5,6 unsaturated bicyclic heterocycles useful as inhibitors of nod-like receptor protein 3

Abstract

Disclosed are novel compounds of structural formula (I) and pharmaceutically acceptable salts, hydrates, and solvates thereof, which are inhibitors of NLRP3 and can be used to treat, prevent, manage, ameliorate, control, and suppress diseases mediated by NLPR3. The compounds of structural formula I can be used to treat, prevent, or manage diseases, disorders, and conditions mediated by NLRP3, such as, 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.

Description

Cross-references to related applications

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 505,807, filed June 2, 2023, the entire contents of which are incorporated herein by reference. Background Technology

[0002] Inflammasomes act as central signaling hubs in the innate immune system. They are multi-protein complexes assembled after activation of intracellular pattern recognition receptors (PRRs) by multiple pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs). Inflammasomes have been shown to be formed from nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) and proteins containing Pyrin and HIN200 domains (Van Opdenbosch N and Lamkanfi M. Immunity, 2019, 18 June; 50(6): 1352-1364). Inflammasome activation triggers a cascade of events that release pro-inflammatory cytokines and promote a form of inflammatory cell death called pyroptosis induced by gasdermin activation. Pyroptosis is a unique form of inflammatory cell death that not only leads to the release of cytokines but also to the release of other intracellular components that promote a broader 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 extensively studied of all inflammasomes. NLRP3 can be activated by a variety of stimuli, including environmental crystals, pollutants, host-derived DAMPs, and protein aggregates (Tartey S and Kaneganti TD. Immunology, April 2019; 156(4):329-338). Risk-associated molecular patterns involving NLRP3 include uric acid and cholesterol crystals that contribute to gout and atherosclerosis, amyloid-P fibrils that are neurotoxic in Alzheimer's disease, and asbestos particles that contribute to mesothelioma (Kelley et al., Int J Mol Sci, July 6, 2019; 20(13)). In addition, NLRP3 is activated by the following: infectious agents, such as Vibrio cholerae; fungal pathogens, such as Aspergillus Jumigatus and Candida albicans; adenoviruses, influenza A viruses and SARS-CoV-2 (Tartey and Kaneganti, 2019 (see above); Fung et al., Emerg Microbes Infect, 14 March 2020; 9(1):558-570).

[0004] The activation mechanism of NLRP3 in humans remains unclear. It has been proposed that the NLRP3 inflammasome requires regulation at both the transcriptional and posttranscriptional levels (Yang Y et al., Cell Death Dis, February 12, 2019; 10(2): 128). NOD-like receptor protein 3 (NLRP3) is a gene encoding a protein consisting of an N-terminal pyrin domain, a nucleotide binding site domain (NBD), and a C-terminal leucine-rich repeat (LRR) motif (Inoue et al., Immunology, 2013, 139, 11-18; Sharif et al., Nature, June 2019; 570(7761):338-343).

[0005] In response to the sterile inflammatory danger signals PAMP or DAMP, NLRP3 interacts with adaptor proteins, apoptosis-associated speckle-like protein (ASC) containing a caspase recruitment domain, and the protease caspase-1 to form the NLRP3 inflammasome. Upon activation, proaspase-1 undergoes autoproteolytic cleavage and cleaves pyroporin D (Gsdmd) to produce an N-terminal Gsdmd molecule, which causes pore formation in the plasma membrane and leads to a lytic form of cell death called pyroptosis. Alternatively, caspase-1 cleaves the pro-inflammatory cytokines pro-IL-1β and pro-IL-18 to allow the release of their biologically active forms (Kelley et al., 2019 – see above). NLRP3 inflammasome activation leads to the release of the inflammatory cytokines IL-1β (interleukin-1β) and IL-18 (interleukin-18), the dysregulation of which can lead to a variety of diseases.

[0006] Dysregulation of the NLRP3 inflammasome or its downstream mediators is associated with many immune diseases, inflammatory diseases, autoimmune diseases, and autoinflammatory diseases. Activation of the NLRP3 inflammasome is associated with the following diseases and conditions: cold pyridine-associated periodic syndrome; sickle cell disease; systemic lupus erythematosus; abnormal pain; graft-versus-host disease; liver diseases (including non-alcoholic steatohepatitis (NASH), chronic liver disease, viral hepatitis, alcoholic steatohepatitis, and alcoholic liver disease); inflammatory bowel disease (including Crohn's disease and ulcerative colitis); inflammatory joint diseases (including gout, pseudogout, arthropathy, osteoarthritis, and rheumatoid arthritis); other rheumatic diseases (including dermatomyositis, Still's disease, and juvenile idiopathic arthritis); and kidney-related diseases (including hyperoxaluria, lupus nephritis, hypertensive nephropathy, hemodialysis-associated inflammation, diabetic nephropathy, diabetic kidney disease, and other inflammatory diseases) (Miyamae T. Paediatr Drugs, April 1, 2012, 14(2): 109-17; Szabo G and Petrasek J. Nat Rev Gastroenterol). Hepatol, July 2015; 12(7):387-400; Zhen Y and Zhang H. Front Immunol, February 28, 2019; 10:276; VandeWalle L et al., Nature, August 7, 2014; 512(7512):69-73; Knauf et al., Kidney Int, November 2013; 84(5):895-901; Krishnan et al., Br J Pharmacol, February 2016; l 73(4):752-65); Shahzad et al., Kidney Int, January 2015; 87(1):74-84; Jankovic et al., J Exp Med. September 23, 2013; 210(10):1899-910). The occurrence and progression of neuroinflammatory conditions (such as brain infections, acute injuries, multiple sclerosis, amyotrophic lateral sclerosis, and other neurodegenerative diseases such as Parkinson's and Alzheimer's) are also associated with NLRP3 inflammasome activation (Sarkar et al., NPJ Parkinsons Dis, 2017 Oct 17; 3:30).

[0007] Cardiovascular and metabolic disorders (such as atherosclerosis, type I and II diabetes and diabetic complications including 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, Sep 21, 2017; 377(12):1119-1131; and Toldo S and Abbate A, Nat Rev Cardiol, Apr 2018; l5(4):203-214). NLRP3-associated skin conditions include wound healing and scar formation; inflammatory skin conditions (such as acne, atopic dermatitis, hidradenitis suppurativa, and psoriasis) (Kelly et al., Br J Dermatol, Dec 2015; l 73(6)). NLRP3 inflammasome activity has also been associated with respiratory conditions such as asthma, sarcoidosis, acute respiratory distress syndrome, and severe acute respiratory syndrome (SARS) (Nieto-Torres et al., Virology, Nov 2015; 485:330-9) and eye diseases including age-related macular degeneration (AMD) and diabetic retinopathy (Doyle et al., Nat Med, May 2012; 18(5):791-8). Cancers associated with NLRP3 include myeloproliferative neoplasms, leukemia, myelodysplastic syndromes, myelofibrosis, lung cancer, and colon cancer (Ridker et al., Lancet, Oct 21, 2017; 390(10105): 1833-1842; Derangere et al., Cell Death Differ. Dec 2014; 21(12): 1914-24; Basiorka et al., Lancet Haematol, Sep 2018; 5(9): e393-e402; Zhang et al., Hum Immunol, Jan 2018; 79(1): 57-62).

[0008] Immune diseases and inflammatory conditions are often difficult to diagnose or treat efficiently and effectively. Most treatments include symptom management, slowing disease progression, lifestyle modifications, and surgery.

[0009] For diseases and conditions associated with NLRP3 inflammasome activation and dysregulation, NLRP3 inhibitors remain needed to provide novel treatments. Compounds of Formula I may be used to treat and prevent diseases, conditions, and lesions mediated by the formation and spread of NLRP3 inflammasomes.

[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 describe NLRP3 inhibitors, including 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 US 11,618,751. Contents

[0011] This development and construction of a new type of compound: , And its pharmaceutically acceptable salts, hydrates and solvates.

[0012] The compound of structure I and its embodiments are inhibitors of NOD-like receptor protein 3 (NLRP3) and can be used to treat and prevent diseases, symptoms and conditions mediated by NLRP3, such as, but not limited to, gout, pseudogout (chondrocalcinosis), cold pyrrolizine-associated periodic syndrome (CAPS), NASH, fibrosis, heart failure, idiopathic pericarditis, atopic dermatitis, inflammatory bowel disease, Alzheimer's disease, Parkinson's disease and traumatic brain injury.

[0013] This disclosure also relates to pharmaceutical compositions comprising a compound of structural formula I or a pharmaceutically acceptable salt, hydrate or solvate thereof and a pharmaceutically acceptable carrier.

[0014] Methods for treating, managing, preventing, alleviating, improving, suppressing or controlling conditions, diseases and illnesses that may respond to inhibition of NLRP3 receptors in subjects in need by administering the compounds and pharmaceutical compositions disclosed herein.

[0015] This disclosure also relates to the use of compounds of structural formula I in the preparation of medicaments for the treatment of diseases, symptoms and conditions that may respond to inhibition of the NLRP3 receptor.

[0016] This disclosure also relates to treating or preventing diseases, symptoms, and conditions by combining a compound of formula I with a therapeutically effective amount of another agent that can be used to treat said diseases, symptoms, and conditions. This disclosure also relates to methods for preparing compounds of formula I. Detailed Implementation

[0017] This disclosure relates to novel compounds of structural formula I: and its pharmaceutically acceptable salts, hydrates and solvates, among which X is selected independently from the following group: (1) =C(R 4 )-,and (2) =N-; R 1 Selected from the following group: (1) -C 3-12 cycloalkyl, (2) -C 3-12 Cycloalkenyl, (3) -C 2-11 Cyclohexane, (4) -C 2-11 Cyclohexene group, (5) Aryl, (6) Mixed aromatics, (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 Cyclohexane, (12) -C 1-6 Alkyl-C 2-11 Cyclohexene group, (13) -C 1-6 alkyl-aryl, and (14) -C 1-6 Alkyl-heteroaryl, Where R 1 Not replaced or selected from one to six R a The substituents are replaced; R 2 Selected from the following group: (1) Hydrogen, (2) CN, (3) -CF3, (4) -CHF2, (5) -C 1-6 Alkyl groups, and (6) Halogens, Wherein the alkyl group is unsubstituted or is selected from one to five R... b The substituents are replaced; R 3 Selected from the following group: (1) Aryl, and (2) Mixed aryl, Among them, the aryl and heteroaryl groups are either unsubstituted or selected from one to five R groups. c The substituents are replaced; R 4 Selected from the following group: (1) Hydrogen, (2) CN, (3) -C 1-6 alkyl, (4) -OC 1-6 Alkyl groups, and (5) Halogens, Each alkyl group is unsubstituted or is selected from one to five R. dThe substituents are replaced; R 5 Selected from the following group: (1) Hydrogen, (2) CN, (3) -C 1-6 alkyl, (4) -OC 1-6 Alkyl groups, and (5) Halogens, Each alkyl group is unsubstituted or is selected from one to five R. e The substituents are replaced; Each R a Select independently from the following groups: (1) CN, (2) Oxygenation, (3) -OH, (4) Halogens, (5) -C 1-6 alkyl, (6) -C 1-6 Alkyl-OH, (7) -OC 1-6 alkyl, (8) -C 3-6 cycloalkyl, (9) -C 2-6 Cyclohexane, (10) Aryl, (11) Mixed aromatics, (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 Cyclohexane, (18) -(CH2) p -OC 1-6 alkyl, (19) -(CH2) p -OC 3-6 cycloalkyl, (20) -(CH2) p -OC2-6 Cyclohexane, (21) -(CH2) p -O-aryl, (22) -(CH2) p -O-heteroaryl, (23) -(CH2) p -S(O) r R f ,and (24) -N(R g )2, Each R a Unsubstituted or selected from one to six halogens, CF3, OH, C 1-6 Alkyl and -OC 1-6 Substituents of alkyl groups; Each R b Select independently from the following groups: (1) CF3, (2) Halogens, (3) -C 1-6 Alkyl groups, and (4) -C 3-6 cycloalkyl; Each R c Select independently from the following groups: (1) CN, (2) -OH, (3) Oxygenation, (4) Halogens, (5) -C 1-6 alkyl, (6) -OC 1-6 alkyl, (7) -C 3-6 cycloalkyl, (8) -C 2-6 Cyclohexane, (9) Aryl, (10) Mixed aromatics, (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 Cyclohexane, (15) -(CH2) q -OC1-6 alkyl, (16) -(CH2) q -OC 3-6 cycloalkyl, (17) -(CH2) q -OC 2-6 Cyclohexane, (18) -(CH2) q -O-aryl, (19) -(CH2) q -O-heteroaryl, (20) -OC 1-6 Alkyl-C 3-6 cycloalkyl, (21) -OC 1-6 Alkyl-C 2-6 Cyclohexane, (22) -OC 1-6 Alkyl-aryl, (23) -OC 1-6 Alkyl-heteroaryl, (24) -(CH2) q -S(O) r R h , (25) -N(R i )2, (26) -C(O)R j ,and (27) -C(O)NR i , Each R c Unsubstituted or selected from one to six halogens, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 Substituents of alkyl groups; Each R d Select independently from the following groups: (1) Hydrogen, (2) OH (3) Halogens, and (4) -C 1-6 alkyl; Each R e Select independently from the following groups: (1) Hydrogen, (2) OH, (3) Halogens, and (4) -C 1-6 alkyl; Each Rf Select independently from the following groups: (1) Hydrogen, (2) -C 1-6 alkyl, (3) -C 3-6 cycloalkyl, and (4) -C 2-6 Cycloalkyl; Each R g Select independently from the following groups: (1) Hydrogen, (2) -C 1-6 alkyl, (3) -C 3-6 cycloalkyl, (4) -C 2-6 Cyclohexane, (5) Aryl, (6) Mixed aromatics, (7) -C(O)C 1-6 Alkyl groups, and (8) -S(O) r R f , The alkyl group may be unsubstituted or substituted with one to three substituents selected from the following: CF3, halogen, OH, and -OC. 1-6 alkyl; Each R h Select independently from the following groups: (1) Hydrogen, (2) -C 1-6 alkyl, (3) -C 3-6 cycloalkyl, and (4) -C 2-6 Cycloalkyl; Each R i Select independently from the following groups: (1) Hydrogen, (2) -C 1-6 alkyl, (3) -C 3-6 cycloalkyl, and (4) -C 2-6 Cycloalkyl; Each R j Select independently from the following groups: (1) OH, (2) -C 1-6 alkyl, (3) -C 3-6 cycloalkyl, and (4) -C 2-6Cyclohexane, The alkyl group may be unsubstituted or substituted with one to three substituents selected from the following: CF3, halogen, OH, and -OC. 1-6 alkyl; p is 0, 1, 2, 3, 4, 5 or 6; q is 0, 1, 2, 3, 4, 5, or 6; and r is 1 or 2.

[0018] This disclosure has many embodiments, summarized below. This disclosure includes compounds as shown, and also includes individual diastereomers, enantiomers, and epimers of the compounds, as well as mixtures of their diastereomers and / or enantiomers, including racemic mixtures.

[0019] In another embodiment of the invention, X is independently selected from the group consisting of: =C(R) 4 )- and =N-. In one type of this implementation, X is =C(R) 4 In another type of implementation, X is =N-.

[0020] In one implementation, R 1 Selected from the following group: -C 3-12 cycloalkyl, -C 3-12 Cycloalkenyl, -C 2-11 Cycloalkyl, -C 2-11 Cyclohexene, 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-C 2-11 Cycloalkyl, -C 1-6 Alkyl-C 2-11 Cyclohexene, -C 1-6 Alkyl-aryl and -C 1-6 alkyl-heteroaryl, wherein R 1 Not replaced or selected from one to six R a The substituents are replaced by the substituents.

[0021] In another implementation, R 1 Selected from the following group: -C 3-12 cycloalkyl, -C 2-11 Cycloalkyl, aryl, heteroaryl, -C 1-6 Alkyl, -C 1-6 Alkyl -OH, -C 1-6 Alkyl-C 3-12 cycloalkyl, -C 1-6Alkyl-C 2-11 Cycloalkyl, -C 1-6 Alkyl-aryl and -C 1-6 alkyl-heteroaryl, wherein R 1 Not replaced or selected from one to six R a The substituents are replaced by the substituents.

[0022] In another implementation, R 1 Selected from the following group: -C 3-12 cycloalkyl, -C 2-11 Cycloalkyl, 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 Cyclohexane, wherein R 1 Not replaced or selected from one to six R a The substituents are replaced by the substituents.

[0023] In another implementation, R 1 Selected from the following group: -C 3-12 cycloalkyl, -C 2-11 Cycloalkyl, 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 Cyclohexane, wherein R 1 Not replaced or selected from one to six R a The substituents are replaced by the substituents.

[0024] In another implementation, R 1 Selected from the following group: -C 3-12 cycloalkyl, -C 2-11 Cycloalkyl, heteroaryl, -C 1-6 Alkyl -OH, -C 1-6 Alkyl-C 3-12 cycloalkyl and -C 1-6 Alkyl-C 2-11 Cyclohexane, wherein R 1 Not replaced or selected from one to six R a The substituents are replaced by the substituents.

[0025] In another implementation, R 1 Selected from the following group: -C 3-12 cycloalkyl, -C 2-11 Cycloalkyl, -C 1-6 Alkyl-C3-12 cycloalkyl and -C 1-6 Alkyl-C 2-11 Cyclohexane, wherein R 1 Not replaced or selected from one to six R a The substituents are replaced by the substituents.

[0026] In another implementation, R 1 Selected from the following group: -C 3-12 cycloalkyl and -C 2-11 Cyclohexane, wherein R 1 Not replaced or selected from one to six R a The substituents are replaced. In one type of this embodiment, R 1 Selected from the following group: bicyclo[3.1.1]heptane, piperidine, 8-azabicyclo[3.2.1]octane and octahydroindazine, wherein R 1 Not replaced or selected from one to six R a The substituents are replaced by the substituents.

[0027] In another implementation, R 1 -C 3-12 cycloalkyl, wherein R 1 Not replaced or selected from one to six R a The substituents are replaced. In one type of this embodiment, R 1 It is a bicyclic [3.1.1]heptane, wherein the bicyclic [3.1.1]heptane is unsubstituted or has one to six components selected from R. a The substituents are replaced by the substituents.

[0028] In another implementation, R 1 C 2-11 Cyclohexaalkyl groups, wherein the cyclohexaalkyl groups are unsubstituted or composed of one to six radicals selected from R. a The substituents are replaced. In one type of this embodiment, R 1 Piperidine, wherein the piperidine is unsubstituted or is selected from one to six R... a The substituents are replaced. In another type of this embodiment, R 1 Selected from the group consisting of piperidine, 8-azabicyclo[3.2.1]octane and octahydroindazine, wherein R 1 Not replaced or selected from one to six R a The substituents are replaced by the substituents.

[0029] In another implementation, R 2 Selected from the following groups: hydrogen, CN, -CF3, -CHF2, -C 1-6 Alkyl and halogen, wherein R 2 Not replaced or selected from one to five R b The substituents are replaced. In one type of this embodiment, R2 Selected from the following group: hydrogen and -C 1-6 Alkyl groups, wherein the alkyl group is unsubstituted or composed of one to five radicals selected from R. b The substituent is replaced. In a subclass of this class, R 2 It is hydrogen or -CH3, wherein -CH3 is unsubstituted or is selected from one to three R. b The substituents are replaced. In another type of this embodiment, R 2 -C 1-6 Alkyl, wherein R 2 Not replaced or selected from one to five R b The substituent is replaced. In a subclass of this class, R 2 It is -CH3, where R 2 Not replaced or selected from one to three R b The substituents are replaced. In another type of this embodiment, R 2 It is hydrogen.

[0030] In another embodiment of the invention, R 3 Selected from the following group: aryl and heteroaryl, wherein R 3 Not replaced or selected from one to five R c The substituents are replaced. In one type of this embodiment, R 3 Selected from the following group: phenyl, benzothiophene, and indene, wherein R 3 Not replaced or selected from one to five R c The substituents are replaced by the substituents.

[0031] In another implementation, R 3 It is a heteroaryl group, wherein the heteroaryl group is unsubstituted or is selected from one to five R groups. c The substituents are replaced. In one type of this embodiment, R 3 It is benzothiophene, where R 3 Not replaced or selected from one to five R c The substituents are replaced by the substituents.

[0032] In another implementation, R 3 It is an aryl group, wherein the aryl group is unsubstituted or is selected from one to five R groups. c The substituents are replaced. In one type of this embodiment, R 3 It is phenyl or indene, wherein R 3 Not replaced or selected from one to five R c The substituents are replaced. In another type of this embodiment, R 3 It is a phenyl group, which is unsubstituted or has one to five derivatives selected from R. c The substituents are replaced. In another type of this embodiment, R 3For indene, which is not replaced or is selected from one to five R... c The substituents are replaced by the substituents.

[0033] In another embodiment of the invention, R 4 Selected from the following groups: hydrogen, CN, -C 1-6 Alkyl, -OC 1-6 Alkyl groups and halogens, wherein each alkyl group is unsubstituted or composed of one to five radicals selected from R. d The substituents are replaced by the substituents.

[0034] In another embodiment of the invention, R 4 It is hydrogen or -C 1-6 Alkyl groups, wherein each alkyl group is unsubstituted or composed of one to five radicals selected from R. d The substituents are replaced by the substituents.

[0035] In another embodiment of the invention, R 4 -C 1-6 Alkyl groups, wherein each alkyl group is unsubstituted or composed of one to five radicals selected from R. d The substituents are replaced by the substituents.

[0036] In another embodiment of the invention, R 4 It is hydrogen.

[0037] In another embodiment of the invention, R 5 Selected from the following groups: hydrogen, CN, -C 1-6 Alkyl, -OC 1-6 Alkyl groups and halogens, wherein each alkyl group is unsubstituted or composed of one to five radicals selected from R. e The substituents are replaced by the substituents.

[0038] In another embodiment of the invention, R 5 Selected from the following groups: hydrogen, CN, -C 1-6 Alkyl, -OC 1-6 Alkyl groups and halogens, wherein each alkyl group is unsubstituted or composed of one to five radicals selected from R. e The substituents are replaced by the substituents.

[0039] In another embodiment of the invention, R 5 It is hydrogen or -C 1-6 Alkyl groups, wherein each alkyl group is unsubstituted or composed of one to five radicals selected from R. e The substituents are replaced. In one type of this embodiment, R 5 It is hydrogen or -CH3.

[0040] In another embodiment of the invention, R 5 -C 1-6 Alkyl groups, wherein each alkyl group is unsubstituted or composed of one to five radicals selected from R.e The substituents are replaced. In one type of this embodiment, R 5 It is -CH3.

[0041] In another embodiment of the invention, R 5 It is hydrogen.

[0042] In another implementation, each R a Independently selected from the following groups: CN, oxo, -OH, halogen, -C 1-6 Alkyl, -C 1-6 Alkyl-OH, -OC 1-6 Alkyl, -C 3-6 cycloalkyl, -C 2-6 Cycloalkyl, 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 Cyclohexane, -(CH2) p -OC 1-6 Alkyl group, -(CH2) p -OC 3-6 Cycloalkyl, -(CH2) p -OC 2-6 Cyclohexane, -(CH2) p -O-aryl, -(CH2) p -O-heteroaryl, -(CH2) p -S(O) r R f and -N(R) g )2, where each R a Unsubstituted or selected from one to six halogens, CF3, OH, C 1-6 Alkyl and -OC 1-6 Alkyl groups are substituted.

[0043] In another implementation, each R a Independently selected from the following groups: CN, oxo, -OH, halogen, -C 1-6 Alkyl, -C 1-6 Alkyl-OH, -OC 1-6 Alkyl, -C 3-6 cycloalkyl, -C 2-6 Cycloalkyl, aryl, heteroaryl, -C 1-6 Alkyl-aryl, -C 1-6 Alkyl-heteroaryl, -C1-6 Alkyl-C 3-6 cycloalkyl, -C 1-6 Alkyl-C 2-6 Cyclohexane, -(CH2) p -S(O) r R f and -N(R) g )2, where each R a Unsubstituted or selected from one to six halogens, CF3, OH, C 1-6 Alkyl and -OC 1-6 Alkyl groups are substituted.

[0044] In another implementation, each R a Independently selected from the following groups: CN, oxo, -OH, halogen, -C 1-6 Alkyl, -C 1-6 Alkyl-OH, -OC 1-6 Alkyl, -C 3-6 cycloalkyl, -C 2-6 Cycloalkyl, -C 1-6 Alkyl-C 3-6 cycloalkyl, -C 1-6 Alkyl-C 2-6 Cyclohexane, -(CH2) p -S(O) r R f and -N(R) g )2, wherein each CH2, alkyl, cycloalkyl, and heteroalkyl group is independently unsubstituted or surrounded by one to six groups selected from halogens, CF3, OH, C 1-6 Alkyl and -OC 1-6 Alkyl groups are substituted.

[0045] In another implementation, each R a Independently selected from the following groups: CN, oxo, -OH, halogen, -C 1-6 Alkyl, -C 1-6 Alkyl-OH, -OC 1-6 Alkyl, -C 3-6 cycloalkyl, -C 2-6 Cycloalkyl, aryl, heteroaryl, -C 1-6 Alkyl-C 3-6 cycloalkyl, -C 1-6 Alkyl-C 2-6 Cyclohexane, -(CH2) p -S(O) r R f and -N(R) g )2, wherein each CH2, alkyl, cycloalkyl, and heteroalkyl group is independently unsubstituted or surrounded by one to six groups selected from halogens, CF3, OH, C1-6 Alkyl and -OC 1-6 Alkyl groups are substituted.

[0046] In another implementation, each R a Independently selected from the following groups: CN, oxo, -OH, halogen, -C 1-6 Alkyl, -C 1-6 Alkyl-OH, -OC 1-6 Alkyl, -C 3-6 cycloalkyl, -C 2-6 Cycloalkyl, aryl, heteroaryl, -C 1-6 Alkyl-C 3-6 cycloalkyl and -C 1-6 Alkyl-C 2-6 Cyclohexaalkyl, wherein each CH2, alkyl, cycloalkyl and cyclohexaalkyl group is independently unsubstituted or surrounded by one to six elements selected from halogens, CF3, OH, C 1-6 Alkyl and -OC 1-6 Alkyl groups are substituted.

[0047] In another implementation, each R a Independently selected from the following groups: 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 )2, wherein each CH2, alkyl and cycloalkyl group is independently unsubstituted or substituted by one to six groups selected from halogens, CF3, OH, C 1-6 Alkyl and -OC 1-6 Alkyl groups are substituted.

[0048] In another implementation, each R a Independently selected from the following groups: 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 Cycloalkyl, wherein each CH2, alkyl, and cycloalkyl group is independently unsubstituted or surrounded by one to six elements selected from halogens, CF3, OH, C. 1-6 Alkyl and -OC 1-6 Alkyl groups are substituted.

[0049] In another implementation, each R a Independently selected from the following groups: -OH, -C 1-6 Alkyl and -C 3-6 Cycloalkyl groups, wherein each alkyl group and the cycloalkyl group are independently unsubstituted or surrounded by one to six elements selected from halogens, CF3, OH, C. 1-6 Alkyl and -OC 1-6 The alkyl group is substituted. In one type of embodiment, each R... a Independently selected from the group consisting of -OH, -CH3, -CD3, -CH2CH3, -CH(CH3)2, and cyclobutyl. In another type of embodiment, each R a Independently selected from the group consisting of -OH, -CH3, -CH2CH3, -CH(CH3)2, and cyclobutyl. In another type of embodiment, each R a Independently selected from the group consisting of -OH, -CH3, -CD3, -CH2CH3, and -CH(CH3)2. In another type of embodiment, each R a It is independently selected from the following groups: -OH, -CH3, -CH2CH3 and -CH(CH3)2.

[0050] In another implementation, each R a -OH or -C 1-6 Alkyl groups, wherein each alkyl group is unsubstituted or composed of one to six radicals selected from halogens, CF3, OH, C 1-6 Alkyl and -OC 1-6 The alkyl group is substituted. In one type of embodiment, each R... a It is independently selected from the following groups: -OH, -CH3 and -CH2CH3.

[0051] In another implementation, each R a It is -OH.

[0052] In another implementation, each R a -C 1-6 Alkyl groups, wherein each alkyl group is unsubstituted or composed of one to six radicals selected from halogens, CF3, OH, C 1-6 Alkyl and -OC 1-6 The alkyl group is substituted. In one type of embodiment, each R... a It is -CH3 or -CH2CH3.

[0053] In another embodiment of the invention, each R b Independently selected from the following groups: CF3, halogen, -C 1-6 Alkyl and -C 3-6 Cycloalkyl. In one type of this embodiment, each R bIndependently selected from the following group: CF3, halogens, and -C 1-6 Alkyl groups. In another type of this embodiment, each R b For CF3. In another type of this implementation, each R b For halogens. In another type of this embodiment, each R... b -C 1-6 alkyl.

[0054] In another embodiment of the invention, each R c Independently selected from the following groups: CN, -OH, oxo, halogen, -C 1-6 Alkyl, -OC 1-6 Alkyl, -C 3-6 cycloalkyl, -C 2-6 Cycloalkyl, 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 Cyclohexane, -(CH2) q -OC 1-6 Alkyl group, -(CH2) q -OC 3-6 Cycloalkyl, -(CH2) q -OC 2-6 Cyclohexane, -(CH2) q -O-aryl, -(CH2) q -O-heteroaryl, -OC 1-6 Alkyl-C 3-6 cycloalkyl, -OC 1-6 Alkyl-C 2-6 Cycloalkyl, -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 , where each R c Unsubstituted or selected from one to six halogens, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 Alkyl groups are substituted.

[0055] In another implementation, each R cIndependently selected from the following groups: CN, -OH, oxo, halogen, -C 1-6 Alkyl, -OC 1-6 Alkyl, -C 3-6 cycloalkyl, -C 2-6 Cycloalkyl, aryl, heteroaryl, -(CH2) q -S(O) r R h -N(R) i )2、-C(O)R j and -C(O)NR i , where each R c Unsubstituted or selected from one to six halogens, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 Alkyl groups are substituted.

[0056] In another implementation, each R c Independently selected from the following groups: CN, -OH, oxo, halogen, -C 1-6 Alkyl, -OC 1-6 Alkyl group, -(CH2) q -S(O) r R h -N(R) i )2、-C(O)R j and -C(O)NR i Each alkyl group is unsubstituted or is selected from one to six alkyl groups selected from halogens, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 Alkyl groups are substituted.

[0057] In another implementation, each R c Independently selected from the following groups: CN, -OH, oxo, halogen, -C 1-6 Alkyl, -OC 1-6 Alkyl, -C 3-6 cycloalkyl and -N(R) i )2, where each R c Unsubstituted or selected from one to six halogens, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 The alkyl group is substituted. In one type of embodiment, each R... c Independently selected from the group consisting of: -OH, Cl, F, -CH3, -CF3, -OCHF2, cyclopropyl, and NH2. In another type of embodiment, each R cIt is independently selected from the following groups: -OH, Cl, -CH3, -CF3 and -OCHF2.

[0058] In another implementation, each R c Independently selected from the following groups: -OH, halogen, -C 1-6 Alkyl, -C 3-6 cycloalkyl and -N(R) i )2, where each R c Unsubstituted or selected from one to six halogens, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 The alkyl group is substituted. In one type of embodiment, each R... c Independently selected from the group consisting of: -OH, Cl, F, -CH3, -CF3, -OCHF2, cyclopropyl, and NH2. In another type of embodiment, each R c It is independently selected from the following groups: -OH, Cl, -CH3, -CF3 and -OCHF2.

[0059] In another implementation, each R c Independently selected from the following groups: -OH, halogen, -C 1-6 Alkyl and -OC 1-6 Alkyl groups, wherein each alkyl group is unsubstituted or is composed of one to six elements selected from halogens, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 The alkyl group is substituted. In one type of embodiment, each R... c Independently selected from the group consisting of -OH, Cl, F, -CH3, -CF3, and -OCHF2. In another type of this embodiment, each R c It is independently selected from the following groups: -OH, Cl, -CH3, -CF3 and -OCHF2.

[0060] In another implementation, each R c Independently selected from the following groups: -OH and -C 1-6 Alkyl groups, wherein each alkyl group is unsubstituted or is composed of one to six elements selected from halogens, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 The alkyl group is substituted. In one type of embodiment, each R... c It is independently selected from the following groups: -OH, -CH3, and -CF3.

[0061] In another implementation, each R c It is selected independently from the group: -OH.

[0062] In another implementation, each R c Select independently from the following group: -C 1-6 Alkyl groups, wherein each alkyl group is unsubstituted or is composed of one to six elements selected from halogens, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 The alkyl group is substituted. In one type of embodiment, each R... c It is independently selected from the following groups: -OH, -CH3, and -CF3.

[0063] In another embodiment of the invention, each R d Independently selected from the following group: hydrogen, OH, halogens and -C 1-6 Alkyl group. In another embodiment of the invention, each R d Independently selected from the following group: hydrogen, halogens, and -C 1-6 Alkyl group. In another embodiment of the invention, each R d Independently selected from the following groups: hydrogen and -C 1-6 Alkyl. In one type of this embodiment, each R d -C 1-6 Alkyl groups. In another type of this embodiment, each R d It is hydrogen.

[0064] In another embodiment of the invention, each R e Independently selected from the following group: hydrogen, OH, halogens and -C 1-6 Alkyl group. In another embodiment of the invention, each R e Independently selected from the following group: hydrogen, halogens, and -C 1-6 Alkyl group. In another embodiment of the invention, each R e Independently selected from the following groups: hydrogen and -C 1-6 Alkyl. In one type of this embodiment, each R e -C 1-6 Alkyl groups. In another type of this embodiment, each R e It is hydrogen.

[0065] In another implementation, each R f Independently selected from the following group: hydrogen, -C 1-6 Alkyl, -C 3-6 cycloalkyl and -C 2-6 Cyclohexaalkyl. In another embodiment, each R f Independently selected from the following groups: hydrogen and -C 1-6 Alkyl. In one type of this embodiment, each R fIndependently selected from the group consisting of hydrogen and CH3. In another embodiment, each R f -C 1-6 Alkyl. In one type of this embodiment, each R f For CH3. In another implementation, each R f It is hydrogen.

[0066] In another embodiment of the invention, each R g Independently selected from the following group: hydrogen, -C 1-6 Alkyl, -C 3-6 cycloalkyl, -C 2-6 Cycloalkyl, aryl, heteroaryl, -C(O)C 1-6 Alkyl groups and -S(O) r R f The alkyl, cycloalkyl, cyclohexyl, aryl, and heteroaryl groups may be unsubstituted or substituted by one to three substituents selected from the following: CF3, halogen, OH, and -OC. 1-6 Alkyl. In one type of this embodiment, each R g Independently selected from the following group: hydrogen, -C 1-6 Alkyl, -C 3-6 cycloalkyl, -C 2-6 Cycloalkyl, -C(O)C 1-6 Alkyl groups and -S(O) r R f The alkyl, cycloalkyl, and heteroalkyl groups may be unsubstituted or substituted with one to three substituents selected from the following: CF3, halogen, OH, and -OC. 1-6 alkyl.

[0067] In another implementation, each R g Independently selected from the following group: hydrogen, -C 1-6 Alkyl, -C(O)C 1-6 Alkyl groups and -S(O) r R f The alkyl group may be unsubstituted or substituted with one to three substituents selected from the following: CF3, halogen, OH and -OC. 1-6 Alkyl group. In another embodiment, each R g It is hydrogen or -C 1-6 Alkyl group, wherein the alkyl group may be unsubstituted or substituted by one to three substituents selected from the following: CF3, halogen, OH and -OC. 1-6 Alkyl. In one type of this embodiment, each R g -C 1-6 Alkyl group, wherein the alkyl group may be unsubstituted or substituted by one to three substituents selected from the following: CF3, halogen, OH and -OC. 1-6 Alkyl groups. In another type of this embodiment, each Rg It is hydrogen.

[0068] In another embodiment of the invention, each R h Independently selected from the following group: hydrogen, -C 1-6 Alkyl, -C 3-6 cycloalkyl and -C 2-6 Cyclohexaalkyl. In another embodiment, each R h Independently selected from the following groups: hydrogen and -C 1-6 Alkyl. In one type of this embodiment, each R h Independently selected from the group consisting of hydrogen and CH3. In another embodiment, each R h -C 1-6 Alkyl. In one type of this embodiment, each R h For CH3. In another implementation, each R h It is hydrogen.

[0069] In another embodiment of the invention, each R i Independently selected from the following group: hydrogen, -C 1-6 Alkyl, -C 3-6 cycloalkyl and -C 2-6 Cyclohexaalkyl. In another embodiment, each R i Independently selected from the following groups: hydrogen and -C 1-6 Alkyl. In one type of this embodiment, each R i Independently selected from the group consisting of hydrogen and CH3. In another embodiment, each R i -C 1-6 Alkyl. In one type of this embodiment, each R i For CH3. In another implementation, each R i It is hydrogen.

[0070] In another embodiment of the invention, each R j Independently selected from the following groups: OH, -C 1-6 Alkyl, -C 3-6 cycloalkyl and -C 2-6 Cyclohexaalkyl, wherein the alkyl, cycloalkyl, and cyclohexaalkyl groups may be unsubstituted or substituted by one to three substituents selected from the following: CF3, halogen, OH, and -OC. 1-6 Alkyl group. In another embodiment of the invention, each R j Independently selected from the following groups: OH, -C 1-6 Alkyl, -C 3-6 cycloalkyl and -C 2-6 Cyclohexaalkyl. In another embodiment, each R j Independently selected from the following groups: OH and -C 1-6Alkyl. In one type of this embodiment, each R j Independently selected from the group consisting of OH and CH3. In another embodiment, each R j -C 1-6 Alkyl. In one type of this embodiment, each R j For CH3. In another implementation, each R j It is OH.

[0071] 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.

[0072] 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.

[0073] In another embodiment, r is 1 or 2. In another embodiment, r is 1. In another embodiment, r is 2.

[0074] In another embodiment, this disclosure relates to compounds of structural formula Ia: , Or its pharmaceutically acceptable salts, hydrates or solvates.

[0075] In another embodiment, this disclosure relates to compounds of structural formula Ib: , Or its pharmaceutically acceptable salts, hydrates or solvates.

[0076] In another embodiment, this disclosure relates to compounds of structural formula Ic: , Or its pharmaceutically acceptable salts, hydrates or solvates.

[0077] In another embodiment, this disclosure relates to compounds of structural formula Id: , Or its pharmaceutically acceptable salts, hydrates or solvates.

[0078] In another embodiment, this disclosure relates to compounds of structural formula Ie: , Or its pharmaceutically acceptable salts, hydrates or solvates.

[0079] Compounds of structural formula I include compounds of structural formulas Ia, Ib, Ic, Id, and Ie, as well as their pharmaceutically acceptable salts, hydrates, and solvates.

[0080] In another embodiment, this disclosure relates to compounds of structural formula I, wherein: X is =C(R) 4 )- or =N-; R 1 Selected from the following group: (1) -C 3-12 cycloalkyl, (2) -C 2-11 Cyclohexane, (3) Mixed aryl, (4) -C 1-6 Alkyl-OH, (5) -C 1-6 Alkyl-C 3-12 cycloalkyl, and (6) -C 1-6 Alkyl-C 2-11 Cyclohexane, Where R 1 Not replaced or selected from one to six R a The substituents are replaced; R 2 Selected from the following group: hydrogen and -C 1-6Alkyl groups, wherein the alkyl group is unsubstituted or composed of one to five radicals selected from R. b The substituents are replaced; R 3 It is a heteroaryl group, wherein the heteroaryl group is unsubstituted or is selected from one to five R groups. c The substituents are replaced; R 4 It is hydrogen or -C 1-6 Alkyl groups, wherein each alkyl group is unsubstituted or composed of one to five radicals selected from R. d The substituents are replaced by the substituents; and R 5 It is hydrogen or -C 1-6 Alkyl groups, wherein each alkyl group is unsubstituted or composed of one to five radicals selected from R. e The substituents are replaced; And the other substituents are as defined above; Or its pharmaceutically acceptable salts, hydrates and solvates.

[0081] In another embodiment, this disclosure relates to compounds of structural formula I, wherein: X is =C(R) 4 )- or =N-; R 1 C 2-11 Cyclohexaalkyl groups, wherein the cyclohexaalkyl groups are unsubstituted or composed of one to six radicals selected from R. a The substituents are replaced; R 2 Selected from the following group: hydrogen and -C 1-6 Alkyl groups, wherein the alkyl group is unsubstituted or composed of one to five radicals selected from R. b The substituents are replaced; R 3 It is an aryl group, wherein the aryl group is unsubstituted or is selected from one to five R groups. c The substituents are replaced; R 4 It is hydrogen; and R 5 It is hydrogen; And the other substituents are as defined above; Or its pharmaceutically acceptable salts, hydrates and solvates.

[0082] In another embodiment, this disclosure relates to compounds of structural formula I, wherein: X is =N-; R 1 C 2-11 Cyclohexaalkyl groups, wherein the cyclohexaalkyl groups are unsubstituted or composed of one to six radicals selected from R. a The substituents are replaced; R 2Selected from the following group: hydrogen and -C 1-6 Alkyl groups, wherein the alkyl group is unsubstituted or composed of one to five radicals selected from R. b The substituents are replaced; R 3 It is an aryl group, wherein the aryl group is unsubstituted or is selected from one to five R groups. c The substituents are replaced; R 4 It is hydrogen; and R 5 It is hydrogen; And the other substituents are as defined above; Or its pharmaceutically acceptable salts, hydrates and solvates.

[0083] Illustrative but non-limiting examples of the compounds disclosed herein that can be used as inhibitors of NLRP3 include the following compounds: (1) ( R )-2-(7-(1-ethylpiperidin-3-yl)-7 H -pyrrolo[2,3- c ]pyridazine-3-yl)-3-methyl-5-(trifluoromethyl)phenol; (2) ( R )-2-(7-(1-ethylpiperidin-3-yl)-4-methyl-7 H -pyrrolo[2,3- c ]pyridazine-3-yl)-5-(trifluoromethyl)phenol; (3) ( R )-2-(7-(1-ethylpiperidin-3-yl)-7 H -imidazo[4,5- c ]pyridazine-3-yl)-3-methyl-5-(trifluoromethyl)phenol; (4) R )-3-methyl-2-(7-(1-methylpiperidin-3-yl)-7 H -imidazo[4,5- c ]pyridazine-3-yl)-5-(trifluoromethyl)phenol; (5) S )-3-methyl-2-(7-(1-methylpiperidin-3-yl)-7 H -imidazo[4,5- c ]pyridazine-3-yl)-5-(trifluoromethyl)phenol; (6) ( R )-2-(4-methyl-7-(piperidin-3-yl)-7 H -imidazo[4,5- c ]pyridazine-3-yl)-5-(trifluoromethyl)phenol; (7) (3 S 4 R )-3-(3-(2-hydroxy-4-(trifluoromethyl)phenyl)-4-methyl-7 H -imidazo[4,5- c ]pyridazine-7-yl)piperidin-4-ol; (8) R )-2-(7-(1-ethylpiperidin-3-yl)-4-methyl-7 H -imidazo[4,5- c ]pyridazine-3-yl)-5-(trifluoromethyl)phenol; (9) R )-2-(7-(1-methylpiperidin-3-yl)-7 H -imidazo[4,5- c ]pyridazine-3-yl)-5-(trifluoromethyl)phenol; (10) ( S )-2-(7-(1-methylpiperidin-3-yl)-7 H -imidazo[4,5- c ]pyridazine-3-yl)-5-(trifluoromethyl)phenol; (11) ( R )-3-(2-(difluoromethoxy)-4-(trifluoromethyl)phenyl)-7-(1-ethylpiperidin-3-yl)-4-methyl-7 H -imidazo[4,5- c ]pyridazine; (12) ( R )-2-(4-methyl-7-(1-methylpiperidin-3-yl)-7 H -imidazo[4,5- c ]pyridazine-3-yl)-5-(trifluoromethyl)phenol; (13) (3 S 4 R )-3-(3-(2-hydroxy-4-(trifluoromethyl)phenyl)-4-methyl-7 H -imidazo[4,5- c ]pyridazine-7-yl)-1-methylpiperidin-4-ol; and (14) (3 S 4 R )-1-Ethyl-3-(3-(2-hydroxy-4-(trifluoromethyl)phenyl)-4-methyl-7 H -imidazo[4,5- c ]pyridazine-7-yl)piperidin-4-ol; (15) ( R )-5-chloro-2-(4-methyl-7-(piperidin-3-yl)-7H -imidazo[4,5- c ]pyridazine-3-yl)phenol; (16) ( R )-2-(4,6-dimethyl-7-(1-methylpiperidin-3-yl)-7 H -imidazo[4,5- c ]pyridazine-3-yl)-5-(trifluoromethyl)phenol; (17) ( R )-5-(4-methyl-7-(1-methylpiperidin-3-yl)-7 H -imidazo[4,5- c ]pyridazine-3-yl)benzo[ b Thiophene-4-ol; (18) ( R )-5-(4-methyl-7-(1-methylpiperidin-3-yl)-7 H -imidazo[4,5- c ]pyridazine-3-yl)-2,3-dihydro-1 H -Indene-4-ol; (19) ( R )-5-chloro-2-(4-methyl-7-(1-methylpiperidin-3-yl)-7 H -imidazo[4,5- c ]pyridazine-3-yl)phenol; and (20) ( R )-5-chloro-2-(7-(1-ethylpiperidin-3-yl)-4-methyl-7 H -imidazo[4,5- c ]pyridazine-3-yl)phenol; Or its pharmaceutically acceptable salt.

[0084] Further illustrative but non-limiting examples of the compounds disclosed herein that can be used as inhibitors of NLRP3 include the following compounds: (1)( R )-2-(7-(1-ethylpiperidin-3-yl)-7 H -imidazo[4,5- c ]pyridazine-3-yl)-3-methyl-5-(trifluoromethyl)phenol; (2)( R )-2-(4-methyl-7-(piperidin-3-yl)-7 H -imidazo[4,5- c ]pyridazine-3-yl)-5-(trifluoromethyl)phenol; (3) ( R )-2-(7-(1-ethylpiperidin-3-yl)-4-methyl-7H -imidazo[4,5- c ]pyridazine-3-yl)-5-(trifluoromethyl)phenol; and (4) R )-2-(4-methyl-7-(1-methylpiperidin-3-yl)-7 H -imidazo[4,5- c ]pyridazine-3-yl)-5-(trifluoromethyl)phenol; Or its pharmaceutically acceptable salts, hydrates or solvates.

[0085] While the specific stereochemistry described above is preferred, other stereoisomers, including diastereomers, enantiomers, epiomers, and mixtures thereof, may also be used to treat NLRP3-mediated diseases.

[0086] Synthetic methods for preparing these compounds are disclosed in the examples shown below. Where synthetic details are not provided in the examples, those skilled in the art of medicinal chemistry or synthetic organic chemistry can readily prepare the compounds 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, diastereomers, and mixtures thereof, are also compounds disclosed herein.

[0087] definition “Ac” represents the acetyl group, which is CH3C(=O)-.

[0088] "alkyl" refers to a saturated carbon chain, which can be straight-chain, branched, or a combination thereof, unless otherwise defined. Other groups with the prefix "alkane," such as alkoxy and alkanoyl, can also be straight-chain, branched, or a combination thereof, unless otherwise defined. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, etc. In one embodiment, the alkyl group is methyl or ethyl. In another embodiment, the alkyl group is methyl. In yet another embodiment, the alkyl group is ethyl.

[0089] "Alkenyl" refers to a carbon chain containing at least one carbon-carbon double bond, and can be straight-chain, branched, or a combination thereof, unless otherwise defined. Examples of alkenyl groups include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl, etc.

[0090] "Alynyl" refers to a carbon chain containing at least one carbon-carbon triple bond, and can be straight-chain, branched, or a combination thereof, unless otherwise defined. Examples of alkynyl groups include ethynyl, propynyl, 3-methyl-1-pentynyl, 2-heptyynyl, etc.

[0091] "Cycloalkyl" refers to a saturated monocyclic, bicyclic, spirocyclic, fused, or bridged carbocyclic ring having a specified number of carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. In one embodiment, the cycloalkyl group is -C. 3-12 Cycloalkyl.

[0092] "Cycloalkenyl" refers to a monocyclic, bicyclic, spirocyclic, fused, or bridged carbocyclic ring having a specified number of carbon atoms and at least one double bond. Examples of cycloalkenyl groups include cyclopropene, cyclobutane, cyclopentene, cyclohexene, and cycloheptene.

[0093] "Cyclohexaalkyl" refers to 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 having at least one cyclic heteroatom selected from N, NH, S (including SO and SO2), and O, or having at least one partially unsaturated ring having at least one cyclic heteroatom selected from N, NH, S (including SO and SO2), and O. The cyclohexaalkyl ring may be substituted at the ring carbon and / or ring nitrogen or sulfur. The cyclohexaalkyl ring may be fused to an aryl or heteroaryl ring. Examples of cyclohexaalkyl include tetrahydrofuranyl, pyrroliyl, tetrahydrothiophenyl, aziridine, piperazine, piperidinyl, morpholinyl, oxacyclobutane, and tetrahydropyranyl. In one embodiment, the cyclohexaalkyl is C10. 2-11 Cycloalkyl groups. In another embodiment, C 2-11 The cyclohexaalkyl group is piperidine.

[0094] "Cyclohepenyl" refers to a monocyclic, bicyclic, spirocyclic, fused, or bridging ring or ring system having a specified number of carbon atoms and containing at least one double bond and at least one heteroatom selected from N, NH, S (including SO and SO2), and O. Examples of cyclohepenyl groups include dihydropyran and dihydrofuran.

[0095] "Aryl" refers to a monocyclic, bicyclic, or tricyclic carbocyclic aromatic ring or ring system containing 6-14 carbon atoms, wherein at least one ring is aromatic. Examples of aryl groups include phenyl, indene, and naphthalene. In one embodiment, the aryl group is phenyl. In another embodiment, the aryl group is indene.

[0096] "Heteroaryl" refers to a monocyclic, bicyclic, or tricyclic ring or ring system containing 5-14 ring atoms and at least one cyclic heteroatom selected from N, NH, S (including SO and SO2), and O, wherein at least one ring containing a heteroatom is aromatic. Examples of heteroaryl groups include pyrrole, isoxazolyl, isothiazolyl, pyrazolyl, pyridinyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazole, triazolyl, tetrazolyl, furanyl, triazinyl, thiophene, pyrimidinyl, pyrazinyl, benzoisooxazolyl, benzooxazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, benzothiophene, quinolinyl, indolyl, isoquinolinyl, quinazolinyl, dibenzofuranyl, etc. In one embodiment, the heteroaryl group is benzothiophene.

[0097] "Halogen" includes fluorine, chlorine, bromine, and iodine. In one embodiment, the halogen is fluorine, chlorine, or bromine. In another embodiment, the halogen is fluorine or chlorine. In another embodiment, the halogen is chlorine or bromine. In another embodiment, the halogen is fluorine. In another embodiment, the halogen is chlorine. In another embodiment, the halogen is bromine.

[0098] “Me” stands for methyl.

[0099] "Oxyto" means =O.

[0100] "Saturation" refers to a structure containing only single bonds.

[0101] "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.

[0102] When any variable (e.g., R) 1 R a When a substituent (e.g., ) appears more than once in any constituent or in structural formula I, its definition for each occurrence is independent of its definition for each other occurrence. Furthermore, combinations of substituents and / or variables are permitted only if such combinations produce stable compounds. The wavy line across bonds in substituent variables indicates connection points.

[0103] Under the naming convention used throughout this disclosure, the join point is described first, followed by the end portion of the sidechain. For example, C 1-5 alkyl carbonyl amino C 1-6 Alkyl substituents are equivalent to: In selecting the compounds disclosed herein, those skilled in the art will recognize that various substituents, namely R... 1 R 2The selection of materials must follow well-known principles regarding the connectivity and stability of chemical structures.

[0104] The term "substituted" should be considered as including multiple degrees of substitution of the specified substituent. When multiple substituent moieties are disclosed or claimed, the substituted compound can be independently monosubstituted or polysubstituted by one or more of the disclosed or claimed substituent moieties. Independent substitution means that (two or more) substituents can be the same or different.

[0105] The phrase “pharmaceutically acceptable” is used in this document to refer to compounds, materials, compositions, salts, and / or dosage forms that would be safe and suitable for administration to humans or animals using reasonable medical judgment and in accordance with all applicable government regulations.

[0106] Compounds of Formula I may contain one or more asymmetric centers and thus may exist as racemic and racemic mixtures, single enantiomers, mixtures of diastereomers, and single diastereomers. This disclosure is intended to cover all such isomeric forms of compounds of Formula I.

[0107] The independent synthesis of optical isomers and diastereomers, or their chromatographic separation, can be achieved by appropriate modifications of the methods disclosed herein, as is known in the art. Their absolute stereochemistry can be determined by X-ray crystallography of the crystalline product or intermediate, and, if necessary, by derivatization of the crystalline product or intermediate with a reagent containing an asymmetric center of known absolute configuration or a sufficient number of atoms to obtain an absolute classification.

[0108] If desired, racemic mixtures of compounds can be separated to isolate individual enantiomers. Separation can be performed using methods known in the art, such as coupling the racemic mixture of compounds with an enantiomerically pure compound to form a mixture of diastereomers, followed by separation of the individual diastereomers by standard methods such as fractional crystallization or chromatography. The coupling reaction typically uses an enantiomerically pure acid or base to form a salt. The diastereomeric derivative can then be converted to a pure enantiomer by cleavage of the added chiral residues. Racemic mixtures of compounds can also be directly separated by chromatographic methods employing a chiral stationary phase, methods known in the art.

[0109] Alternatively, any enantiomer of the compound can be obtained by stereoselective synthesis using optically pure starting materials or reagents with known configurations, through methods known in the art.

[0110] Some of the compounds described herein contain alkene double bonds, and unless otherwise stated, both E and Z geometric isomers are intended to be included.

[0111] A tautomer is defined as a compound in which a rapid proton migration occurs from one atom of the compound to another. Some of the compounds described herein can exist as tautomers with different hydrogen connection sites. Such examples can be ketones and their enol forms, referred to as keto-enol tautomers. Individual tautomers and mixtures thereof are covered by compounds of structural formula I.

[0112] In compounds of Formula I, atoms may exhibit their natural isotopic abundance, or one or more atoms may be artificially enriched into specific isotopes having the same atomic number but a different atomic mass or mass number than those predominantly found in nature. This disclosure is intended to include all suitable isotopic variants of compounds of Formula I. For example, different isotopic forms of hydrogen (H) include protium (… 1 H), deuterium ( 2 H or D) and tritium (H or D) 3 H). Protium is the dominant hydrogen isotope found in nature. Deuterium enrichment can provide certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or can provide compounds that can be used as standards for characterizing biological samples. Tritium is radioactive and therefore can provide radiolabeled compounds that can be used as tracers in metabolic or kinetic studies. Isotope-enriched compounds of Formula I can be prepared without excessive experimentation using conventional techniques well known to those skilled in the art or using methods similar to those described in the schemes and examples herein, using suitable isotope-enriching reagents and / or intermediates.

[0113] Furthermore, some of the crystalline forms of the compounds disclosed herein may exist as polymorphs and are therefore intended to be included in this disclosure. Additionally, some of the compounds disclosed herein may form solvates with water or common organic solvents. Such solvates are covered within the scope of this disclosure.

[0114] The compounds disclosed herein are typically administered in enantiomeric form. Racemic mixtures can be separated into their individual enantiomers by any of a variety of conventional methods. These include chiral chromatography, derivatization with chiral adjuvants followed by separation by chromatography or crystallization, and fractional crystallization of diastereomer salts.

[0115] Salt It should be understood that, as used herein, references to the compounds disclosed herein are also intended to include pharmaceutically acceptable salts, as well as non-pharmaceutically acceptable salts when used as precursors to free compounds or their pharmaceutically acceptable salts, or in other synthetic operations.

[0116] The compounds disclosed herein can 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, wherein the base or acid includes inorganic or organic bases and inorganic or organic acids. Salts of basic compounds encompassed within the term "pharmaceutically acceptable salt" refer to non-toxic salts of the compounds disclosed herein, which are typically prepared by reacting a free base with a suitable organic or inorganic acid. Representative salts of the basic compounds disclosed herein include, but are not limited to, the following: acetates, benzenesulfonates, benzoates, bicarbonates, bisulfates, tartrates, borates, bromides, camphorsulfonates, carbonates, chlorides, clavulanates, citrates, dihydrochlorides, edetates, ethanedisulfonates, propionate ester dodecane sulfate, ethanesulfonates, formates, fumarates, gluconate, gluconate, glutamates, glycolyllars-anilate, hexylresorcinol salts, hyaluronic acid salts, hydrobromide salts, and salts. Salts, hydroxynaphthylcarboxylate, iodides, hydroxyethyl sulfonates, lactates, lacturonates, lysine, malates, maleates, mandelates, methanesulfonates, methyl bromides, methyl nitrates, methyl sulfates, mucilages, naphthalene sulfonates, nitrates, N-methylglucosamine ammonium salts, oleates, oxalates, pyruvate (bishydroxynaphthyl), palmitate, pantothenates, phosphates, diphosphates, polygalacturonates, salicylates, stearates, sulfates, basic acetates, succinates, tannins, tartrates, 8-chlorotheophylline salts, toluenesulfonates, triethyliodide salts, trifluoroacetate salts, and valerates. When the compounds of this disclosure contain an acidic moiety, suitable pharmaceutically acceptable salts include, but are not limited to, salts derived from inorganic bases, including aluminum, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, manganese, manganese sulfide, potassium, sodium, zinc, etc. Particularly preferred are ammonium salts, calcium salts, magnesium salts, potassium salts, and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic alkaloids include primary, secondary, and tertiary amines, cyclic amines, and salts of basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, heparin, isopropylamine, lysine, methylglucosamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc.

[0117] Furthermore, in the presence of a carboxylic acid (-COOH) or alcohol group in the compounds disclosed herein, pharmaceutically acceptable esters of carboxylic acid derivatives, such as methyl esters, ethyl esters, or neopentyloxymethyl esters, or acyl derivatives of alcohols, such as... O -acetyl group, O - Neopentanoyl, O -benzoyl andO -Amino acyl groups. Including those esters and acyl groups known in the art for altering solubility or hydrolytic properties for use as sustained-release or prodrug formulations.

[0118] The term "prodrug" refers to a compound that is rapidly converted into a parent compound in vivo, for example, by hydrolysis in the blood, such as a prodrug of formula I being converted into a compound of formula I or its salt; a full discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.CS Symposium Series and Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference. This disclosure includes prodrugs, solvates, and, in particular, hydrates of compounds of formula I.

[0119] utility Compounds of Formula I are potent inhibitors of Nod-like receptor protein 3 (NLPR3). Compounds of Formula I, along with their pharmaceutically acceptable salts, hydrates, and solvates, are effective in treating diseases, symptoms, and conditions mediated by the inhibition of Nod-like receptor protein 3 (NLPR3).

[0120] This disclosure relates to the treatment or prevention of NLRP3-mediated diseases, conditions, or illnesses such as inflammation, autoimmune diseases, cancer, infections, diseases or conditions of the central nervous system, metabolic diseases, cardiovascular diseases, fibrotic diseases or fibrosis, respiratory diseases, kidney diseases, liver diseases, ophthalmic or eye diseases, skin diseases, lymphatic diseases, rheumatic diseases, graft-versus-host disease, abnormal pain, or NLRP3-related diseases in subjects who have been identified as carrying a germline or somatic non-silent mutation of NLRP3.

[0121] Diseases, conditions, or illnesses mediated by NLRP3 include, but are not limited to: gout, pseudogout, osteoarthritis, familial cold autoinflammatory syndrome, Muckle-Wells syndrome, neonatal multisystem inflammatory disease, diabetes, NASH, sepsis, age-related macular degeneration, diabetic retinopathy, liver fibrosis, kidney fibrosis, atherosclerosis, heart failure, peripheral artery disease, myeloproliferative neoplasms, leukemia, myelodysplastic syndrome, myelofibrosis, lung cancer, colon cancer, Parkinson's disease, Alzheimer's disease, traumatic brain injury, spinal cord injury, amyotrophic lateral sclerosis, multiple sclerosis, atopic dermatitis, hidradenitis suppurativa, pericarditis, myocarditis, preeclampsia, dermatomyositis, Still's disease, juvenile idiopathic arthritis, age-related macular degeneration, diabetic retinopathy, acute kidney disease, chronic kidney disease, or rare kidney diseases. Diseases, conditions, or illnesses mediated by Nod-like receptor protein 3 (NLPR3) include, but are 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.

[0122] In one implementation, the condition, disease, or symptom is an inflammatory joint disease such as gout, pseudogout, or osteoarthritis.

[0123] In another implementation, cold pyridine-associated autoinflammatory syndrome is familial cold autoinflammatory syndrome, Muckle-Wells syndrome, or a neonatal multisystem inflammatory disease.

[0124] In another implementation, the metabolic disease is diabetes.

[0125] In another implementation, the liver disease is NASH.

[0126] In another implementation, the infection is sepsis.

[0127] In another implementation, the ophthalmological or eye disease is age-related macular degeneration or diabetic retinopathy.

[0128] In another implementation, the fibrotic disease is liver fibrosis or kidney fibrosis.

[0129] In some implementation schemes, cardiovascular disease is defined as atherosclerosis, heart failure, or peripheral artery disease.

[0130] In another implementation, the cancer is myeloproliferative neoplasm, leukemia, myelodysplastic syndrome, myelofibrosis, lung cancer, or colon cancer.

[0131] In another implementation, the condition, disease, or symptom of the central nervous system is Parkinson's disease, Alzheimer's disease, traumatic brain injury, spinal cord injury, amyotrophic lateral sclerosis, or multiple sclerosis.

[0132] In another implementation, the skin condition is atopic dermatitis or hidradenitis suppurativa (HS).

[0133] In another implementation, the inflammatory disease is pericarditis or myocarditis.

[0134] In another implementation, the inflammatory disease is preeclampsia.

[0135] In another implementation, the rheumatic disease is dermatomyositis, Still's disease, or juvenile idiopathic arthritis.

[0136] In another implementation, the eye disease is age-related macular degeneration or diabetic retinopathy.

[0137] In another implementation, the kidney disease is acute kidney disease, chronic kidney disease, or rare kidney disease.

[0138] One or more of these conditions or diseases can be treated, managed, prevented, alleviated, improved, or controlled by administering a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof to a patient in need of treatment.

[0139] Compounds of Formula I may also be used to prepare medicines for the treatment, prevention, management, relief, improvement or control of one or more of the following conditions, diseases or symptoms, including but not limited to: gout, pseudogout, osteoarthritis, familial cold autoinflammatory syndrome, Muckle-Wells syndrome, neonatal multisystem inflammatory disease, diabetes, NASH, sepsis, age-related macular degeneration, diabetic retinopathy, liver fibrosis, kidney fibrosis, atherosclerosis, heart failure, peripheral artery disease, myeloproliferative neoplasms, leukemia, myelodysplastic syndrome, myelofibrosis, lung cancer, colon cancer, Parkinson's disease, Alzheimer's disease, traumatic brain injury, spinal cord injury, amyotrophic lateral sclerosis, multiple sclerosis, atopic dermatitis, hidradenitis suppurativa, pericarditis, myocarditis, preeclampsia, dermatomyositis, Still's disease, juvenile idiopathic arthritis, age-related macular degeneration, diabetic retinopathy, acute kidney disease, chronic kidney disease or rare kidney disease. Compounds of Formula I may also be used to prepare medicines for the treatment, prevention, management, relief, improvement or control of one or more of the following conditions, diseases or symptoms, including 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.

[0140] The preferred use of the compound is to treat 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 prepare a medicament for treating one or more of the following diseases: 1) Gout, 2) False gout, 3) Cold pyridine-associated periodic syndrome, 4) Non-alcoholic steatohepatitis (NAH), 5) Fibrosis, 6) Osteoarthritis, 7) Atherosclerosis, 8) Atopic dermatitis, 9) Hidradenitis suppurativa, 10) Alzheimer's disease, and 11) Parkinson's disease.

[0141] Treatment of a disease, condition or symptom mediated by NLPR3 or the NLPR3 inflammasome pathway means administering a compound of formula I to a subject suffering from the disease, condition or symptom.

[0142] One outcome of treatment can be the reduction of disease, symptoms, or conditions mediated by the NLPR3 or NLPR3 inflammasome pathway. Another outcome of treatment can be the alleviation of disease, symptoms, or conditions mediated by the NLPR3 or NLPR3 inflammasome pathway. Another outcome of treatment can be the improvement of disease, symptoms, or conditions mediated by the NLPR3 or NLPR3 inflammasome pathway. Another outcome of treatment can be the suppression of disease, symptoms, or conditions mediated by the NLPR3 or NLPR3 inflammasome pathway. Another outcome of treatment can be the management of disease, symptoms, or conditions mediated by the NLPR3 or NLPR3 inflammasome pathway. Another outcome of treatment can be the prevention of disease, symptoms, or conditions mediated by the NLPR3 or NLPR3 inflammasome pathway.

[0143] Prevention of disease, condition, or illness mediated by NLPR3 or the NLPR3 inflammasome pathway refers to the administration of a compound of formula I to a subject at risk of developing such disease, condition, or illness. One outcome of prevention may be the reduction of such disease, condition, or illness in a subject at risk of developing such disease, condition, or illness mediated by NLPR3 or the NLPR3 inflammasome pathway. Another outcome of prevention may be the suppression of such disease, condition, or illness in a subject at risk of developing such disease, condition, or illness mediated by NLPR3 or the NLPR3 inflammasome pathway. Another outcome of prevention may be the improvement of such disease, condition, or illness in a subject at risk of developing such disease, condition, or illness mediated by NLPR3 or the NLPR3 inflammasome pathway. Another outcome of prevention may be the relief of such disease, condition, or illness in a subject at risk of developing such disease, condition, or illness mediated by NLPR3 or the NLPR3 inflammasome pathway. Another outcome of prevention could be managing the disease, condition, or illness in subjects at risk of developing a disease, condition, or illness mediated by the NLPR3 or NLPR3 inflammasome pathway.

[0144] The terms “application of” and / or “administration” of a compound shall be understood as referring to the delivery of a compound of formula I or a prodrug of a compound of formula I to an individual or mammal in need of treatment.

[0145] To implement the treatment method of the present invention, the application of a compound of formula I is carried out by administering an effective amount of a compound of formula I to a mammal requiring such treatment or prevention. The need for prophylactic administration according to the method of this disclosure is determined by using known risk factors. Ultimately, the effective amount of a single compound is determined by the physician or veterinarian in charge of the case, but depends on factors such as the exact disease to be treated, the severity of the disease and other diseases or conditions suffered by the patient, the route of administration chosen, other drugs and treatments that the patient may require concurrently, and other factors in the physician's judgment.

[0146] The usefulness of the compounds of the present invention in these diseases or conditions can be confirmed in animal disease models reported in the literature.

[0147] Application and Dosage Range Compounds of Formula I can be administered to mammals, especially humans, using any suitable route of administration. For example, administration can be by oral, intravenous, infusion, subcutaneous, transdermal, intramuscular, intradermal, transmucosal, intramucosal, rectal, topical, parenteral, ocular, pulmonary, or nasal routes. Dosage forms include tablets, lozenges, dispersants, suspensions, solutions, capsules, creams, ointments, and aerosols. Oral administration of compounds of Formula I is preferred.

[0148] When treating or preventing conditions, diseases, and / or illnesses requiring inhibition of NLRP3, the appropriate dose level will generally be from about 0.0001 to 500 mg per kg of patient body weight per day, which may be administered in a single or multiple doses. In one embodiment, the appropriate dose level may be from about 0.001 to 500 mg per kg of patient body weight per day. In another embodiment, the appropriate dose level may be from about 0.001 to about 250 mg / kg per day. In another embodiment, the appropriate dose level may be from about 0.01 to about 250 mg / kg per day. In another embodiment, the appropriate dose level may be from about 0.1 to about 100 mg / kg per day. In another embodiment, the appropriate dose level may be from about 0.05 to 100 mg / kg per day. In another embodiment, the appropriate dose level may be from about 0.1 to 50 mg / kg per day. In another embodiment, the appropriate dose level may be from about 0.05 to 0.5 mg / kg per day. In another embodiment, the appropriate dose level may be from about 0.5 to 5 mg / kg per day. In another embodiment, the appropriate dose level may be from about 5 to 50 mg / kg per day.For oral administration, the composition is preferably provided in tablet form containing 0.01 to 1000 mg of the active ingredient, particularly in doses of 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, 120.0, 125.0, 130.0, 140.0, 150.0, and 160.0 mg. 170.0, 175.0, 180.0, 190.0, 200.0, 210.0, 220.0, 225.0, 230.0, 240.0, 250.0, 260.0, 270.0, 275.0, 280.0, 290.0, 300.0, 310.0, 320.0, 325.0, 330.0, 340.0, 350.0, 360.0, 370.0, 375.0, 380.0, 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 The active ingredient is available in doses of 670.0, 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, with dosage adjusted symptomatically for the patient to be treated. The compound can be administered at a frequency of 1 to 8 times daily; preferably 1 to 4 times daily; more preferably once or twice daily, and even more preferably once daily. This dosage regimen can be adjusted to provide the best therapeutic response.

[0149] However, it should be understood that specific dose levels and dosing frequencies for any particular patient can vary and will depend on a variety of factors, including the activity of the specific compound used, the metabolic stability and duration of action of the compound, age, weight, general health condition, sex, diet, route and timing of administration, excretion rate, drug combination, severity of the specific condition, and the host receiving treatment.

[0150] Compounds of Formula I can be used in pharmaceutical compositions comprising (a) the compound or a pharmaceutically acceptable salt thereof and (b) a pharmaceutically acceptable carrier. Compounds of Formula I can be used in pharmaceutical compositions wherein the compound of Formula I or a pharmaceutically acceptable salt thereof is the sole active ingredient. Compounds of Formula I can also be used in pharmaceutical compositions comprising one or more other active pharmaceutical ingredients.

[0151] As in pharmaceutical compositions, the term "composition" is intended to cover products comprising one or more active ingredients and one or more inert ingredients constituting a carrier, as well as any product directly or indirectly resulting from: any combination, complexation, or aggregation of any two or more ingredients, or dissociation of one or more ingredients, or other types of reaction or interaction of one or more ingredients. Therefore, the pharmaceutical compositions disclosed herein cover any composition prepared by mixing a compound of formula I or a pharmaceutically acceptable salt, hydrate, or solvate thereof, and a pharmaceutically acceptable carrier.

[0152] Compounds of Formula I can be used in combination with other medications that can also be used to treat or improve diseases or conditions for which compounds of Formula I are used. These other medications can be administered concurrently or sequentially with compounds of Formula I via the usual route and dosage. In treating patients with chronic inflammatory conditions, more than one medication may be administered. Compounds of Formula I are generally administered to patients who are already taking one or more other medications for these conditions. When a patient's pain does not respond adequately to treatment, the compound is typically administered to patients who are already being treated with one or more analgesic compounds.

[0153] Combination therapies also include those in which the compound of formula I and one or more other drugs are administered at different overlapping schedules. It is also anticipated that when used in combination with one or more other active ingredients, the compound of formula I and the other active ingredients can be administered at lower doses than when used individually. Therefore, the pharmaceutical compositions disclosed herein include those containing one or more other active ingredients in addition to the compound of formula I.

[0154] Examples of other active ingredients that can be administered in combination with compounds of structural formula I, as well as separately or in the same pharmaceutical composition, include, but are not limited to: (i) Anti-fatty denaturant agents; (ii) Anti-inflammatory agents; (iii) Immunocology agent; (iv) Lipid-lowering agents; (v) Cholesterol-lowering agents; (vi) Blood glucose lowering agents, including SGLT2 inhibitors; (vii) Anti-angiogenic agents; (viii) Nonsteroidal anti-inflammatory drugs ("NSAIDs"); (ix) Acetylsalicylic acid drugs (ASA), including aspirin; acetaminophen; (x) Regenerative therapy treatment; (xi) Checkpoint inhibitors, including anti-PD1 and anti-PDL1 inhibitors; (xii) Chemotherapy procedure; (xiii) Radiotherapy; (xiv) Surgical procedure; (xv) Uric acid-lowering therapy; (xvi) Anabolic agents and cartilage regeneration therapy; (xvii) Anti-fibrotic agent; (xviii) JAK inhibitors; (xix) TNF-α inhibitors; (xx) antihypertensive agents; and (xxi) STING / cGAS antagonist Its pharmaceutically acceptable salt.

[0155] In another embodiment, the pharmaceutical composition comprises: 1) The compound of claim 1 or a pharmaceutically acceptable salt thereof; 2) One or more compounds selected from the group below, or pharmaceutically acceptable salts thereof: (i) Anti-fatty denaturant agents; (ii) Anti-inflammatory agents; (iii) Tumor immunotherapy agents; (iv) Lipid-lowering agents; (v) Cholesterol-lowering agents; (vi) Blood glucose lowering agents, including SGLT2 inhibitors; (vii) Anti-angiogenic agents; (viii) Nonsteroidal anti-inflammatory drugs ("NSAIDs"); (ix) Acetylsalicylic acid drugs (ASA), including aspirin; acetaminophen; (x) Regenerative therapy treatment; (xi) Checkpoint inhibitors, including anti-PD1 and anti-PDL1 inhibitors; (xii) Chemotherapy procedure; (xiii) Radiotherapy; (xiv) Surgical procedure; (xv) Uric acid-lowering therapy; (xvi) Anabolic agents and cartilage regeneration therapy; (xvii) Anti-fibrotic agent; (xviii) JAK inhibitors; (xix) TNF-α inhibitors; (xx) antihypertensive agents; and (xxi) STING / cGAS antagonists; and Its pharmaceutically acceptable salt; and (3) Pharmaceutically acceptable carrier.

[0156] Specific compounds used in combination with compounds of structural formula I include: anti-fatty denaturants, including but not limited to DGAT2 inhibitors.

[0157] Suitable anti-inflammatory agents include, but are not limited to, TNFα inhibitors, JAK inhibitors, and NSAIDs.

[0158] Suitable lipid-lowering agents include, but are not limited to, statins and PCSK9.

[0159] Suitable tumor immunotherapy agents include, but are not limited to, PD-L1 inhibitors and PD-1 inhibitors, as well as STING antagonists.

[0160] Suitable hypoglycemic agents include, but are not limited to, insulin, SGLT2 inhibitors, metformin, and GLP1-agonists.

[0161] Suitable anti-angiogenic agents include, but are not limited to, anti-VEG-F therapy.

[0162] Suitable NSAIDs or nonsteroidal anti-inflammatory drugs include, but are not limited to, aspirin, diclofenac, diflunisal, etodoxacin, fenprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, meclofenamic acid, meloxicam, naproxen, naproxen sodium, oxapzin, piroxicam, sulindac, and tometetin.

[0163] Suitable analgesics include, but are not limited to, acetaminophen and duloxetine.

[0164] The above combinations include compounds of structural formula I with not only one other active compound but also with two or more other active compounds. Non-limiting examples include combinations of compounds with two or more active compounds selected from: anti-fatty denaturants, anti-inflammatory agents, lipid-lowering agents, anti-fibrotic agents, tumor immunomodulators, hypoglycemic agents and anti-angiogenic agents, NSAIDs (nonsteroidal anti-inflammatory drugs), and analgesics.

[0165] This disclosure also provides a method for treating or preventing NLRP3-mediated diseases, symptoms, or conditions, comprising administering to a patient who requires such treatment or is at risk of developing an NLRP3-mediated disease a therapeutically effective amount of an NLRP3 inhibitor and a certain amount of one or more active ingredients, such that together they provide effective relief.

[0166] In another aspect of this disclosure, a pharmaceutical composition is provided comprising an NLRP3 inhibitor and one or more active ingredients, as well as at least one pharmaceutically acceptable carrier or excipient.

[0167] Therefore, according to another aspect of this disclosure, use of an NLRP3 inhibitor and one or more active ingredients in the preparation of a medicament for treating or preventing NLRP3-mediated diseases, symptoms, or conditions is provided. Therefore, in yet another or alternative aspect of this disclosure, a product is provided comprising an NLRP3 inhibitor and one or more active ingredients in a combination formulation for simultaneous, separate, or sequential use in the treatment or prevention of NLRP3-mediated diseases, symptoms, or conditions. Such a combination formulation may, for example, be in a dual-package form.

[0168] It should be understood that, for the treatment or prevention of cardiovascular metabolic diseases, neurodegenerative diseases and inflammatory joint diseases, fibrosis, and cancer, compounds of structural formula I can be used in combination with another agent that is effective in treating the disease, condition, or illness.

[0169] This disclosure also provides a method for treating or preventing chronic inflammatory conditions, the method comprising administering to a patient requiring such treatment a quantity of a compound of formula I and a quantity of another agent effective in treating the condition, disease, or ailment, such that together they provide effective relief.

[0170] This disclosure also provides a method for treating or preventing chronic inflammatory conditions, comprising administering to a patient requiring such treatment a quantity of a compound of formula I and a quantity of another agent that can be used to treat the particular condition, symptom, or disease, such that together they provide effective relief.

[0171] The term "therapeuticly effective amount" refers to the amount of a compound of formula I that elicits a biological or medical response in cells, tissues, systems, animals, or humans that is being sought by researchers, veterinarians, doctors, or other clinicians, including the relief of symptoms of the condition being treated. The novel therapeutic methods disclosed herein target conditions known to those skilled in the art. The term "mammal" includes humans and companion animals such as dogs and cats.

[0172] The weight ratio of the compound of Formula I to the second active ingredient can vary and will depend on the effective dose of each ingredient. Typically, the effective dose of each will be used. Therefore, for example, when the compound of Formula I is combined with an anti-fatty denaturant, the weight ratio of the compound of Formula I is typically in the range of about 1000:1 to about 1:1000, preferably about 200:1 to about 1:200. Combinations of the compound of Formula I with other active ingredients will also typically be within the aforementioned range, but in each case, the effective dose of each active ingredient should be used.

[0173] Synthesis method The following reaction schemes and examples illustrate methods for synthesizing compounds of structural formula I disclosed herein. These reaction schemes and examples are provided for illustrative purposes and should not be construed as limiting the scope of this disclosure in any way. Unless otherwise stated, all substituents are as defined above. Compounds of structural formula I can be prepared using several strategies based on synthetic transformations known in the organic synthesis literature. The scope of this disclosure is defined by the appended claims. Compound names were generated in Chemdraw version 21.0.0.28.

[0174] instrument Reversed-phase chromatography was performed on a Waters 150 equipped with columns selected from the following: Phenomenex Synergi C18 (250 mm x 30 mm x 4 μm), Phenomenex Luna C18 (250 mm x 21 mm x 5 μm), Agilent Zorbax Bonus-RP (150 mm x 21 mm x 5 μm), and Waters X-Select CSH C18 (150 mm x 19 mm x 5 μm). Conditions included high pH (0-100% acetonitrile / water eluent containing 0.1% v / v NH4OH) or low pH (0-100% acetonitrile / water eluent containing 0.1% v / v TFA or formic acid), and some examples are noted. SFC chiral separation was performed on a Waters Thar 80 SFC or a Berger MG II preparative SFC system.

[0175] LC / MS determinations were performed on 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 x 50 mm column; a mobile phase containing A: 0.1% TFA / water and B: 0.1% TFA / acetonitrile; a gradient of 10% B to 90% B over 2.0 min, followed by a hold at 90% B for 0.4 min; and a flow rate of 0.5 mL / min. Unless otherwise specified, protons or electrons were acquired according to standard analytical techniques using a Bruker 500 MHz NEONMR spectrometer equipped with a 5 mm iProbe. 1 ¹H NMR, and report the results of the spectral analysis. Chemical shift (δ) values ​​are reported in delta (δ) units and parts per million (ppm). 1 The chemical shifts in the 1H NMR spectrum relative to the signal of the residual undeuterated solvent are given (CDCl3 reference δ 7.26 ppm; DMSO). d -6 reference δ 2.50ppm, CD3OD reference δ 3.31ppm). Multivariates are reported by the following abbreviations: s = singlet, d = doublet, t = triplet, q = quartet, dd = double doublet, dt = double triplet, m = overlap of multiplets or non-equivalent resonances. Coupling constant ( J Report in Hertz (Hz).

[0176] Chiral separation method: The general preparation conditions for separating diastereomers or mixtures of enantiomers of compounds using chiral SFC are as follows:

[0177] abbreviation "In molecules" "Indicates the stereocenter; Ac represents the acetyl group; Ad2" indicates the stereocenter. n -BuP Pd G2 is chlorine [(di(1-adamantyl)- N [-Butylphosphine)-2-(2-aminobiphenyl)-palladium(II); OAc is acetate; AcOH is acetic acid; aq. is aqueous; B2pin2 is bis(pinacolyl)diboron; BPin ester is pinacolyl borate; Boc or boc is tert-butoxycarbonyl; br is a broad peak; ℃ is degrees Celsius; calc'd is a calculated value; cat. is catalysis; δ is chemical shift; d is a doublet; D is deuterium; DCM is dichloromethane; dd is a doublet; DIPEA is N , N -Diisopropylethylamine; DMA is dimethylacetamide; DMF is dimethylformamide; DMSO is dimethyl sulfoxide; DMSO- d6 dppf is deuterated dimethyl sulfoxide; dtbpf is 1,1'-bis(diphenylphosphino)ferrocene; dtbpf is bis(di-tert-butylphosphino)ferrocene; ESI is electrospray ionization; Et is ethyl; Et3N is triethylamine; EtOAc is ethyl acetate; EtOH is ethanol; FA is formic acid; g is gram; h is hour; HPLC is high performance liquid chromatography; Hz is Hertz; i Pr is isopropyl; J 1 is the coupling constant; L is liter; LC is liquid chromatography; LCMS is liquid chromatography / mass spectrometry; m is multiplet; M is molar; Me is methyl; MeCN is acetonitrile; MeOD- d 4 represents deuterated methanol; MeOH represents methanol; mg represents milligrams; MHz represents megahertz; min represents minutes; mL represents milliliters; mM represents millimoles; mmol represents millimoles; µL represents microliters; MPLC represents medium-pressure liquid chromatography; MS represents mass spectrometry. n -BuOH is just -Butanol; nM is nanomolar; NMP is N-methylpyrrolidone; NMR is nuclear magnetic resonance; PdCl2(dppf) or Pd(dppf)Cl2 is [1,1′-bis-(diphenylphosphino)-ferrocene]palladium(II) chloride; PG is a protecting group; Ph is phenyl; POCl3 is phosphorus oxychloride; q is a quartet; qd is a quartet; rac For racemic mixtures; s represents a singlet; sat. represents saturation; SFC is a supercritical fluid chromatography method; S N Ar represents nucleophilic aromatic substitution; t represents a triplet peak. t -AmOH represents tert-amyl alcohol; t -Bu or t Bu is tert-butyl; tert TFA is trifluoroacetic acid; THF is tetrahydrofuran; TLC is thin-layer chromatography; tt is triplet peak; 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 percentage.

[0178] General Solution Option A Scheme A illustrates the synthetic procedure for preparing the biarylpyridazine derivative of formula A-4. The dihaloaminopyridazine A-1 undergoes regioselective S-reaction with various primary amines. NAr, yields a diamine, such as A-2. Cyclation of diamine A-2 with a suitable orthoester yields an imidazopyridazine of formula A-3. Cross-coupling with a suitable aryl nucleophile (e.g., arylboronic acid) and a palladium catalyst yields a biaryl product, followed by in-situ deprotection, where applicable, to give a compound of formula A-4.

[0179] Option B Scheme B illustrates the synthetic procedure for preparing the biarylpyridazine derivative of formula B-7. Methyltrihalopyridazine B-1 reacts regioselectively with sodium benzenesulfinate to generate sulfone B-2, which can then be processed in S... N Coupled with various primary amines under Ar conditions, aminopyridazines, such as B-3, are formed. Substitution of sulfones with sodium azide yields aminoazidopyridazine B-4, which can be reduced to diaminopyridazine B-5 upon treatment with Zn in AcOH. Cyclization of diamine B-5 with a suitable orthoester yields imidazopyridazines of formula B-6. Cross-coupling with a suitable aryl nucleophile (e.g., arylboronic acid) and a palladium catalyst yields a biaryl product, which (where applicable) is deprotected in situ to give compounds of formula B-7.

[0180] Option C Scheme C illustrates the synthetic procedure for preparing a C-5 biarylpyrrolopyridazine derivative. A trihalopyridazine C-1 undergoes monoselective cross-coupling with a suitable vinyl boron reagent to yield a vinyl derivative, such as C-2. The vinyl derivative C-2 reacts with various primary amines in the presence of a base (e.g., DIPEA) to produce a C-3 dihydropyrrolopyridazine. Oxidation with manganese oxide in a suitable solvent (e.g., toluene) at elevated temperatures yields a pyrrolopyridazine core represented by C-4. Cross-coupling using a suitable aryl nucleophile (e.g., arylboronic acid) and a palladium catalyst yields the biaryl product, followed by in-situ deprotection, where applicable, to obtain the compound of formula C-5.

[0181] Option D Scheme D illustrates the synthetic process for preparing the biarylpyrrolopyridazine derivative of formula D-5. Various primary amines are alkylated with bromopentyne D-1 to generate aminoalkynes of formula D-2. The aminoalkyne D-2 is then reacted with dichlorotetraazine in the presence of a base (e.g., Et3N) and at elevated temperatures via S... NAr, heterodiels-Alder cycloaddition, and reverse Diels-Alder reactions directly yield pyridazinopyrrolidines of formula D-3. Oxidation with manganese oxide in a suitable solvent (e.g., toluene) at elevated temperatures gives the pyrrolopyridazine core represented by D-4. Cross-coupling with a suitable aryl nucleophile (e.g., arylboronic acid) and a palladium catalyst yields the biaryl product, followed by in-situ deprotection, where applicable, to give compounds of formula D-5.

[0182] Option E Scheme E illustrates the synthetic process for preparing the biarylpyridazine derivative of formula E-3. N -Boc cyclic amine E-1 can be deprotected with an acid (e.g., TFA or HCl) to give a secondary amine, such as E-2. E-2 is reductively amination with a suitable aldehyde or ketone in the presence of a reducing agent (e.g., sodium cyanoborohydride or sodium triacetoxyborohydride) to give a trialkylamine of formula E-3.

[0183] Intermediate 1 ( R )-6-chloro- N 3 -(1-Ethylpiperidin-3-yl)pyridazine-3,4-diamine 3,6-Dichloropyridazine-4-amine (Ambeed, 800 mg, 4.88 mmol) and ( R 1-Ethylpiperidin-3-amine (Enamine, 688 mg, 5.37 mmol) in n The reaction mixture was suspended in BuOH (1.63 mL). The reaction mixture was heated to 150 °C and maintained for 2 days. The reaction mixture was then cooled to room temperature, filtered, and purified by preparative reversed-phase HPLC (C18 stationary phase, MeCN / water + 0.1% TFA) to give the title compound. LCMS [M+H] + = 256.2 (calculated value 256.2).

[0184] Table 1. The following intermediates are prepared using a procedure similar to that described for intermediate 1, using suitable starting materials.

[0185] Intermediate 3 (R )-6-chloro- N 3 -(1-Ethylpiperidin-3-yl)-5-methylpyridazine-3,4-diamine Step 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 EtOAc, the layers were separated, and the aqueous layer was extracted with EtOAc (x2). The organic layers were combined, concentrated, and the crude residue was purified by silica gel chromatography (EtOAc: petroleum ether) to give the title compound. LCMS [M+H] + = 197.1 (calculated value 196.9).

[0186] Step 2: 3,6-Dichloro-5-methylpyridazine-4-phenyl 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 to 40 °C and maintained for 48 hours. The reaction mixture was then cooled to room temperature and diluted with water and EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc (x3). The organic layers were combined, concentrated, and the resulting crude residue was purified by silica gel chromatography (EtOAc: petroleum ether) to give the title compound. LCMS [M+H] + = 303.1 (calculated value 303.0).

[0187] Step 3: 6-Chloro-3-((( R )-1-Ethylpiperidin-3-yl)amino)-5-methylpyridazine-4-ylbenzenesulfinate: with ( R A solution of 3,6-dichloro-5-methylpyridazine-4-sulfinylphenyl ester (1.5 g, 4.95 mmol) in 1,4-dioxane (30 mL) was treated with 1-ethylpiperidin-3-amine (Enamine, 952 mg, 7.42 mmol) and K₂CO₃ (3.08 g, 22.3 mmol). The resulting mixture was heated to 100 °C and held for 12 hours. After cooling to room temperature, the reaction mixture was filtered and purified by preparative reversed-phase HPLC (C18 stationary phase, MeCN / water + 0.05% TFA) to give the title compound. LCMS [M+H] + =395.1 (Calculated value 395.1).

[0188] Step 4: ( R )-4-azido-6-chloro- N-(1-Ethylpiperidin-3-yl)-5-methylpyridazin-3-amine: 6-chloro-3-((( R A solution of 1-ethylpiperidin-3-yl)amino)-5-methylpyridazin-4-ylbenzenesulfinate (500 mg, 1.27 mmol) in 1,4-dioxane (8 mL) and DMSO (2 mL) was obtained. The resulting mixture was heated to 50 °C and held for 12 hours. After cooling to room temperature, the reaction mixture was filtered and purified by preparative reversed-phase HPLC (C18 stationary phase, MeCN / water + 0.05% NH4OH + 10 mM NH4HCO3) to give the title compound. LCMS [M+H] + =296.2 (calculated value 296.1).

[0189] Step 5: (R )-6-chloro- N 3 -(1-Ethylpiperidin-3-yl)-5-methylpyridazine-3,4-diamine: ( R )-4-azido-6-chloro- N A solution of 3-(1-ethylpiperidin-3-yl)-5-methylpyridazin-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 give the title compound. LCMS [M+H] + = 270.1 (calculated value 270.1).

[0190] Table 2. The following intermediates were prepared using suitable commercially available amines using a procedure similar to that described for intermediate 3. A modified procedure was used in step 4, with pure DMSO as the solvent and a reaction temperature of 60°C. The compounds were purified by silica gel chromatography instead of reversed-phase HPLC in all component steps.

[0191] Intermediate 6 ( R )-3-chloro-7-(1-ethylpiperidin-3-yl)-7 H -imidazo[4,5- c ]pyridazine Treatment with HCl (4 M, in 1,4-dioxane, 380 µL, 1.52 mmol) R )-6-chloro- N3 A suspension of 1-(1-ethylpiperidin-3-yl)pyridazine-3,4-diamine (intermediate 1, 400 mg, 1.56 mmol) in trimethyl orthoformate (4.2 mL). The reaction mixture was heated to 100 °C and held 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 give the title compound. LCMS [M+H] + = 266.2 (calculated value 266.1).

[0192] Table 3. The following intermediates are prepared using a procedure similar to that described for intermediate 6, using suitable starting materials.

[0193] Intermediate 11 ( R )-3-(3-chloro-7 H -pyrrolo[2,3- c tert-butyl pyridazine-7-yl)piperidine-1-carboxylate Step 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 min. Pd(dppf)Cl₂ (482 mg, 0.658 mmol) was then added, and the mixture was heated to 50 °C and maintained for 1.5 h 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 dried over Na₂SO₄, filtered, and the solvent was removed. The resulting crude residue containing the title compound was used in the next step without further purification.

[0194] Step 2: ( R )-3-(3-chloro-5,6-dihydro-7 H -pyrrolo[2,3- c 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 (…) were added. R3-Aminopiperidine-1-carboxylic acid tert-butyl ester (Pharmablock, 122 µL, 0.686 mmol). The vial was sealed, and the reaction mixture was heated to 150 °C and maintained for 2 hours. The reaction mixture was then cooled to room temperature and concentrated. The resulting crude residue was purified by silica gel chromatography (EtOAc:hexane) to give the title compound. LCMS [M+H] + = 339.3 (calculated value 339.2).

[0195] Step 3: ( R )-3-(3-chloro-7 H -pyrrolo[2,3- c tert-butyl pyridazine-7-yl)piperidine-1-carboxylate: treated with MnO2 (225 mg, 2.59 mmol) R )-3-(3-chloro-5,6-dihydro-7 H -pyrrolo[2,3- c A solution of tert-butyl pyridazine-7-yl)piperidine-1-carboxylate (135 mg, 0.398 mmol) in toluene (8 mL). The reaction mixture was heated to 125 °C and maintained for 2.5 days. The reaction mixture was then cooled to room temperature, filtered through a Celite® filter, and concentrated. The resulting crude residue was purified by silica gel chromatography (EtOAc:hexane) to give the title compound. LCMS [M+Na] + = 359.2 (calculated value 359.1).

[0196] Intermediate 12 ( R )-3-(3-chloro-4-methyl-7 H -pyrrolo[2,3- c tert-butyl pyridazine-7-yl)piperidine-1-carboxylate Step 1: ( R 3-(pentan-3-yn-1-ylamino)piperidine-1-carboxylic acid tert-butyl ester: treated with 5-bromopentan-2-yne (Enamine, 1.00 g, 6.80 mmol) R A suspension of tert-butyl 3-aminopiperidine-1-carboxylate (Pharmablock, 1.50 g, 7.48 mmol) and K₂CO₃ (1.41 g, 10.2 mmol) in MeCN (27 mL) was prepared. The mixture was heated to 80 °C with stirring and maintained for 12 hours. The reaction mixture was then cooled to room temperature, filtered, and concentrated. The resulting crude residue was purified by silica gel chromatography (EtOAc:hexane) to give the title compound. LCMS [M+H] += 267.2 (calculated value 267.2).

[0197] Step 2: ( R )-3-(3-chloro-4-methyl-5,6-dihydro-7 H -pyrrolo[2,3- c tert-butyl pyridazine-7-yl)piperidine-1-carboxylate: with Et3N (77 µL, 0.550 mmol) and ( R 3-(pentan-3-yn-1-ylamino)piperidin-1-carboxylic acid tert-butyl ester (133 mg, 0.5 mmol) was used to treat a sealed tube containing a solution of 3,6-dichloro-1,2,4,5-tetraazine (Pharmablock, 75 mg, 0.500 mmol) in THF (2 mL). The reaction mixture was heated to 110 °C and held for 16 hours. The reaction mixture was then cooled to room temperature and diluted with water and EtOAc. The mixture was filtered through Celite®. The layers were separated, and the aqueous layer was extracted with EtOAc (x3). The organic layers were combined, dried over anhydrous MgSO4, filtered, and concentrated. The resulting crude residue was purified by silica gel chromatography (EtOAc: hexane) to give the title compound. LCMS [M+H] + = 353.2 (calculated value 353.2).

[0198] Step 3: ( R )-3-(3-chloro-4-methyl-7 H -pyrrolo[2,3- c tert-butyl pyridazine-7-yl)piperidine-1-carboxylate: treated with MnO2 (103 mg, 1.19 mmol) R )-3-(3-chloro-4-methyl-5,6-dihydro-7 H -pyrrolo[2,3- c A solution of tert-butyl pyridazine-7-yl)piperidine-1-carboxylate (70 mg, 0.20 mmol) in toluene (4 mL). The reaction mixture was heated to 125 °C and maintained for 2.5 days. The reaction mixture was then cooled to room temperature, filtered through a Celite® filter, and concentrated. The resulting crude residue was purified by silica gel chromatography (EtOAc:hexane) to give the title compound. LCMS [M+Na] + = 373.3 (calculated value 373.1).

[0199] Intermediate 13 2-(2-(ethoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentane Step 1: 3-Methyl-5-(trifluoromethyl)phenol: Trimethyl-1,3,5,2,4,6-trioxaborane (Aldrich, 1.04 kg, 4.15 mol, 50 wt%, in THF) was added in portions 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) under a N₂ atmosphere. The resulting mixture was stirred at 100 °C for 12 hours, then cooled to 25 °C. The reaction was then quenched with ice water at 0 °C and diluted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous Na₂SO₄, and concentrated. The crude residue was purified by silica gel chromatography (EtOAc: petroleum ether) to obtain the title compound. LCMS [MH] – = 175.1 (calculated value 175.0).

[0200] Step 2: 2-Iodo-3-methyl-5-(trifluoromethyl)phenol: NaH (128.5 g, 3.21 mol, 60 wt%) was added to a stirred solution of 3-methyl-5-(trifluoromethyl)phenol (283 g, 1.61 mol) in toluene (1.42 L) under a nitrogen atmosphere at 0 °C. The resulting mixture was stirred at 0 °C for 30 min, followed by the addition of a solution of I2 (306.1 g, 1.21 mmol) in toluene (5.66 L) in portions. The reaction was stirred at 20 °C for 3 h, then quenched by pouring over a water / ice bath. The mixture was diluted with EtOAc and the layers were separated. The organic layer was washed with brine, dried over 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.

[0201] Step 3: 1-(ethoxymethoxy)-2-iodo-3-methyl-5-(trifluoromethyl)benzene: Chloromethyl ethyl ether (290 g, 3.07 mol) was added 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) under a nitrogen atmosphere at 0 °C. The resulting mixture was stirred at room temperature for 8 hours, then cooled to 0 °C and quenched by adding ice water. The mixture was diluted with EtOAc, the organic layer was separated, washed with brine, and dried over anhydrous Na₂SO₄. The solvent was removed under reduced pressure, and the crude residue was purified by silica gel chromatography (EtOAc: petroleum ether) to give the title compound. 1 H NMR (300 MHz, DMSO-d 6 ) 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).

[0202] Step 4: 2-(2-(ethoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane: 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-dicyclohexylphosphine (32.1 g, 91.6 mmol) in 1,4-dioxane (3.3 L) was placed under a nitrogen atmosphere. The resulting solution was stirred at 100 °C for 6 hours, then cooled to 25 °C and quenched with ice water. The resulting mixture was filtered, and the solid residue was washed with EtOAc. The organic filtrate layer was separated, washed with brine, dried over anhydrous Na₂SO₄, and concentrated. The resulting crude residue was purified by silica gel chromatography (EtOAc: petroleum ether), and the desired fraction was concentrated. The resulting solid was dissolved in hexane and stirred at -30°C for 5 minutes. The precipitated solid was collected by filtration to obtain the title compound. 1 H 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).

[0203] Intermediate 14 2-(2-(difluoromethoxy)-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentane 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). The resulting mixture was degassed, and the reaction was stirred at 85 °C for 13 h under N2. After cooling to room temperature, the reaction mixture was concentrated, and the resulting crude residue was purified by silica gel chromatography (EtOAc: petroleum ether) to give the title compound. 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).

[0204] Example 1 ( R )-2-(7-(1-ethylpiperidin-3-yl)-7 H -pyrrolo[2,3- c ]pyridazine-3-yl)-3-methyl-5-(trifluoromethyl)phenol Step 1: ( R )-3-(3-(2-(ethoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl)-7 H -pyrrolo[2,3- c tert-butyl pyridazine-7-yl)piperidine-1-carboxylate: Fill the first vial with ( R )-3-(3-chloro-7 H -pyrrolo[2,3- cThe reaction mixture was prepared by purging tert-butyl pyridazine-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-dioxaborhecyclopentane (intermediate 13,125 mg, 0.347 mmol), XPhos Pd G3 (16.6 mg, 0.019 mmol), and potassium carbonate (160 mg, 1.16 mmol), followed by vacuum evacuation and backfilling with N2. In a second vial, a solvent mixture of 1,4-dioxane (1.2 mL) and water (0.3 mL) was purged with N2 for 15 min and then added to the first vial. The reaction mixture was heated to 100 °C and held for 3 h, then cooled to room temperature and diluted with water and DCM. The layers were separated, and the aqueous layer was extracted with DCM (x3). The organic layers were combined, dried over anhydrous MgSO4, filtered, and concentrated. The crude residue was purified by silica gel chromatography (EtOAc:hexane) to give the title compound. LCMS [M+H] + = 535.2 (calculated value 535.3).

[0205] Step 2: ( R )-3-methyl-2-(7-(piperidin-3-yl)-7 H -pyrrolo[2,3- c Pyridazine-3-yl)-5-(trifluoromethyl)phenol hydrochloride: treated with HCl (4 M, in 1,4-dioxane, 283 µL, 1.13 mmol) R )-3-(3-(2-(ethoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl)-7 H -pyrrolo[2,3- c A solution of tert-butyl 1-pyridazine-7-yl)piperidine-1-carboxylate (121 mg, 0.226 mmol) in 1,4-dioxane (2.3 mL). 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 give the title compound. LCMS [M+H] + = 377.2 (calculated value 377.2).

[0206] Step 3: (R)-2-(7-(1-ethylpiperidin-3-yl)-7H-pyrrolo[2,3-c]pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol: treated with sodium triacetoxyborohydride (74 mg, 0.35 mmol). R )-3-methyl-2-(7-(piperidin-3-yl)-7 H -pyrrolo[2,3-c A solution of pyridazine-3-yl)-5-(trifluoromethyl)phenol hydrochloride (72 mg, 0.174 mmol) and acetaldehyde (20 µL, 0.35 mmol) in DCM (1.7 mL). The resulting reaction mixture was stirred at 25 °C for 1 hour, then quenched with water and separated using 10% MeOH / DCM. The layers were separated, and the aqueous layer was extracted with 10% MeOH / DCM (x2). The organic layers were combined, dried over anhydrous MgSO4, filtered, and concentrated. The resulting crude residue was dissolved in DMSO, filtered, and purified by preparative reversed-phase HPLC (C18 stationary phase, MeCN / water + 0.05% FA) to give the title compound. LCMS [M+H] + =405.2, (calculated value 405.2). 1 H NMR (500 MHz, DMSO-d6) 10.02 (s, 1H), 8.15 (d, J = 3.1Hz, 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).

[0207] Table 4. The following compounds were prepared using suitable starting materials using a procedure similar to that described for Example 1.

[0208] Example 3 ( R )-2-(7-(1-ethylpiperidin-3-yl)-7 H -imidazo[4,5- c ]pyridazine-3-yl)-3-methyl-5-(trifluoromethyl)phenol Step 1: ( R)-3-(2-(ethoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl)-7-(1-ethylpiperidin-3-yl)-7 H -imidazo[4,5- c Pyridazine: Fill a small vial with ( R )-3-chloro-7-(1-ethylpiperidin-3-yl)-7 H -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-dioxaborhecyclopentane (intermediate 13, 203 mg, 0.564 mmol), XPhos Pd G3 (26 mg, 0.030 mmol), and potassium carbonate (260 mg, 1.88 mmol). The vials were then evacuated and backfilled with nitrogen (3x). In a second vial, a solvent mixture of 1,4-dioxane (2 mL) and water (0.5 mL) was purged with nitrogen for 15 min and then added to the first vial. The reaction mixture was heated to 100 °C and held for 3 h. 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 (x3).] The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated. The resulting crude residue was purified by silica gel chromatography (MeOH:DCM) to obtain the title compound. LCMS [M+H] + = 464.4 (calculated value 464.2).

[0209] Step 2: ( R )-2-(7-(1-ethylpiperidin-3-yl)-7 H -imidazo[4,5- c Pyridazine-3-yl)-3-methyl-5-(trifluoromethyl)phenol: treated with HCl (4 M, in 1,4-dioxane, 81 µL, 0.324 mmol) R )-3-(2-(ethoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl)-7-(1-ethylpiperidin-3-yl)-7 H -imidazo[4,5- c A solution of pyridazine (30 mg, 0.065 mmol) in 1,4-dioxane (0.65 mL) was prepared. 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 dissolved in DMSO, filtered, and purified by preparative reversed-phase HPLC (C18 stationary phase, MeCN / water + 0.05% FA) to give the title compound. LCMS [M+H]+ =406.4 (Calculated value 406.2). 1 H NMR (500 MHz, MeOD- d 4) 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).

[0210] Table 5. The following compounds were prepared using suitable starting materials using a procedure similar to that described for Example 3.

[0211] Example 7 ( R )-2-(7-(1-ethylpiperidin-3-yl)-4-methyl-7 H -imidazo[4,5- c ]pyridazine-3-yl)-5-(trifluoromethyl)phenol Treatment 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) R )-3-chloro-7-(1-ethylpiperidin-3-yl)-4-methyl-7 H A solution of 1,4-dioxane (3 mL) and water (8,40 mg, 0.143 mmol) was prepared. The mixture was degassed with argon and then heated to 100 °C and held for 12 hours. After cooling to room temperature, the reaction mixture was filtered and concentrated. The resulting crude residue was purified by preparative reversed-phase HPLC (C18 stationary phase, MeCN / water + 0.05% TFA) to give the title compound. LCMS [M+H] + = 406.2 (calculated value 406.2). 1 H NMR (400 MHz, MeOD-d 4) 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).

[0212] Table 6. The following compounds were prepared using suitable starting materials using a procedure similar to that described for Example 7.

[0213] Example 10 ( R )-2-(4-methyl-7-(1-methylpiperidin-3-yl)-7 H -imidazo[4,5- c ]pyridazine-3-yl)-5-(trifluoromethyl)phenol Treatment with formaldehyde (37%, in water, 24 µL, 0.318 mmol) and sodium triacetoxyborohydride (34 mg, 0.159 mmol) R )-2-(4-methyl-7-(piperidin-3-yl)-7 H -imidazo[4,5- c The title compound was prepared by mixing pyridazine-3-yl)-5-(trifluoromethyl)phenol (Example 5, 20 mg, 0.053 mmol) in MeOH (0.27 mL) and THF (0.27 mL). The reaction mixture was stirred at 25 °C for 1 hour. The reaction was then quenched with 4 drops of AcOH and concentrated. The resulting crude residue was dissolved in DMSO, filtered, and purified by preparative reversed-phase HPLC (C18 stationary phase, MeCN / water + 0.1% TFA) to give the title compound. LCMS [M+H] += 392.3 (calculated value 392.2). 1 H NMR (500 MHz, MeOD- d 4) 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).

[0214] Example 10 (Alternative Synthesis) ( R )-2-(4-methyl-7-(1-methylpiperidin-3-yl)-7 H -imidazo[4,5- c ]pyridazine-3-yl)-5-(trifluoromethyl)phenol Step 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 EtOAc, the layers were separated, and the aqueous layer was extracted with EtOAc (x2). The organic layers were combined, concentrated, and the crude residue was purified by silica gel chromatography (EtOAc: petroleum ether) to give the title compound. LCMS [M+H] + = 197.1 (calculated value 196.9).

[0215] Step 2: 3,6-Dichloro-5-methylpyridazine-4-phenyl 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 to 40 °C and maintained for 48 hours. The reaction mixture was then cooled to room temperature and diluted with water and EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc (x3). The organic layers were combined, concentrated, and the resulting crude residue was purified by silica gel chromatography (EtOAc: petroleum ether) to give the title compound. LCMS [M+H] += 303.1 (calculated value 303.0).

[0216] Step 3: ( R 3-((6-chloro-5-methyl-4-(phenylsulfonyl)pyridazin-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester: Prepare two 40 mL scintillation bottles in duplicate. In each bottle, use ( R A solution of 3,6-dichloro-5-methylpyridazine-4-sulfinyl phenyl ester (750 mg, 2.47 mmol) in 1,4-dioxane (15 mL) was treated with tert-butyl 3-aminopiperidine-1-carboxylate (Aldrich, 743 mg, 3.71 mmol) and K₂CO₃ (1.54 g, 11.1 mmol). The resulting mixture was heated to 100 °C and held for 5 hours. After cooling to room temperature, the reaction mixtures were combined, filtered, and concentrated under vacuum. The resulting crude residue was purified by silica gel chromatography ([25% EtOH / EtOAc]:hexane) to give the title compound. LCMS [M+Na] + = 489.4 (calculated value 489.1).

[0217] Step 4: ( R 3-((4-azido-6-chloro-5-methylpyridazin-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester: treated with NaN3 (1.25 g, 19.3 mmol) R A solution of tert-butyl 6-((6-chloro-5-methyl-4-(phenylsulfonyl)pyridazin-3-yl)amino)piperidine-1-carboxylate (1.50 g, 3.21 mmol) in DMSO (23 mL). The resulting mixture was heated to 60 °C and held for 5 hours. After cooling to room temperature, the reaction mixture was quenched with water and extracted with EtOAc (3x). The combined organic layers were washed with water (2x) and brine, dried over anhydrous MgSO4, filtered, and concentrated under vacuum. The resulting crude residue was purified by silica gel chromatography (MeOH:DCM) to give the title compound. LCMS [M+H] + = 368.2 (calculated value 368.2).

[0218] Step 5: ( R )-3-((4-amino-6-chloro-5-methylpyridazin-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester: ( RA solution of tert-butyl 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 give the title compound. LCMS [M+H] + = 342.2 (calculated value 342.2).

[0219] Step 6: ( R )-3-(3-chloro-4-methyl-7 H -imidazo[4,5- c tert-butyl pyridazine-7-yl)piperidine-1-carboxylate: treated with HCl (4 M, in 1,4-dioxane, 40 µL, 0.161 mmol) R A solution of tert-butyl 1-((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 prepared. The reaction mixture was heated to 100 °C and held for 2 hours. After cooling to room temperature, the reaction mixture was concentrated under vacuum. The resulting crude residue was purified by silica gel chromatography (MeOH:DCM) to give the title compound. LCMS [M+H] + = 352.4 (calculated value 352.2).

[0220] Step 7: ( R )-3-(3-(2-hydroxy-4-(trifluoromethyl)phenyl)-4-methyl-7 H -imidazo[4,5- c tert-butyl pyridazine-7-yl)piperidine-1-carboxylate: Fill a vial with ( R )-3-(3-chloro-4-methyl-7 H -imidazo[4,5- cThe reaction mixture consisted of tert-butyl pyridazine-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 vials were then evacuated and backfilled with nitrogen (3x). In a second vial, a solvent mixture of 1,4-dioxane (10.6 mL) and water (2.7 mL) was purged with nitrogen for 15 min and then added to the first vial. The reaction mixture was heated to 100 °C and held for 3 h. 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 (x3). The organic layers were combined, dried over anhydrous MgSO4, filtered, and concentrated under vacuum. The crude residue was purified by silica gel chromatography (MeOH:DCM) to obtain the title compound. LCMS [M+H] + = 478.4, (calculated value 478.2).

[0221] Step 8: ( R )-2-(4-methyl-7-(piperidin-3-yl)-7 H -imidazo[4,5- c Pyridazine-3-yl)-5-(trifluoromethyl)phenol: treated with HCl (4 M, in 1,4-dioxane, 1.32 mL, 5.27 mmol) R )-3-(3-(2-hydroxy-4-(trifluoromethyl)phenyl)-4-methyl-7 H -imidazo[4,5- c A solution of tert-butyl pyridazine-7-yl)piperidine-1-carboxylate (503 mg, 1.05 mmol) in DCM (10.5 mL). 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, eluted first with MeOH and then with 7 M ammonia / MeOH. The 7 M ammonia layer was concentrated under vacuum to give the title compound. LCMS [M+H] + = 378,2, (calculated value 378.2).

[0222] Step 9: ( R )-2-(4-methyl-7-(1-methylpiperidin-3-yl)-7 H -imidazo[4,5- cPyridazine-3-yl)-5-(trifluoromethyl)phenol: treated with formaldehyde (37%, in water, 24 µL, 0.318 mmol) and sodium triacetoxyborohydride (34 mg, 0.159 mmol) R )-2-(4-methyl-7-(piperidin-3-yl)-7 H -imidazo[4,5- c A mixture of pyridazine-3-yl)-5-(trifluoromethyl)phenol (20 mg, 0.053 mmol) in MeOH (0.27 mL) and THF (0.27 mL) was prepared. The reaction mixture was stirred at 25 °C for 1 hour. The reaction was then quenched with 4 drops of AcOH and concentrated. The resulting crude residue was dissolved in DMSO, filtered, and purified by preparative reversed-phase HPLC (C18 stationary phase, MeCN / water + 0.1% TFA) to give the title compound. LCMS [M+H] + = 392.3 (calculated value 392.2). 1 H NMR (500 MHz, MeOD- d 4) 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).

[0223] Table 7. The following compounds were prepared using a procedure similar to that described for Example 10, with suitable starting materials and aldehydes.

[0224] Table 8. The following intermediates are prepared using a procedure similar to that described for intermediate 3, using suitable commercially available amines.

[0225] Table 9. The following intermediates are prepared using a procedure similar to that described for intermediate 6, with suitable starting materials.

[0226] Intermediate 18 (4-hydroxybenzo[ b]Thiophene-5-yl)boronic acid Step 1: 5,5-Dibromo-6,7-dihydrobenzo[ b ]thiophene-4(5 H )-Ketone: A solution of CuBr2 (5.87 g, 26.3 mmol) in EtOAc (30 mL) was stirred at 80 °C for 10 minutes. Then, 6,7-dihydrobenzo-[ b ]thiophene-4(5 H A solution of 1.00 g (6.57 mmol) of the ketone (Combi-Blocks, 1.00 g, 6.57 mmol) in CHCl3 (30 mL) was prepared, and the resulting mixture was stirred at 80 °C for 12 hours. The reaction mixture was then cooled to room temperature, diluted with EtOAc, and filtered through Al2O3. The filtrate was washed with a saturated aqueous solution of NaHCO3, dried over anhydrous Na2SO4, filtered, and concentrated. The crude residue was purified by silica gel chromatography (EtOAc: petroleum ether) to give the title compound. LCMS [M+H] + = 310.9 (calculated value 310.9).

[0227] Step 2: 5-Bromobenzo[ b Thiophene-4-ol: To 5,5-dibromo-6,7-dihydrobenzo[ b ]thiophene-4(5 H The ketone (1.58 g, 5.10 mmol) was added to a solution of Li₂CO₃ (2.26 g, 30.6 mmol) in DMF (30 mL). 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 (EtOAc: petroleum ether) to give the title compound. 1 H NMR (400 MHz, CDCl3) δ7.51 (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).

[0228] Step 3: (4-hydroxybenzo[ b ]Thiophene-5-yl)boronic acid: 5-bromobenzo[ bA mixture of 1-thiophene-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 for 12 hours. The reaction mixture was then filtered and concentrated under reduced pressure. The resulting crude residue was purified by MPLC (C18 stationary phase, MeCN / water + 0.5% TFA) to give the title compound. LCMS [M+H] + = 194.5 (calculated value 195.0).

[0229] Intermediate 19 (4-hydroxy-2,3-dihydro-1) H -indole-5-yl)boronic acid Step 1: 5-Bromo-2,3-dihydro-1 H -Indene-4-ol: towards 2,3-dihydro-1 H In a solution of 1-indene-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. 1-Bromopyrrolidine-2,5-dione (1.33 g, 7.45 mmol) was added to this solution in fractions. The reaction mixture was warmed to room temperature and stirred for 12 hours. The reaction mixture was then washed with water and brine, and the organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated. The resulting crude residue was purified by silica gel chromatography (EtOAc: petroleum ether) to give the title compound. 1 H NMR (400 MHz, CDCl3) δ 7.15 (d, J = 8.0 Hz, 1H), 6.62 (d, J = 8.0Hz, 1H), 5.43 - 5.32 (m, 1H), 2.83 (dt, J = 17.3, 7.6 Hz, 4H), 2.10 – 1.97 ppm(m, 2H).

[0230] Step 2: (4-hydroxy-2,3-dihydro-1) H 5-Indene-5-yl)boronic acid: 5-bromo-2,3-dihydro-1-bromo-2,3-dihydro-1-yl)boronic acid under N2 atmosphere HA mixture of indene-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. DIPEA (0.123 mL, 0.704 mmol) was then added dropwise, and the reaction mixture was warmed 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 reversed-phase HPLC (C18 stationary phase, MeCN / water + 0.1% TFA) to give the title compound. LCMS [M+H] + = 179.2 (calculated value 179.1).

[0231] Table 10. The following compounds were prepared using suitable starting materials using a procedure similar to that described for Example 3.

[0232] Table 11. The following compounds were prepared using suitable starting materials using a procedure similar to that described for Example 7.

[0233] Table 12. The following compounds were prepared using a procedure similar to that described for Example 10, with suitable starting materials and aldehydes.

[0234] Table 13. The following intermediates are prepared using a procedure similar to that described for intermediate 3, using suitable commercially available amines.

[0235] Table 14. The following intermediates are prepared using a procedure similar to that described for intermediate 6, using suitable starting materials.

[0236] Intermediate 23 (alternative synthesis) (1 R ,2 R 5 R and 1 S ,2 S 5 S )-2-(3-chloro-4-methyl-7 H -imidazo[4,5- c ]pyridazine-7-yl)-8-azabicyclo[3.2.1] tert-butyl octane-8-carboxylate Step 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 EtOAc, the layers were separated, and the aqueous layer was extracted with EtOAc (x2). The organic layers were combined, concentrated, and the crude residue was purified by silica gel chromatography (EtOAc: petroleum ether) to give the title compound. LCMS [M+H] + = 197.1 (calculated value 196.9).

[0237] Step 2: 3,6-Dichloro-5-methylpyridazine-4-phenyl 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 to 40 °C and maintained for 48 hours. The reaction mixture was then cooled to room temperature and diluted with water and EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc (x3). The organic layers were combined, concentrated, and the resulting crude residue was purified by silica gel chromatography (EtOAc: petroleum ether) to give the title compound. LCMS [M+H] + = 303.1 (calculated value 303.0).

[0238] Step 3: (1) R ,2 R 5 R and 1 S ,2 S 5 S )-2-((6-chloro-5-methyl-4-(phenylsulfonyl)pyridazin-3-yl)amino)-8-azabicyclo[3.2.1] tert-butyl octane-8-carboxylate: with (1 R ,2 R 5 R and 1 S ,2 S 5 SA solution of 3,6-dichloro-5-methylpyridazine-4-sulfinyl phenyl ester (580 mg, 1.91 mmol) in 1,4-dioxane (10 mL) was treated with tert-butyl octane-8-carboxylate (Combi-Blocks, 433 mg, 1.91 mmol) and Na₂CO₃ (608 mg, 5.74 mmol). The resulting mixture was heated to 100 °C and held for 12 hours. After cooling to room temperature, the reaction mixture was quenched with water and extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The resulting crude residue was purified by silica gel chromatography (EtOAc: petroleum ether) to give the title compound. LCMS [M+H] + =493.1 (Calculated value 493.2).

[0239] Step 4: (1) R ,2 R 5 R and 1 S ,2 S 5 S )-2-((4-azido-6-chloro-5-methylpyridazin-3-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester: treated with NaN3 (844 mg, 13.0 mmol) (1 R ,2 R 5 R and 1 S ,2 S 5 S A solution of tert-butyl octane-8-carboxylate (800 mg, 1.62 mmol) in DMF (12 mL) was obtained. The resulting mixture was heated to 50 °C and held for 12 hours. After cooling to 0 °C, the reaction mixture was quenched with water and extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The crude residue was purified by silica gel chromatography (EtOAc: petroleum ether) to give the title compound. LCMS [M+H] + = 394.1 (calculated value 394.2).

[0240] Step 5: (1) R ,2 R 5 R and 1 S ,2 S 5 S)-2-((4-amino-6-chloro-5-methylpyridazin-3-yl)amino)-8-azabicyclo[3.2.1] tert-butyl octane-8-carboxylate: (1 R ,2 R 5 R and 1 S ,2 S 5 S A solution of tert-butyl 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, filtered, and washed with brine (2x). The resulting organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum to give the title compound. LCMS [M+H] + = 368.1 (calculated value 368.2).

[0241] Step 6: (1) R ,2 R 5 R and 1 S ,2 S 5 S )-2-(3-chloro-4-methyl-7 H -imidazo[4,5- c [3.2.1]Tertibutyl octane-8-carboxylate: treated with HCl (4 M, in 1,4-dioxane, 8.2 µL, 0.033 mmol) (1) R ,2 R 5 R and 1 S ,2 S 5 S A solution of 2-((4-amino-6-chloro-5-methylpyridazin-3-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (240 mg, 0.652 mmol) in trimethyl orthoformate (0.3 mL). The reaction mixture was heated to 100 °C and held for 30 min. After cooling to room temperature, the reaction mixture was concentrated under vacuum. The resulting crude residue was purified by silica gel chromatography (EtOAc: petroleum ether) to give the title compound. LCMS [M+H] + = 378.1 (calculated value 378.2).

[0242] Intermediate 26 5-(3-chloro-4-methyl-7-) H-imidazo[4,5- c [[3.1.1]heptamethrin-7-yl]bicyclo[3.1.1]hept-1-amine Treatment of (5-(3-chloro-4-methyl-7-) with TFA (36 mg, 0.318 mmol) H -imidazo[4,5- c A solution of tert-butyl carbamate (intermediate 24, 40 mg, 0.106 mmol) in DCM (1 mL) was obtained. The resulting mixture was stirred at 20 °C for 1 hour. The reaction mixture was then concentrated under vacuum, and the resulting crude residue was purified by preparative reversed-phase HPLC (C18 stationary phase, MeCN / water + 0.1% TFA) to give the title compound. LCMS [M+H] + = 278.0, (calculated value 278.1).

[0243] Table 15. The following compounds were prepared using suitable starting materials using a procedure similar to that described for Example 3.

[0244] Table 16. The following compounds were prepared using suitable starting materials using a procedure similar to that described for Example 7.

[0245] Table 17. The following compounds were prepared using suitable starting materials and ketones in a procedure similar to that described for Example 10. DCM was used as the solvent instead of a mixture of THF and MeOH. For Example 22, the reaction temperature was increased to 50°C.

[0246] Examples 24 and 25 2-(7-((1 R ,2 R 5 S )-8-azabicyclo[3.2.1]oct-2-yl)-4-methyl-7 H -imidazo-[4,5- c ]pyridazine-3-yl)-5-(trifluoromethyl)phenol, and 2-(7-((1 S ,2 S 5 R )-8-azabicyclo[3.2.1]oct-2-yl)-4-methyl-7 H -imidazo-[4,5- c]pyridazine-3-yl)-5-(trifluoromethyl)phenol Step 1: (1 R ,2 R 5 R and 1 S ,2 S 5 S )-2-(3-(2-hydroxy-4-(trifluoromethyl)phenyl)-4-methyl-7 H -imidazo[4,5- c [3.2.1]Tertiaryl(7-yl)-8-azabicyclo[3.2.1]octane-8-carbamate tert-butyl ester: prepared with cesium carbonate (103 mg, 0.318 mmol) and Ad2 n -BuP Pd G2 (7.1 mg, 0.011 mmol) treatment (1 R ,2 R 5 R and 1 S ,2 S 5 S )-2-(3-chloro-4-methyl-7 H -imidazo[4,5- c [3.2.1]-Octane-8-carbamate tert-butyl ester (intermediate 23, 40 mg, 0.106 mmol) and (2-hydroxy-4-(trifluoromethyl)phenyl)boronic acid (Combi-Blocks, 26 mg, 0.127 mmol) in t A solution of -AmOH (1 mL) and water (0.2 mL) was prepared. The reaction mixture was heated to 100 °C and maintained for 3 hours, then cooled to room temperature and diluted with water and EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc (2x). The organic layers were combined, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The resulting crude residue was purified by preparative TLC (EtOAc: petroleum ether) to give the title compound. LCMS [M+H] + = 504.1, (calculated value 504.2).

[0247] Step 2: 2-(7-((1) R ,2 R 5 S )-8-azabicyclo[3.2.1]oct-2-yl)-4-methyl-7 H -imidazo[4,5- c ]pyridazine-3-yl)-5-(trifluoromethyl)phenol and 2-(7-((1 S ,2 S5 R )-8-azabicyclo[3.2.1]oct-2-yl)-4-methyl-7 H -imidazo[4,5- c ]pyridazine-3-yl)-5-(trifluoromethyl)phenol: treated with TFA (51 mg, 0.447 mmol) (1 R ,2 R 5 R and 1 S ,2 S 5 S )-2-(3-(2-hydroxy-4-(trifluoromethyl)phenyl)-4-methyl-7 H -imidazo[4,5- c A solution of tert-butyl octane-8-carboxylate (45 mg, 0.089 mmol) in DCM (1 mL). The resulting mixture was stirred at 20 °C for 1 hour.

[0248] The reaction mixture was then directly concentrated under vacuum, and the resulting crude residue was purified by preparative reversed-phase HPLC (C18 stationary phase, MeCN / water + 0.1% TFA). The resulting racemic mixture was separated by chiral method A, and the isomers were eluted more rapidly to give 2-(7-((1) R ,2 R 5 S )-8-azabicyclo[3.2.1]oct-2-yl)-4-methyl-7 H -imidazo[4,5- c ]pyridazine-3-yl)-5-(trifluoromethyl)phenol (Example 24), and the isomer eluted more slowly yielded 2-(7-((1 S ,2 S 5 R )-8-azabicyclo[3.2.1]oct-2-yl)-4-methyl-7 H -imidazo[4,5- c [Pyridazine-3-yl)-5-(trifluoromethyl)-phenol (Example 25). Example 24: LCMS [M+H] + = 404.1, (calculated value 404.2). 1 H NMR (400 MHz, MeOD- d 4) δ8.90 (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). Example 25: LCMS [M+H] + = 404.1, (calculated value 404.2). 1 H NMR (400 MHz, MeOD- d 4) 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).

[0249] Example 26 5-Chloro-3-fluoro-2-(4-methyl-7-(( R )-1-Methylpiperidin-3-yl)-7 H -imidazo-[4,5- c ]pyridazine-3-yl)phenol Step 1: 3-(4-chloro-2-fluoro-6-methoxyphenyl)-4-methyl-7-( R )-1-Methylpiperidin-3-yl)-7 H -imidazo[4,5- c [Pyridazine: Treatment of nitrogen atmosphere with 1,4-dioxane (1.25 mL) and water (0.25 mL)] R )-3-chloro-4-methyl-7-(1-methylpiperidin-3-yl)-7 H -imidazo[4,5- cA mixture of 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 prepared. The resulting mixture was heated to 100 °C and held for 12 hours. After cooling to room temperature, the reaction mixture was directly purified by preparative reversed-phase HPLC (C18 stationary phase, MeCN / water + 0.1% TFA) to give the title compound. LCMS [M+H] + = 390.1, (calculated value 390.1).

[0250] Step 2: 5-Chloro-3-fluoro-2-(4-methyl-7-(( R )-1-Methylpiperidin-3-yl)-7 H -imidazo[4,5- c ]pyridazine-3-yl)phenol: 3-(4-chloro-2-fluoro-6-methoxyphenyl)-4-methyl-7-( R )-1-Methylpiperidin-3-yl)-7 H -imidazo[4,5- c A solution of 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 was then cooled to 0 °C, quenched with MeOH, and concentrated. The resulting crude residue was purified by preparative reversed-phase HPLC (C18 stationary phase, MeCN / water + 0.05% FA) to give the title compound. LCMS [M+H] + = 376.2, (calculated value 376.1). 1 H NMR (500 MHz, DMSO- d 6 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).

[0251] Example 27 ( R )-3-cyclopropyl-2-fluoro-6-(4-methyl-7-(1-methylpiperidin-3-yl)-7 H -imidazo-[4,5- c ]pyridazine-3-yl)phenol Step 1: ( R )-3-(4-chloro-3-fluoro-2-methoxyphenyl)-4-methyl-7-(1-methylpiperidin-3-yl)-7 H -imidazo[4,5- c [Pyridazine: Treatment of nitrogen atmosphere with 1,4-dioxane (3.1 mL) and water (0.63 mL)] R )-3-chloro-4-methyl-7-(1-methylpiperidin-3-yl)-7 H -imidazo[4,5- c A mixture of pyridazine (intermediate 16, 100 mg, 0.376 mmol), 2-(4-chloro-3-fluoro-2-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentane (AOB Chem, 108 mg, 0.376 mmol), K₂CO₃ (156 mg, 1.13 mmol), and PdCl₂ (dppf) (28 mg, 0.038 mmol) was prepared. The resulting mixture was heated to 100 °C and held for 12 hours. The reaction mixture was then cooled to room temperature and concentrated directly under vacuum. The resulting crude residue was dissolved in DMSO, filtered, and purified by preparative reversed-phase HPLC (C18 stationary phase, MeCN / water + 0.1% TFA). The desired fractions were collected and diluted with EtOAc, water, and a saturated aqueous solution of NaHCO₃. The layers were separated, and the aqueous layer was extracted with EtOAc (2x). The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated under vacuum to obtain the title compound. LCMS [M+H] + = 390.2, (calculated value 390.1).

[0252] Step 2: ( R )-3-(4-cyclopropyl-3-fluoro-2-methoxyphenyl)-4-methyl-7-(1-methylpiperidin-3-yl)-7 H -imidazo[4,5- c Pyridazine: Treatment of nitrogen atmosphere with cyclopropyl zinc bromide(II) (0.5 M, in THF, 0.51 mL, 0.254 mmol)R )-3-(4-chloro-3-fluoro-2-methoxyphenyl)-4-methyl-7-(1-methylpiperidin-3-yl)-7 H -imidazo[4,5- c A mixture of pyridazine (33 mg, 0.085 mmol) and PdCl2 (dppf) (6.2 mg, 0.0085 mmol) in 1,4-dioxane (0.85 mL) was prepared. The resulting mixture was heated to 70 °C and held for 3 hours. After cooling to room temperature, the reaction mixture was quenched with saturated NH4Cl aqueous solution and extracted with EtOAc (4x). The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated under vacuum. The resulting crude residue was then purified by preparative reversed-phase HPLC (C18 stationary phase, MeCN / water + 0.1% TFA) to give the title compound. LCMS [M+H] + = 396.3, (calculated value 396.2).

[0253] Step 3: ( R )-3-cyclopropyl-2-fluoro-6-(4-methyl-7-(1-methylpiperidin-3-yl)-7 H -imidazo[4,5- c ]pyridazine-3-yl)phenol: ( R )-3-(4-cyclopropyl-3-fluoro-2-methoxyphenyl)-4-methyl-7-(1-methylpiperidin-3-yl)-7 H -imidazo[4,5- c A solution of 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 dropwise addition of MeOH and concentrated under vacuum. The resulting crude residue was purified by preparative reversed-phase HPLC (C18 stationary phase, MeCN / water + 0.05% FA) to give the title compound. LCMS [M+H] + =382.3, (calculated value 382.2). 1 H NMR (500 MHz, DMSO- d 6 δ 8.88 (s, 1H), 8.47 (d, J = 5.5Hz, 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).

[0254] Examples 28 and 29 2-(4-methyl-7-((1) S ,2 S 5 R )-8-methyl-8-azabicyclo[3.2.1]oct-2-yl)-7 H -imidazo-[4,5- c ]pyridazine-3-yl)-5-(trifluoromethyl)phenol, and 2-(4-methyl-7-((1) R ,2 R 5 S )-8-methyl-8-azabicyclo[3.2.1]oct-2-yl)-7 H -imidazo-[4,5- c ]pyridazine-3-yl)-5-(trifluoromethyl)phenol Step 1: (1 R ,2 R 5 R and 1 S ,2 S 5 S )-2-(3-(2-hydroxy-4-(trifluoromethyl)phenyl)-4-methyl-7 H -imidazo[4,5- c [3.2.1]Tertiaryl(7-yl)-8-azabicyclo[3.2.1]octane-8-carbamate tert-butyl ester: prepared with cesium carbonate (103 mg, 0.318 mmol) and Ad2 n -BuP Pd G2 (7.1 mg, 0.011 mmol) treatment (1 R ,2 R 5 R and 1 S ,2 S 5 S )-2-(3-chloro-4-methyl-7 H-imidazo[4,5- c A solution of tert-butyl 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 prepared. The reaction mixture was heated to 100 °C and held for 3 hours, then cooled to room temperature and diluted with water and EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc (2x). The organic layers were combined, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The resulting crude residue was then purified by preparative TLC (EtOAc: petroleum ether) to give the title compound. LCMS [M+H] + = 504,1, (calculated value 504.2).

[0255] Step 2: 2-(7-((1) R ,2 R 5 S and 1 S ,2 S 5 R )-8-azabicyclo[3.2.1]oct-2-yl)-4-methyl-7 H -imidazo[4,5- c ]pyridazine-3-yl)-5-(trifluoromethyl)phenol: treated with TFA (40 mg, 0.348 mmol) (1 R ,2 R 5 R and 1 S ,2 S 5 S )-2-(3-(2-hydroxy-4-(trifluoromethyl)phenyl)-4-methyl-7 H -imidazo[4,5- c A solution of tert-butyl octane-8-carboxylate (35 mg, 0.070 mmol) in DCM (0.7 mL) was prepared. The reaction mixture was stirred at 20 °C for 1 hour. The reaction mixture was then washed with a saturated aqueous solution of NaHCO3 and concentrated under vacuum to give the title compound, which was used in the next step without further purification. LCMS [M+H] + = 404.2, (calculated value 404.2).

[0256] Step 3: 2-(4-methyl-7-((1) R ,2 R 5 S)-8-methyl-8-azabicyclo[3.2.1]oct-2-yl)-7 H -imidazo[4,5- c ]pyridazine-3-yl)-5-(trifluoromethyl)phenol and 2-(4-methyl-7-((1 S ,2 S 5 R )-8-methyl-8-azabicyclo[3.2.1]oct-2-yl)-7 H -imidazo[4,5- c ]pyridazine-3-yl)-5-(trifluoromethyl)phenol: 2-(7-((1 R ,2 R 5 S and 1 S ,2 S 5 R )-8-azabicyclo[3.2.1]oct-2-yl)-4-methyl-7 H -imidazo[4,5- c A solution of pyridazine-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 cyanoborohydride (22 mg, 0.347 mmol) was added. The resulting reaction mixture was heated to 25 °C and stirred for 30 min. The reaction mixture was then concentrated directly under vacuum, and the resulting crude residue was purified by preparative reversed-phase HPLC (C18 stationary phase, MeCN / water + 0.1% TFA). The resulting racemic mixture was separated by chiral method B, and the isomer eluted more rapidly to give 2-(4-methyl-7-((1) S ,2 S 5 R )-8-methyl-8-azabicyclo[3.2.1]oct-2-yl)-7 H -imidazo[4,5- c ]pyridazine-3-yl)-5-(trifluoromethyl)phenol (Example 28), and the isomer eluted more slowly yielded 2-(4-methyl-7-((1 R ,2 R 5 S )-8-methyl-8-azabicyclo[3.2.1]oct-2-yl)-7 H -imidazo[4,5- c [Pyridazine-3-yl)-5-(trifluoromethyl)phenol (Example 29). Example 28: LCMS [M+H] + = 418.1, (calculated value 418.2). 1 HNMR (400 MHz, MeOD-d 4) δ 8.90 (s, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.30 (d, J = 8.2Hz, 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 (400MHz, MeOD- d 4) 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).

[0257] Table 18. The following compounds were prepared using suitable starting materials following a procedure similar to that described for Examples 28 and 29. Racemic products were separated using the chiral SFC method specified in the table; for enantiomer pairs, the isomers that eluted faster were listed first.

[0258] Example 32 2-(7-(5-aminobicyclo[3.1.1]hept-1-yl)-4-methyl-7 H -imidazo[4,5- c ]pyridazine-3-yl)-5-(trifluoromethyl)phenol Using cesium carbonate (42 mg, 0.130 mmol) and Ad2 n-BuP Pd G2 (2.9 mg, 0.0043 mmol) treatment of 5-(3-chloro-4-methyl-7-) H -imidazo[4,5- c [Pyridazine-7-yl]bicyclo[3.1.1]hept-1-amine (intermediate 26, 12 mg, 0.042 mmol) and (2-hydroxy-4-(trifluoromethyl)phenyl)boronic acid (Combi-Blocks, 9.8 mg, 0.043 mmol) in t A solution of -AmOH (0.5 mL) and water (0.1 mL) was prepared. The reaction mixture was heated to 100 °C under nitrogen and held for 2 hours, then cooled to room temperature and extracted with EtOAc (2x). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The resulting crude residue was purified by preparative reversed-phase HPLC (C18 stationary phase, MeCN / water + 0.05% NH₄OH + 10 mM NH₄HCO₃) to give the title compound. LCMS [M+H] + = 404.1, (calculated value 404.2). 1 H NMR (400 MHz, MeOD- d 4) 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).

[0259] Table 19. The following compounds were prepared using suitable intermediates following a procedure similar to that described for Example 32. Racemic products were separated using the chiral SFC method specified in the table; for enantiomer pairs, the isomers that eluted faster were listed first.

[0260] Example 35 ( R )-2-(4-methyl-7-(1-(methyl- d 3)piperidin-3-yl)-7 H -imidazo[4,5- c ]pyridazine-3-yl)-5-(trifluoromethyl)phenol Will( R )-2-(4-methyl-7-(piperidin-3-yl)-7 H -imidazo[4,5- c [Pyridazine-3-yl)-5-(trifluoromethyl)phenol (Example 5, 40 mg, 0.106 mmol) in MeOD- d The solution in 4 (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 vacuum, and the resulting crude residue was purified by preparative reversed-phase HPLC (C18 stationary phase, MeCN / water + 0.1% TFA). The fractions containing the title compound were combined, treated with saturated aqueous NaHCO₃ solution to neutralize the pH, and then extracted with EtOAc (3x). The organic layers were combined, dried over anhydrous MgSO₄, filtered, and concentrated to give the title compound. LCMS [M+H] + = 395.3, (calculated value 395.2). 1 H NMR (500MHz, DMSO- d 6 ) 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).

[0261] Examples of pharmaceutical compositions As one specific embodiment of the oral pharmaceutical composition, the 100 mg potency tablet comprises 100 mg of any of the examples, 268 mg of microcrystalline cellulose, 20 mg of croscarmellose sodium, and 4 mg of magnesium stearate. First, the active ingredient, microcrystalline cellulose, and croscarmellose sodium are blended. Then, the mixture is lubricated with magnesium stearate and compressed into tablets.

[0262] Bioassay Activation of the typical NLRP3 inflammasome requires two steps: initiation and activation. Initiation signals, such as pathogen-activated molecular patterns (PAMPs) or danger-activated molecular patterns (DAMPs), are recognized by Toll-like receptors, leading to nuclear factor κB (NF-κB)-mediated signaling. This, in turn, upregulates the transcription of inflammasome-related components, including inactive NLRP3 and prolL-1β (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 step is activation, which induces oligomerization of NLRP3, followed by the assembly of NLRP3, CARD-containing apoptosis-associated speckle-like protein (ASC), and procysteine-1 into the inflammasome complex. This triggers the conversion of pro-cysteine-1 to caspase-1 and 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 initiates the nucleation of ASCs and an event commonly referred to as “ASC speck” formation occurs because discrete intracellular spots are found in the cells after staining and visualization of ASCs using common immunocytochemical methods.

[0263] The ability of compounds to inhibit NLRP3 inflammasome activation was measured in vitro by monitoring the formation of ASC spots in human monocyte THP-1 cells after stimulation. THP-1 cells (ATCC catalog number #TIB-202) were maintained in complete growth medium containing Roswell Park Memorial Institute RPMI (ATCC catalog number #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 seeded at a density of 20,000 cells / well in 384-well plates (Cell Carrier Ultra microplates coated with poly-D-lysine, Perkin Elmer catalog number #6057500) supplemented with 10 ng / ml phorbol 12-myristate 13-acetate (PMA; Sigma catalog number #P8139) and then incubated overnight. The following day, the medium was replaced with assay medium [RPMI (Gibco catalog #11875-093), 0.01% bovine serum albumin (BSA)]. The compound was serially diluted in DMSO and added to the wells one hour before adding 12.5 μg / ml bacitracin (Enzo Lifescience, catalog #ALX-350-233-M005). All incubations were performed at 37°C (5% CO2 / 95% air). After 3 hours of treatment with bacitracin, the cells were fixed with 4% paraformaldehyde and stored at 4°C until immunofluorescence staining.

[0264] Immunofluorescence staining: As described below, the anti-ASC antibody (MBL catalog number #D086-3) was desalted and labeled with the Alexa 488 antibody labeling kit (Thermo catalog number #A20181) before use. After fixation, the following steps were performed at room temperature. First, the cells were permeabilized with 0.3% Triton X-100 / 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 then stained for 1 hour with a mixture of ASC-Alexa 488 antibody (1:200 diluted in blocking buffer) and nuclear staining agent DRAQ5 (1:5000 in blocking buffer, Thermo catalog number #62251) in blocking buffer. After washing with 0.3% Tween-20 / PBS, the plates were imaged using the Opera Phenix high-content screening system. The number of DRAQ5 positive cells containing ASC spots in each well was quantified.

[0265] Data Analysis: EC was calculated using an internally developed program within the TIBCO Spotfire software via standard curve fitting analysis. 50 value.

[0266] The compounds of the present invention inhibit NLRP3 inflammasome activation in the above bioassays and have an EC50 concentration of less than 5 micromolar. 50 Values. Specific EC values ​​of the compounds in Examples 1-35 in the above bioassays. 50 The values ​​are listed in Table I.

[0267] Table I. EC values ​​of the examples of inhibiting NLRP3 inflammasome activation in the above bioassays 50 Value (nM)

[0268] The scope of the claims should not be limited to the preferred embodiments set forth in the examples, but should be given the broadest interpretation consistent with the entire specification.

[0269] While this disclosure has been described and illustrated in conjunction with certain specific embodiments thereof, those skilled in the art will understand that various adaptations, changes, modifications, substitutions, deletions, or additions can be made to the procedures and schemes without departing from the scope of this disclosure. For example, due to the varying responsiveness of treated mammals to any indication of a compound of structural formula I described above, an effective dose different from the specific dose set forth above may be applicable. Observed specific pharmacological responses may vary depending on and are contingent upon the specific active compound selected or the presence of a drug carrier, as well as the type of formulation and route of administration employed, and such anticipated variations or differences in outcomes are covered for the purposes and practice of this disclosure.

Claims

1. A compound with structural formula I: Or its pharmaceutically acceptable salt, wherein X is selected independently from the following group: (1) =C(R 4 )-,and (2) =N-； R 1 Selected from the following group: (1) -C 3-12 cycloalkyl, (2) -C 3-12 Cycloalkenyl, (3) -C 2-11 Cyclohexane, (4) -C 2-11 Cyclohexene group, (5) Aryl, (6) Mixed aromatics, (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 Cyclohexane, (12) -C 1-6 Alkyl-C 2-11 Cyclohexene group, (13) -C 1-6 alkyl-aryl, and (14) -C 1-6 Alkyl-heteroaryl, Where R 1 Not replaced or selected from one to six R a The substituents are replaced; R 2 Selected from the following group: (1) Hydrogen, (2) CN, (3) -CF3, (4) -CHF2, (5) -C 1-6 Alkyl groups, and (6) Halogens, Wherein the alkyl group is unsubstituted or is selected from one to five R... b The substituents are replaced; R 3 Selected from the following group: (1) Aryl, and (2) Mixed aryl, Among them, the aryl and heteroaryl groups are either unsubstituted or selected from one to five R groups. c The substituents are replaced; R 4 Selected from the following group: (1) Hydrogen, (2) CN, (3) -C 1-6 alkyl, (4) -OC 1-6 Alkyl groups, and (5) Halogens, Each alkyl group is unsubstituted or is selected from one to five R. d The substituents are replaced; R 5 Selected from the following group: (1) Hydrogen, (2) CN, (3) -C 1-6 alkyl, (4) -OC 1-6 Alkyl groups, and (5) Halogens, Each alkyl group is unsubstituted or is selected from one to five R. e The substituents are replaced; Each R a Select independently from the following groups: (1) CN, (2) Oxygenation, (3) -OH, (4) Halogens, (5) -C 1-6 alkyl, (6) -C 1-6 Alkyl-OH, (7) -OC 1-6 alkyl, (8) -C 3-6 cycloalkyl, (9) -C 2-6 Cyclohexane, (10) Aryl, (11) Mixed aromatics, (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 Cyclohexane, (18) -(CH2) p -OC 1-6 alkyl, (19) -(CH2) p -OC 3-6 cycloalkyl, (20) -(CH2) p -OC 2-6 Cyclohexane, (21) -(CH2) p -O-aryl, (22) -(CH2) p -O-heteroaryl, (23) -(CH2) p -S(O) r R f ,and (24) -N(R g )2, Each R a Unsubstituted or selected from one to six halogens, CF3, OH, C 1-6 Alkyl and -OC 1-6 Substituents of alkyl groups; Each R b Select independently from the following groups: (1) CF3, (2) Halogens, (3) -C 1-6 Alkyl groups, and (4) -C 3-6 cycloalkyl; Each R c Select independently from the following groups: (1) CN, (2) -OH, (3) Oxygenation, (4) Halogens, (5) -C 1-6 alkyl, (6) -OC 1-6 alkyl, (7) -C 3-6 cycloalkyl, (8) -C 2-6 Cyclohexane, (9) Aryl, (10) Mixed aromatics, (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 Cyclohexane, (15) -(CH2) q -OC 1-6 alkyl, (16) -(CH2) q -OC 3-6 cycloalkyl, (17) -(CH2) q -OC 2-6 Cyclohexane, (18) -(CH2) q -O-aryl, (19) -(CH2) q -O-heteroaryl, (20) -OC 1-6 Alkyl-C 3-6 cycloalkyl, (21) -OC 1-6 Alkyl-C 2-6 Cyclohexane, (22) -OC 1-6 Alkyl-aryl, (23) -OC 1-6 Alkyl-heteroaryl, (24) -(CH2) q -S(O) r R h , (25) -N(R i )2, (26) -C(O)R j ,and (27) -C(O)NR i , Each R c Unsubstituted or selected from one to six halogens, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 Substituents of alkyl groups; Each R d Select independently from the following groups: (1) Hydrogen, (2) OH, (3) Halogens, and (4) -C 1-6 alkyl; Each R e Select independently from the following groups: (1) Hydrogen, (2) OH, (3) Halogens, and (4) -C 1-6 alkyl; Each R f Select independently from the following groups: (1) Hydrogen, (2) -C 1-6 alkyl, (3) -C 3-6 cycloalkyl, and (4) -C 2-6 Cycloalkyl; Each R g Select independently from the following groups: (1) Hydrogen, (2) -C 1-6 alkyl, (3) -C 3-6 cycloalkyl, (4) -C 2-6 Cyclohexane, (5) Aryl, (6) Mixed aryl, (7) -C(O)C 1-6 Alkyl groups, and (8) -S(O) r R f , The alkyl group may be unsubstituted or substituted with one to three substituents selected from the following: CF3, halogen, OH, and -OC. 1-6 alkyl; Each R h Select independently from the following groups: (1) Hydrogen, (2) -C 1-6 alkyl, (3) -C 3-6 cycloalkyl, and (4) -C 2-6 Cycloalkyl; Each R i Select independently from the following groups: (1) Hydrogen, (2) -C 1-6 alkyl, (3) -C 3-6 cycloalkyl, and (4) -C 2-6 Cycloalkyl; Each R j Select independently from the following groups: (1) OH, (2) -C 1-6 alkyl, (3) -C 3-6 cycloalkyl, and (4) -C 2-6 Cyclohexane, The alkyl group may be unsubstituted or substituted with one to three substituents selected from the following: CF3, halogen, OH, and -OC. 1-6 alkyl; p is 0, 1, 2, 3, 4, 5 or 6; q is 0, 1, 2, 3, 4, 5, or 6; and r is 1 or 2.

2. The compound according to claim 1, having structural formula Ia: ， Or its pharmaceutically acceptable salt.

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

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

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein... R 1 Selected from the following group: (1) -C 3-12 cycloalkyl, (2) -C 2-11 Cyclohexane, (3) Mixed aryl, (4) -C 1-6 Alkyl-OH, (5) -C 1-6 Alkyl-C 3-12 cycloalkyl, and (6) -C 1-6 Alkyl-C 2-11 Cyclohexane, Where R 1 Not replaced or selected from one to six R a The substituents are replaced by the substituents.

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein... R 1 C 2-11 Cyclohexaalkyl groups, wherein the cyclohexaalkyl groups are unsubstituted or composed of one to six radicals selected from R. a The substituents are replaced by the substituents.

7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein... R 2 Selected from the following group: hydrogen and -C 1-6 Alkyl groups, wherein the alkyl group is unsubstituted or composed of one to five radicals selected from R. b The substituents are replaced by the substituents.

8. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein... R 3 It is a heteroaryl group, wherein the heteroaryl group is unsubstituted or is selected from one to five R groups. c The substituents are replaced by the substituents.

9. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein... R 3 It is an aryl group, wherein the aryl group is unsubstituted or is selected from one to five R groups. c The substituents are replaced by the substituents.

10. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein... R 4 It is hydrogen or -C 1-6 Alkyl groups, wherein each alkyl group is unsubstituted or composed of one to five radicals selected from R. d The substituents are replaced by the substituents; and R 5 It is hydrogen or -C 1-6 Alkyl groups, wherein each alkyl group is unsubstituted or composed of one to five radicals selected from R. e The substituents are replaced by the substituents.

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

12. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein... R 1 Selected from the following group: (1) -C 3-12 cycloalkyl, (2) -C 2-11 Cyclohexane, (3) Mixed aryl, (4) -C 1-6 Alkyl-OH, (5) -C 1-6 Alkyl-C 3-12 cycloalkyl, and (6) -C 1-6 Alkyl-C 2-11 Cyclohexane, Where R 1 Not replaced or selected from one to six R a The substituents are replaced; R 2 Selected from the following group: hydrogen and -C 1-6 Alkyl groups, wherein the alkyl group is unsubstituted or composed of one to five radicals selected from R. b The substituents are replaced; R 3 It is a heteroaryl group, wherein the heteroaryl group is unsubstituted or is selected from one to five R groups. c The substituents are replaced; R 4 It is hydrogen or -C 1-6 Alkyl groups, wherein each alkyl group is unsubstituted or composed of one to five radicals selected from R. d The substituents are replaced by the substituents; and R 5 It is hydrogen or -C 1-6 Alkyl groups, wherein each alkyl group is unsubstituted or composed of one to five radicals selected from R. e The substituents are replaced by the substituents.

13. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein... R 1 C 2-11 Cyclohexaalkyl groups, wherein the cyclohexaalkyl groups are unsubstituted or composed of one to six radicals selected from R. a The substituents are replaced; R 2 Selected from the following group: hydrogen and -C 1-6 Alkyl groups, wherein the alkyl group is unsubstituted or composed of one to five radicals selected from R. b The substituents are replaced; R 3 It is an aryl group, wherein the aryl group is unsubstituted or is selected from one to five R groups. c The substituents are replaced; R 4 It is hydrogen; and R 5 It is hydrogen.

14. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: (1) ( R )-2-(7-(1-ethylpiperidin-3-yl)-7 H -pyrrolo[2,3- c ]pyridazine-3-yl)-3-methyl-5-(trifluoromethyl)phenol; (2) ( R )-2-(7-(1-ethylpiperidin-3-yl)-4-methyl-7 H -pyrrolo[2,3- c ]pyridazine-3-yl)-5-(trifluoromethyl)phenol; (3) ( R )-2-(7-(1-ethylpiperidin-3-yl)-7 H -imidazo[4,5- c ]pyridazine-3-yl)-3-methyl-5-(trifluoromethyl)phenol; (4) R )-3-methyl-2-(7-(1-methylpiperidin-3-yl)-7 H -imidazo[4,5- c ]pyridazine-3-yl)-5-(trifluoromethyl)phenol; (5) S )-3-methyl-2-(7-(1-methylpiperidin-3-yl)-7 H -imidazo[4,5- c ]pyridazine-3-yl)-5-(trifluoromethyl)phenol; (6) ( R )-2-(4-methyl-7-(piperidin-3-yl)-7 H -imidazo[4,5- c ]pyridazine-3-yl)-5-(trifluoromethyl)phenol; (7) (3 S 4 R )-3-(3-(2-hydroxy-4-(trifluoromethyl)phenyl)-4-methyl-7 H -imidazo[4,5- c ]pyridazine-7-yl)piperidin-4-ol; (8) R )-2-(7-(1-ethylpiperidin-3-yl)-4-methyl-7 H -imidazo[4,5- c ]pyridazine-3-yl)-5-(trifluoromethyl)phenol; (9) R )-2-(7-(1-methylpiperidin-3-yl)-7 H -imidazo[4,5- c ]pyridazine-3-yl)-5-(trifluoromethyl)phenol; (10) ( S )-2-(7-(1-methylpiperidin-3-yl)-7 H -imidazo[4,5- c ]pyridazine-3-yl)-5-(trifluoromethyl)phenol; (11) ( R )-3-(2-(difluoromethoxy)-4-(trifluoromethyl)phenyl)-7-(1-ethylpiperidin-3-yl)-4-methyl-7 H -imidazo[4,5- c ]pyridazine; (12) ( R )-2-(4-methyl-7-(1-methylpiperidin-3-yl)-7 H -imidazo[4,5- c ]pyridazine-3-yl)-5-(trifluoromethyl)phenol; (13) (3 S 4 R )-3-(3-(2-hydroxy-4-(trifluoromethyl)phenyl)-4-methyl-7 H -imidazo[4,5- c ]pyridazine-7-yl)-1-methylpiperidin-4-ol; and (14) (3 S 4 R )-1-Ethyl-3-(3-(2-hydroxy-4-(trifluoromethyl)phenyl)-4-methyl-7 H -imidazo[4,5- c ]pyridazine-7-yl)piperidin-4-ol; (15) ( R )-5-chloro-2-(4-methyl-7-(piperidin-3-yl)-7 H -imidazo[4,5- c ]pyridazine-3-yl)phenol; (16) ( R )-2-(4,6-dimethyl-7-(1-methylpiperidin-3-yl)-7 H -imidazo[4,5- c ]pyridazine-3-yl)-5-(trifluoromethyl)phenol; (17) ( R )-5-(4-methyl-7-(1-methylpiperidin-3-yl)-7 H -imidazo[4,5- c ]pyridazine-3-yl)benzo[ b Thiophene-4-ol; (18) ( R )-5-(4-methyl-7-(1-methylpiperidin-3-yl)-7 H -imidazo[4,5- c ]pyridazine-3-yl)-2,3-dihydro-1 H -Indene-4-ol; (19) ( R )-5-chloro-2-(4-methyl-7-(1-methylpiperidin-3-yl)-7 H -imidazo[4,5- c ]pyridazine-3-yl)phenol; and (20) ( R )-5-chloro-2-(7-(1-ethylpiperidin-3-yl)-4-methyl-7 H -imidazo[4,5- c ]pyridazine-3-yl)phenol.

15. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: (1) ( R )-2-(7-(1-ethylpiperidin-3-yl)-7 H -imidazo[4,5- c ]pyridazine-3-yl)-3-methyl-5-(trifluoromethyl)phenol; (2) ( R )-2-(4-methyl-7-(piperidin-3-yl)-7 H -imidazo[4,5- c ]pyridazine-3-yl)-5-(trifluoromethyl)phenol; (3) ( R )-2-(7-(1-ethylpiperidin-3-yl)-4-methyl-7 H -imidazo[4,5- c ]pyridazine-3-yl)-5-(trifluoromethyl)phenol; and (4) R )-2-(4-methyl-7-(1-methylpiperidin-3-yl)-7 H -imidazo[4,5- c ]pyridazine-3-yl)-5-(trifluoromethyl)phenol.

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

17. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating, in mammals in need, a condition or disease that responds to inhibition of NLRP3.

18. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment, prevention or control of inflammatory diseases, fibrotic diseases, cardiovascular diseases, metabolic diseases or neurodegenerative diseases.

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

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

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

22. The compound of claim 1 or a pharmaceutically acceptable salt thereof, used in a therapeutic manner.

23. A method for treating or preventing a condition, illness, or disease that responds to inhibition of NLRP3 in a patient in need, the method comprising administering a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof.

24. The method of claim 23, wherein the disease is selected from: inflammatory diseases, fibrotic diseases, cardiovascular diseases, metabolic diseases and neurodegenerative diseases.

25. The method of claim 24, wherein the condition is an inflammatory condition.

26. The method of claim 25, wherein the inflammatory condition is selected from: autoimmune diseases, autoinflammatory diseases, inflammatory joint diseases, inflammatory skin diseases, and neuroinflammatory diseases.

27. The method of claim 25, wherein the condition is selected from: atherosclerosis, non-alcoholic steatohepatitis, Alzheimer's disease, and Parkinson's disease.

Images