, 0.159 mmol), and potassium carbonate (1.38 g, 9.95 mmol). The vial was then evacuated and filled with nitrogen (3×). In a second vial, a solvent mixture of 1,4-dioxane (10.6 mL) and water (2.7 mL) was spurged with nitrogen for 15 minutes and then added to the first vial. The reaction mixture was heated at 100°C for 3 hours. Next, the reaction mixture was cooled to room temperature and diluted with water and DCM. The layers were separated, and the aqueous layer was extracted with DCM (×3). The combined organic layers were dehydrated with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The resulting crude residue was purified by silica gel chromatography (MeOH:DCM) to obtain the title compound.

[0255] LCMS [M+H] + = 478.4, (calculated value 478.2).

[0256] Step 8: (R)-2-(4-methyl-7-(piperidine-3-yl)-7H-imidazo[4,5-c]pyridazin-3-yl)-5-(trifluoromethyl)phenol: A solution of tert-butyl (R)-3-(3-(2-hydroxy-4-(trifluoromethyl)phenyl)-4-methyl-7H-imidazo[4,5-c]pyridazin-7-yl)piperidine-1-carboxylate (503 mg, 1.05 mmol) in DCM (10.5 mL) was treated with HCl (4 M in 1,4-dioxane, 1.32 mL, 5.27 mmol). The reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was then diluted with MeOH and loaded onto a Biotage Isolute® SCX-2 ion exchange column. Elution was performed twice, once with MeOH and again with 7 M ammonia in MeOH. The 7 M ammonia layer was concentrated under reduced pressure to obtain the title compound. LCMS [M+H] + = 378.2 (calculated value 378.2).

[0257] Stage 9: (R)-2-(4-methyl-7-(1-methylpiperidine-3-yl)-7H-imidazo[4,5-c]pyridazin-3-yl)-5-(trifluoromethyl)phenol: A mixture of (R)-2-(4-methyl-7-(piperidine-3-yl)-7H-imidazo[4,5-c]pyridazin-3-yl)-5-(trifluoromethyl)phenol (20 mg, 0.053 mmol) in MeOH (0.27 mL) and THF (0.27 mL) was treated with formaldehyde (37% in water, 24 μL, 0.318 mmol) and sodium triacetoxyborohydride (34 mg, 0.159 mmol). The reaction mixture was stirred at 25°C for 1 hour. The reaction product was then quenched with 4 drops of AcOH and concentrated. The resulting crude residue was placed in DMSO, filtered, and purified by preparative reverse-phase HPLC (C18 stationary phase, MeCN / water + 0.1% TFA) to obtain the title compound.

[0258] LCMS [M+H] + = 392.3 (calculated value 392.2). 1 H NMR (500 MHz, MeOD-d4) δ 8.88 (s, 1H), 7.48 (d, J = 7.8 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.24 (s, 1H), 5.10 - 5.00 (m, 1H), 3.40 - 3.28 (m, 2H), 3.08 - 2.88 (m, 2H), 2.51 (s, 3H), 2.51 (s, 3H), 2.36 - 2.21 (m, 2H), 2.04 - 1.83 (m, 2H).

[0259] Table 7. The following compounds were prepared using appropriate starting materials and aldehydes, following the same procedure as described for Example 10. [Table 8]

[0260] Table 8. The following intermediates were prepared using appropriate commercially available amines and the same procedure as described for intermediate 3. [Table 9]

[0261] Table 9. The following intermediates were prepared using appropriate starting materials and the same procedure as described for intermediate 6. [Table 10]

[0262] Intermediate 18 (4-hydroxybenzo[b]thiophene-5-yl)boronic acid [ka] Stage 1: 5,5-dibromo-6,7-dihydrobenzo[b]thiophene-4(5H)-one: A solution of CuBr2 (5.87 g, 26.3 mmol) in SiO2 (30 mL) was stirred at 80°C for 10 minutes. Then, a solution of 6,7-dihydrobenzo-[b]thiophene-4(5H)-one (Combi-Blocks, 1.00 g, 6.57 mmol) in CHCl3 (30 mL) was added dropwise, and the resulting mixture was stirred at 80°C for 12 hours. The reaction mixture was cooled to room temperature, diluted with SiO2, and filtered over Al2O3. The filtrate was washed with saturated aqueous NaHCO3, dehydrated with anhydrous Na2SO4, filtered, and concentrated. The resulting crude residue was purified by silica gel chromatography (SiO2: petroleum ether) to obtain the title compound.

[0263] LCMS [M+H] + = 310.9, (calculated value 310.9).

[0264] Stage 2: 5-bromobenzo[b]thiophene-4-ol: To a solution of 5,5-dibromo-6,7-dihydrobenzo[b]thiophene-4(5H)-one (1.58 g, 5.10 mmol) in DMF (30 mL), Li2CO3 (2.26 g, 30.6 mmol) was added. The resulting mixture was stirred at 100°C for 12 hours. The reaction mixture was then cooled to room temperature, filtered, and concentrated under reduced pressure. The resulting crude residue was purified by silica gel chromatography (siRNA: petroleum ether) to obtain the title compound.

[0265] 1 H NMR (400 MHz, CDCl3) δ 7.51 (d, J = 5.5 Hz, 1H), 7.40 (s, 1H), 7.39 (d, J = 1.7 Hz, 1H), 7.36 - 7.32 (m, 1H), 5.87 (s, 1H).

[0266] Stage 3: (4-hydroxybenzo[b]thiophen-5-yl)boronic acid: A mixture of 5-bromobenzo[b]-thiophen-4-ol (400 mg, 1.75 mmol), B2(OH)4 (313 mg, 3.49 mmol), and chloro[(di(1-adamantyl)-n-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) (117 mg, 0.175 mmol) in MeOH (5 mL) was stirred at room temperature under an N2 atmosphere for 12 hours. The reaction mixture was then filtered and concentrated under reduced pressure. The resulting crude residue was purified using MPLC (C18 stationary phase, MeCN / water + 0.5% TFA) to obtain the title compound.

[0267] LCMS [M+H] + = 194.5, (calculated value 195.0).

[0268] Intermediate 19 (4-Hydroxy-2,3-dihydro-1H-inden-5-yl)boronic acid [ka] Stage 1: 5-bromo-2,3-dihydro-1H-inden-4-ol: To a solution of 2,3-dihydro-1H-inden-4-ol (Combi-Blocks, 1.00 g, 7.45 mmol) in DCM (50 mL), diisopropylamine (9.1 mg, 0.090 mmol) was added, and the resulting mixture was cooled to 0°C. To this solution, 1-bromopyrrolidine-2,5-dione (1.33 g, 7.45 mmol) was added in small increments. The reaction mixture was heated to room temperature and stirred for 12 hours. The reaction mixture was then washed with water and brine, the organic layer was dehydrated with anhydrous Na2SO4, filtered, and concentrated. The resulting crude residue was purified by silica gel chromatography (siRNA: petroleum ether) to obtain the title compound.

[0269] 1 H NMR (400 MHz, CDCl3) δ 7.15 (d, J = 8.0 Hz, 1H), 6.62 (d, J = 8.0 Hz, 1H), 5.43 - 5.32 (m, 1H), 2.83 (dt, J = 17.3, 7.6 Hz, 4H), 2.10 - 1.97 ppm (m, 2H).

[0270] Step 2: (4-hydroxy-2,3-dihydro-1H-inden-5-yl)boronic acid: A mixture of 5-bromo-2,3-dihydro-1H-inden-4-ol (50 mg, 0.235 mmol), B2(OH)4 (42.1 mg, 0.469 mmol), and chloro[(di(1-adamantyl)-n-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) (15.7 mg, 0.023 mmol) in MeOH (2 mL) was cooled to 0°C under an N2 atmosphere. Then, DIPEA (0.123 mL, 0.704 mmol) was added dropwise, and the reaction mixture was then heated to room temperature and stirred for 12 hours. The reaction mixture was then filtered and concentrated under reduced pressure. The resulting crude residue was purified by preparative reverse-phase HPLC (C18 stationary phase, MeCN / water + 0.1% TFA) to obtain the title compound.

[0271] LCMS [M+H] + = 179.2, (calculated value 179.1).

[0272] Table 10. The following compounds were prepared using appropriate starting materials and the same procedure as described in Example 3. [Table 11]

[0273] Table 11. The following compounds were prepared using appropriate starting materials and the same procedure as described in Example 7. [Table 12]

[0274] Table 12. The following compounds were prepared using appropriate starting materials and aldehydes, following the same procedure as described in Example 10. [Table 13]

[0275] Table 13. The following intermediates were prepared using appropriate commercially available amines, following the same procedure as described for intermediate 3. [Table 14]

[0276] Table 14. The following intermediates were prepared using appropriate starting materials and the same procedure as described for intermediate 6. [Table 15]

[0277] Intermediate 23 (alternative synthesis) tert-butyl (1R,2R,5R and 1S,2S,5S)-2-(3-chloro-4-methyl-7H-imidazo[4,5-c]pyridazin-7-yl)-8-azabicyclo[3.2.1]octano-8-carboxylate [ka] Stage 1: 3,4,6-Trichloro-5-methylpyridazine: A solution of 4-bromo-5-methylpyridazine-3,6-diol (enamine, 1.20 g, 5.85 mmol) and POCl3 (10 mL, 107 mmol) was stirred at 100°C for 2 hours. The mixture was cooled to room temperature and slowly added to water. The mixture was diluted with ethyl acetate, the layers were separated, and the aqueous layer was extracted with ethyl acetate (×2). The combined organic layers were concentrated, and the resulting crude residue was purified by silica gel chromatography (ethyl acetate: petroleum ether) to obtain the title compound.

[0278] LCMS [M+H] + = 197.1 (calculated value 196.9).

[0279] Stage 2: Phenyl 3,6-dichloro-5-methylpyridazine-4-sulfinate:A solution of 3,4,6-trichloro-5-methylpyridazine (6.4 g, 32.4 mmol) in THF (50 mL) and DMSO (10 mL) was treated with sodium benzenesulfinate (5.6 g, 34.0 mmol). The resulting reaction mixture was heated at 40°C for 48 hours. The reaction mixture was then cooled to room temperature and diluted with water and phosphate. The layers were separated, and the aqueous layer was extracted with phosphate (×3). The combined organic layers were concentrated, and the resulting crude residue was purified by silica gel chromatography (phosphate: petroleum ether) to obtain the title compound.

[0280] LCMS [M+H] + = 303.1 (calculated value 303.0).

[0281] Step 3: tert-butyl (1R,2R,5R and 1S,2S,5S)-2-((6-chloro-5-methyl-4-(phenylsulfonyl)pyridazin-3-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate: A solution of phenyl 3,6-dichloro-5-methylpyridazine-4-sulfinate (580 mg, 1.91 mmol) in 1,4-dioxane (10 mL) was treated with tert-butyl (1R,2R,5R and 1S,2S,5S)-2-amino-8-azabicyclo[3.2.1]octane-8-carboxylate (Combi-Blocks, 433 mg, 1.91 mmol) and Na2CO3 (608 mg, 5.74 mmol). The resulting mixture was heated at 100°C for 12 hours. After cooling to room temperature, the reaction mixture was quenched with water and extracted with SiO(3×). The combined organic layers were washed with brine, dehydrated with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude residue was purified by silica gel chromatography (SiO: petroleum ether) to obtain the title compound.

[0282] LCMS [M+H] + = 493.1 (calculated value 493.2).

[0283] Step 4: tert-butyl (1R,2R,5R and 1S,2S,5S)-2-((4-azido-6-chloro-5-methylpyridazin-3-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate:A solution of tert-butyl (1R,2R,5R and 1S,2S,5S)-2-((6-chloro-5-methyl-4-(phenylsulfonyl)pyridazin-3-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate (800 mg, 1.62 mmol) in DMF (12 mL) was treated with NaN3 (844 mg, 13.0 mmol). The resulting mixture was heated at 50°C for 12 hours. After cooling to 0°C, the reaction mixture was quenched with water and extracted with SiO(3×). The combined organic layers were washed with brine, dehydrated with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude residue was purified by silica gel chromatography (SiO: petroleum ether) to obtain the title compound.

[0284] LCMS [M+H] + = 394.1 (calculated value 394.2).

[0285] Step 5: tert-butyl (1R,2R,5R and 1S,2S,5S)-2-((4-amino-6-chloro-5-methylpyridazin-3-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate: A solution of tert-butyl (1R,2R,5R and 1S,2S,5S)-2-((4-azido-6-chloro-5-methylpyridazin-3-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate (480 mg, 1.22 mmol) in DCM (5 mL) and AcOH (1 mL) was cooled to 0°C and treated with zinc (159 mg, 2.44 mmol). The resulting mixture was stirred at 0°C for 1 hour. The reaction mixture was diluted with DCM, then filtered and washed with brine (2 ×). The resulting organic layer was dehydrated with anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the title compound.

[0286] LCMS [M+H] + = 368.1 (calculated value 368.2).

[0287] Step 6: tert-butyl (1R,2R,5R and 1S,2S,5S)-2-(3-chloro-4-methyl-7H-imidazo[4,5-c]pyridazin-7-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate:A solution of tert-butyl (1R,2R,5R and 1S,2S,5S)-2-((4-amino-6-chloro-5-methylpyridazin-3-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate (240 mg, 0.652 mmol) in trimethyl orthoformate (0.3 mL) was treated with HCl (4 M in 1,4-dioxane, 8.2 μL, 0.033 mmol). The reaction mixture was heated at 100°C for 30 minutes. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The resulting crude residue was purified by silica gel chromatography (HCl: petroleum ether) to obtain the title compound.

[0288] LCMS [M+H] + = 378.1 (calculated value: 378.2).

[0289] Intermediate 26 5-(3-chloro-4-methyl-7H-imidazo[4,5-c]pyridazin-7-yl)bicyclo[3.1.1]heptan-1-amine [ka] A solution of tert-butyl (5-(3-chloro-4-methyl-7H-imidazo[4,5-c]pyridazin-7-yl)bicyclo[3.1.1]-heptan-1-yl) carbamate (intermediate 24, 40 mg, 0.106 mmol) in DCM (1 mL) was treated with TFA (36 mg, 0.318 mmol). The resulting mixture was stirred at 20°C for 1 hour. The reaction mixture was then concentrated under reduced pressure, and the resulting crude residue was purified by preparative reverse-phase HPLC (C18 stationary phase, MeCN / water + 0.1% TFA) to obtain the title compound.

[0290] LCMS [M+H] + = 278.0, (calculated value 278.1).

[0291] Table 15. The following compounds were prepared using appropriate starting materials and the same procedure as described in Example 3. [Table 16]

[0292] Table 16. The following compounds were prepared using appropriate starting materials and the same procedure as described in Example 7. [Table 17]

[0293] Table 17. The following compounds were prepared using appropriate starting materials and ketones, following the same procedure as described in Example 10. DCM was used as the solvent instead of the THF-MeOH mixture. In Example 22, the reaction temperature was increased to 50°C. [Table 18]

[0294] Examples 24 and 25 2-(7-((1R,2R,5S)-8-azabicyclo[3.2.1]octan-2-yl)-4-methyl-7H-imidazo-[4,5-c]pyridazin-3-yl)-5-(trifluoromethyl)phenol, and, 2-(7-((1S,2S,5R)-8-azabicyclo[3.2.1]octan-2-yl)-4-methyl-7H-imidazo-[4,5-c]pyridazin-3-yl)-5-(trifluoromethyl)phenol [ka] Step 1: tert-butyl (1R,2R,5R and 1S,2S,5S)-2-(3-(2-hydroxy-4-(trifluoromethyl)phenyl)-4-methyl-7H-imidazo[4,5-c]pyridazin-7-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate:A solution of tert-butyl (1R,2R,5R and 1S,2S,5S)-2-(3-chloro-4-methyl-7H-imidazo[4,5-c]pyridazin-7-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (intermediate 23, 40 mg, 0.106 mmol) and (2-hydroxy-4-(trifluoromethyl)phenyl)boronic acid (Combi-Blocks, 26 mg, 0.127 mmol) in t-AmOH (1 mL) and water (0.2 mL) was treated with cesium carbonate (103 mg, 0.318 mmol) and Ad2n-BuP Pd G2 (7.1 mg, 0.011 mmol). The reaction mixture was heated at 100°C for 3 hours, then cooled to room temperature and diluted with water and ELISA. The layers were separated, and the aqueous layer was extracted with SiO(2×). The combined organic layers were washed with brine, dehydrated with anhydrous Na2SO4, filtered, and concentrated. The resulting crude residue was purified by preparative TLC (SiO: petroleum ether) to obtain the title compound.

[0295] LCMS [M+H] + = 504.1, (calculated value 504.2).

[0296] Stage 2: 2-(7-((1R,2R,5S)-8-azabicyclo[3.2.1]octan-2-yl)-4-methyl-7H-imidazo[4,5-c]pyridazin-3-yl)-5-(trifluoromethyl)phenol, and 2-(7-((1S,2S,5R)-8-azabicyclo[3.2.1]octan-2-yl)-4-methyl-7H-imidazo[4,5-c]pyridazin-3-yl)-5-(trifluoromethyl)phenol:A solution of tert-butyl (1R,2R,5R and 1S,2S,5S)-2-(3-(2-hydroxy-4-(trifluoromethyl)phenyl)-4-methyl-7H-imidazo[4,5-c]pyridazin-7-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (45 mg, 0.089 mmol) in DCM (1 mL) was treated with TFA (51 mg, 0.447 mmol). The resulting mixture was stirred at 20°C for 1 hour. The reaction mixture was then concentrated directly under reduced pressure, and the resulting crude residue was purified by preparative reverse-phase HPLC (C18 stationary phase, MeCN / water + 0.1% TFA). The resulting racemic mixture was separated by chiral method A, yielding 2-(7-((1R,2R,5S)-8-azabicyclo[3.2.1]octan-2-yl)-4-methyl-7H-imidazo[4,5-c]pyridazin-3-yl)-5-(trifluoromethyl)phenol (Example 24) as a rapidly eluting isomer, and 2-(7-((1S,2S,5R)-8-azabicyclo[3.2.1]octan-2-yl)-4-methyl-7H-imidazo[4,5-c]pyridazin-3-yl)-5-(trifluoromethyl)-phenol (Example 25) as a slowly eluting isomer.

[0297] Example 24: LCMS [M+H] + = 404.1, (calculated value 404.2). 1 H NMR (400 MHz, MeOD-d4) δ 8.90 (s, 1H), 7.50 (d, J = 7.9 Hz, 1H), 7.31 (d, J = 7.7 Hz, 1H), 7.26 (s, 1H), 5.13 (br d, J = 10.8 Hz, 1H), 4.22 (br d, J = 5.2 Hz, 1H), 3.79 (br s, 1H), 2.64 (qd, J = 12.7, 5.9 Hz, 1H), 2.54 (s, 3H), 2.27 (br d, J = 12.3 Hz, 1H), 2.09 - 1.78 (m, 6H).

[0298] Example 25: LCMS [M+H] += 404.1, (calculated value 404.2). 1 H NMR (400 MHz, MeOD-d4) δ 8.91 (s, 1H), 7.50 (d, J = 7.7 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.26 (s, 1H), 5.16 (br d, J = 11.4 Hz, 1H), 4.30 (br d, J = 5.7 Hz, 1H), 3.88 (br s, 1H), 2.67 (qd, J = 12.7, 6.0 Hz, 1H), 2.54 (s, 3H), 2.29 (br d, J = 13.4 Hz, 1H), 2.14 - 1.83 (m, 6H).

[0299] Example 26 5-Chloro-3-fluoro-2-(4-methyl-7-((R)-1-methylpiperidine-3-yl)-7H-imidazo-[4,5-c]pyridazine-3-yl)phenol [ka] Stage 1: 3-(4-chloro-2-fluoro-6-methoxyphenyl)-4-methyl-7-((R)-1-methylpiperidine-3-yl)-7H-imidazo[4,5-c]pyridazine: A mixture of (R)-3-chloro-4-methyl-7-(1-methylpiperidine-3-yl)-7H-imidazo[4,5-c]pyridazine (intermediate 16, 80 mg, 0.300 mmol), (4-chloro-2-fluoro-6-methoxyphenyl)boronic acid (Ambeed, 49 mg, 0.240 mmol), K2CO3 (124 mg, 0.900 mmol), and PdCl2 (dppf) (22 mg, 0.030 mmol) was treated under nitrogen with 1,4-dioxane (1.25 mL) and water (0.25 mL). The resulting mixture was heated at 100°C for 12 hours. After cooling to room temperature, the reaction mixture was directly purified by preparative reverse-phase HPLC (C18 stationary phase, MeCN / water + 0.1% TFA) to obtain the title compound.

[0300] LCMS [M+H] + = 390.1, (calculated value 390.1). Stage 2: 5-Chloro-3-fluoro-2-(4-methyl-7-((R)-1-methylpiperidine-3-yl)-7H-imidazo[4,5-c]pyridazin-3-yl)phenol:A solution of 3-(4-chloro-2-fluoro-6-methoxyphenyl)-4-methyl-7-((R)-1-methylpiperidine-3-yl)-7H-imidazo[4,5-c]pyridazine (10 mg, 0.026 mmol) in DCM (1 mL) was cooled to 0°C and treated with BBr3 (1 M in heptane, 0.128 mL, 0.128 mmol). The resulting mixture was stirred for 16 hours and then slowly heated to room temperature. The reaction product was then cooled to 0°C, quenched with MeOH, and concentrated. The resulting crude residue was purified by preparative reverse-phase HPLC (C18 stationary phase, MeCN / water + 0.05% FA) to obtain the title compound.

[0301] LCMS [M+H] + = 376.2, (calculated value 376.1). 1 H NMR (500 MHz, DMSO-d6) δ 8.86 (s, 1H), 8.46 (d, J = 3.1 Hz, 1H), 6.75 - 6.59 (m, 1H), 4.99 - 4.78 (m, 1H), 2.71 - 2.62 (m, 2H), 2.35 (s, 3H), 2.26 (s, 3H), 2.21 - 2.11 (m, 2H), 1.83 - 1.62 (m, 2H), 1.27 - 1.20 (m, 1H), 0.83 (dt, J = 21.3, 6.6 Hz, 1H).

[0302] Example 27 (R)-3-Cyclopropyl-2-Fluoro-6-(4-Methyl-7-(1-Methylpiperidine-3-yl)-7H-Imidazo-[4,5-c]Pyridazine-3-yl)phenol [ka] Stage 1: (R)-3-(4-chloro-3-fluoro-2-methoxyphenyl)-4-methyl-7-(1-methylpiperidine-3-yl)-7H-imidazo[4,5-c]pyridazine:A mixture of (R)-3-chloro-4-methyl-7-(1-methylpiperidine-3-yl)-7H-imidazo[4,5-c]pyridazine (intermediate 16, 100 mg, 0.376 mmol), 2-(4-chloro-3-fluoro-2-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (AOB Chem, 108 mg, 0.376 mmol), K2CO3 (156 mg, 1.13 mmol), and PdCl2 (dppf) (28 mg, 0.038 mmol) was treated under nitrogen with 1,4-dioxane (3.1 mL) and water (0.63 mL). The resulting mixture was heated at 100°C for 12 hours. The reaction mixture was then cooled to room temperature and concentrated directly under reduced pressure. The obtained crude residue was dissolved in DMSO, filtered, and purified by preparative reverse-phase HPLC (C18 stationary phase, MeCN / water + 0.1% TFA). The fraction of interest was collected and then diluted with SiO2, water, and saturated aqueous NaHCO3. The layers were separated, and the aqueous layer was extracted with SiO2 (2×). The combined organic layers were dehydrated with anhydrous MgSO4, filtered, and concentrated under reduced pressure to obtain the title compound.

[0303] LCMS [M+H] + = 390.2, (calculated value 390.1).

[0304] Step 2: (R)-3-(4-cyclopropyl-3-fluoro-2-methoxyphenyl)-4-methyl-7-(1-methylpiperidine-3-yl)-7H-imidazo[4,5-c]pyridazine: A mixture of (R)-3-(4-chloro-3-fluoro-2-methoxyphenyl)-4-methyl-7-(1-methylpiperidine-3-yl)-7H-imidazo[4,5-c]pyridazine (33 mg, 0.085 mmol) and PdCl2 (dppf) (6.2 mg, 0.0085 mmol) in 1,4-dioxane (0.85 mL) was treated with cyclopropyl zinc(II) bromide (0.5 M in THF, 0.51 mL, 0.254 mmol) under nitrogen. The resulting mixture was heated at 70°C for 3 hours. After cooling to room temperature, the reaction mixture was quenched with saturated aqueous solution NH4Cl and extracted with ELISA (4×). The combined organic layer was dehydrated with anhydrous MgSO4, filtered, and concentrated under reduced pressure. Next, the crude residue obtained was purified by preparative reverse-phase HPLC (C18 stationary phase, MeCN / water + 0.1% TFA) to obtain the title compound.

[0305] LCMS [M+H] + = 396.3, (calculated value 396.2).

[0306] Step 3: (R)-3-cyclopropyl-2-fluoro-6-(4-methyl-7-(1-methylpiperidine-3-yl)-7H-imidazo[4,5-c]pyridazin-3-yl)phenol: A solution of (R)-3-(4-cyclopropyl-3-fluoro-2-methoxyphenyl)-4-methyl-7-(1-methylpiperidine-3-yl)-7H-imidazo[4,5-c]pyridazine (15 mg, 0.038 mmol) in DCM (1.5 mL) was cooled to 0°C and treated with BBr3 (1 M in heptane, 0.190 mL, 0.190 mmol). The resulting mixture was stirred for 16 hours and then slowly heated to room temperature. After cooling to 0°C, the reaction was quenched by adding MeOH dropwise and concentrated under reduced pressure. The resulting crude residue was purified by preparative reverse-phase HPLC (C18 stationary phase, MeCN / water + 0.05% FA) to obtain the title compound.

[0307] LCMS [M+H] + = 382.3, (calculated value 382.2). 1 H NMR (500 MHz, DMSO-d6) δ 8.88 (s, 1H), 8.47 (d, J = 5.5 Hz, 1H), 6.97 (d, J = 8.1 Hz, 1H), 6.53 (s, 1H), 4.88 (d, J = 9.6 Hz, 1H), 3.06 - 3.00 (m, 1H), 2.72 - 2.62 (m, 2H), 2.39 (s, 3H), 2.27 (s, 3H), 2.23 - 2.06 (m, 3H), 1.83 - 1.64 (m, 2H), 1.02 (d, J = 8.4 Hz, 2H), 0.89 - 0.79 (m, 1H), 0.78 (d, J = 5.2 Hz, 2H).

[0308] Examples 28 and 29 2-(4-methyl-7-((1S,2S,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)-7H-imidazo-[4,5-c]pyridazin-3-yl)-5-(trifluoromethyl)phenol, and, 2-(4-methyl-7-((1R,2R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)-7H-imidazo-[4,5-c]pyridazin-3-yl)-5-(trifluoromethyl)phenol [ka] Step 1: tert-butyl (1R,2R,5R and 1S,2S,5S)-2-(3-(2-hydroxy-4-(trifluoromethyl)phenyl)-4-methyl-7H-imidazo[4,5-c]pyridazin-7-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate: A solution of tert-butyl (1R,2R,5R and 1S,2S,5S)-2-(3-chloro-4-methyl-7H-imidazo[4,5-c]pyridazin-7-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (intermediate 23, 40 mg, 0.106 mmol) and (2-hydroxy-4-(trifluoromethyl)phenyl)boronic acid (Combi-Blocks, 26 mg, 0.127 mmol) in t-AmOH (1 mL) and water (0.2 mL) was treated with cesium carbonate (103 mg, 0.318 mmol) and Ad2n-BuP Pd G2 (7.1 mg, 0.011 mmol). The reaction mixture was heated at 100°C for 3 hours, then cooled to room temperature and diluted with water and ELISA. The layers were separated, and the aqueous layer was extracted with SiO(2×). The combined organic layers were washed with brine, dehydrated with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude residue was then purified by preparative TLC (SiO: petroleum ether) to obtain the title compound.

[0309] LCMS [M+H] + = 504, 1, (calculated value 504.2).

[0310] Stage 2: 2-(7-((1R,2R,5S and 1S,2S,5R)-8-azabicyclo[3.2.1]octan-2-yl)-4-methyl-7H-imidazo[4,5-c]pyridazin-3-yl)-5-(trifluoromethyl)phenol: A solution of tert-butyl (1R,2R,5R and 1S,2S,5S)-2-(3-(2-hydroxy-4-(trifluoromethyl)phenyl)-4-methyl-7H-imidazo[4,5-c]pyridazin-7-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (35 mg, 0.070 mmol) in DCM (0.7 mL) was treated with TFA (40 mg, 0.348 mmol). The reaction mixture was stirred at 20°C for 1 hour. The reaction mixture was then washed with saturated aqueous NaHCO3 and concentrated under reduced pressure to obtain the title compound. This compound was used in the next step without further purification.

[0311] LCMS [M+H] + = 404.2, (calculated value 404.2).

[0312] Stage 3: 2-(4-methyl-7-((1R,2R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)-7H-imidazo[4,5-c]pyridazin-3-yl)-5-(trifluoromethyl)phenol, and 2-(4-methyl-7-((1S,2S,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)-7H-imidazo[4,5-c]pyridazin-3-yl)-5-(trifluoromethyl)phenol:A solution of 2-(7-((1R,2R,5S and 1S,2S,5R)-8-azabicyclo[3.2.1]octan-2-yl)-4-methyl-7H-imidazo[4,5-c]pyridazin-3-yl)-5-(trifluoromethyl)phenol (28 mg, 0.069 mmol) and formaldehyde (17 mg, 0.21 mmol) in MeOH (1 mL) was cooled to 0°C, and sodium borohydride (22 mg, 0.347 mmol) was added. The resulting reaction mixture was heated to 25°C and stirred for 30 minutes. The reaction mixture was then concentrated directly under reduced pressure, and the resulting crude residue was purified by preparative reverse-phase HPLC (C18 stationary phase, MeCN / water + 0.1% TFA). The resulting racemic mixture was separated by chiral method B to obtain 2-(4-methyl-7-((1S,2S,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)-7H-imidazo[4,5-c]pyridazin-3-yl)-5-(trifluoromethyl)phenol (Example 28) as a rapidly eluting isomer, and 2-(4-methyl-7-((1R,2R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)-7H-imidazo[4,5-c]pyridazin-3-yl)-5-(trifluoromethyl)phenol (Example 29) as a slowly eluting isomer.

[0313] Example 28: LCMS [M+H] + = 418.1, (calculated value 418.2). 1 H NMR (400 MHz, MeOD-d4) δ 8.90 (s, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.30 (d, J = 8.2 Hz, 1H), 7.24 (s, 1H), 5.20 - 5.10 (m, 1H), 3.98 (br d, J = 2.9 Hz, 1H), 3.48 (br s, 1H), 2.57 - 2.49 (m, 7H), 2.33 - 2.16 (m, 2H), 2.11 - 1.96 (m, 2H), 1.95 - 1.80 (m, 3H). Example 29: LCMS [M+H] + = 418.1, (calculated value 418.2).1 H NMR (400 MHz, MeOD-d4) δ 8.89 (s, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.30 (d, J = 7.9 Hz, 1H), 7.24 (s, 1H), 5.19 - 5.05 (m, 1H), 3.92 (br d, J = 4.4 Hz, 1H), 3.40 (br s, 1H), 2.51 (d, J = 16.6 Hz, 7H), 2.27 - 2.13 (m, 2H), 2.09 - 1.96 (m, 2H), 1.92 - 1.80 (m, 3H).

[0314] Table 18. The following compounds were prepared using appropriate starting materials, following the same procedures as those described for Examples 28 and 29. The racemic products were separated using the chiral SFC method specified in the table; for enantiomer pairs, the rapidly eluting isomer is listed first.

[0315] [Table 19]

[0316] Example 32 2-(7-(5-aminobicyclo[3.1.1]heptan-1-yl)-4-methyl-7H-imidazo[4,5-c]pyridazin-3-yl)-5-(trifluoromethyl)phenol [ka] A solution of 5-(3-chloro-4-methyl-7H-imidazo[4,5-c]pyridazin-7-yl)bicyclo[3.1.1]heptan-1-amine (intermediate 26 mg, 12 mg, 0.042 mmol) and (2-hydroxy-4-(trifluoromethyl)phenyl)boronic acid (Combi-Blocks, 9.8 mg, 0.043 mmol) in t-AmOH (0.5 mL) and water (0.1 mL) was treated with cesium carbonate (42 mg, 0.130 mmol) and Ad2n-BuP Pd G2 (2.9 mg, 0.0043 mmol). The reaction mixture was heated under nitrogen at 100°C for 2 hours, then cooled to room temperature and extracted with ELISA (2×). The organic layers were combined, washed with brine, dehydrated with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The obtained crude residue was purified by preparative reverse-phase HPLC (C18 stationary phase, MeCN / water + 0.05% NH4OH + 10 mM NH4HCO3) to obtain the title compound.

[0317] LCMS [M+H] + = 404.1, (calculated value 404.2). 1 H NMR (400 MHz, MeOD-d4) δ 8.64 (s, 1H), 7.49 (d, J = 7.7 Hz, 1H), 7.30 (d, J = 7.4 Hz, 1H), 7.24 (s, 1H), 2.76 - 2.66 (m, 2H), 2.57 - 2.46 (m, 5H), 2.40 - 2.32 (m, 2H), 2.15 - 2.04 (m, 2H), 1.99 - 1.86 (m, 2H).

[0318] Table 19. The following compounds were prepared using appropriate intermediates, following the same procedure as described for Example 32. The racemic products were separated using the chiral SFC method specified in the table; for enantiomer pairs, the rapidly eluting isomer is listed first. [Table 20]

[0319] Example 35 (R)-2-(4-methyl-7-(1-(methyl-d 3 (Piperidin-3-yl)-7H-imidazo[4,5-c]pyridazine-3-yl)-5-(trifluoromethyl)phenol [ka] A solution of (R)-2-(4-methyl-7-(piperidine-3-yl)-7H-imidazo[4,5-c]pyridazin-3-yl)-5-(trifluoromethyl)phenol (Example 5, 40 mg, 0.106 mmol) in MeOD-d4 (0.21 mL) was cooled to 0°C and treated with deuterated formaldehyde (20 wt% in D2O, 85 μL, 0.530 mmol) and NaBD4 (13.3 mg, 0.318 mmol). The resulting mixture was slowly heated to 25°C and stirred for 12 hours. The reaction mixture was then concentrated directly under reduced pressure, and the resulting crude residue was purified by preparative reverse-phase HPLC (C18 stationary phase, MeCN / water + 0.1% TFA). The fractions containing the title compound were combined, treated with saturated aqueous NaHCO3 to neutralize the pH, and then extracted with ELISA (3×). The combined organic layers were dehydrated with anhydrous MgSO4, filtered, and concentrated to obtain the title compound.

[0320] LCMS [M+H] + = 395.3, (calculated value 395.2). 1 H NMR (500 MHz, DMSO-d6) δ 8.88 (s, 1H), 7.48 (d, J = 7.8 Hz, 1H), 7.30 (d, J = 8.1 Hz, 1H), 7.26 (s, 1H), 4.87 (t, J = 9.6 Hz, 1H), 3.59 - 3.51 (m, 2H), 2.69 (br s, 1H), 2.38 (s, 3H), 2.26 - 2.03 (m, 3H), 1.76 (br s, 1H), 1.69 (d, J = 10.2 Hz, 1H).

[0321] Examples of pharmaceutical compositions As a specific embodiment of the oral pharmaceutical composition, a 100 mg potency tablet comprises 100 mg of any one of the above examples, 268 mg of microcrystalline cellulose, 20 mg of croscarmellose sodium, and 4 mg of magnesium stearate. The active substance, microcrystalline cellulose, and croscarmellose are first mixed. Then, this mixture is smoothed with magnesium stearate and compressed into a tablet.

[0322] Biological assays Activation of the canonical NLRP3 inflammasome requires two steps: priming and activation. When priming signals, such as pathogen-activating molecular patterns (PAMPs) or danger-activating molecular patterns (DAMPs), are recognized by Toll-like receptors, signal transduction occurs via nuclear factor-κB (NF-KB). As a result, the transcription of inflammasome-related components, including inactive NLRP3 and prolL-1β, is upregulated (Bauernfeind et al., J. Immunol. 2009, 183, 787 - 791; Franchi et al., Nat. Immunol. 2012, 13, 325 - 332; Franchi et al., J. Immunol. 2014, 193, 4214 - 4222). The second stage is activation, which induces oligomerization of NLRP3, followed by the assembly of NLRP3, apoptosis-associated plaque-like proteins including CARD(ASC), and procaspase-1 to form an inflammasome complex. This triggers the conversion of procaspase-1 to caspase-1, leading to the production and secretion of mature IL-1β and IL-18 (Kim et al., J. Inflamm. 2015, 12, 41; Ozaki et al., J. Inflamm. Res. 2015, 8, 15 - 27; Rabeony et al., Eur. J. Immunol. 2015, 45, 2847). During the assembly of the inflammasome complex, oligomerization of NLRP3 induces ASC nucleation and an event commonly referred to as "ASC SPECK" formation (which is observed as discrete punctate structures within the cell after staining and visualizing ASCs using common immunocytochemical methods).

[0323] The ability of compounds to inhibit NLRP3 inflammasome activation was measured in vivo by monitoring ASC-SPECK formation in stimulated human monocytic THP-1 cells. THP-1 cells (ATCC catalog #TIB-202) were maintained in complete growth medium containing Roswell Park Memorial Institute RPMI (ATCC catalog #30-2001), 10% heat-inactivated fetal bovine serum, 1X penicillin / streptomycin, and 0.05 mM 2-mercaptoethanol. At the start of the assay, undifferentiated THP-1 cells were cultured at a density of 20,000 cells per well in complete growth medium supplemented with 10 ng / mL phorbol 12-myristate-13-acetic acid (PMA; Sigma catalog #P8139) in 384-well plates (Poly-D-lysine coated Cell Carrier Ultra microplates, Perkin Elmer catalog #6057500), followed by overnight incubation. The following day, the culture medium was replaced with assay medium [RPMI (Gibco catalog #11875-093), 0.01% bovine serum albumin (BSA)]. The compound was serially diluted with DMSO, and then 12.5 μg / mL of gramicidin (Enzo Lifescience, catalog #ALX-350-233-M005) was added to the wells one hour before addition. All incubations were performed at 37°C (5% CO2 / 95% air). After 3 hours of treatment with gramicidin, the cells were fixed with 4% paraformaldehyde and stored at 4°C until immunofluorescence staining.

[0324] Immunofluorescence staining:The anti-ASC antibody (MBL catalog #D086-3) was desalted and labeled with the Alexa 488 antibody labeling kit (Thermo catalog #A20181), and then used as described below. After fixation, the following steps were performed at room temperature. The cells were first permeabilized with 0.3% Triton X-100 in phosphate-buffered saline (PBS) for 15 minutes, and then incubated for 1 hour in blocking buffer containing 5% goat serum, 0.3% tween-20, and 0.03% sodium azide in PBS. The cells were stained for 1 hour with a mixture of ASC-Alexa488 antibody (diluted 1:200 in blocking buffer) and nuclear stain DRAQ5 (1:5000 in blocking buffer, Thermo catalog #62251). After washing with 0.3% Tween-20 in PBS, the plates were imaged using the Opera Phenix High Content Screening System. The number of DRAQ5-positive cells, including ASC SPECKS, was quantified within each well.

[0325] Data analysis: EC 50 The values ​​were calculated using a standard curve fitting analysis with an internally developed program for the TIBCO Spotfire software.

[0326] The compounds of the present invention inhibit the activation of the NLRP3 inflammasome in the above biological assay, and exhibit an EC of less than 5 micromoles. 50 It has a value. Specific EC values ​​of the compounds in Examples 1-35 in the above biological assay. 50 The values ​​are listed in Table I.

[0327] [Table 21] TIFF2026509042000058.tif62165

[0328] The scope of the "Claims" should not be limited by the preferred embodiments described in the Examples, and the broadest interpretation consistent with this Specification as a whole should be given.

[0329] While this disclosure has been described and illustrated with reference to specific embodiments thereof, those skilled in the art will understand that various adaptations, changes, modifications, substitutions, deletions, or additions to the procedures and protocols may be made without departing from the scope of this disclosure. For example, effective doses other than those specified above may be applied as a result of variations in the responsiveness of mammals treated for any indication with the compound represented by structural formula I shown above. The specific pharmacological response observed may vary depending on or in response to the presence or absence of a selected specific active compound or pharmaceutical carrier, and the type of formulation and mode of administration employed. Such expected variations or differences in the results are intended in accordance with the purposes and practices of this disclosure.

Claims

1. Structural formula I: 【Chemistry 1】 [During the ceremony, X is, (1) = C(R ４ ) - and, (2) = N - Selected independently from the group; R １ teeth, (1)-C ３－１２ Cycloalkyl, (2)-C ３－１２ Cycloalkenyl, (3)-C ２－１１ Cycloheteroalkyl, (4)-C ２－１１ Cycloheteralkenyl, (5) Ariel, (6) Heteroaryl, (7)-C １－６ Alkyl, (8)-C １－６ alkyl-OH, (9)-C １－６ Alkyl-C ３－１２ Cycloalkyl, (10)-C １－６ Alkyl-C ３－１２ Cycloalkenyl, (11)-C １－６ Alkyl-C ２－１１ Cycloheteroalkyl, (12)-C １－６ Alkyl-C ２－１１ Cycloheteralkenyl, (13)-C １－６ Alkyl-aryl, and (14)-C １－６ Alkyl-heteroaryl Selected from the group, where R １ is either not substituted, or R ａ It is substituted with 1 to 6 substituents selected from; R ２ teeth, (1) Hydrogen, (2) CN, (3)-CF ３ 、 (4)-CHF ２ 、 (5)-C １－６ Alkyl, and (6) Halogen Selected from the group, where alkyl is either unsubstituted or R ｂ It is substituted with 1 to 5 substituents selected from; R ３ teeth, (1) Aryl, and, (2) Heteroaryl Selected from the group, where aryl and heteroaryl are either unsubstituted or R ｃ It is substituted with 1 to 5 substituents selected from; R ４ teeth, (1) Hydrogen, (2) CN, (3)-C １－６ Alkyl, (4)-O-C １－６ Alkyl, and (5) Halogen Selected from the group, where each alkyl is either unsubstituted or R ｄ It is substituted with 1 to 5 substituents selected from; R ５ teeth, (1) Hydrogen, (2) CN, (3)-C １－６ Alkyl, (4)-O-C １－６ Alkyl, and (5) Halogen Selected from the group, where each alkyl is either unsubstituted or R ｅ It is substituted with 1 to 5 substituents selected from; Each R ａ teeth, (1) CN, (2) Oxo, (3) -OH, (4) Halogen, (5)-C １－６ Alkyl, (6)-C １－６ alkyl-OH, (7)-O-C １－６ Alkyl, (8)-C ３－６ Cycloalkyl, (9)-C ２－６ Cycloheteroalkyl, (10) Ariel, (11) Heteroaryl, (12)-C(O)C １－６ Alkyl, (13)-C(O)C ３－６ Cycloalkyl, (14)-C １－６ Alkyl-aryl, (15)-C １－６ Alkyl-heteroaryl, (16)-C １－６ Alkyl-C ３－６ Cycloalkyl, (17)-C １－６ Alkyl-C ２－６ Cycloheteroalkyl, (18)-(CH ２ ) ｐ -O-C １－６ Alkyl, (19)-(CH ２ ) ｐ -O-C ３－６ Cycloalkyl, (20)-(CH ２ ) ｐ -O-C ２－６ Cycloheteroalkyl, (21)-(CH ２ ) ｐ -O-aryl, (22)-(CH ２ ) ｐ -O-heteroaryl, (23)-(CH ２ ) ｐ -S(O) ｒ R ｆ , and, (24)-N(R ｇ ) ２ Independently selected from the group, where each R ａ is either not substituted, or halogen, CF ３ OH, C １－６ Alkyl and -OC １-６ It is substituted with 1 to 6 substituents selected from alkyl groups; Each R ｂ teeth, (1)CF ３ 、 (2) Halogen, (3)-C １－６ Alkyl, and (4)-C ３－６ Cycloalkyl Selected independently from the group; Each R ｃ teeth, (1) CN, (2) -OH, (3) Oxo, (4) Halogen, (5)-C １－６ Alkyl, (6)-O-C １－６ Alkyl, (7)-C ３－６ Cycloalkyl, (8)-C ２－６ Cycloheteroalkyl, (9) Ariel, (10) Heteroaryl, (11)-C １－６ Alkyl-aryl, (12)-C １－６ Alkyl-heteroaryl, (13)-C １－６ Alkyl-C ３－６ Cycloalkyl, (14)-C １－６ Alkyl-C ２－６ Cycloheteroalkyl, (15)-(CH ２ ) ｑ -O-C １－６ alkyl, (16)-(CH ２ ) ｑ -O-C ３－６ Cycloalkyl, (17)-(CH ２ ) ｑ -O-C ２－６ Cycloheteroalkyl, (18)-(CH ２ ) ｑ -O-aryl, (19)-(CH ２ ) ｑ -O-heteroaryl, (20)-OC １－６ Alkyl-C ３－６ Cycloalkyl, (21)-OC １－６ Alkyl-C ２－６ Cycloheteroalkyl, (22)-OC １－６ Alkyl-aryl, (23)-OC １－６ Alkyl-heteroaryl, (24)-(CH ２ ) ｑ -S(O) ｒ R ｈ 、 (25)-N(R ｉ ) ２ 、 (26)-C(O)R ｊ , and, (27)-C(O)NR ｉ Independently selected from the group, where each R ｃ is either not substituted, or halogen, CF ３ CF ２ H, OCF ３ , CN, CH ２ CF ３ CF ２ CH ３ , -C １－６ Alkyl and -OC １－６ It is substituted with 1 to 6 substituents selected from alkyl groups; Each R ｄ teeth, (1) Hydrogen, (2) OH, (3) Halogens, and (4)-C １－６ Alkyl Selected independently from the group; Each R ｅ teeth, (1) Hydrogen, (2) OH, (3) Halogens, and (4)-C １－６ Alkyl Selected independently from the group; Each R ｆ teeth, (1) Hydrogen, (2)-C １－６ Alkyl, (3)-C ３－６ Cycloalkyl, and, (4)-C ２－６ Cycloheteroalkyl Selected independently from the group; Each R ｇ teeth, (1) Hydrogen, (2)-C １－６ Alkyl, (3)-C ３－６ Cycloalkyl, (4)-C ２－６ Cycloheteroalkyl, (5) Ariel, (6) Heteroaryl, (7) - C(O)C １－６ Alkyl, and (8)-S(O) ｒ R ｆ Independently selected from the group, where alkyl is either unsubstituted or CF ３ , halogens, OH and -OC １－６ It can be substituted with 1 to 3 substituents selected from alkyl groups; Each R ｈ teeth, (1) Hydrogen, (2)-C １－６ Alkyl, (3)-C ３－６ Cycloalkyl, and, (4)-C ２－６ Cycloheteroalkyl Selected independently from the group; Each R ｉ teeth, (1) Hydrogen, (2)-C １－６ Alkyl, (3)-C ３－６ Cycloalkyl, and, (4)-C ２－６ Cycloheteroalkyl Selected independently from the group; Each R ｊ teeth, (1) OH, (2)-C １－６ Alkyl, (3)-C ３－６ Cycloalkyl, and, (4)-C ２－６ Cycloheteroalkyl Independently selected from the group, where alkyl is either unsubstituted or CF ３ , halogens, OH and -OC １－６ It can be substituted with 1 to 3 substituents selected from alkyl groups; p is 0, 1, 2, 3, 4, 5, or 6; q is 0, 1, 2, 3, 4, 5 or 6; and, r is either 1 or 2. A compound represented by or a pharmaceutically acceptable salt thereof.

2. Structural formula Ia: 【Chemistry 2】 A compound according to claim 1, or a pharmaceutically acceptable salt thereof, represented by [formula].

3. X is = C(R ４ ) - The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

4. X is = N- The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

5. R １ teeth, (1)-C ３－１２ Cycloalkyl, (2)-C ２－１１ Cycloheteroalkyl, (3) Heteroaryl, (4)-C １－６ alkyl-OH, (5)-C １－６ Alkyl-C ３－１２ Cycloalkyl, and, (6)-C １－６ Alkyl-C ２－１１ Cycloheteroalkyl Selected from the group, where R １ is either not substituted, or R ａ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, substituted with 1 to 6 substituents selected from the above.

6. R １ C ２－１１ It is a cycloheteroalkyl group, where the cycloheteroalkyl group is either unsubstituted or R ａ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, substituted with 1 to 6 substituents selected from the above.

7. R ２ is hydrogen and -C １－６ Selected from the group of alkyls, where alkyl is either unsubstituted or R ｂ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, substituted with 1 to 5 substituents selected from the above.

8. R ３ is a heteroaryl compound, where the heteroaryl compound is either unsubstituted or R ｃ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, substituted with 1 to 5 substituents selected from the above.

9. R ３ is an aryl, where the aryl is either unsubstituted or R ｃ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, substituted with 1 to 5 substituents selected from the above.

10. R ４ is hydrogen or -C １－６ It is an alkyl group, where each alkyl group is either unsubstituted or R ｄ It is substituted with 1 to 5 substituents selected from; and, R ５ is hydrogen or -C １－６ It is an alkyl group, where each alkyl group is either unsubstituted or R ｅ Substituted with 1 to 5 substituents selected from; The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

11. R ４ is hydrogen; and, R ５ It is hydrogen; The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

12. R １ teeth, (1)-C ３－１２ Cycloalkyl, (2)-C ２－１１ Cycloheteroalkyl, (3) Heteroaryl, (4)-C １－６ alkyl-OH, (5)-C １－６ Alkyl-C ３－１２ Cycloalkyl, and, (6)-C １－６ Alkyl-C ２－１１ Cycloheteroalkyl Selected from the group, where R １ is either not substituted, or R ａ It is substituted with 1 to 6 substituents selected from; R ２ is hydrogen and -C １－６ Selected from the group of alkyls, where alkyl is either unsubstituted or R ｂ It is substituted with 1 to 5 substituents selected from; R ３ is a heteroaryl compound, where the heteroaryl compound is either unsubstituted or R ｃ It is substituted with 1 to 5 substituents selected from; R ４ is hydrogen or -C １－６ It is an alkyl group, where each alkyl group is either unsubstituted or R ｄ It is substituted with 1 to 5 substituents selected from; and, R ５ is hydrogen or -C １－６ It is an alkyl group, where each alkyl group is either unsubstituted or R ｅ Substituted with 1 to 5 substituents selected from; The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

13. R １ C ２－１１ It is a cycloheteroalkyl group, where the cycloheteroalkyl group is either unsubstituted or R ａ It is substituted with 1 to 6 substituents selected from; R ２ is hydrogen and -C １－６ Selected from the group of alkyls, where alkyl is either unsubstituted or R ｂ It is substituted with 1 to 5 substituents selected from; R ３ is an aryl, where the aryl is either unsubstituted or R ｃ It is substituted with 1 to 5 substituents selected from; R ４ is hydrogen; and, R ５ It is hydrogen; The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

14. below, (1) (R)-2-(7-(1-ethylpiperidine-3-yl)-7H-pyrrolo[2,3-c]pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; (2) (R)-2-(7-(1-ethylpiperidine-3-yl)-4-methyl-7H-pyrrolo[2,3-c]pyridazin-3-yl)-5-(trifluoromethyl)phenol; (3) (R)-2-(7-(1-ethylpiperidine-3-yl)-7H-imidazo[4,5-c]pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; (4) (R)-3-methyl-2-(7-(1-methylpiperidine-3-yl)-7H-imidazo[4,5-c]pyridazin-3-yl)-5-(trifluoromethyl)phenol; (5) (S)-3-methyl-2-(7-(1-methylpiperidine-3-yl)-7H-imidazo[4,5-c]pyridazin-3-yl)-5-(trifluoromethyl)phenol; (6) (R)-2-(4-methyl-7-(piperidine-3-yl)-7H-imidazo[4,5-c]pyridazin-3-yl)-5-(trifluoromethyl)phenol; (7) (3S,4R)-3-(3-(2-hydroxy-4-(trifluoromethyl)phenyl)-4-methyl-7H-imidazo[4,5-c]pyridazin-7-yl)piperidine-4-ol; (8) (R)-2-(7-(1-ethylpiperidine-3-yl)-4-methyl-7H-imidazo[4,5-c]pyridazin-3-yl)-5-(trifluoromethyl)phenol; (9) (R)-2-(7-(1-methylpiperidine-3-yl)-7H-imidazo[4,5-c]pyridazin-3-yl)-5-(trifluoromethyl)phenol; (10) (S)-2-(7-(1-methylpiperidine-3-yl)-7H-imidazo[4,5-c]pyridazin-3-yl)-5-(trifluoromethyl)phenol; (11) (R)-3-(2-(difluoromethoxy)-4-(trifluoromethyl)phenyl)-7-(1-ethylpiperidine-3-yl)-4-methyl-7H-imidazo[4,5-c]pyridazine; (12) (R)-2-(4-methyl-7-(1-methylpiperidine-3-yl)-7H-imidazo[4,5-c]pyridazin-3-yl)-5-(trifluoromethyl)phenol; (13) (3S,4R)-3-(3-(2-hydroxy-4-(trifluoromethyl)phenyl)-4-methyl-7H-imidazo[4,5-c]pyridazin-7-yl)-1-methylpiperidine-4-ol; And, (14) (3S,4R)-1-ethyl-3-(3-(2-hydroxy-4-(trifluoromethyl)phenyl)-4-methyl-7H-imidazo[4,5-c]pyridazin-7-yl)piperidine-4-ol; (15) (R)-5-chloro-2-(4-methyl-7-(piperidine-3-yl)-7H-imidazo[4,5-c]pyridazin-3-yl)phenol; (16) (R)-2-(4,6-dimethyl-7-(1-methylpiperidine-3-yl)-7H-imidazo[4,5-c]pyridazin-3-yl)-5-(trifluoromethyl)phenol; (17) (R)-5-(4-methyl-7-(1-methylpiperidine-3-yl)-7H-imidazo[4,5-c]pyridazine-3-yl)benzo[b]thiophen-4-ol; (18) (R)-5-(4-methyl-7-(1-methylpiperidine-3-yl)-7H-imidazo[4,5-c]pyridazin-3-yl)-2,3-dihydro-1H-inden-4-ol; (19) (R)-5-chloro-2-(4-methyl-7-(1-methylpiperidine-3-yl)-7H-imidazo[4,5-c]pyridazin-3-yl)phenol; And, (20) (R)-5-chloro-2-(7-(1-ethylpiperidine-3-yl)-4-methyl-7H-imidazo[4,5-c]pyridazin-3-yl)phenol; A compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the above.

15. below, (1) (R)-2-(7-(1-ethylpiperidine-3-yl)-7H-imidazo[4,5-c]pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; (2) (R)-2-(4-methyl-7-(piperidine-3-yl)-7H-imidazo[4,5-c]pyridazin-3-yl)-5-(trifluoromethyl)phenol; (3) (R)-2-(7-(1-ethylpiperidine-3-yl)-4-methyl-7H-imidazo[4,5-c]pyridazin-3-yl)-5-(trifluoromethyl)phenol; And, (4) (R)-2-(4-methyl-7-(1-methylpiperidine-3-yl)-7H-imidazo[4,5-c]pyridazin-3-yl)-5-(trifluoromethyl)phenol; A compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the above.

16. A pharmaceutical composition comprising the compound described in claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

17. Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof for preparing a pharmacopoeia useful for treating disorders, symptoms, or diseases in which NLRP3 inhibition occurs in the relevant mammals.

18. Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment, prevention, or control of inflammatory disorders, fibrotic disorders, cardiovascular disorders, metabolic disorders, or neurodegenerative disorders.

19. The use according to claim 18, wherein the disorder is an inflammatory disorder.

20. The use according to claim 19, wherein the inflammatory disorder is selected from autoimmune disorders, autoinflammatory disorders, inflammatory joint disorders, inflammatory skin disorders, and neuroinflammatory disorders.

21. The use according to claim 17, wherein the disorder is selected from atherosclerosis, non-alcoholic steatohepatitis, Alzheimer's disease, and Parkinson's disease.

22. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, for use in therapeutic purposes.

23. A method for treating or preventing a disorder, symptom, or disease in response to NLRP3 inhibition in a patient in need, the method comprising administering a therapeutically effective amount of the compound described in claim 1 or a pharmaceutically acceptable salt thereof.

24. The method according to claim 23, wherein the disorder is selected from inflammatory disorders, fibrotic disorders, cardiovascular disorders, metabolic disorders, or neurodegenerative disorders.

25. The method according to claim 24, wherein the disorder is an inflammatory disorder.

26. The method according to claim 25, wherein the inflammatory disorder is selected from autoimmune disorders, autoinflammatory disorders, inflammatory joint disorders, inflammatory skin disorders, and neuroinflammatory disorders.

27. The method according to claim 25, wherein the disorder is selected from atherosclerosis, non-alcoholic steatohepatitis, Alzheimer's disease, and Parkinson's disease.

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