Method for preparing carbamate derivatives

Abstract

The present disclosure relates to a method for preparing a compound of formula (IX): (IX); or a pharmaceutically acceptable salt thereof. The present disclosure also relates to compounds prepared by the method, pharmaceutical compositions containing the compounds, and their uses, for example, in the treatment of disorders, such as disorders involving inflammasome activity.

Description

[Technical Field]

[0001] Related Applications This application claims priority to International Patent Application No. PCT / CN2022 / 123712, filed October 5, 2022, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] background Autoimmune diseases are associated with the overproduction of proinflammatory factors. One of them is interleukin-1 (IL-1), which is produced by activated macrophages, monocytes, fibroblasts, and other components of the innate immune system, such as dendritic cells. IL-1 is involved in a variety of cellular activities, including cell proliferation, differentiation, and apoptosis (Masters, SL, et al., Annu. Rev. Immunol. 2009. 27:621-68).

[0003] In humans, 22 NLR proteins are classified into four NLR subfamilies according to their N-terminal domains: NLRA contains a CARD-AT domain, NLRB (NAIP) contains a BIR domain, NLRC (including NOD1 and NOD2) contains a CARD domain, and NLRP contains a pyrin domain. Many NLR family members are involved in inflammasome formation.

[0004] Although inflammasome activation appears to have evolved as a critical component of host immunity against pathogens, the NLRP3 inflammasome is unique in its ability to activate in response to endogenous sterile danger signals. Many such sterile signals have been elucidated, and their formation has been linked to specific disease states. For example, uric acid crystals found in patients with gout are potent triggers of NLRP3 activation. Similarly, cholesterol crystals found in patients with atherosclerosis may also promote NLRP3 activation. Recognition of the role of sterile danger signals as NLRP3 activators has led to the implication of IL-1 and IL-18 in a wide range of pathophysiological indications, including metabolic, physiological, inflammatory, hematological, and immunological disorders.

[0005] The present disclosure arose out of a need to provide novel methods for preparing compounds for the specific modulation of NLRP3-dependent cellular processes. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Masters, SL, et. al., Annu. Rev. Immunol. 2009. 27:621-68 Summary of the Invention

[0007] overview In some aspects, the present disclosure provides methods of preparing compounds of formula (IX) described herein (eg, Compound No. 9a or 9b).

[0008] In some aspects, the present disclosure provides a method for preparing a compound of formula (IX) (e.g., Compound No. 9a or 9b) or a salt thereof, comprising one or more of steps (i)-(vii): (i) contacting Compound No. 1 or a salt thereof with a hydrogenation agent, thereby forming Compound No. 2 or a salt thereof; (ii) reacting Compound No. 3 with an esterifying agent, thereby forming a compound of formula (IV) (e.g., Compound No. 4); (iii) contacting Compound No. 2 or a salt thereof with a compound of formula (IV) (e.g., Compound No. 4), thereby forming a compound of formula (V) (e.g., Compound No. 5) or a salt thereof; (iv) contacting a compound of formula (V) (e.g., Compound No. 5) or a salt thereof with a reducing agent, thereby forming a compound of formula (VI) (e.g., Compound No. 6a or 6b) or a salt thereof; (v) contacting Compound No. 7 or a salt thereof with a CO generating agent, thereby forming Compound No. 8 or a salt thereof; (vi) contacting a compound of formula (VI) (e.g., Compound No. 6a or 6b) or a salt thereof with Compound No. 8 or a salt thereof, thereby forming a compound of formula (IX) (e.g., Compound No. 9a or 9b) or a salt thereof; or (vii) purifying the compound of formula (IX) (e.g., compound No. 9a or 9b) or a salt thereof.

[0009] In some aspects, the present disclosure provides a method for preparing a compound of formula (IX) (e.g., compound No. 9a or 9b) or a salt thereof, comprising steps (i) to (vii): (i) contacting Compound No. 1 or a salt thereof with a hydrogenation agent, thereby forming Compound No. 2 or a salt thereof; (ii) contacting Compound No. 3 with an esterifying agent, thereby forming a compound of formula (IV) (e.g., Compound No. 4); (iii) contacting Compound No. 2 or a salt thereof with a compound of formula (IV) (e.g., Compound No. 4), thereby forming a compound of formula (V) (e.g., Compound No. 5) or a salt thereof; (iv) contacting a compound of formula (V) (e.g., Compound No. 5) or a salt thereof with a reducing agent, thereby forming a compound of formula (VI) (e.g., Compound No. 6a or 6b) or a salt thereof; (v) contacting Compound No. 7 or a salt thereof with a CO generating agent, thereby forming Compound No. 8 or a salt thereof; (vi) contacting a compound of formula (VI) (e.g., Compound No. 6a or 6b) or a salt thereof with Compound No. 8 or a salt thereof, thereby forming a compound of formula (IX) (e.g., Compound No. 9a or 9b) or a salt thereof; and (vii) purifying the compound of formula (IX) (e.g., compound No. 9a or 9b) or a salt thereof.

[0010] In some aspects, the present disclosure provides a method of preparing a compound of formula (V) (e.g., Compound No. 5) or a salt thereof, comprising: (iii) contacting Compound No. 2 or a salt thereof with a compound of formula (IV) (e.g., Compound No. 4), thereby forming a compound of formula (V) (e.g., Compound No. 5) or a salt thereof.

[0011] In some aspects, the present disclosure provides compounds prepared by the methods described herein.

[0012] In some aspects, the present disclosure provides pharmaceutical compositions comprising a compound of formula (IX) described herein (e.g., Compound No. 9a or 9b) or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

[0013] In some aspects, the present disclosure provides a method of inhibiting inflammasome (e.g., NLRP3 inflammasome) activity (e.g., in vitro or in vivo), the method comprising contacting a cell with a compound of formula (IX) described herein (e.g., compound No. 9a or 9b) or a pharmaceutically acceptable salt thereof (e.g., in an effective amount).

[0014] In some aspects, the present disclosure provides a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof, the method comprising administering to the subject (e.g., in a therapeutically effective amount) a compound of formula (IX) described herein (e.g., compound No. 9a or 9b) or a pharmaceutically acceptable salt thereof.

[0015] In some aspects, the present disclosure provides a compound of formula (IX) described herein (e.g., compound No. 9a or 9b), or a pharmaceutically acceptable salt thereof, for use in inhibiting inflammasome (e.g., NLRP3 inflammasome) activity (e.g., in vitro or in vivo).

[0016] In some aspects, the present disclosure provides a compound of formula (IX) described herein (e.g., compound No. 9a or 9b) or a pharmaceutically acceptable salt thereof for use in treating or preventing a disease or disorder disclosed herein.

[0017] In some aspects, the present disclosure provides the use of a compound of formula (IX) described herein (e.g., compound No. 9a or 9b) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for inhibiting inflammasome (e.g., NLRP3 inflammasome) activity (e.g., in vitro or in vivo).

[0018] In some aspects, the present disclosure provides the use of a compound of formula (IX) described herein (e.g., compound No. 9a or 9b) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0019] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs.In this specification, the singular form "a," "an," or "the" includes the plural unless the context clearly dictates otherwise.Although methods and materials similar or equivalent to those described herein can be used in practicing or testing the present disclosure, suitable methods and materials are described below.All publications, patent applications, patents, and other references mentioned herein are incorporated by reference.The references cited herein are not admitted to be prior art to the claimed invention.In case of conflict, the present specification, including definitions, will prevail.In addition, the materials, methods, and examples are merely illustrative and are not intended to be limiting.In the event of a conflict between the chemical structure and name of a compound disclosed herein, the chemical structure will prevail.

[0020] Other features and advantages of the present disclosure will become apparent from the following detailed description and claims. DETAILED DESCRIPTION OF THE INVENTION

[0021] Detailed Description Autoimmune diseases are associated with the overproduction of proinflammatory factors, one of which is interleukin-1 (IL-1), which is produced by activated macrophages, monocytes, fibroblasts, and other components of the innate immune system, such as dendritic cells, and is involved in a variety of cellular activities, including cell proliferation, differentiation, and apoptosis (Seth L. et al. Rev. Immunol. 2009. 27:621-68).

[0022] Cytokines from the IL-1 family are highly active and are primarily associated with acute and chronic inflammation as key mediators of inflammation (Sims J. et al. Nature Reviews Immunology 10, 89-102 (February 2010)). Excessive production of IL-1 is thought to be a mediator of several autoimmune and autoinflammatory diseases. Autoinflammatory diseases are characterized by recurrent and unprovoked inflammation in the absence of autoantibodies, infections, or antigen-specific T lymphocytes.

[0023] Proinflammatory cytokines of the IL-1 superfamily, including IL-1α, IL-1β, IL-18, and IL-36α, β, and λ, are produced in response to pathogens and other cellular stressors as part of the host innate immune response. Unlike many other secreted cytokines, which are processed and released through the standard cellular secretory apparatus consisting of the endoplasmic reticulum and Golgi apparatus, IL-1 family members lack the leader sequence required for endoplasmic reticulum translocation and are therefore retained intracellularly after translation. In addition, IL-1β, IL-18, and IL-36α, β, and λ are synthesized as procytokines that require proteolytic activation to become optimal ligands for binding to their corresponding receptors on target cells.

[0024] In the cases of IL-1α, IL-1β, and IL-18, multimeric protein complexes known as inflammasomes are now known to be responsible for the activation of IL-1β and IL-18 proforms and the extracellular release of these cytokines. Inflammasome complexes typically consist of sensor molecules such as NLRs (nucleotide-oligomeric domain (NOD)-like receptors), the adaptor molecule ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain (CARD)), and procaspase-1. In response to diverse "danger signals," including pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs), inflammasome subunits oligomerize to form intracellular supramolecular structures. PAMPs can include molecules such as peptidoglycan, viral DNA or RNA, and bacterial DNA or RNA. On the other hand, DAMPs consist of a wide range of endogenous and exogenous sterile triggers, including monosodium urate crystals, silica, alum, asbestos, fatty acids, ceramides, cholesterol crystals, and beta-amyloid peptide aggregates. Assembly of the inflammasome platform drives the autocatalytic activity of procaspase-1, generating a highly active cysteine ​​protease responsible for the activation and release of pro-IL-1β and pro-IL-18. Thus, the release of these pro-inflammatory cytokines is achieved only in response to inflammasome sensors that detect and respond to specific molecular danger signals.

[0025] In humans, 22 NLR proteins are classified into four NLR subfamilies according to their N-terminal domains: NLRA contains a CARD-AT domain, NLRB (NAIP) contains a BIR domain, NLRC (including NOD1 and NOD2) contains a CARD domain, and NLRP contains a pyrin domain. Many NLR family members, including NLRP1, NLRP3, NLRP6, NLRP7, NLRP12, and NLRC4 (IPAF), are involved in inflammasome formation.

[0026] Two other structurally distinct inflammasome structures containing PYHIN domains (pyrin and HIN domain-containing proteins), namely, Absent in Melanoma 2 (AIM2) and IFNλ-inducible protein 16 (IFI16) (Latz et al., Nat Rev Immunol, 2013, 13(6), 397-311), function as intracellular DNA sensors. Pyrin (encoded by the MEFV gene) represents another type of inflammasome platform associated with pro-IL-1β activation (Chae et al., Immunity 34, 755-768, 2011).

[0027] The activation and release of IL-1β and IL-18 from monocytes and macrophages requires the assembly of an inflammasome platform, ensuring that their production is carefully orchestrated as a whole through a two-step process. First, cells must encounter a priming ligand (e.g., the TLR4 receptor ligand LPS or a proinflammatory cytokine such as TNFα) that leads to NFkB-dependent transcription of NLRP3, pro-IL-1β, and pro-IL-18. The newly translated pro-cytokine remains intracellular and inactive unless the producing cell encounters a second signal that leads to activation of the inflammasome scaffold and maturation of pro-caspase-1.

[0028] In addition to the proteolytic activation of pro-IL-1β and pro-IL-18, active caspase-1 also triggers a form of inflammatory cell death known as pyroptosis through cleavage of gasdermin-D. Pyroptosis allows the mature forms of IL-1β and IL-18 to be externalized along with the release of alarmin molecules (compounds that promote inflammation and activate innate and adaptive immunity), such as high-mobility group box 1 protein (HMGB1), IL-33, and IL-1α.

[0029] Although inflammasome activation appears to have evolved as a critical component of host immunity against pathogens, the NLRP3 inflammasome is unique in its ability to activate in response to endogenous and exogenous sterile danger signals. Many such sterile signals have been elucidated, and their formation has been linked to specific disease states. For example, uric acid crystals found in patients with gout are potent triggers of NLRP3 activation. Similarly, cholesterol crystals found in patients with atherosclerosis may also promote NLRP3 activation. Recognition of the role of sterile danger signals as NLRP3 activators has led to the implication of IL-1β and IL-18 in a wide range of pathophysiological indications, including metabolic, physiological, inflammatory, hematological, and immunological disorders.

[0030] The association with human disease is best exemplified by the discovery that mutations in the NLRP3 gene leading to gain of function confer a variety of autoinflammatory conditions collectively known as cryopyrin-associated periodic syndromes (CAPS), including familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease (NOMID) (Hoffman et al., Nat Genet. 29(3) (2001) 301-305). Similarly, sterile mediator-induced activation of NLRP3 has been implicated in a wide range of disorders, including joint degeneration (gout, rheumatoid arthritis, osteoarthritis), cardiometabolic disorders (type 2 diabetes, atherosclerosis, hypertension), central nervous system disorders (Alzheimer's disease, Parkinson's disease, multiple sclerosis), gastrointestinal disorders (Crohn's disease, ulcerative colitis), pulmonary disorders (chronic obstructive pulmonary disease (COPD), asthma, idiopathic pulmonary fibrosis), and liver disorders (fibrosis, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis (NASH)). Furthermore, NLRP3 activation is thought to promote renal inflammation and thus contribute to chronic kidney disease (CKD).

[0031] Current treatment options for diseases involving IL-1 as a contributing factor in the pathogenesis include the IL-1 receptor antagonist anakinra, an Fc-containing fusion construct of the extracellular domain of the IL-1 receptor and IL-1 receptor accessory protein (rilonacept), and the anti-IL-1β monoclonal antibody canakinumab. For example, canakinumab is approved for CAPS, tumor necrosis factor receptor-associated periodic syndrome (TRAPS), hyperimmunoglobulin D syndrome (HIDS) / mevalonate kinase deficiency (MKD), familial Mediterranean fever (FMF), and gout.

[0032] Several small molecules have been reported to inhibit the function of the NLRP3 inflammasome. For example, glyburide is a specific inhibitor of NLRP3 activation, albeit at micromolar concentrations that are unlikely to be reached in vivo. Nonspecific agents such as parthenolide, Bay 11-7082, and 3,4-methylenedioxy-β-nitrostyrene have been reported to reduce NLRP3 activation, but are expected to have limited therapeutic utility due to the fact that they share a common structural feature consisting of an olefin that is activated by substitution with an electron-withdrawing group; this structural feature may lead to the undesired formation of covalent adducts with protein-borne thiol groups. Some natural products, such as β-hydroxybutyrate, sulforaphane, quercetin, and salvianolic acid, have also been reported to suppress NLRP3 activation. Similarly, numerous effectors / modulators of other molecular targets have been reported to attenuate NLRP3 activation, including agonists of the G protein-coupled receptor TGR5, the sodium-glucose cotransporter inhibitor epigliflozin, the dopamine receptor antagonist A-68930, the serotonin reuptake inhibitor fluoxetine, fenamic acid nonsteroidal anti-inflammatory drugs, and the beta-adrenergic receptor blocker nebivolol. The usefulness of these molecules as therapeutic agents for the chronic treatment of NLRP3-dependent inflammatory disorders remains to be established. A series of sulfonylurea-containing molecules was previously identified as potent and selective inhibitors of post-translational processing of pro-IL-1β (Perregaux et al., J Pharmacol. Exp. Ther. 299, 187-197, 2001). Recently, an exemplary molecule from this study, CP-456,773, was characterized as a specific inhibitor of NLRP3 activation (Coll et al., Nat Med 21.3 (2015): 248-255.).

[0033] The present disclosure relates to methods for preparing compounds useful for modulating NLRP3-dependent cellular processes. In some embodiments, methods for preparing compounds that have improved physicochemical, pharmacological, and pharmaceutical properties relative to existing NLRP3-modulating compounds are desired.

[0034] Compounds of the present disclosure The structures of formulas (IV) to (VI), (VI-a), (VI-b), (IX), (IX-a), and (IX-b), and the structures of compound numbers 1 to 6, 6a, 6b, 7 to 9, 9a, and 9b are as set forth in Table I below, wherein R 1 is understood to be as described herein.

[0035] (Table I) TIFF2025533123000001.tif132143TIFF2025533123000002.tif133143

[0036] In some embodiments, each R 1 are independently C1 to C6 alkyl.

[0037] In some embodiments, each R 1 is independently methyl, ethyl, propyl, butyl, pentyl, or hexyl.

[0038] In some embodiments, each R 1 is independently methyl, ethyl, or propyl.

[0039] In some embodiments, each R 1 is methyl.

[0040] In some embodiments, each R 1 is ethyl.

[0041] In some embodiments, each R 1 is propyl.

[0042] In some embodiments, each R 1is n-propyl.

[0043] In some embodiments, each R 1 is i-propyl.

[0044] Methods of the present disclosure In some aspects, the present disclosure provides methods for preparing Compound No. 9a, or a salt thereof, according to Scheme A.

[0045] In some embodiments, compound number 1 is dechlorinated (e.g., via hydrogenation) to compound number 2. In some embodiments, compound number 3 is converted to compound number 4 via an esterification reaction (e.g., in the presence of an esterifying agent). In some embodiments, compound number 2 is reacted with compound number 4 to provide compound number 5. In some embodiments, compound number 7 is converted to compound number 8 (e.g., via reaction with a CO generating agent). In some embodiments, compound number 5 is reduced to compound number 6a, which is reacted with compound number 8 to form compound number 9a (e.g., in the presence of a base). In some embodiments, compound number 9a is purified.

[0046] In some embodiments, the method for preparing Compound No. 9a or a salt thereof comprises at least one of the seven steps shown in Scheme A. TIFF2025533123000003.tif82151

[0047] In some aspects, the present disclosure provides a method for preparing a compound of formula (IX) (e.g., Compound No. 9a or 9b) or a salt thereof, comprising one or more of steps (i)-(vii): (i) contacting Compound No. 1 or a salt thereof with a hydrogenation agent, thereby forming Compound No. 2 or a salt thereof; (ii) reacting Compound No. 3 with an esterifying agent, thereby forming a compound of formula (IV) (e.g., Compound No. 4); (iii) contacting Compound No. 2 or a salt thereof with a compound of formula (IV) (e.g., Compound No. 4), thereby forming a compound of formula (V) (e.g., Compound No. 5) or a salt thereof; (iv) contacting a compound of formula (V) (e.g., Compound No. 5) or a salt thereof with a reducing agent, thereby forming a compound of formula (VI) (e.g., Compound No. 6a or 6b) or a salt thereof; (v) contacting Compound No. 7 or a salt thereof with a CO generating agent, thereby forming Compound No. 8 or a salt thereof; (vi) contacting a compound of formula (VI) (e.g., Compound No. 6a or 6b) or a salt thereof with Compound No. 8 or a salt thereof, thereby forming a compound of formula (IX) (e.g., Compound No. 9a or 9b) or a salt thereof; or (vii) purifying the compound of formula (IX) (e.g., compound No. 9a or 9b) or a salt thereof.

[0048] In some embodiments, the method comprises one or more of steps (iii), (iv), and (vi).

[0049] In some embodiments, the method comprises step (iii).

[0050] In some embodiments, the method comprises step (iv).

[0051] In some embodiments, the method comprises steps (iii) and (iv).

[0052] In some embodiments, the method comprises step (vi).

[0053] In some embodiments, the method comprises steps (iii), (iv), and (vi).

[0054] In some embodiments, the method comprises one or more of steps (iii), (iv), and (vi), and step (vii).

[0055] In some embodiments, the method comprises steps (iii), (iv), and (vi), and (vii).

[0056] In some aspects, the present disclosure provides a method for preparing a compound of formula (IX) (e.g., compound No. 9a or 9b) or a salt thereof, comprising steps (i) to (vii): (i) contacting Compound No. 1 or a salt thereof with a hydrogenation agent, thereby forming Compound No. 2 or a salt thereof; (ii) contacting Compound No. 3 with an esterifying agent, thereby forming a compound of formula (IV) (e.g., Compound No. 4); (iii) contacting Compound No. 2 or a salt thereof with a compound of formula (IV) (e.g., Compound No. 4), thereby forming a compound of formula (V) (e.g., Compound No. 5) or a salt thereof; (iv) contacting a compound of formula (V) (e.g., Compound No. 5) or a salt thereof with a reducing agent, thereby forming a compound of formula (VI) (e.g., Compound No. 6a or 6b) or a salt thereof; (v) contacting Compound No. 7 or a salt thereof with a CO generating agent, thereby forming Compound No. 8 or a salt thereof; (vi) contacting a compound of formula (VI) (e.g., Compound No. 6a or 6b) or a salt thereof with Compound No. 8 or a salt thereof, thereby forming a compound of formula (IX) (e.g., Compound No. 9a or 9b) or a salt thereof; and (vii) purifying the compound of formula (IX) (e.g., compound No. 9a or 9b) or a salt thereof.

[0057] In some embodiments, the compound of formula (IV) is compound number 4.

[0058] In some embodiments, the compound of formula (VI) or a salt thereof is Compound No. 5 or a salt thereof.

[0059] In some embodiments, the compound of formula (VI) or a salt thereof is Compound No. 6 or a salt thereof.

[0060] In some embodiments, the compound of formula (VI) or a salt thereof is a compound of formula (VI-a) or a salt thereof:

[0061] In some embodiments, the compound of formula (VI) or a salt thereof is Compound No. 6a or a salt thereof.

[0062] In some embodiments, the compound of formula (VI) or a salt thereof is a compound of formula (VI-b) or a salt thereof:

[0063] In some embodiments, the compound of formula (VI) or a salt thereof is Compound No. 6b or a salt thereof.

[0064] In some embodiments, the compound of formula (IX) or salt thereof is Compound No. 9.

[0065] In some embodiments, the compound of formula (IX) or a salt thereof is a compound of formula (IX-a) or a salt thereof:

[0066] In some embodiments, the compound of formula (IX) or a salt thereof is Compound No. 9a or a salt thereof.

[0067] In some embodiments, the compound of formula (IX) or a salt thereof is a compound of formula (IX-b) or a salt thereof:

[0068] In some embodiments, the compound of formula (IX) or a salt thereof is Compound No. 9b or a salt thereof.

[0069] Process (i) In some embodiments, in step (i), the hydrogenation agent is hydrogen.

[0070] In some embodiments, in step (i), the hydrogenation agent is an alkene or an alkyne.

[0071] In some embodiments, in step (i), the contacting is carried out in the presence of a hydrogenation catalyst.

[0072] In some embodiments, the hydrogenation catalyst is a homogeneous catalyst.

[0073] In some embodiments, the hydrogenation catalyst is a heterogeneous catalyst.

[0074] In some embodiments, the hydrogenation catalyst is a metal catalyst.

[0075] In some embodiments, the hydrogenation catalyst is a nickel catalyst, a platinum catalyst, a palladium catalyst, a rhodium catalyst, or a ruthenium catalyst.

[0076] In some embodiments, the hydrogenation catalyst is a palladium catalyst (eg, palladium on carbon (Pd / C)).

[0077] In some embodiments, the hydrogenation catalyst is a nickel catalyst (eg, Raney nickel).

[0078] In some embodiments, in step (i), the contacting is carried out in the presence of a base. In some embodiments, the base is an inorganic base (e.g., potassium carbonate (K2CO3)).

[0079] In some embodiments, in step (i), the contacting is carried out in the presence of a solvent. In some embodiments, the solvent is an organic solvent. In some embodiments, the solvent is an aprotic solvent (e.g., tetrahydrofuran (THF)).

[0080] In some embodiments, in step (i), the contacting is carried out at a temperature of 25±15°C, 25±10°C, or 25±5°C (e.g., about 25°C).

[0081] In some embodiments, in step (i), the contacting is carried out for 25±20 hours, 25±15 hours, 25±10 hours, 25±5 hours, 25±4 hours, 25±3 hours, 25±2 hours, or 25±1 hours (e.g., about 25 hours).

[0082] In some embodiments, step (i) comprises filtering a solution of Compound No. 2 or a salt thereof (e.g., in THF).

[0083] In some embodiments, Compound No. 2 or a salt thereof is isolated and / or purified prior to contacting with a compound of Formula (IV) (e.g., Compound No. 4).

[0084] In some embodiments, Compound No. 2 or a salt thereof is not isolated and / or purified prior to contacting with a compound of Formula (IV) (e.g., Compound No. 4).

[0085] In some embodiments, step (i) provides a solution of Compound No. 2 or a salt thereof (e.g., in THF).

[0086] Process (ii) In some embodiments, in step (ii), the esterifying agent is an alcohol.

[0087] In some embodiments, the esterifying agent is R 1 -OH, where R 1 is C1-C6 alkyl.

[0088] In some embodiments, the esterifying agent is methanol, ethanol, or propanol. In some embodiments, the esterifying agent is propanol. In some embodiments, the esterifying agent is isopropanol (iPrOH; propan-2-ol).

[0089] In some embodiments, in step (ii), the contacting is carried out in the presence of an esterification catalyst. In some embodiments, the esterification catalyst is a base catalyst (e.g., 4-dimethylaminopyridine (DMAP)).

[0090] In some embodiments, in step (ii), the contacting is carried out in the presence of a base. In some embodiments, the base is an organic base (e.g., pyridine).

[0091] In some embodiments, the contacting step in step (ii) is carried out in the presence of a solvent. In some embodiments, the solvent is an organic solvent. In some embodiments, the solvent is an aprotic solvent (e.g., tetrahydrofuran (THF)).

[0092] In some embodiments, step (ii) comprises filtering a solution of a compound of formula (IV) (e.g., Compound No. 4) (e.g., in n-heptane).

[0093] Process (iii) In some aspects, the present disclosure provides a method of preparing a compound of formula (V) (e.g., Compound No. 5) or a salt thereof, comprising: (iii) contacting Compound No. 2 or a salt thereof with a compound of formula (IV) (e.g., Compound No. 4), thereby forming a compound of formula (V) (e.g., Compound No. 5) or a salt thereof.

[0094] In some embodiments, in step (iii), the contacting is carried out in the presence of a salt. In some embodiments, the salt is a potassium salt (e.g., potassium tert-butoxide (tBuOK)).

[0095] In some embodiments, in step (iii), the contacting is carried out in the presence of an alcohol, hi some embodiments, the alcohol is isopropanol (iPrOH; propan-2-ol).

[0096] In some embodiments, step (iii) further comprises adding an acid to the formed compound of Formula (V) (e.g., Compound No. 5) or salt thereof, thereby adjusting the pH value to 7.0±2.0, 7.0±1.5, 7.0±1.0, 7.0±0.9, 7.0±0.8, 7.0±0.7, 7.0±0.6, 7.0±0.5, 7.0±0.4, 7.0±0.3, 7.0±0.2, or 7.0±0.1 (e.g., about 7.0).

[0097] In some embodiments, the acid is an organic acid (eg, acetic acid (AcOH)).

[0098] In some embodiments, step (iii) further comprises crystallizing the compound of Formula (V) (e.g., Compound No. 5) or a salt thereof in the presence of an organic solvent. In some embodiments, the organic solvent comprises isopropyl acetate and n-heptane.

[0099] Process (iv) In some aspects, the present disclosure provides a method of preparing a compound of formula (VI) (e.g., Compound No. 6a or 6b) or a salt thereof, comprising: (iv) contacting a compound of formula (V) (e.g., Compound No. 5) or a salt thereof with a reducing agent, thereby forming a compound of formula (VI) (e.g., Compound No. 6a or 6b) or a salt thereof.

[0100] In some embodiments, in step (iv), the reducing agent is a monosaccharide. In some embodiments, the reducing agent is glucose. In some embodiments, the reducing agent is D-glucose. In some embodiments, the reducing agent is L-glucose.

[0101] In some embodiments, in step (iv), the contacting is carried out in the presence of a reduction catalyst.

[0102] In some embodiments, the reduction catalyst comprises an enzyme catalyst.

[0103] In some embodiments, the reduction catalyst comprises a molecular catalyst.

[0104] In some embodiments, the reduction catalyst comprises a ketoreductase (KRED).

[0105] In some embodiments, the reduction catalyst comprises glutamate dehydrogenase (GDH).

[0106] In some embodiments, the reduction catalyst comprises a dinucleotide phosphate (eg, as a cofactor).

[0107] In some embodiments, the reduction catalyst comprises nicotinamide adenine dinucleotide phosphate (NADP) as a cofactor.

[0108] In some embodiments, the reduction catalyst comprises a ketoreductase (KRED), a glutamate dehydrogenase (GDH), and a nicotinamide adenine dinucleotide phosphate (NADP).

[0109] In some embodiments, the reduction involves hydride transfer from a reduction catalyst (eg, an NADP cofactor) to a reducing agent (eg, glucose).

[0110] In some embodiments, the contacting step is carried out in the presence of a buffer solution. In some embodiments, the buffer solution comprises a phosphate salt (e.g., dipotassium phosphate (KHPO)). In some embodiments, the buffer solution has a pH value of 7.0±2.0, 7.0±1.5, 7.0±1.0, 7.0±0.9, 7.0±0.8, 7.0±0.7, 7.0±0.6, 7.0±0.5, 7.0±0.4, 7.0±0.3, 7.0±0.2, or 7.0±0.1 (e.g., about 7.0).

[0111] In some embodiments, the contacting step is carried out in the presence of a dipolar aprotic solvent (eg, dimethyl sulfoxide (DMSO)).

[0112] In some embodiments, step (iv) further comprises extracting the formed compound of Formula (VI) (e.g., Compound No. 6a or 6b) or a salt thereof with an aprotic solvent (e.g., 2-methyltetrahydrofuran (2-MeTHF)).

[0113] In some embodiments, step (iv) provides a solution of a compound of formula (VI) (e.g., compound number 6a or 6b) or a salt thereof (e.g., in 2-methyltetrahydrofuran (2-MeTHF)).

[0114] Process (v) In some embodiments, in step (v), the CO generating agent is triphosgene.

[0115] In some embodiments, in step (v), the contacting is carried out in the presence of a base. In some embodiments, the base is an organic base (e.g., triethylamine (TEA)).

[0116] In some embodiments, in step (v), the contacting is carried out in the presence of a solvent. In some embodiments, the solvent is an aprotic organic solvent (e.g., toluene).

[0117] In some embodiments, step (v) comprises filtering a solution of Compound No. 8 or a salt thereof (e.g., in toluene).

[0118] In some embodiments, step (v) provides a solution (e.g., in toluene) of Compound No. 8 or a salt thereof.

[0119] Process (vi) In some embodiments, in step (vi), the contacting step is carried out in the presence of a base. In some embodiments, the base is an organic base (e.g., 4-dimethylaminopyridine (DMAP)).

[0120] In some embodiments, the contacting step in step (vi) is carried out in the presence of a solvent. In some embodiments, the solvent is an aprotic organic solvent. In some embodiments, the solvent comprises 2-methyltetrahydrofuran (2-MeTHF). In some embodiments, the solvent further comprises toluene.

[0121] In some embodiments, step (vi) further comprises washing the formed compound of Formula (IX) (e.g., Compound No. 9a or 9b) or a salt thereof with an acid solution. In some embodiments, the acid solution comprises citric acid (e.g., about 5% citric acid).

[0122] In some embodiments, step (vi) further comprises washing the formed compound of Formula (IX) (e.g., Compound No. 9a or 9b) or a salt thereof with a base solution. In some embodiments, the acid solution comprises sodium bicarbonate (NaHCO; e.g., about 5% NaHCO).

[0123] In some embodiments, step (vi) further comprises crystallizing the compound of Formula (IX) (e.g., Compound No. 9a or 9b) or a salt thereof in the presence of an organic solvent. In some embodiments, the organic solvent comprises isopropyl acetate and n-heptane.

[0124] Process (vii) In some embodiments, step (vii) comprises crystallizing the compound of Formula (IX) (e.g., Compound No. 9a or 9b) or a salt thereof in the presence of an organic solvent. In some embodiments, the organic solvent comprises isopropyl acetate and n-heptane.

[0125] In some embodiments, the isopropyl acetate and n-heptane are present in a ratio of about 1:1, about 1:2, about 1:3, about 1:4, or about 1:5.

[0126] Compounds prepared by this method In some aspects, the present disclosure provides compounds prepared by the methods disclosed herein.

[0127] In some aspects, the present disclosure provides a compound of formula (V) or a salt thereof: In some embodiments, the compound is Compound No. 5 or a salt thereof.

[0128] In some embodiments, the compound is Compound No. 5 or a salt thereof having a purity of about 90% or greater, about 95% or greater, about 96% or greater, about 97% or greater, about 98% or greater, about 99% or greater, about 99.5% or greater, about 99.6% or greater, about 99.7% or greater, about 99.8% or greater, or about 99.9% or greater.

[0129] In some aspects, the present disclosure provides a compound of formula (VI) or a salt thereof: hi some embodiments, the compound is Compound No. 6 or a salt thereof.

[0130] In some aspects, the present disclosure provides a compound of formula (VI-a) or a salt thereof: hi some embodiments, the compound is Compound No. 6a or a salt thereof.

[0131] In some embodiments, the compound is Compound No. 6a or a salt thereof having an enantiomeric excess (ee) of about 90% or greater, about 95% or greater, about 96% or greater, about 97% or greater, about 98% or greater, about 99% or greater, about 99.5% or greater, about 99.6% or greater, about 99.7% or greater, about 99.8% or greater, or about 99.9% or greater.

[0132] In some embodiments, the compound is Compound No. 6a or a salt thereof having a purity of about 90% or greater, about 95% or greater, about 96% or greater, about 97% or greater, about 98% or greater, about 99% or greater, about 99.5% or greater, about 99.6% or greater, about 99.7% or greater, about 99.8% or greater, or about 99.9% or greater.

[0133] In some aspects, the present disclosure provides a compound of formula (VI-b) or a salt thereof: hi some embodiments, the compound is Compound No. 6b or a salt thereof.

[0134] In some embodiments, the compound is Compound No. 6b or a salt thereof, having an enantiomeric excess (ee) of about 90% or greater, about 95% or greater, about 96% or greater, about 97% or greater, about 98% or greater, about 99% or greater, about 99.5% or greater, about 99.6% or greater, about 99.7% or greater, about 99.8% or greater, or about 99.9% or greater.

[0135] In some embodiments, the compound is Compound No. 6b or a salt thereof having a purity of about 90% or greater, about 95% or greater, about 96% or greater, about 97% or greater, about 98% or greater, about 99% or greater, about 99.5% or greater, about 99.6% or greater, about 99.7% or greater, about 99.8% or greater, or about 99.9% or greater.

[0136] In some aspects, the present disclosure provides a compound of formula (IX) or a salt thereof: hi some embodiments, the compound is Compound No. 9 or a salt thereof.

[0137] In some aspects, the present disclosure provides a compound of formula (IX-a) or a salt thereof: hi some embodiments, the compound is Compound No. 9a or a salt thereof.

[0138] In some embodiments, the compound is Compound No. 9a or a salt thereof having an enantiomeric excess (ee) of about 90% or greater, about 95% or greater, about 96% or greater, about 97% or greater, about 98% or greater, about 99% or greater, about 99.5% or greater, about 99.6% or greater, about 99.7% or greater, about 99.8% or greater, or about 99.9% or greater.

[0139] In some embodiments, the compound is Compound No. 9a or a salt thereof having a purity of about 90% or greater, about 95% or greater, about 96% or greater, about 97% or greater, about 98% or greater, about 99% or greater, about 99.5% or greater, about 99.6% or greater, about 99.7% or greater, about 99.8% or greater, or about 99.9% or greater.

[0140] In some aspects, the present disclosure provides a compound of formula (IX-b) or a salt thereof: In some embodiments, the compound is Compound No. 9b or a salt thereof.

[0141] In some embodiments, the compound is Compound No. 9b or a salt thereof, having an enantiomeric excess (ee) of about 90% or greater, about 95% or greater, about 96% or greater, about 97% or greater, about 98% or greater, about 99% or greater, about 99.5% or greater, about 99.6% or greater, about 99.7% or greater, about 99.8% or greater, or about 99.9% or greater.

[0142] In some embodiments, the compound is Compound No. 9b or a salt thereof having a purity of about 90% or greater, about 95% or greater, about 96% or greater, about 97% or greater, about 98% or greater, about 99% or greater, about 99.5% or greater, about 99.6% or greater, about 99.7% or greater, about 99.8% or greater, or about 99.9% or greater.

[0143] Biological assays The compounds prepared by the methods described herein can be characterized using a variety of assays known to those skilled in the art to determine whether the compounds have biological activity. For example, molecules can be characterized by conventional assays, including but not limited to the assays described below, to determine whether they have the expected activity, binding activity, and / or binding specificity.

[0144] Furthermore, high-throughput screening can be used to speed up the analysis using such assay.As a result, it may be possible to use techniques known in the art to rapidly screen the molecules described herein for activity.The general methodology for carrying out high-throughput screening is described, for example, in Devlin (1998) High Throughput Screening, Marcel Dekker; and U.S. Patent No. 5,763,263.High-throughput assay can use one or more different assay techniques, including but not limited to:

[0145] Various in vitro or in vivo biological assays may be suitable for detecting the effects of the compounds of the present disclosure, including, but not limited to, enzyme activity assays, electrophoretic mobility shift assays, reporter gene assays, in vitro cell viability assays, and assays described herein.

[0146] In some embodiments, the biological away is a biological away that tests inhibitory activity against IL-1β release upon NLRP3 activation in peripheral blood mononuclear cells (PBMCs).

[0147] In some embodiments, the biological assay is a PBMC IC50 determination assay.

[0148] In some embodiments, compounds are tested for their inhibitory activity on IL-1β release upon NLRP3 activation in blood cells (e.g., peripheral blood mononuclear cells (PBMCs)).

[0149] In some embodiments, PBMCs are isolated, seeded into wells of a plate, and incubated for a period of time (e.g., 3 hours with lipopolysaccharide). After incubation, the medium is replaced, a compound (e.g., a compound of the present disclosure) is added to the well, and the cells can be incubated. The cells are then stimulated (e.g., with ATP or nigericin), and the cell culture medium is collected for analysis.

[0150] In some embodiments, release of IL-1β into the medium is determined by quantitative detection of IL-1β in the medium (eg, using ELISA).

[0151] In some embodiments, PBMCs are isolated (e.g., from buffy coats). The isolated cells are seeded into wells and incubated (e.g., with lipopolysaccharide for 3 hours). Compounds are then added and the cells are incubated. The cells are then stimulated, and the medium is collected from the wells for analysis.

[0152] In some embodiments, release of IL-1β into the medium is determined by quantitative detection (eg, of IL-1β in the medium using HTRF®).

[0153] Pharmaceutical Compositions In some aspects, the present disclosure provides pharmaceutical compositions comprising a compound of formula (IX) described herein (e.g., Compound No. 9a or 9b) or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

[0154] The pharmaceutical composition containing the active compound of the present disclosure can be prepared in a generally known manner, for example, by conventional mixing, dissolving, granulating, sugar-coating, wet grinding, emulsifying, encapsulating, encapsulating or lyophilizing process.Pharmaceutical composition can be prepared in a conventional manner using one or more pharmaceutically acceptable carriers, comprising one or more excipients and / or auxiliary substances that facilitate the processing of active compound into pharmaceutically usable preparations.Those skilled in the art will understand that suitable formulation can depend on the selected route of administration.

[0155] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions, and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers may include physiological saline, bacteriostatic water, Cremophor EL (BASF, Parsippany, NJ), or phosphate-buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringability exists. The composition must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. Prevention of microbial action can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal and the like.In many cases, it is preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol and sorbitol, and sodium chloride in the composition.Prolonged absorption of injection compositions can be achieved by including agents that delay absorption, for example, aluminum monostearate and gelatin in the composition.

[0156] Sterile injectable solution can be prepared by incorporating active compound into appropriate solvent with one or combination of above-listed components as needed in required amount, and then sterilize by filtering.Generally, dispersion is prepared by incorporating active compound into sterile vehicle that contains basic dispersion medium and other components that are required from above-listed components.In the case of sterile powder that is used to prepare sterile injectable solution, the preparation method is vacuum drying and freeze-drying, which produces powder of active compound and any additional required components from the solution that is previously sterilized and filtered.

[0157] Oral compositions can contain one or more inert diluents or one or more pharmaceutically acceptable edible carriers.They can be enclosed in gelatin capsules or compressed into tablets.For the purpose of oral therapeutic administration, active compounds can be incorporated with excipients and can be used in the form of tablets, lozenges or capsules.Oral compositions can also be prepared using fluid carriers for use as mouthwash, and the compound in the fluid carrier is applied to the oral cavity, swished, and expectorated or swallowed.Pharmaceutically compatible binding agents and / or auxiliary materials can be included as part of the composition. Tablets, pills, capsules, troches, and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth, or gelatin; a filler such as starch or lactose; a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricating agent such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

[0158] For administration by inhalation, the compounds are delivered in the form of an aerosol spray from a pressured container or dispenser which contains a suitable propellant, eg, a gas such as carbon dioxide, or a nebulizer.

[0159] Systemic administration can also be by transmucosal or transdermal means.For transmucosal or transdermal administration, a penetrant suitable for the barrier to be permeated is used in the formulation.Such penetrants are generally known in the art, and for example, for transmucosal administration, include surfactants, bile salts, and fusidic acid derivatives.Transmucosal administration can be achieved through the use of nasal sprays or suppositories.For transdermal administration, active compounds are formulated into ointments, salves, gels, or creams as are generally known in the art.

[0160] The active compound can be prepared with one or more pharmaceutically acceptable carriers that can protect the compound against rapid elimination from the body, such as controlled-release formulations, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparing such formulations will be apparent to those skilled in the art.

[0161] For the sake of ease of administration and uniformity of dosage, it can be particularly advantageous to prepare oral or parenteral compositions in dosage unit form.Dosage unit form used herein refers to a physically separate unit that is suitable as a unitary dosage for the object to be treated; each unit contains a predetermined amount of active compound that is calculated to produce desired therapeutic effect together with required pharmaceutical carrier.The specification of dosage unit form of the present disclosure is determined by and directly depends on the unique characteristics of active compound and the specific therapeutic effect that should be achieved.

[0162] In therapeutic applications, dosages of pharmaceutical compositions used in accordance with the present disclosure will vary depending on the agent, the age, weight, and clinical condition of the recipient patient, and the experience and judgment of the clinician or practitioner administering the treatment, among other factors influencing the selected dosage. Generally, the dose should be sufficient to result in a slowing, and preferably regression, of disease symptoms, and preferably complete regression of the disease.

[0163] It will be appreciated that the pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

[0164] How to use In some aspects, the present disclosure provides a method of preventing or treating a disease in a subject, the method comprising administering to the subject (e.g., in a therapeutically effective amount) a compound of formula (IX) described herein (e.g., compound No. 9a or 9b) or a pharmaceutically acceptable salt thereof.

[0165] In some aspects, the present disclosure provides a method of treating a disease in a subject, the method comprising administering to the subject (e.g., in a therapeutically effective amount) a compound of formula (IX) described herein (e.g., compound No. 9a or 9b) or a pharmaceutically acceptable salt thereof.

[0166] In some aspects, the present disclosure provides a compound of formula (IX) described herein (e.g., Compound No. 9a or 9b) or a pharmaceutically acceptable salt thereof for use in preventing or treating a disease in a subject.

[0167] In some aspects, the present disclosure provides a compound of formula (IX) described herein (e.g., compound No. 9a or 9b) or a pharmaceutically acceptable salt thereof for use in treating a disease in a subject.

[0168] In some aspects, the present disclosure provides the use of a compound of formula (IX) described herein (e.g., Compound No. 9a or 9b) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for preventing or treating a disease in a subject.

[0169] In some aspects, the present disclosure provides the use of a compound of formula (IX) described herein (e.g., Compound No. 9a or 9b) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a disease in a subject.

[0170] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is administered in a therapeutically effective amount.

[0171] In some embodiments, the disease or disorder is associated with associated inflammasome activity. In some embodiments, the disease or disorder is a disease or disorder in which inflammasome activity is implicated.

[0172] In some embodiments, the disease or disorder is an inflammatory disorder, an autoinflammatory disorder, an autoimmune disorder, a neurodegenerative disease, or cancer.

[0173] In some embodiments, the disease or disorder is an inflammatory disorder, an autoinflammatory disorder, and / or an autoimmune disorder.

[0174] In some embodiments, the disease or disorder is selected from cryopyrin-associated autoinflammatory syndromes (CAPS; e.g., familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurological, cutaneous, and articular (CINCA) syndrome / neonatal-onset multisystem inflammatory disease (NOMID)), familial Mediterranean fever (FMF), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), gout, rheumatoid arthritis, osteoarthritis, Crohn's disease, chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD), fibrosis, obesity, type 2 diabetes, multiple sclerosis, dermatological diseases (e.g., acne), and neuroinflammation manifested in protein misfolding diseases (e.g., prion diseases).

[0175] In some embodiments, the disease or disorder is a neurodegenerative disease.

[0176] In some embodiments, the disease or disorder is Parkinson's disease or Alzheimer's disease.

[0177] In some embodiments, the disease or disorder is a dermatological disease.

[0178] In some embodiments, the dermatological condition is acne.

[0179] In some embodiments, the disease or disorder is cancer.

[0180] In some embodiments, the cancer is metastatic cancer, gastrointestinal cancer, skin cancer, non-small cell lung carcinoma, brain cancer (eg, glioblastoma), or colorectal adenocarcinoma.

[0181] In some aspects, the present disclosure provides a method of inhibiting inflammasome (e.g., NLRP3 inflammasome) activity in a subject (e.g., in vitro or in vivo), the method comprising contacting a cell (e.g., in an effective amount) with a compound of formula (IX) described herein (e.g., compound No. 9a or 9b) or a pharmaceutically acceptable salt thereof.

[0182] In some aspects, the present disclosure provides a compound of formula (IX) described herein (e.g., compound No. 9a or 9b), or a pharmaceutically acceptable salt thereof, for use in inhibiting inflammasome (e.g., NLRP3 inflammasome) activity in a subject (e.g., in vitro or in vivo).

[0183] In some aspects, the present disclosure provides the use of a compound of formula (IX) described herein (e.g., compound No. 9a or 9b) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for inhibiting inflammasome (e.g., NLRP3 inflammasome) activity (e.g., in vitro or in vivo).

[0184] In some embodiments, the inflammasome is the NLRP3 inflammasome.

[0185] In some embodiments, the subject is an animal.

[0186] In some embodiments, the subject is a mammal.

[0187] In some embodiments, the subject is a human.

[0188] In some embodiments, the subject is a cell.

[0189] In some embodiments, the subject is a cell population.

[0190] definition Unless otherwise stated, the following terms used in the specification and claims have the following meanings specified below.

[0191] As used herein, the term "about" means approximately, in the vicinity, roughly, or around.When the term "about" is used in conjunction with a numerical range, the term modifies the range by extending the boundaries above and below the stated numerical value.In general, the term "about" is used herein to modify numerical values ​​above and below the stated value by 20%, 10%, 5%, 3%, or 1% variation.

[0192] As used herein, the term "CO-generating agent" refers to an agent that can be a source of CO during a reaction. In some embodiments, the agent is capable of forming an isocyanate or equivalent when reacted with an amine.

[0193] As used herein, "alkyl," "C1, C2, C3, C4, C5, or C6 alkyl," or "C1-C6 alkyl" is intended to include C1, C2, C3, C4, C5, or C6 straight-chain (linear) saturated aliphatic hydrocarbon groups and C3, C4, C5, or C6 branched saturated aliphatic hydrocarbon groups. For example, C1-C6 alkyl is intended to include C1, C2, C3, C4, C5, and C6 alkyl groups. Examples of alkyl include moieties having 1 to 6 carbon atoms, such as, but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, or n-hexyl. In some embodiments, a straight-chain or branched alkyl has 6 or fewer carbon atoms (e.g., C1-C6 for straight chain, C3-C6 for branched chain). In some embodiments, a straight-chain or branched alkyl has 4 or fewer carbon atoms.

[0194] It is understood that the compounds described herein include not only the compounds themselves, but also their salts and solvates, if applicable.For example, salts can be formed between anion and the positively charged group (such as amino) on substituted benzene compound.Suitable anions can include chloride, bromide, iodide, sulfate, bisulfate, sulfamate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, glutamate, glucuronate, glutarate, maleate, maleate, succinate, fumarate, tartrate, tosylate, salicylate, lactate, naphthalenesulfonate and acetate (such as trifluoroacetate).

[0195] As used herein, the phrases "one or more of A, B, or C," "one or more of A, B, or C," "one or more of A, B, and C," "one or more of A, B, and C," "selected from the group consisting of A, B, and C," "selected from A, B, and C," and the like, are used interchangeably and all refer to a selection from the group consisting of A, B, and / or C, i.e., one or more A, one or more B, one or more C, or any combination thereof, unless otherwise indicated.

[0196] It should be understood that throughout the description where a composition is described as having, including, or comprising specified components, it is contemplated that the composition also consists essentially of or consists of the listed components. Similarly, where a method or process is described as having, including, or comprising specified process steps, the process also consists essentially of or consists of the listed processing steps. Furthermore, it should be understood that the order of steps or the order for performing certain actions is immaterial so long as the invention remains operable. Furthermore, two or more steps or actions can be performed simultaneously.

[0197] It will be appreciated that the synthetic processes of the present disclosure can accommodate a wide variety of functional groups and therefore can employ a variety of substituted starting materials. While the processes generally provide the desired final compound at or near the completion of the overall process, in certain instances it may be desirable to further convert the compound to its pharmaceutically acceptable salt.

[0198] It will be appreciated that compounds of formula (IX) (e.g., Compound No. 9a or 9b) or pharmaceutically acceptable salts thereof can be prepared in a variety of ways using commercially available starting materials, using compounds known in the literature, or from readily prepared intermediates by employing standard synthetic methods and procedures that are either known to those skilled in the art or will be apparent to those skilled in the art in light of the teachings herein. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be obtained from the relevant scientific literature or from standard textbooks in the field. Examples include, but are not limited to, any one or several sources, Smith, MB, March, J., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5, incorporated herein by reference. th edition, John Wiley & Sons: New York, 2001;Greene, TW, Wuts, PGM, Protective Groups in Organic Synthesis, 3 rdedition, John Wiley & Sons: New York, 1999; R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), are useful and recognized reference texts of organic synthesis known to those skilled in the art.

[0199] Those skilled in the art will note that the order of certain steps, such as the introduction and removal of protecting groups, may be changed during the reaction sequences and synthetic schemes described herein. Those skilled in the art will recognize that certain groups may need to be protected from reaction conditions through the use of protecting groups. Protecting groups may also be used to distinguish similar functional groups in a molecule. For a list of protecting groups and how to introduce and remove these groups, see Greene, TW, Wuts, PGM, Protective Groups in Organic Synthesis, 3 rd edition, John Wiley & Sons: New York, 1999.

[0200] Unless otherwise stated, any reference to a method of treatment or prevention is understood to include the use of a compound of formula (IX) (e.g., compound number 9a or 9b) or a pharmaceutically acceptable salt thereof to provide treatment or prevention as described herein. Unless otherwise stated, any reference to a method of treatment or prevention is further understood to include the use of a compound of formula (IX) (e.g., compound number 9a or 9b) or a pharmaceutically acceptable salt thereof to prepare a medicament for treating or preventing such a condition. Treatment or prevention includes treatment or prevention of humans or non-human animals, including rodents and other disease models.

[0201] Unless otherwise stated, any description of a method of treatment is understood to include the use of a compound of formula (IX) (e.g., compound number 9a or 9b) or a pharmaceutically acceptable salt thereof to provide treatment as described herein. Unless otherwise stated, any description of a method of treatment is further understood to include the use of a compound of formula (IX) (e.g., compound number 9a or 9b) or a pharmaceutically acceptable salt thereof to prepare a medicament for treating such a condition. Treatment includes treatment of humans or non-human animals, including rodents and other disease models.

[0202] As used herein, the term "subject" includes human and non-human animals, as well as cell lines, cell cultures, tissues, and organs. In some embodiments, the subject is a mammal. The mammal can be, for example, a human or a suitable non-human mammal, such as a primate, mouse, rat, dog, cat, cow, horse, goat, camel, sheep, or pig. The subject can also be a bird or poultry. In some embodiments, the subject is a human.

[0203] As used herein, the term "subject in need thereof" refers to a subject who has a disease or is at increased risk of developing a disease. A subject in need thereof can be a subject who has previously been diagnosed or identified as having a disease or disorder disclosed herein. A subject in need thereof can also be a subject suffering from a disease or disorder disclosed herein. Alternatively, a subject in need thereof can be a subject who is at increased risk of developing such a disease or disorder compared to the population as a whole (i.e., a subject who is more susceptible to developing such a disorder compared to the population as a whole). A subject in need thereof can have a refractory or resistant disease or disorder disclosed herein (i.e., a disease or disorder disclosed herein that does not respond or has not yet responded to treatment). A subject can be resistant at the start of treatment or can become resistant during treatment. In some embodiments, a subject in need thereof has tried and failed all known effective treatments for a disease or disorder disclosed herein. In some embodiments, a subject in need thereof has previously undergone at least one treatment.

[0204] As used herein, the term "treating" or "treat" refers to the management and care of a patient for the purpose of combating a disease, condition, or disorder, and includes the administration of a compound of the present disclosure, or a pharmaceutically acceptable salt, polymorph, or solvate thereof, to alleviate the symptoms or complications of the disease, condition, or disorder, or to eliminate the disease, condition, or disorder. The term "treat" can also include treatment of a cell in vitro or treatment of an animal model.

[0205] It is to be understood that a compound of formula (IX) (e.g., compound No. 9a or 9b) or a pharmaceutically acceptable salt thereof can also be used or can be used to prevent a related disease, condition, or disorder, or to identify suitable candidates for such purposes.

[0206] As used herein, the terms "preventing," "prevent," or "protecting against" refer to reducing or eliminating the onset of symptoms or complications of such disease, condition, or disorder.

[0207] It should be understood that one skilled in the art can refer to general reference texts for detailed descriptions of the known techniques discussed herein or equivalent techniques. These texts include Ausubel et al., Current Protocols in Molecular Biology, John Wiley and Sons, Inc. (2005); Sambrook et al., Molecular Cloning, A Laboratory Manual (3 rd edition), Cold Spring Harbor Press, Cold Spring Harbor, New York (2000);Coligan et al., Current Protocols in Immunology, John Wiley & Sons, NY;Enna et al., Current Protocols in Pharmacology, John Wiley & Sons, NY;Fingl et al., The Pharmacological Basis of Therapeutics (1975), Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 18 thOf course, these texts can also be referenced when making or using aspects of the present disclosure.

[0208] As used herein, the term "pharmaceutical composition" refers to a formulation containing a compound of Formula (IX) (e.g., Compound No. 9a or 9b) or a pharmaceutically acceptable salt thereof in a form suitable for administration to a subject. In some embodiments, the pharmaceutical composition is in bulk or unit dosage form. The unit dosage form may be in any of a variety of forms, including, for example, a capsule, an IV bag, a tablet, a single pump on an aerosol inhaler, or a vial. The amount of active ingredient (e.g., a formulation of a disclosed compound or its salt, hydrate, solvate, or isomer) in a unit dose of the composition is an effective amount and varies depending on the particular treatment involved. Those skilled in the art will recognize that it may sometimes be necessary to make routine variations to the dosage depending on the age and condition of the patient. The dosage also depends on the route of administration. Various routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalation, buccal, sublingual, intrapleural, intrathecal, intranasal and the like.The dosage form for topical or transdermal administration of the compound of the present disclosure includes powder, spray, ointment, paste, cream, lotion, gel, solution, patch and inhalant.In one embodiment, active compound is mixed under sterile conditions with one or more pharmaceutically acceptable carriers and any necessary preservatives, buffer or propellant.

[0209] As used herein, the term "pharmaceutically acceptable" refers to compounds, anions, cations, materials, compositions, carriers, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0210] As used herein, the term "pharmaceutically acceptable excipient" means an excipient that is generally safe, non-toxic, and not biologically or otherwise undesirable and is useful in preparing pharmaceutical compositions, and includes excipients that are acceptable for veterinary and human pharmaceutical use. As used in the specification and claims, "pharmaceutically acceptable excipient" can include both one such excipient and more than one such excipient.

[0211] It should be understood that the pharmaceutical compositions of the present disclosure are formulated to be compatible with their intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., ingestion), inhalation, transdermal (topical), and transmucosal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can contain the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycol, glycerin, propylene glycol, or other synthetic solvents; an antibacterial agent such as benzyl alcohol or methylparaben; an antioxidant such as ascorbic acid or sodium bisulfite; a chelating agent such as ethylenediaminetetraacetic acid; a buffer such as acetate, citrate, or phosphate, and an agent for adjusting osmolality such as sodium chloride or dextrose. pH can be adjusted with acids or bases such as hydrochloric acid or sodium hydroxide. Parenteral preparations can be enclosed in ampoules, disposable syringes, or multiple-dose vials made of glass or plastic.

[0212] It should be understood that the compound or pharmaceutical composition of the present disclosure can be administered to a subject by many well-known methods currently used for chemotherapy treatment.For example, the compound of the present disclosure can be injected into the bloodstream or body cavity, or can be taken orally, or can be applied through the skin using a patch.The selected dose should be sufficient to constitute effective treatment, but should not be so high as to cause unacceptable side effects.The status of disease state (for example, disease or disorder disclosed herein) and the health condition of the patient should preferably be carefully monitored during treatment and for a reasonable period after treatment.

[0213] As used herein, the term "therapeutically effective amount" refers to the amount of a pharmaceutical agent to treat, alleviate, or prevent a identified disease or condition, or to exhibit a detectable therapeutic or inhibitory effect.The effect can be detected by any assay method known in the art.The exact effective amount for a subject depends on the subject's weight, size, and health; the nature and extent of the condition; and the therapeutic agent or combination of therapeutic agents selected for administration.The therapeutically effective amount for a given situation can be determined by routine experimentation, which is within the skill and judgment of the clinician.

[0214] As used herein, the term "effective amount" refers to the amount of a pharmaceutical agent to treat or alleviate a identified disease or condition, or to exhibit a detectable therapeutic or inhibitory effect.The effect can be detected by any assay method known in the art.The exact effective amount for a subject depends on the subject's weight, size, and health; the nature and extent of the condition; and the therapeutic agent or combination of therapeutic agents selected for administration.The therapeutically effective amount for a given situation can be determined by routine experimentation, which is within the skill and judgment of the clinician.

[0215] It is understood that for any compound, the therapeutically effective amount or effective dose can be estimated first either in cell culture assays, for example, cell culture assays of neoplastic cells, or in animal models, usually rats, mice, rabbits, dogs, or pigs. Animal models can also be used to determine appropriate concentration ranges and administration routes. Such information can then be used to determine useful doses and routes for administration in humans. Therapeutic / prophylactic efficacy and toxicity can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, for example, ED 50 (the dose that is therapeutically effective in 50% of the population) and LD 50 (the dose lethal to 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, which is the LD 50 / ED 50 Pharmaceutical compositions that exhibit large therapeutic indices are preferred. The dosage can vary within this range depending on the dosage form employed, sensitivity of the patient, and the route of administration.

[0216] Dosage and administration are adjusted to provide a sufficient level of the active agent or to maintain the desired effect.Factors that can be taken into consideration include the severity of the disease state, the subject's general health condition, the subject's age, weight, and sex, diet, administration time and frequency, drug combinations, reaction sensitivity, and treatment tolerance / response.

[0217] Pharmaceutical compositions containing a compound of formula (IX) (e.g., compound number 9a or 9b) or a pharmaceutically acceptable salt thereof can be prepared in a generally known manner, for example, by conventional mixing, dissolving, granulating, dragee-making, wet-grinding, emulsifying, encapsulating, encapsulating, or lyophilizing processes. Pharmaceutical compositions can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers, including excipients and / or auxiliary substances that facilitate the processing of a compound of formula (IX) (e.g., compound number 9a or 9b) or a pharmaceutically acceptable salt thereof into a pharmaceutically usable preparation. The appropriate formulation depends on the selected route of administration.

[0218] The compound of formula (IX) (e.g., compound number 9a or 9b) or a pharmaceutically acceptable salt thereof can be prepared with one or more pharmaceutically acceptable carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems.

[0219] It will be appreciated that the pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

[0220] For compounds of the present disclosure that are capable of further forming salts, it is to be understood that all such forms are also contemplated within the scope of the present claimed disclosure.

[0221] As used herein, the term "pharmaceutically acceptable salt" refers to a derivative of the compound disclosed in the present invention, which is modified by making an acid or base salt of the parent compound.Examples of pharmaceutically acceptable salts may include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like.Pharmaceutically acceptable salts may include conventional non-toxic salts or quaternary ammonium salts of the parent compound, for example, formed from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, 1,2-ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, glycollyarsanilic acid, hexylresorcinic acid, hydrabamic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxymaleic acid, hydroxynaphthoic acid, isethionic acid, These may include, but are not limited to, salts derived from inorganic and organic acids selected from lactic acid, lactobionic acid, laurylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, napsylic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, subacetic acid, succinic acid, sulfamic acid, sulfanilic acid, sulfuric acid, tannic acid, tartaric acid, toluenesulfonic acid, and commonly occurring amino acids such as glycine, alanine, phenylalanine, arginine, and the like.

[0222] In some embodiments, the pharmaceutically acceptable salt is a sodium salt, a potassium salt, a calcium salt, a magnesium salt, a diethylamine salt, a choline salt, a meglumine salt, a benzathine salt, a tromethamine salt, an ammonia salt, an arginine salt, or a lysine salt. In some embodiments, the pharmaceutically acceptable salt is a sodium salt.

[0223] Other examples of pharmaceutically acceptable salts may include hexanoic acid, cyclopentanepropionic acid, pyruvic acid, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo-[2.2.2]-oct-2-ene-1-carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, muconic acid, and the like. The present disclosure also encompasses salts formed when an acidic proton present in the parent compound is either replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinated to an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. It is understood that in the salt form, the ratio of the compound to the cation or anion of the salt can be 1:1, or any ratio other than 1:1, for example, 3:1, 2:1, 1:2, or 1:3.

[0224] It should be understood that all references to pharmaceutically acceptable salts may include the solvent addition forms (solvates) or crystal forms (polymorphs), as defined herein, of the same salt.

[0225] Techniques for formulation and administration of the disclosed compounds of this disclosure are described in Remington: The Science and Practice of Pharmacy, 1999. th, edition, Mack Publishing Co., Easton, PA (1995). In some embodiments, a compound of formula (IX) (e.g., Compound No. 9a or 9b) or a pharmaceutically acceptable salt thereof is used in a pharmaceutical preparation in combination with one or more pharmaceutically acceptable carriers or diluents. Suitable pharmaceutically acceptable carriers include, but are not limited to, inert solid fillers or inert diluents, and sterile aqueous or organic solutions. The compound is present in such pharmaceutical compositions in an amount sufficient to provide the desired dosage amount within the range described herein.

[0226] All percentages and ratios used herein are by weight unless otherwise indicated. Other features and advantages of the present disclosure will become apparent from the various examples. The examples provided illustrate various components and methodologies useful in practicing the present disclosure. The examples do not limit the claimed disclosure. Based on the present disclosure, one skilled in the art can identify and adopt other components and methodologies useful in practicing the present disclosure.

[0227] In the synthetic schemes described herein, compounds may be depicted in one specific configuration for simplicity.This specific configuration should not be interpreted as limiting the present disclosure to one or another isomer, tautomer, positional isomer or stereoisomer, nor does it exclude the mixture of isomers, tautomers, positional isomers or stereoisomers;However, it will be understood that a given isomer, tautomer, positional isomer or stereoisomer may have a higher level of activity than another isomer, tautomer, positional isomer or stereoisomer.

[0228] All publications and patent documents cited in this specification are incorporated herein by reference as if each such publication or document was specifically and individually indicated to be incorporated herein by reference. Citation of publications and patent documents is not intended as an admission that any is pertinent prior art, nor does it constitute any admission as to the contents or date thereof. Having now described the invention by written description, those skilled in the art will recognize that the invention can be practiced in a variety of embodiments, and that the foregoing description and the following examples are intended to be illustrative and not limiting of the scope of the claims which follow.

[0229] Having described the present disclosure, the following examples are offered by way of illustration and not by way of limitation.

[0230] Exemplary Embodiments Exemplary Embodiment 1. A method for preparing a compound of formula (IX) (e.g., compound No. 9a or 9b) or a salt thereof, comprising one or more of steps (i) to (vii): (i) contacting Compound No. 1 or a salt thereof with a hydrogenation agent, thereby forming Compound No. 2 or a salt thereof; (ii) contacting compound No. 3 with an esterifying agent, thereby forming a compound of formula (IV); (iii) contacting Compound No. 2 or a salt thereof with a compound of formula (IV), thereby forming a compound of formula (V) or a salt thereof; (iv) contacting the compound of formula (V) or a salt thereof with a reducing agent, thereby forming a compound of formula (VI) or a salt thereof; (v) contacting Compound No. 7 or a salt thereof with a CO generating agent, thereby forming Compound No. 8 or a salt thereof; (vi) contacting a compound of formula (VI) or a salt thereof with compound No. 8 or a salt thereof, thereby forming a compound of formula (IX) (e.g., compound No. 9a or 9b) or a salt thereof; or (vii) purifying the compound of formula (IX) or a salt thereof.

[0231] Exemplary Embodiment 2. A method of preparing a compound of formula (V) or a salt thereof, comprising: (iii) contacting Compound No. 2 or a salt thereof with a compound of formula (IV), thereby forming a compound of formula (V) or a salt thereof.

[0232] Exemplary Embodiment 3. A method of preparing a compound of formula (VI) or a salt thereof, comprising: (iv) contacting the compound of formula (V) or a salt thereof with a reducing agent, thereby forming a compound of formula (VI) or a salt thereof.

[0233] Exemplary Embodiment 4. The method of any one of the preceding exemplary embodiments, wherein the compound of formula (IV) is compound number 4.

[0234] Exemplary Embodiment 5. The method of any one of the preceding exemplary embodiments, wherein the compound of formula (V) or a salt thereof is Compound No. 5 or a salt thereof.

[0235] Exemplary Embodiment 6. The method of any one of the preceding exemplary embodiments, wherein the compound of formula (VI) or a salt thereof is Compound No. 6 or a salt thereof.

[0236] Exemplary Embodiment 7. The compound of Formula (VI) or a salt thereof is a compound of Formula (VI-a) or a salt thereof; The method of any one of the preceding exemplary embodiments, optionally wherein the compound of Formula (VI) or salt thereof is Compound No. 6a or a salt thereof.

[0237] Exemplary Embodiment 8. The compound of Formula (VI) or a salt thereof is a compound of Formula (VI-b) or a salt thereof; The method of any one of the preceding exemplary embodiments, optionally wherein the compound of Formula (VI) or a salt thereof is Compound No. 6b or a salt thereof.

[0238] Exemplary Embodiment 9. The method of any one of the preceding exemplary embodiments, wherein the compound of formula (IX) or a salt thereof is Compound No. 9.

[0239] Exemplary Embodiment 10. The compound of Formula (IX) or a salt thereof is a compound of Formula (IX-a) or a salt thereof; The method of any one of the preceding exemplary embodiments, optionally wherein the compound of Formula (IX) or salt thereof is Compound No. 9a or a salt thereof.

[0240] Exemplary Embodiment 11. The compound of Formula (IX) or a salt thereof is a compound of Formula (IX-b) or a salt thereof; The method of any one of the preceding exemplary embodiments, optionally wherein the compound of Formula (IX) or a salt thereof is Compound No. 9b or a salt thereof.

[0241] Exemplary Embodiment 12. The method of any one of the preceding exemplary embodiments, wherein in step (i), the hydrogenation agent is hydrogen.

[0242] Exemplary Embodiment 13. In step (i), the contacting is carried out in the presence of a hydrogenation catalyst; Optionally, the hydrogenation catalyst is Raney nickel.

[0243] Exemplary Embodiment 14. In step (i), the contacting is carried out in the presence of a base; Optionally, the base is potassium carbonate (K2CO3).

[0244] Exemplary Embodiment 15. The method of any one of the preceding exemplary embodiments, wherein Compound No. 2, or a salt thereof, is isolated and / or purified prior to contacting with the compound of Formula (IV).

[0245] Exemplary Embodiment 16. The method of any one of the preceding exemplary embodiments, wherein Compound No. 2, or a salt thereof, is not isolated or purified prior to contacting with the compound of Formula (IV).

[0246] Exemplary Embodiment 17. In step (ii), the esterifying agent is an alcohol; Optionally, the esterifying agent is isopropanol (iPrOH; propan-2-ol).

[0247] Exemplary Embodiment 18. In step (ii), the contacting is carried out in the presence of an esterification catalyst; Optionally, the esterification catalyst is 4-dimethylaminopyridine (DMAP).

[0248] Exemplary Embodiment 19. In step (ii), the contacting is carried out in the presence of a base; Optionally, the base is pyridine.

[0249] Exemplary Embodiment 20. In step (iii), the contacting is carried out in the presence of a salt; Optionally, the salt is potassium tert-butoxide (tBuOK).

[0250] Exemplary Embodiment 21. In step (iii), the contacting is carried out in the presence of an alcohol; Optionally, the alcohol is isopropanol (iPrOH; propan-2-ol).

[0251] Exemplary Embodiment 22. In step (iv), the reducing agent is a monosaccharide; optionally, the reducing agent is glucose; and Optionally, the reducing agent is D-glucose.

[0252] Exemplary Embodiment 23. In step (iv), the contacting is carried out in the presence of a reduction catalyst; The method of any one of the preceding exemplary embodiments, optionally wherein the reduction catalyst comprises a ketoreductase (KRED), a glutamate dehydrogenase (GDH), and a nicotinamide adenine dinucleotide phosphate (NADP).

[0253] Exemplary Embodiment 24. The method of any one of the preceding exemplary embodiments, wherein in step (v), the CO-generating agent is triphosgene.

[0254] Exemplary Embodiment 25. In step (v), the contacting is carried out in the presence of a base; Optionally, the base is triethylamine (TEA).

[0255] Exemplary Embodiment 26. In step (vi), the contacting is carried out in the presence of a base; Optionally, the base is 4-dimethylaminopyridine (DMAP).

[0256] Exemplary Embodiment 27. Step (vii) comprises crystallizing the compound of Formula (IX) or a salt thereof in the presence of an organic solvent; optionally, the organic solvent comprises isopropyl acetate and n-heptane; and The method of any one of the preceding exemplary embodiments, optionally wherein the isopropyl acetate and n-heptane are present in a ratio of about 1:1, about 1:2, about 1:3, about 1:4, or about 1:5.

[0257] Exemplary Embodiment 28. A compound prepared by the method of any one of the preceding exemplary embodiments.

[0258] Exemplary Embodiment 29. Optionally, the compound is Compound No. 5 or a salt thereof; and Optionally, the compound of Formula (V) or a salt thereof is Compound No. 5 or a salt thereof having a purity of about 90% or more, about 95% or more, about 96% or more, about 97% or more, about 98% or more, about 99% or more, about 99.5% or more, about 99.6% or more, about 99.7% or more, about 99.8% or more, or about 99.9% or more.

[0259] Exemplary Embodiment 30. Optionally, the compound is Compound No. 6 or a salt thereof; optionally, the compound is Compound No. 6a or a salt thereof; and Optionally, the compound is (a) an enantiomeric excess (ee) of about 90% or greater, about 95% or greater, about 96% or greater, about 97% or greater, about 98% or greater, about 99% or greater, about 99.5% or greater, about 99.6% or greater, about 99.7% or greater, about 99.8% or greater, or about 99.9% or greater; and / or (b) A compound of Formula (VI) or a salt thereof, which is Compound No. 6a or a salt thereof, having a purity of about 90% or more, about 95% or more, about 96% or more, about 97% or more, about 98% or more, about 99% or more, about 99.5% or more, about 99.6% or more, about 99.7% or more, about 99.8% or more, or about 99.9% or more.

[0260] Exemplary Embodiment 31. Optionally, the compound is Compound No. 9 or a salt thereof; optionally, the compound is Compound No. 9a or a salt thereof; and Optionally, the compound is (a) an enantiomeric excess (ee) of about 90% or greater, about 95% or greater, about 96% or greater, about 97% or greater, about 98% or greater, about 99% or greater, about 99.5% or greater, about 99.6% or greater, about 99.7% or greater, about 99.8% or greater, or about 99.9% or greater; and / or (b) A compound of Formula (IX) or a salt thereof, which is Compound No. 9a or a salt thereof, having a purity of about 90% or more, about 95% or more, about 96% or more, about 97% or more, about 98% or more, about 99% or more, about 99.5% or more, about 99.6% or more, about 99.7% or more, about 99.8% or more, or about 99.9% or more.

[0261] Exemplary Embodiment 32. A pharmaceutical composition comprising a compound of formula (IX) or a pharmaceutically acceptable salt thereof, as described in any one of the preceding exemplary embodiments, and one or more pharmaceutically acceptable carriers or excipients.

[0262] Exemplary Embodiment 33. A method for preventing or treating a disease in a subject, comprising administering to the subject a compound of formula (IX) or a pharmaceutically acceptable salt thereof, as described in any one of the preceding exemplary embodiments.

[0263] Exemplary Embodiment 34. A compound of Formula (IX), or a pharmaceutically acceptable salt thereof, according to any one of the preceding exemplary embodiments for use in preventing or treating a disease in a subject.

[0264] Exemplary Embodiment 35. Use of a compound of Formula (IX), or a pharmaceutically acceptable salt thereof, as described in any one of the preceding exemplary embodiments in the manufacture of a medicament for preventing or treating a disease in a subject.

[0265] Exemplary Embodiment 36. A method of inhibiting inflammasome activity in a subject, comprising contacting a cell with a compound of formula (IX) or a pharmaceutically acceptable salt thereof as described in any one of the preceding exemplary embodiments.

[0266] Exemplary Embodiment 37. A compound of formula (IX) or a pharmaceutically acceptable salt thereof, as described in any one of the preceding exemplary embodiments, for use in inhibiting inflammasome activity in a subject.

[0267] Exemplary Embodiment 38. Use of a compound of formula (IX), or a pharmaceutically acceptable salt thereof, as described in any one of the preceding exemplary embodiments in the manufacture of a medicament for inhibiting inflammasome activity.

[0268] Exemplary Embodiment 39. The method, compound, or use of any one of the preceding exemplary embodiments, wherein the subject is a human. [Example]

[0269] Having described the present disclosure, the following examples are offered by way of illustration and not by way of limitation.

[0270] It is understood that all values ​​presented in the examples are approximate and subject to equipment and / or experimental variation.

[0271] Example 1. Exemplary Synthesis of Compound No. 9a An exemplary synthesis of Compound No. 9a was carried out according to the following synthetic scheme and procedures. TIFF2025533123000004.tif86158

[0272] Process 1 Step 1 was carried out using the equipment listed in Table 1A and following the procedure listed in Table 1B.

[0273] (Table 1A) Equipment used in step 1 TIFF2025533123000005.tif55128

[0274] Table 1B: Exemplary Procedure for Step 1 TIFF2025533123000006.tif235158

[0275] The products of the process were evaluated using the chromatographic conditions shown in Table 1C, and the results are summarized in Table 1D.

[0276] Table 1C: Chromatographic conditions for evaluating the products of step 1 TIFF2025533123000007.tif94157

[0277] Table 1D. Evaluation of the products of Step 1 TIFF2025533123000008.tif64147

[0278] Process 2 Step 2 was carried out using the equipment described in Table 2A and following the procedure described in Table 2B.

[0279] (Table 2A) Equipment used in step 2 TIFF2025533123000009.tif74128

[0280] Table 2B: Exemplary Procedure for Step 2 TIFF2025533123000010.tif118158TIFF2025533123000011.tif226158TIFF2025533123000012.tif118158

[0281] The products of the process were evaluated using the chromatographic conditions shown in Table 2C, and the results are summarized in Table 2D.

[0282] Table 2C: Chromatographic conditions for evaluating the products of step 2 TIFF2025533123000013.tif88148

[0283] Table 2D: Evaluation of the products of step 2 TIFF2025533123000014.tif20133

[0284] Process 3 Step 3 was carried out using the equipment described in Table 3A and following the procedure described in Table 3B.

[0285] (Table 3A) Equipment used in step 3 TIFF2025533123000015.tif79128

[0286] Table 3B: Exemplary Procedure for Step 3 TIFF2025533123000016.tif194157TIFF2025533123000017.tif232157TIFF2025533123000018.tif223157TIFF2025533123000019.tif68157

[0287] The products of the process were evaluated using the chromatographic conditions shown in Table 3C, and the results are summarized in Table 3D.

[0288] Table 3C: Chromatographic conditions for evaluating the products of step 3 TIFF2025533123000020.tif98146

[0289] Table 3D: Evaluation of the products of step 3 TIFF2025533123000021.tif30135

[0290] Process 4 Step 4 was carried out using the equipment described in Table 4A and following the procedure described in Table 4B.

[0291] (Table 4A) Equipment used in step 4 TIFF2025533123000022.tif157128

[0292] Table 4B: Exemplary Procedure for Step 4 TIFF2025533123000023.tif192164TIFF2025533123000024.tif231164TIFF2025533123000025.tif30164

[0293] The products of the process were evaluated using the chromatographic conditions shown in Table 4C, and the results are summarized in Table 4D.

[0294] Table 4C: Chromatographic conditions for evaluating the product of step 4 TIFF2025533123000026.tif97143

[0295] Table 4D: Evaluation of the products of step 4 TIFF2025533123000027.tif30128

[0296] Process 5 Step 5 was carried out using the equipment described in Table 5A and following the procedures described in Table 5B. The products of the step were evaluated and the results are summarized in Table 5C.

[0297] (Table 5A) Equipment used in step 5 TIFF2025533123000028.tif55128

[0298] Table 5B: Exemplary Procedure for Step 5 TIFF2025533123000029.tif196164

[0299] Table 5C: Evaluation of the products of step 5 TIFF2025533123000030.tif20133

[0300] Process 6 Step 6 was carried out using the equipment listed in Table 6A and following the procedure listed in Table 6B.

[0301] (Table 6A) Equipment used in step 6 TIFF2025533123000031.tif123128

[0302] Table 6B: Exemplary Procedure for Step 6 TIFF2025533123000032.tif157164TIFF2025533123000033.tif226164TIFF2025533123000034.tif146164

[0303] The products of the process were evaluated using the chromatographic conditions shown in Table 6C, and the results are summarized in Table 6D.

[0304] Table 6C: Chromatographic conditions for evaluating the product of step 6 TIFF2025533123000035.tif173163

[0305] Table 6D: Evaluation of the products of step 6 TIFF2025533123000036.tif39141

[0306] Process 7 Step 7 was carried out using the equipment listed in Table 7A and following the procedure listed in Table 7B.

[0307] (Table 7A) Equipment used in step 7 TIFF2025533123000037.tif79128

[0308] Table 7B: Exemplary Procedure for Step 7 TIFF2025533123000038.tif230164

[0309] The products of the process were evaluated using the chromatographic conditions shown in Table 7C, and the results are summarized in Table 7D.

[0310] Table 7C: Chromatographic conditions for evaluating the product of step 7 TIFF2025533123000039.tif74152

[0311] Table 7D: Evaluation of the products of step 7 TIFF2025533123000040.tif20133

[0312] equivalent The details of one or more aspects of the present disclosure are set forth in the accompanying description above. Although any methods and materials similar or equivalent to those described herein can be used in practicing or testing the present disclosure, preferred methods and materials are currently described. Other features, goals, and advantages of the present disclosure will be apparent from the description and claims. In this specification and the appended claims, the singular form "a," "an," or "the" can include plural referents unless the context clearly dictates otherwise. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs. All patents and publications cited herein are incorporated by reference.

[0313] The foregoing description has been presented for purposes of illustration only, and it is not intended to limit the disclosure to the precise form disclosed, but rather to be limited by the claims appended hereto.

Claims

1. A method for preparing a compound of formula (IX) (e.g., compound No. 9a or 9b) or a salt thereof, comprising one or more of steps (i) to (vii): (i) contacting Compound No. 1 or a salt thereof with a hydrogenation agent, thereby forming Compound No. 2 or a salt thereof; (ii) contacting compound No. 3 with an esterifying agent, thereby forming a compound of formula (IV); (iii) contacting Compound No. 2 or a salt thereof with the compound of formula (IV), thereby forming a compound of formula (V) or a salt thereof; (iv) contacting the compound of formula (V) or a salt thereof with a reducing agent, thereby forming a compound of formula (VI) or a salt thereof; (v) contacting Compound No. 7 or a salt thereof with a CO generating agent, thereby forming Compound No. 8 or a salt thereof; (vi) contacting the compound of formula (VI) or a salt thereof with compound No. 8 or a salt thereof, thereby forming a compound of formula (IX) (e.g., compound No. 9a or 9b) or a salt thereof; or (vii) purifying the compound of formula (IX) or a salt thereof.

2. A method for preparing a compound of formula (V) or a salt thereof, comprising: (iii) contacting Compound No. 2 or a salt thereof with a compound of formula (IV), thereby forming a compound of formula (V) or a salt thereof.

3. A process for preparing a compound of formula (VI) or a salt thereof, comprising: (iv) contacting the compound of formula (V) or a salt thereof with a reducing agent, thereby forming a compound of formula (VI) or a salt thereof.

4. 10. The method of any one of the preceding claims, wherein the compound of formula (IX) or a salt thereof is: (a) Compound No. 9; (b) a compound of formula (IX-a) or a salt thereof; optionally, the compound of formula (IX) or a salt thereof is compound number 9a or a salt thereof; or (c) A compound of formula (IX-b) or a salt thereof; optionally, the compound of formula (IX) or a salt thereof is compound number 9b or a salt thereof.

5. In step (i), the contacting step is carried out in the presence of a hydrogenation catalyst; Optionally, the hydrogenation catalyst is Raney nickel.

10. The method of any one of the preceding claims.

6. In step (i), the contacting step is carried out in the presence of a base; Optionally, the base is potassium carbonate (K 2 CO 3 ) 10. The method of any one of the preceding claims.

7. In step (ii), the esterifying agent is an alcohol; Optionally, the esterifying agent is isopropanol (iPrOH; propan-2-ol); 10. The method of any one of the preceding claims.

8. In step (ii), the contacting step is carried out in the presence of an esterification catalyst; Optionally, the esterification catalyst is 4-dimethylaminopyridine (DMAP).

10. The method of any one of the preceding claims.

9. In step (ii), the contacting step is carried out in the presence of a base; Optionally, the base is pyridine.

10. The method of any one of the preceding claims.

10. In step (iii), the contacting step is carried out in the presence of a salt; Optionally, the salt is potassium tert-butoxide (tBuOK); 10. The method of any one of the preceding claims.

11. In step (iii), the contacting step is carried out in the presence of an alcohol; Optionally, the alcohol is isopropanol (iPrOH; propan-2-ol); 10. The method of any one of the preceding claims.

12. In step (iv), the reducing agent is a monosaccharide; Optionally, the reducing agent is glucose; and Optionally, the reducing agent is D-glucose.

10. The method of any one of the preceding claims.

13. In step (iv), the contacting step is carried out in the presence of a reduction catalyst; Optionally, the reduction catalyst comprises a ketoreductase (KRED), a glutamate dehydrogenase (GDH), and a nicotinamide adenine dinucleotide phosphate (NADP).

10. The method of any one of the preceding claims.

14. In step (v), the CO generating agent is triphosgene, and the contacting step is carried out in the presence of a base; Optionally, the base is triethylamine (TEA).

10. The method of any one of the preceding claims.

15. In step (vi), the contacting step is carried out in the presence of a base; Optionally, the base is 4-dimethylaminopyridine (DMAP).

10. The method of any one of the preceding claims.

16. step (vii) comprising crystallizing the compound of formula (IX) or a salt thereof in the presence of an organic solvent; Optionally, the organic solvent comprises isopropyl acetate and n-heptane; and Optionally, the isopropyl acetate and n-heptane are present in a ratio of about 1:1, about 1:2, about 1:3, about 1:4, or about 1:

5.

10. The method of any one of the preceding claims.

17. optionally, Compound No. 9 or a salt thereof; optionally, Compound No. 9a or a salt thereof; and Optionally, (a) an enantiomeric excess (ee) of about 90% or greater, about 95% or greater, about 96% or greater, about 97% or greater, about 98% or greater, about 99% or greater, about 99.5% or greater, about 99.6% or greater, about 99.7% or greater, about 99.8% or greater, or about 99.9% or greater; and / or (b) a purity of about 90% or more, about 95% or more, about 96% or more, about 97% or more, about 98% or more, about 99% or more, about 99.5% or more, about 99.6% or more, about 99.7% or more, about 99.8% or more, or about 99.9% or more or a salt thereof, A compound of formula (IX) or a salt thereof:

18. 10. A pharmaceutical composition comprising a compound of formula (IX) or a pharmaceutically acceptable salt thereof as defined in any one of the preceding claims and one or more pharmaceutically acceptable carriers or excipients.

19. A method for inhibiting inflammasome activity in a subject, comprising administering to the subject a compound of formula (IX) or a pharmaceutically acceptable salt thereof according to any one of the preceding claims.

20. 10. A method for preventing or treating a disease in a subject, comprising administering to the subject a compound of formula (IX) or a pharmaceutically acceptable salt thereof according to any one of the preceding claims.

Images