Process for preparation of carbamate derivatives

Abstract

The present disclosure relates to a process for preparing a compound of Formula (IX): (IX) or a pharmaceutically acceptable salt thereof. The disclosure also relates to compounds prepared by the method, pharmaceutical compositions comprising the compounds and uses thereof, e.g., in the treatment of disorders (e.g., in which inflammasome activity is involved).

Description

[0001] Related Applications

[0002] This application claims priority to International Patent Application No. PCT / CN2022 / 123712, filed on October 5, 2022, the entire content of which is incorporated herein by reference. Background Art

[0003] Autoimmune diseases are associated with the overproduction of pro-inflammatory cytokines. One of these 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, S.L. et al., Annu. Rev. Immunol. 2009. 27:621–68).

[0004] In humans, 22 NLR proteins are divided into 4 NLR subfamilies based on 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. Multiple NLR family members are associated with the formation of inflammasomes.

[0005] Although the activation of inflammasomes appears to have evolved as an important part of host immunity against pathogens, the ability of the NLRP3 inflammasome to activate in response to endogenous sterile danger signals is unique. Many such sterile signals have been elucidated, and their formation is associated with specific disease states. For example, uric acid crystals found in patients with gout are potent triggers for NLRP3 activation. Similarly, cholesterol crystals found in patients with atherosclerosis can also promote NLRP3 activation. The recognition of the role of sterile danger signals as NLRP3 activators has led to the association of IL-1 and IL-18 with a variety of pathophysiological indications, including metabolic, physiological, inflammatory, hematological, and immunological disorders.

[0006] This disclosure stems from the need to provide new methods for preparing compounds for the specific regulation of NLRP3-dependent cellular processes. Summary of the Invention

[0007] In some aspects, the present disclosure provides methods for preparing the compounds of formula (IX) described herein (e.g., compound 9a or 9b).

[0008] In some aspects, the present disclosure provides methods for preparing a compound of formula (IX) (e.g., compound 9a or 9b) or a salt thereof, comprising one or more of steps (i)-(vii):

[0009] (i) Contact compound 1 or a salt thereof with a hydrogenating agent to form compound 2 or a salt thereof;

[0010] (ii) React compound 3 with an esterifying agent to form a compound of formula (IV) (e.g., compound 4);

[0011] (iii) Contact compound 2 or a salt thereof with a compound of formula (IV) (e.g., compound 4) to form a compound of formula (V) (e.g., compound 5) or a salt thereof;

[0012] (iv) Contact a compound of formula (V) (e.g., compound 5) or a salt thereof with a reducing agent to form a compound of formula (VI) (e.g., compound 6a or 6b) or a salt thereof;

[0013] (v) Contact compound 7 or a salt thereof with a CO-generating agent to form compound 8 or a salt thereof;

[0014] (vi) Contact a compound of formula (VI) (e.g., compound 6a or 6b) or a salt thereof with compound 8 or a salt thereof to form a compound of formula (IX) (e.g., compound 9a or 9b) or a salt thereof; or

[0015] (vii) Purify the compound of formula (IX) (e.g., compound 9a or 9b) or a salt thereof.

[0016] In some aspects, the present disclosure provides a method for preparing a compound of formula (IX) (e.g., compound 9a or 9b) or a salt thereof, comprising steps (i)-(vii):

[0017] (i) Contact compound 1 or a salt thereof with a hydrogenating agent to form compound 2 or a salt thereof;

[0018] (ii) Contact compound 3 with an esterifying agent to form a compound of formula (IV);

[0019] (iii) Contact compound 2 or a salt thereof with a compound of formula (IV) to form a compound of formula (V) or a salt thereof;

[0020] (iv) Contact a compound of formula (V) or a salt thereof with a reducing agent to form a compound of formula (VI) or a salt thereof;

[0021] (v) Contact compound 7 or a salt thereof with a CO-generating agent to form compound 8 or a salt thereof;

[0022] (vi) Contact a compound of formula (VI) or a salt thereof with compound 8 or a salt thereof to form a compound of formula (IX) or a salt thereof; and

[0023] (vii) Purifying the compound of formula (IX) (e.g., compound 9a or 9b) or a salt thereof.

[0024] In some aspects, the present disclosure provides a method for preparing a compound of formula (V) (e.g., compound 5) or a salt thereof, comprising:

[0025] (iii) Contacting compound 2 or a salt thereof with a compound of formula (IV) (e.g., compound 4) to form a compound of formula (V) (e.g., compound 5) or a salt thereof.

[0026] In some aspects, the present disclosure provides a compound prepared by the methods described herein.

[0027] In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound of formula (IX) (e.g., compound 9a or 9b) or a pharmaceutically acceptable salt thereof as described herein, and one or more pharmaceutically acceptable carriers or excipients.

[0028] In some aspects, the present disclosure provides a method for inhibiting the activity of an inflammasome (e.g., NLRP3 inflammasome) (e.g., in vitro or in vivo), comprising contacting a cell with a compound of formula (IX) (e.g., compound 9a or 9b) or a pharmaceutically acceptable salt thereof as described herein (e.g., in an effective amount).

[0029] In some aspects, the present disclosure provides a method for treating or preventing a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a compound of formula (IX) (e.g., compound 9a or 9b) or a pharmaceutically acceptable salt thereof as described herein (e.g., in a therapeutically effective amount).

[0030] In some aspects, the present disclosure provides a compound of formula (IX) (e.g., compound 9a or 9b) or a pharmaceutically acceptable salt thereof as described herein for inhibiting the activity of an inflammasome (e.g., NLRP3 inflammasome) (e.g., in vitro or in vivo).

[0031] In some aspects, the present disclosure provides a compound of formula (IX) (e.g., compound 9a or 9b) or a pharmaceutically acceptable salt thereof as described herein for treating or preventing a disease or disorder disclosed herein.

[0032] In some aspects, the present disclosure provides the use of a compound of formula (IX) (e.g., compound 9a or 9b) or a pharmaceutically acceptable salt thereof as described herein in the manufacture of a medicament for inhibiting the activity of an inflammasome (e.g., NLRP3 inflammasome) (e.g., in vitro or in vivo).

[0033] In some aspects, the present disclosure provides the use of a compound of formula (IX) (e.g., compound 9a or 9b) described herein or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0034] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In the specification, the singular forms also include the plural forms unless the context clearly dictates otherwise. Suitable methods and materials are described below, however, methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure. 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 control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting. In case of conflict between the chemical structure and the name of the compounds disclosed herein, the chemical structure shall prevail.

[0035] Other features and advantages of the present disclosure will be apparent from the following detailed description and claims. Detailed Description

[0036] Autoimmune diseases are associated with the overproduction of pro-inflammatory cytokines. One of these 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. al. Rev. Immunol. 2009. 27:621–68).

[0037] Cytokines of the IL-1 family are highly active and, as important mediators of inflammation, are mainly associated with acute and chronic inflammation (Sims J. et al. Nature Reviews Immunology 10, 89-102 (February 2010)). The overproduction of IL-1 is considered to be a mediator of certain autoimmune and autoinflammatory diseases. Autoinflammatory diseases are characterized by recurrent and unprovoked inflammation in the absence of autoantibodies, infection, or antigen-specific T lymphocytes.

[0038] The pro-inflammatory cytokines of the IL-1 superfamily include IL-1α, IL-1β, IL-18 and IL-36α, β, λ, and are produced in response to pathogens and other cellular stressors as part of the host innate immune response. Unlike many other secreted cytokines that are processed and released by the standard cellular secretory apparatus consisting of the endoplasmic reticulum and Golgi apparatus, IL-1 family members lack the leader sequence required to enter the endoplasmic reticulum and thus remain intracellular after translation. In addition, IL-1β, IL-18 and IL-36α, β, λ are synthesized as pro-cytokines, which require proteolytic activation to become optimal ligands that bind to their cognate receptors on target cells.

[0039] In the case of IL-1α, IL-1β and IL-18, it is now recognized that a multi-protein complex called the inflammasome is responsible for activating the precursors of IL-1β and IL-18 and releasing these cytokines extracellularly. The inflammasome complex typically consists of a sensor molecule (e.g., NLR (nucleotide oligomerization domain (NOD)-like receptor)), an adaptor molecule ASC (apoptosis-associated speck-like protein containing a CARD (caspase recruitment domain)), and the procaspase-1 precursor. In response to various "danger signals", including pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs), the subunits of the inflammasome oligomerize to form a supramolecular structure intracellularly. PAMPs can include, for example, molecules such as peptidoglycan, viral DNA or RNA, and bacterial DNA or RNA. On the other hand, DAMPs consist of a variety of endogenous or exogenous sterile triggers, including monosodium urate crystals, silica, alum, asbestos, fatty acids, ceramides, cholesterol crystals, and β-amyloid peptide aggregates. The assembly of the inflammasome platform promotes the autocatalysis of the procaspase-1 precursor, generating highly active caspases that are responsible for activating and releasing the pro-IL-1β and pro-IL-18 precursors. Thus, the release of these highly inflammatory cytokines occurs only in response to the detection and response of inflammasome sensors to specific molecular danger signals.

[0040] In humans, 22 NLR proteins are divided into 4 NLR subfamilies based on 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. Multiple NLR family members are associated with the formation of the inflammasome, including NLRP1, NLRP3, NLRP6, NLRP7, NLRP12, and NLRC4 (IPAF).

[0041] Two other structurally distinct inflammasome structures containing the PYHIN domain (proteins containing pyrin and HIN domains), namely absent in melanoma 2 (AIM2) and interferon lambda-induced protein 16 (IFI16) (Latz et al., Nat Rev Immunol, 2013, 13(6), 397 - 311), act as intracellular DNA sensors. Pyrin (encoded by the MEFV gene) represents another inflammasome platform associated with the activation of the IL-1β precursor (Chae et al., Immunity 34, 755 - 768, 2011).

[0042] The assembly of the inflammasome platform is required to achieve the activation and release of IL-1β and IL-18 from monocytes and macrophages, ensuring that their production is carefully coordinated through a two-step process. First, the cell must encounter a priming ligand (such as the TLR4 receptor ligand LPS, or inflammatory cytokines such as TNFα), leading to NFkB-dependent transcription of NLRP3, the IL-1β precursor, and the IL-18 precursor. The newly translated pro-cytokines remain intracellular and inactive unless the producing cell encounters a second signal, leading to the activation of the inflammasome scaffold and the maturation of the caspase-1 precursor.

[0043] In addition to proteolytically activating pro-IL-1β and pro-IL-18, active caspase-1 also initiates a form of inflammatory cell death called pyroptosis by cleaving gasdermin-D. Pyroptosis externalizes the mature forms of IL-1β and IL-18 and releases alarmin molecules (compounds that promote inflammation and activate innate and adaptive immunity), such as high-mobility group box 1 (HMGB1), IL-33, and IL-1α.

[0044] Although the activation of inflammasomes appears to have evolved as an important part of host immunity against pathogens, the ability of the NLRP3 inflammasome to activate in response to endogenous and exogenous sterile danger signals is unique. Many such sterile signals have been elucidated, and their formation is associated with specific disease states. For example, uric acid crystals found in patients with gout are potent triggers for NLRP3 activation. Similarly, cholesterol crystals found in patients with atherosclerosis can also promote NLRP3 activation. The recognition of the role of sterile danger signals as NLRP3 activators has led to the association of IL-1β and IL-18 with a variety of pathophysiological indications, including metabolic, physiological, inflammatory, hematological, and immunological disorders.

[0045] The best illustration of the link to human disease is the discovery that gain-of-function NLRP3 gene mutations cause a spectrum of autoinflammatory disorders, 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 medium-induced NLRP3 activation is associated with a wide variety of disorders, including joint degeneration (gout, rheumatoid arthritis, osteoarthritis), cardiometabolism (type 2 diabetes, atherosclerosis, hypertension), central nervous system (Alzheimer's disease, Parkinson's disease, multiple sclerosis), gastrointestinal tract (Crohn's disease, ulcerative colitis), lung (chronic obstructive pulmonary disease (COPD), asthma, idiopathic pulmonary fibrosis), and liver (fibrosis, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis (NASH)). It is further thought that NLRP3 activation promotes kidney inflammation, leading to chronic kidney disease (CKD).

[0046] Currently, treatment options for diseases in which IL-1 has been shown to be a pathogenic factor include the IL-1 receptor antagonist anakinra, an Fc-containing fusion construct of the IL-1 receptor and the extracellular domain of the 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.

[0047] It has been reported that some small molecules inhibit the function of the NLRP3 inflammasome. For example, glibenclamide is a specific inhibitor of NLRP3 activation, although its concentration is in the micromolar range, which is unlikely to be achieved in vivo. It has been reported that non-specific drugs (such as parthenolide, Bay 11-7082, and 3,4-methylenedioxy-β-nitrostyrene) impair NLRP3 activation, but limited therapeutic utility is expected due to their common structural feature (i.e., consisting of an activated olefin substituted with an electron-withdrawing group); this can lead to the unwanted formation of covalent adducts with the thiol groups of proteins. It has been reported that many natural products, such as β-hydroxybutyrate, sulforaphane, quercetin, and salvianolic acid, also inhibit NLRP3 activation. Similarly, it has been reported that effectors / modulators of many other molecular targets impair NLRP3 activation, including agonists of the G protein-coupled receptor TGR5, the sodium-glucose co-transport inhibitor epigliflozin, the dopamine receptor antagonist A-68930, the serotonin reuptake inhibitor fluoxetine, fenamic acid non-steroidal anti-inflammatory drugs, and the β-adrenergic receptor blocker nebivolol. The utility of these molecules as therapies for the chronic treatment of NLRP3-dependent inflammatory disorders remains to be determined. A series of sulfonylurea-containing molecules were previously identified as potent and selective inhibitors of the post-translational processing of the IL-1β precursor (Perregaux et al., J Pharmacol. Exp. Ther. 299, 187-197, 2001). The exemplary molecule CP-456,773 in this study was recently characterized as a specific inhibitor of NLRP3 activation (Coll et al., Nat Med 21.3 (2015): 248-255.).

[0048] This disclosure relates to methods for preparing compounds that can be used to modulate NLRP3-dependent cellular processes. In some embodiments, there is a need for methods for preparing compounds that have improved physicochemical, pharmacological, and pharmaceutical properties relative to existing NLRP3 modulating compounds.

[0049] The compounds of this disclosure

[0050] It should be understood that the structures of formulas (IV)-(VI), (VI-a), (VI-b), (IX), (IX-a), and (IX-b), and the structures of compounds 1-6, 6a, 6b, 7-9, 9a, and 9b are as described in Table I below, where R 1 As described herein.

[0051] Table I

[0052]

[0053]

[0054] In some embodiments, each R 1 are independently C1-C6 alkyl.

[0055] In some embodiments, each R 1 is independently methyl, ethyl, propyl, butyl, pentyl or hexyl.

[0056] In some embodiments, each R 1 is independently methyl, ethyl or propyl.

[0057] In some embodiments, each R 1 It's methyl.

[0058] In some embodiments, each R 1 It's ethyl.

[0059] In some embodiments, each R 1 It is propyl.

[0060] In some embodiments, each R 1 It's n-propyl.

[0061] In some embodiments, each R 1 It is isopropyl.

[0062] Methods of the present disclosure

[0063] In some aspects, the present disclosure provides a method for preparing compound 9a or a salt thereof according to Scheme A.

[0064] In some embodiments, compound 1 is dechlorinated to compound 2 (e.g., via hydrogenation). In some embodiments, compound 3 is converted to compound 4 via esterification (e.g., in the presence of an esterifying agent). In some embodiments, compound 2 reacts with compound 4 to provide compound 5. In some embodiments, compound 7 is converted to compound 8 (e.g., via reaction with a CO generating agent). In some embodiments, compound 5 is reduced to compound 6a and reacted with compound 8 to form compound 9a (e.g., in the presence of a base). In some embodiments, compound 9a is purified.

[0065] In some embodiments, the method of preparing compound 9a or a salt thereof comprises at least one of the seven steps shown in Scheme A.

[0066]

[0067] In some aspects, the present disclosure provides a method for preparing a compound of formula (IX) (eg, compound 9a or 9b) or a salt thereof, comprising one or more of steps (i)-(vii):

[0068] (i) Contact compound 1 or a salt thereof with a hydrogenating agent to form compound 2 or a salt thereof;

[0069] (ii) React compound 3 with an esterifying agent to form a compound of formula (IV) (e.g., compound 4);

[0070] (iii) Contact compound 2 or a salt thereof with a compound of formula (IV) (e.g., compound 4) to form a compound of formula (V) (e.g., compound 5) or a salt thereof;

[0071] (iv) Contact a compound of formula (V) (e.g., compound 5) or a salt thereof with a reducing agent to form a compound of formula (VI) (e.g., compound 6a or 6b) or a salt thereof;

[0072] (v) Contact compound 7 or a salt thereof with a CO-generating agent to form compound 8 or a salt thereof;

[0073] (vi) Contact a compound of formula (VI) (e.g., compound 6a or 6b) or a salt thereof with compound 8 or a salt thereof to form a compound of formula (IX) (e.g., compound 9a or 9b) or a salt thereof; or

[0074] (vii) Purify a compound of formula (IX) (e.g., compound 9a or 9b) or a salt thereof.

[0075] In some embodiments, the method comprises one or more of steps (iii), (iv), and (vi).

[0076] In some embodiments, the method comprises step (iii).

[0077] In some embodiments, the method comprises step (iv).

[0078] In some embodiments, the method comprises steps (iii) and (iv).

[0079] In some embodiments, the method comprises step (vi).

[0080] In some embodiments, the method comprises steps (iii), (iv), and (vi).

[0081] In some embodiments, the method comprises one or more of steps (iii), (iv), (vi), and (vii).

[0082] In some embodiments, the method comprises steps (iii), (iv), (vi), and (vii).

[0083] In some aspects, the present disclosure provides a method for preparing a compound of formula (IX) (eg, compound 9a or 9b) or a salt thereof, comprising steps (i) to (vii):

[0084] (i) contacting compound 1 or a salt thereof with a hydrogenating agent to form compound 2 or a salt thereof;

[0085] (ii) contacting compound 3 with an esterifying agent to form a compound of formula (IV) (e.g., compound 4);

[0086] (iii) contacting compound 2 or a salt thereof with a compound of formula (IV) (e.g., compound 4) to form a compound of formula (V) (e.g., compound 5) or a salt thereof;

[0087] (iv) contacting a compound of formula (V) (e.g., compound 5) or a salt thereof with a reducing agent to form a compound of formula (VI) (e.g., compound 6a or 6b) or a salt thereof;

[0088] (v) contacting compound 7 or a salt thereof with a CO generating agent to form compound 8 or a salt thereof;

[0089] (vi) contacting a compound of formula (VI) (e.g., compound 6a or 6b) or a salt thereof with compound 8 or a salt thereof, thereby forming a compound of formula (IX) (e.g., compound 9a or 9b) or a salt thereof; and

[0090] (vii) purifying the compound of formula (IX) (eg, compound 9a or 9b) or a salt thereof.

[0091] In some embodiments, the compound of formula (IV) is Compound 4.

[0092] In some embodiments, the compound of formula (VI) or a salt thereof is Compound 5 or a salt thereof.

[0093] In some embodiments, the compound of formula (VI) or a salt thereof is Compound 6 or a salt thereof.

[0094] In some embodiments, the compound of formula (VI) or a salt thereof is a compound of formula (VI-a) or a salt thereof.

[0095] In some embodiments, the compound of formula (VI) or a salt thereof is compound 6a or a salt thereof.

[0096] In some embodiments, the compound of formula (VI) or a salt thereof is a compound of formula (VI-b) or a salt thereof.

[0097] In some embodiments, the compound of formula (VI) or a salt thereof is compound 6b or a salt thereof.

[0098] In some embodiments, the compound of formula (IX) or a salt thereof is Compound 9.

[0099] In some embodiments, the compound of formula (IX) or a salt thereof is a compound of formula (IX-a) or a salt thereof.

[0100] In some embodiments, the compound of formula (IX) or a salt thereof is compound 9a or a salt thereof.

[0101] In some embodiments, the compound of formula (IX) or a salt thereof is a compound of formula (IX-b) or a salt thereof.

[0102] In some embodiments, the compound of formula (IX) or a salt thereof is compound 9b or a salt thereof.

[0103] Step (i)

[0104] In some embodiments, in step (i), the hydrogenating agent is hydrogen.

[0105] In some embodiments, in step (i), the hydrogenating agent is an alkene or an alkyne.

[0106] In some embodiments, in step (i), the contacting is carried out in the presence of a hydrogenation catalyst.

[0107] In some embodiments, the hydrogenation catalyst is a homogeneous catalyst.

[0108] In some embodiments, the hydrogenation catalyst is a heterogeneous catalyst.

[0109] In some embodiments, the hydrogenation catalyst is a metal catalyst.

[0110] In some embodiments, the hydrogenation catalyst is a nickel catalyst, a platinum catalyst, a palladium catalyst, a rhodium catalyst or a ruthenium catalyst.

[0111] In some embodiments, the hydrogenation catalyst is a palladium catalyst (e.g., palladium on carbon (Pd / C)).

[0112] In some embodiments, the hydrogenation catalyst is a nickel catalyst (e.g., Raney nickel).

[0113] 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)).

[0114] 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)).

[0115] 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).

[0116] 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 hour (e.g., about 25 hours).

[0117] In some embodiments, step (i) includes filtering a solution of compound 2 or a salt thereof (e.g., in THF).

[0118] In some embodiments, compound 2 or a salt thereof is separated and / or purified before contacting with the compound of formula (IV) (e.g., compound 4).

[0119] In some embodiments, compound 2 or a salt thereof is not separated or purified before contacting with the compound of formula (IV) (e.g., compound 4).

[0120] In some embodiments, step (i) yields a solution of compound 2 or a salt thereof (e.g., in THF).

[0121] Step (ii)

[0122] In some embodiments, in step (ii), the esterifying agent is an alcohol.

[0123] In some embodiments, the esterifying agent is R 1 -OH, where R 1 is a C1-C6 alkyl group.

[0124] 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 isopropyl alcohol (iPrOH; propan-2-ol).

[0125] 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)).

[0126] 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).

[0127] In some embodiments, in step (ii), 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)).

[0128] In some embodiments, step (ii) comprises filtering a solution (eg, in n-heptane) of the compound of formula (IV) (eg, compound 4).

[0129] Step (iii)

[0130] In some aspects, the present disclosure provides a method for preparing a compound of formula (V) (e.g., compound 5) or a salt thereof, comprising:

[0131] (iii) contacting Compound 2 or a salt thereof with a compound of formula (IV) (eg, Compound 4) to form a compound of formula (V) (eg, Compound 5) or a salt thereof.

[0132] In some embodiments, in step (iii), the contacting is performed in the presence of a salt. In some embodiments, the salt is a potassium salt (eg, potassium tert-butoxide (tBuOK)).

[0133] In some embodiments, in step (iii), the contacting is performed in the presence of an alcohol.

[0134] In some embodiments, the alcohol is isopropyl alcohol (iPrOH; propan-2-ol).

[0135] In some embodiments, step (iii) further comprises adding an acid to the formed compound of formula (V) (e.g., compound 5) or a salt thereof, thereby adjusting the pH 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).

[0136] In some embodiments, the acid is an organic acid (eg, acetic acid (AcOH)).

[0137] In some embodiments, step (iii) further comprises crystallizing the compound of formula (V) (eg, compound 5) or a salt thereof in the presence of an organic solvent. In some embodiments, the organic solvent comprises isopropyl acetate and n-heptane.

[0138] Step (iv)

[0139] In some aspects, the present disclosure provides a method for preparing a compound of formula (VI) (eg, compound 6a or 6b) or a salt thereof, comprising:

[0140] (iv) contacting a compound of formula (V) (eg, compound 5) or a salt thereof with a reducing agent to form a compound of formula (VI) (eg, compound 6a or 6b) or a salt thereof.

[0141] 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.

[0142] In some embodiments, in step (iv), the contacting is carried out in the presence of a reduction catalyst.

[0143] In some embodiments, the reduction catalyst includes an enzyme catalyst.

[0144] In some embodiments, the reduction catalyst includes a molecular catalyst.

[0145] In some embodiments, the reduction catalyst includes ketoreductase (KRED).

[0146] In some embodiments, the reduction catalyst includes glutamate dehydrogenase (GDH).

[0147] In some embodiments, the reduction catalyst includes diphosphate nucleotides (e.g., as cofactors).

[0148] In some embodiments, the reduction catalyst includes nicotinamide adenine dinucleotide phosphate (NADP) as a cofactor.

[0149] In some embodiments, the reduction catalyst includes ketoreductase (KRED), glutamate dehydrogenase (GDH), and nicotinamide adenine dinucleotide phosphate (NADP).

[0150] In some embodiments, the reduction involves the transfer of a hydride from the reduction catalyst (e.g., NADP cofactor) to the reducing agent (e.g., glucose).

[0151] In some embodiments, the contacting is carried out in the presence of a buffer solution. In some embodiments, the buffer solution contains phosphate (e.g., dipotassium hydrogen phosphate (K2HPO4)). In some embodiments, the pH value of the buffer solution is 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).

[0152] In some embodiments, the contacting is carried out in the presence of an aprotic dipolar solvent (e.g., dimethyl sulfoxide (DMSO)).

[0153] In some embodiments, step (iv) further comprises extracting the formed compound of formula (VI) (e.g., compound 6a or 6b) or a salt thereof with an aprotic solvent (e.g., 2-methyltetrahydrofuran (2-MeTHF)).

[0154] In some embodiments, step (iv) yields a solution of the compound of formula (VI) (e.g., compound 6a or 6b) or a salt thereof (e.g., in 2-methyltetrahydrofuran (2-MeTHF)).

[0155] Step (v)

[0156] In some embodiments, in step (v), the CO generator is triphosgene.

[0157] 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)).

[0158] 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).

[0159] In some embodiments, step (v) comprises filtering a solution of compound 8 or a salt thereof (e.g., in toluene).

[0160] In some embodiments, step (v) yields a solution of compound 8 or a salt thereof (e.g., in toluene).

[0161] Step (vi)

[0162] In some embodiments, in step (vi), the contacting is carried out in the presence of a base. In some embodiments, the base is an organic base (e.g., 4-dimethylaminopyridine (DMAP)).

[0163] In some embodiments, in step (vi), the contacting 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.

[0164] In some embodiments, step (vi) further comprises washing the formed compound of formula (IX) (e.g., compound 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).

[0165] In some embodiments, step (vi) further comprises washing the formed compound of formula (IX) (e.g., compound 9a or 9b) or a salt thereof with an alkali solution. In some embodiments, the acid solution comprises sodium bicarbonate (NaHCO3; e.g., about 5% NaHCO3).

[0166] In some embodiments, step (vi) further comprises crystallizing the compound of formula (IX) (e.g., compound 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.

[0167] Step (vii)

[0168] In some embodiments, step (vii) comprises crystallizing the compound of formula (IX) (e.g., compound 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.

[0169] In some embodiments, the proportion of isopropyl acetate and n-heptane present is about 1:1, about 1:2, about 1:3, about 1:4, or about 1:5.

[0170] The compound prepared by this method

[0171] In some aspects, the present disclosure provides a compound prepared by the method disclosed herein.

[0172] In some aspects, the present disclosure provides a compound of formula (V) or a salt thereof. In some embodiments, the compound is compound 5 or a salt thereof.

[0173] In some embodiments, the compound is compound 5 or a salt thereof with a purity of about 90% or higher, about 95% or higher, about 96% or higher, about 97% or higher, about 98% or higher, about 99% or higher, about 99.5% or higher, about 99.6% or higher, about 99.7% or higher, about 99.8% or higher, or about 99.9% or higher.

[0174] In some aspects, the present disclosure provides a compound of formula (VI) or a salt thereof. In some embodiments, the compound is compound 6 or a salt thereof.

[0175] In some aspects, the present disclosure provides a compound of formula (VI-a) or a salt thereof. In some embodiments, the compound is compound 6a or a salt thereof.

[0176] In some embodiments, the compound is compound 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.

[0177] In some embodiments, the compound is compound 6a or a salt thereof having a purity of about 90% or higher, about 95% or higher, about 96% or higher, about 97% or higher, about 98% or higher, about 99% or higher, about 99.5% or higher, about 99.6% or higher, about 99.7% or higher, about 99.8% or higher, or about 99.9% or higher.

[0178] In some aspects, the present disclosure provides a compound of formula (VI-b) or a salt thereof. In some embodiments, the compound is compound 6b or a salt thereof.

[0179] In some embodiments, the compound is compound 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.

[0180] In some embodiments, the compound is compound 6b or a salt thereof having a purity of about 90% or higher, about 95% or higher, about 96% or higher, about 97% or higher, about 98% or higher, about 99% or higher, about 99.5% or higher, about 99.6% or higher, about 99.7% or higher, about 99.8% or higher, or about 99.9% or higher.

[0181] In some aspects, the present disclosure provides a compound of formula (IX) or a salt thereof. In some embodiments, the compound is compound 9 or a salt thereof.

[0182] In some aspects, the present disclosure provides a compound of formula (IX-a) or a salt thereof. In some embodiments, the compound is compound 9a or a salt thereof.

[0183] In some embodiments, the compound is compound 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.

[0184] In some embodiments, the compound is compound 9a or a salt thereof with a purity of about 90% or higher, about 95% or higher, about 96% or higher, about 97% or higher, about 98% or higher, about 99% or higher, about 99.5% or higher, about 99.6% or higher, about 99.7% or higher, about 99.8% or higher, or about 99.9% or higher.

[0185] In some aspects, the present disclosure provides a compound of formula (IX-b) or a salt thereof. In some embodiments, the compound is compound 9b or a salt thereof.

[0186] In some embodiments, the compound is compound 9b or a salt thereof with 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.

[0187] In some embodiments, the compound is compound 9b or a salt thereof with a purity of about 90% or higher, about 95% or higher, about 96% or higher, about 97% or higher, about 98% or higher, about 99% or higher, about 99.5% or higher, about 99.6% or higher, about 99.7% or higher, about 99.8% or higher, or about 99.9% or higher.

[0188] Biological assay

[0189] 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 those described below, to determine whether they have predicted activity, binding activity, and / or binding specificity.

[0190] In addition, high-throughput screening can be used to accelerate the analysis using such assays. Thus, the activity of the molecules described herein can be rapidly screened using techniques known in the art. General methods for performing high-throughput screening have been described, for example, in Devlin (1998) High Throughput Screening, Marcel Dekker and U.S. Patent No. 5,763,263. High-throughput assays can use one or more different assay techniques, including but not limited to the assay techniques described below.

[0191] A variety of in vitro or in vivo biological assays may be suitable for detecting the effects of the compounds of the present disclosure. These in vitro or in vivo biological assays can include but are not limited to enzyme activity assays, electrophoretic mobility shift assays, reporter gene assays, in vitro cell viability assays, and the assays described herein.

[0192] In some embodiments, the bioassay is a bioassay for testing the inhibitory activity against IL-1β release after NLRP3 activation in peripheral blood mononuclear cells (PBMCs).

[0193] In some embodiments, the bioassay is an assay for determining the PBMC IC50.

[0194] In some embodiments, the inhibitory activity of the test compound against IL-1β release after NLRP3 activation in blood cells (such as peripheral blood mononuclear cells (PBMCs)) is tested.

[0195] In some embodiments, PBMCs are isolated and seeded into the wells of a plate and cultured for a period of time (e.g., cultured with lipopolysaccharide for 3 hours). After culturing, the medium is replaced and the compound (e.g., a compound of the present disclosure) is added to the wells, and the cells can be cultured. Next, the cells are stimulated (e.g., with ATP or nigericin) and the cell culture medium is collected for analysis.

[0196] In some embodiments, the release of IL-1β into the culture medium is determined by quantitatively detecting IL-1β in the medium (e.g., using ELISA).

[0197] In some embodiments, PBMCs are isolated (e.g., from the buffy coat). The isolated cells are seeded into the wells and cultured (e.g., cultured with lipopolysaccharide for 3 hours). Then the compound is added and the cells are cultured. Next, the cells are stimulated and the culture medium from the wells is collected for analysis.

[0198] In some embodiments, the release of IL-1β into the culture medium is determined by quantitative detection (e.g., using quantitative detection of IL-1β in the culture medium).

[0199] Pharmaceutical composition

[0200] In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound of formula (IX) as described herein (e.g., compound 9a or 9b) or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

[0201] The pharmaceutical composition containing the active compound of the present disclosure can be manufactured in a generally known manner, for example, by conventional mixing, dissolving, granulating, sugar-coating, grinding, emulsifying, encapsulating, entrapping, or lyophilization processes. The pharmaceutical composition can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers, including one or more excipients and / or adjuvants, which facilitate the processing of the active compound into a pharmaceutically acceptable formulation. Those skilled in the art will understand that the appropriate formulation may depend on the selected route of administration.

[0202] Pharmaceutical compositions suitable for injection include sterile aqueous solutions (when soluble in water) 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, N.J.), or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy injectability is achieved. It must be stable under the conditions of production and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or a dispersion medium containing, for example, water, ethanol, polyols (such as glycerol, propylene glycol, and liquid polyethylene glycol, etc.) and suitable mixtures thereof. For example, the proper fluidity can be maintained by using a coating such as lecithin, by maintaining the required particle size in the case of a dispersion, and by using surfactants. The action of microorganisms can be prevented by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, etc. In many cases, it is preferred to include isotonic agents in the composition, such as sugars, polyols (such as mannitol and sorbitol), and sodium chloride. Prolonged absorption of the injectable composition can be achieved by including agents that delay absorption (such as aluminum monostearate and gelatin) in the composition.

[0203] Sterile injectable solutions can be prepared by incorporating the required amount of the active compound in one or more of the ingredients enumerated above (as required) into a suitable solvent, followed by filter sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile carrier containing a basic dispersion medium and the required other ingredients enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the methods of preparation are vacuum drying and freeze drying to obtain a powder of the active ingredient plus any other required ingredients from a previously sterile filtered solution.

[0204] Oral compositions can include one or more inert diluents or one or more edible pharmaceutically acceptable carriers. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compounds can be mixed with excipients and used in the form of tablets, lozenges, or capsules. A fluid carrier can also be used to prepare oral compositions for use as mouthwashes, wherein the compounds in the fluid carrier are orally administered and then gargled and spat out or swallowed. Pharmaceutically compatible binding agents and / or adjuvant materials can be included as part of the composition. Tablets, pills, capsules, lozenges, etc. can contain any of the following ingredients or compounds of similar nature: binding agents such as microcrystalline cellulose, acacia, or gelatin; excipients such as starch or lactose; disintegrating agents such as alginic acid, Primogel, or corn starch; lubricants such as magnesium stearate or Sterotes; glidants such as colloidal silicon dioxide; sweetening agents such as sucrose or saccharin; or flavoring agents such as peppermint, methyl salicylate, or orange flavoring.

[0205] For administration by inhalation, the compounds are delivered in the form of an aerosol spray from a pressurized container or dispenser which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.

[0206] Systemic administration can also be effected by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the permeation barrier are used in the formulation. Such penetrants are well known in the art and include, for example, detergents, bile salts, and fusidic acid derivatives for transmucosal administration. Transmucosal administration can be effected using nasal sprays or suppositories. For transdermal administration, the active compounds are formulated into ointments, pastes, gels, or creams well known in the art.

[0207] The active compounds can be prepared with one or more pharmaceutically acceptable carriers which can protect the compound from rapid elimination from the body, such as controlled release formulations including implants and microencapsulation delivery systems. Biodegradable, biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid can be used. Methods for preparing such formulations will be apparent to those skilled in the art.

[0208] For ease of administration and uniformity of dosage, it may be particularly advantageous to formulate oral or parenteral compositions in dosage unit form. The dosage unit form used herein refers to physically discrete units suitable as unit doses for the subject to be treated; each unit contains a predetermined quantity of the active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the present disclosure is dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved.

[0209] In therapeutic applications, the dosage of the pharmaceutical compositions used in accordance with the present disclosure will vary depending on the agent, the age, weight, and clinical condition of the patient receiving the agent, and the experience and judgment of the treating clinician or practitioner, as well as other factors that influence the selected dosage. In general, the dosage should be sufficient to cause a reduction in, preferably a regression of, the symptoms of the disease, and preferably also to cause complete regression of the disease.

[0210] It will be understood that the pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

[0211] How to use

[0212] In some aspects, the present disclosure provides methods of preventing or treating a disease in a subject, comprising administering to the subject a compound of Formula (IX) as described herein (e.g., compound 9a or 9b) or a pharmaceutically acceptable salt thereof (e.g., in a therapeutically effective amount).

[0213] In some aspects, the present disclosure provides methods of treating a disease in a subject, comprising administering to the subject a compound of Formula (IX) as described herein (eg, compound 9a or 9b) or a pharmaceutically acceptable salt thereof (eg, in a therapeutically effective amount).

[0214] In some aspects, the present disclosure provides a compound of Formula (IX) as described herein (eg, Compound 9a or 9b), or a pharmaceutically acceptable salt thereof, for use in preventing or treating a disease in a subject.

[0215] In some aspects, the present disclosure provides a compound of Formula (IX) as described herein (eg, Compound 9a or 9b), or a pharmaceutically acceptable salt thereof, for use in treating a disease in a subject.

[0216] In some aspects, the present disclosure provides use of a compound of Formula (IX) as described herein (eg, compound 9a or 9b) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for preventing or treating a disease in a subject.

[0217] In some aspects, the present disclosure provides use of a compound of Formula (IX) as described herein (eg, compound 9a or 9b), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease in a subject.

[0218] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is administered in a therapeutically effective amount.

[0219] In some embodiments, the disease or disorder is associated with inflammasome activity. In some embodiments, the disease or disorder is a disease or disorder associated with inflammasome activity.

[0220] In some embodiments, the disease or disorder is an inflammatory disorder, an autoinflammatory disorder, an autoimmune disorder, a neurodegenerative disease, or cancer.

[0221] In some embodiments, the disease or disorder is an inflammatory disorder, an autoinflammatory disorder, and / or an autoimmune disorder.

[0222] In some embodiments, the disease or disorder is selected from cryopyrin-associated periodic 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, skin diseases (e.g., acne), and neuroinflammation occurring in protein misfolding diseases (e.g., prion diseases).

[0223] In some embodiments, the disease or disorder is a neurodegenerative disease.

[0224] In some embodiments, the disease or disorder is Parkinson's disease or Alzheimer's disease.

[0225] In some embodiments, the disease or disorder is a skin disease.

[0226] In some embodiments, the skin disease is acne.

[0227] In some embodiments, the disease or disorder is cancer.

[0228] In some embodiments, the cancer is metastatic cancer, gastrointestinal cancer, skin cancer, non-small cell lung cancer, brain cancer (e.g., glioblastoma), or colorectal adenocarcinoma.

[0229] In some aspects, the present disclosure provides methods (e.g., in vitro or in vivo) for inhibiting the activity of an inflammasome (e.g., NLRP3 inflammasome) in a subject, including contacting a cell with a compound of formula (IX) described herein (e.g., compound 9a or 9b) or a pharmaceutically acceptable salt thereof (e.g., in an effective amount).

[0230] In some aspects, the present disclosure provides a compound of formula (IX) described herein (e.g., compound 9a or 9b) or a pharmaceutically acceptable salt thereof for inhibiting the activity of an inflammasome (e.g., NLRP3 inflammasome) in a subject (e.g., in vitro or in vivo).

[0231] In some aspects, the present disclosure provides the use of a compound of formula (IX) as described herein (e.g., compound 9a or 9b) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for inhibiting the activity of an inflammasome (e.g., the NLRP3 inflammasome) (e.g., in vitro or in vivo).

[0232] In some embodiments, the inflammasome is the NLRP3 inflammasome.

[0233] In some embodiments, the subject is an animal.

[0234] In some embodiments, the subject is a mammal.

[0235] In some embodiments, the subject is a human.

[0236] In some embodiments, the subject is a cell.

[0237] In some embodiments, the subject is a cell population.

[0238] Definitions

[0239] Unless otherwise indicated, the following terms used in the specification and claims have the following meanings.

[0240] As used herein, the term "about" means approximately, within the range of, roughly, or generally. When the term "about" is used in conjunction with a numerical range, it modifies that range by extending the boundaries above or below the stated numerical values. Generally, the term "about" is used herein to modify a numerical value that varies from the stated value by up to 20%, 10%, 5%, 3%, or 1% higher or lower.

[0241] As used herein, the term "CO generator" refers to a reagent that can serve as a source of CO during a reaction. In some embodiments, the reagent is capable of forming an isocyanate or an equivalent when reacting with an amine.

[0242] 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-chain saturated aliphatic hydrocarbon groups. For example, C1-C6 alkyl is intended to include C1, C2, C3, C4, C5 and C6 alkyl. Examples of alkyl include moieties having one to six carbon atoms, such as but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl or n-hexyl. In some embodiments, the straight-chain or branched-chain alkyl has six or fewer carbon atoms (e.g., straight-chain is C1-C6 and branched-chain is C3-C6). In some embodiments, the straight-chain or branched-chain alkyl has four or fewer carbon atoms.

[0243] It should be understood that the compounds described herein include the compounds themselves, as well as their salts and their solvates (if applicable). For example, salts can be formed between anions and positively charged groups (such as amino groups) on substituted benzene compounds. Suitable anions can include chloride ion, bromide ion, iodide ion, sulfate ion, hydrogen sulfate ion, aminosulfate ion, nitrate ion, phosphate ion, citrate ion, methanesulfonate ion, trifluoroacetate ion, glutamate ion, glucuronate ion, glutarate ion, malate ion, maleate ion, succinate ion, fumarate ion, tartrate ion, toluenesulfonate ion, salicylate ion, lactate ion, naphthalenesulfonate ion and acetate ion (such as trifluoroacetate ion).

[0244] As used herein, the expressions "one or more of A, B or C", "one or more of A, B and C", "one or more A, B or C", "one or more A, B and C", "selected from the group consisting of A, B and C", "selected from A, B and C", etc. are used interchangeably and all refer to being selected from the group consisting of A, B and / or C, i.e., one or more of A, one or more of B, one or more of C or any combination thereof, unless otherwise specified.

[0245] It should be understood that throughout the specification, when a composition is described as having, including or containing a particular component, it is contemplated that the composition also consists essentially of or consists of the said component. Similarly, when a method or process is described as having, including or containing a particular process step, the process also consists essentially of or consists of the said process step. In addition, it should be understood that as long as the present invention remains viable, the order of steps or the order of performing certain actions is not important. In addition, two or more steps or actions can be carried out simultaneously.

[0246] It should be understood that the synthetic methods of the present disclosure can tolerate a wide variety of functional groups, and thus various substituted starting materials can be used. The methods generally provide the desired final compound at or near the end of the overall process, although in some cases the compound may need to be further converted to its pharmaceutically acceptable salt.

[0247] It should be understood that the compounds of formula (IX) (such as compound 9a or 9b) or their pharmaceutically acceptable salts can be prepared in a variety of ways using commercially available starting materials, compounds known in the literature, or readily prepared intermediates, by employing standard synthetic methods and procedures known to those skilled in the art or obvious to those skilled in the art in accordance with the teachings herein. Standard synthetic methods and procedures for the preparation of organic molecules and the transformation and manipulation of functional groups can be obtained from relevant scientific literature or standard textbooks in the field. Although not limited to any one or more sources, classic texts such as Smith, M.B., March, J., March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th Edition, John Wiley & Sons: New York, 2001; Greene, T.W., Wuts, P.G.M., Protective Groups in Organic Synthesis, 3rd Edition, 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, editor, Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), which are hereby incorporated by reference, are useful and recognized reference textbooks for organic synthesis known to those skilled in the art.

[0248] Those of ordinary skill in the art will note that, in the reaction sequences and synthetic schemes described herein, the order of certain steps may be changed, such as the introduction and removal of protecting groups. Those of ordinary skill in the art will recognize that certain groups may need to be protected from the reaction conditions by using protecting groups. Protecting groups can also be used to distinguish similar functional groups in a molecule. A list of protecting groups and how to introduce and remove these groups can be found in Greene, T.W., Wuts, P.G.M., Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons: New York, 1999.

[0249] It should be understood that, unless otherwise indicated, any description of a method of treatment or prevention includes the use of a compound of formula (IX) (e.g., compound 9a or 9b) or a pharmaceutically acceptable salt thereof to provide a treatment or prevention as described herein. It should also be understood that, unless otherwise indicated, any description of a method of treatment or prevention includes the use of a compound of formula (IX) (e.g., compound 9a or 9b) or a pharmaceutically acceptable salt thereof to prepare a medicament for treating or preventing such a disorder. Treatment or prevention includes treatment or prevention in humans or non-human animals (including rodents and other disease models).

[0250] It should be understood that, unless otherwise indicated, any description of a method of treatment includes the use of a compound of formula (IX) (e.g., compound 9a or 9b) or a pharmaceutically acceptable salt thereof to provide a treatment as described herein. It should also be understood that, unless otherwise indicated, any description of a method of treatment includes the use of a compound of formula (IX) (e.g., compound 9a or 9b) or a pharmaceutically acceptable salt thereof to prepare a medicament for treating such a disorder. Treatment includes treatment in humans or non-human animals (including rodents and other disease models).

[0251] As used herein, the term "subject" includes humans 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 fowl. In some embodiments, the subject is a human.

[0252] As used herein, the term "subject in need" refers to a subject having a disease or having an increased risk of developing the disease. A subject in need can be a subject previously diagnosed or identified as having a disease or disorder disclosed herein. A subject in need can also be a subject suffering from a disease or disorder disclosed herein. Alternatively, a subject in need can be a subject having an increased risk of developing such a disease or disorder relative to the general population (i.e., a subject predisposed to developing such a disorder relative to the general population). A subject in need may have a refractory or drug-resistant disease or disorder disclosed herein (i.e., a disease or disorder that does not respond or has not responded to treatment as disclosed herein). The subject may be drug-resistant at the start of treatment or may become drug-resistant during treatment. In some embodiments, a subject in need has received all known effective therapies for the disease or disorder disclosed herein and has failed. In some embodiments, a subject in need has received at least one prior treatment.

[0253] As used herein, the term "treating" or "treat" describes the management and care of a patient for the purpose of combating a disease, condition, or disorder, including administering a compound or a pharmaceutically acceptable salt, polymorph, or solvate thereof disclosed herein, for alleviating symptoms or complications of the disease, condition, or disorder, or eradicating the disease, condition, or disorder. The term "treatment" can also include treatment of in vitro cell or animal models.

[0254] It should be understood that the compound of formula (IX) (e.g., compound 9a or 9b) or a pharmaceutically acceptable salt thereof can or may also be used for preventing a related disease, condition, or disorder, or for identifying suitable candidates for such purposes.

[0255] As used herein, the terms "preventing", "prevent", or "prevention" describe reducing or eliminating the occurrence of symptoms or complications of such a disease, condition, or disorder.

[0256] It should be understood that those skilled in the art can refer to general reference texts to obtain a detailed description of the known or equivalent technologies discussed herein. 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 (3rd ed.), Cold Spring Harbor Press, Cold Spring Harbor, New York (2000); Coligan et al., Current Protocols in Immunology, John Wiley & Sons, N.Y.; Enna et al., Current Protocols in Pharmacology, John Wiley & Sons, N.Y.; Fingl et al., The Pharmacological Basis of Therapeutics (1975), Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 18th ed. (1990). Of course, these texts can also be referred to when preparing or using aspects of the present disclosure.

[0257] As used herein, the term "pharmaceutical composition" is a formulation containing a compound of formula (IX) (e.g., compound 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 form or unit dose form. The unit dose form can be any of a variety of forms, including, for example, capsules, IV bags, tablets, single pumps on aerosol inhalers, or vials. The amount of the active ingredient (e.g., a formulation of the disclosed compound or its salt, hydrate, solvate, or isomer) in the unit dose composition is an effective amount and varies depending on the specific treatment involved. Those skilled in the art will understand that conventional variations in the dosage are sometimes required depending on the age and condition of the patient. The dosage also depends on the route of administration. A variety of routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhaled, oral, sublingual, intrapleural, intrathecal, intranasal, etc. Dosage forms for topical or transdermal administration of the disclosed compounds include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. In one embodiment, the active compound is mixed under sterile conditions with one or more pharmaceutically acceptable carriers and any desired preservatives, buffers, or propellants.

[0258] As used herein, the term "pharmaceutically acceptable" refers to those compounds, anions, cations, materials, compositions, carriers, and / or dosage forms that, within the scope of reasonable medical judgment, are suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problems or complications, and are commensurate with a reasonable benefit / risk ratio.

[0259] As used herein, the term "pharmaceutically acceptable excipient" refers to excipients that are used in the preparation of pharmaceutical compositions, are generally safe, non-toxic, and not biologically or otherwise undesirable, and include excipients acceptable for veterinary and human pharmaceutical use. "Pharmaceutically acceptable excipient" as used in the specification and claims can include one and more than one such excipient.

[0260] 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 administration, such as intravenous, intradermal, subcutaneous, oral (e.g., ingestion), inhalation, transdermal (topical), and transmucosal administration. Solutions or suspensions for parenteral, intradermal, or subcutaneous application may include the following components: a sterile diluent, such as water for injection, saline solution, fixed oils, polyethylene glycols, 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 tonicity, such as sodium chloride or dextrose. The pH value may be adjusted using an acid or a base (e.g., hydrochloric acid or sodium hydroxide). Parenteral preparations may be enclosed in ampoules, disposable syringes, or multi-dose vials made of glass or plastic.

[0261] It should be understood that the compounds or pharmaceutical compositions of the present disclosure can be administered to a subject by many well-known methods currently used for chemotherapy treatment. For example, the compounds of the present disclosure can be injected into the bloodstream or body cavity, orally administered, or applied through the skin using a patch. The selected dose should be sufficient to constitute an effective treatment but not so high as to cause unacceptable side effects. The condition of the disease state (e.g., the diseases or disorders disclosed herein) and the health of the patient should preferably be closely monitored during and for a reasonable period of time after treatment.

[0262] As used herein, the term "therapeutically effective amount" refers to the amount of an agent that treats, ameliorates, or prevents a determined disease or disorder, or exhibits a detectable therapeutic or inhibitory effect. The effect can be detected by any assay known in the art. The precise effective amount for a subject will depend on the subject's weight, size, and health; the nature and extent of the disorder; and the treatment or combination of treatments selected for administration. The therapeutically effective amount for a given situation can be determined by routine experimentation within the skill and judgment of the clinician.

[0263] As used herein, the term "effective amount" refers to the amount of an agent that treats or ameliorates a determined disease or disorder, or exhibits a detectable therapeutic or inhibitory effect. The effect can be detected by any assay known in the art. The precise effective amount for a subject will depend on the subject's weight, size, and health; the nature and extent of the disorder; and the treatment or combination of treatments selected for administration. The therapeutically effective amount for a given situation can be determined by routine experimentation within the skill and judgment of the clinician.

[0264] It should be understood that for any compound, its therapeutically effective amount or effective amount can first be estimated in cell culture assays (such as of tumor cells) or in animal models (usually rats, mice, rabbits, dogs, or pigs). Animal models can also be used to determine appropriate concentration ranges and routes of administration. This information can then be used to determine useful dosages and routes of administration in humans. Therapeutic / preventive efficacy and toxicity can be determined by standard pharmaceutical procedures in cell culture or experimental animals, such as ED 50 (the dose effective in treating 50% of the population) and LD 50 (the dose lethal to 50% of the population). The dose ratio between the toxic and therapeutic effects is the therapeutic index, which can be expressed as the LD 50 / ED 50 ratio. Pharmaceutical compositions that exhibit a large therapeutic index are preferred. The dosage may vary within this range depending on the dosage form employed, the sensitivity of the patient, and the route of administration.

[0265] Adjust the dosage and administration to provide an adequate level of the active agent or to maintain the desired effect. Factors that can be considered include the severity of the disease state, the overall health of the subject, the subject's age, weight, and gender, diet, time and frequency of administration, drug combination, response sensitivity, and tolerance / reactivity to the treatment.

[0266] A pharmaceutical composition containing a compound of formula (IX) (such as compound 9a or 9b) or a pharmaceutically acceptable salt thereof can be manufactured in a generally known manner, for example, by conventional mixing, dissolving, granulating, sugar coating, grinding, emulsifying, encapsulating, entrapping or lyophilization methods. The pharmaceutical composition can be formulated in a conventional manner, using one or more pharmaceutically acceptable carriers, including excipients and / or auxiliaries that facilitate the processing of the compound of formula (IX) (such as, compound 9a or 9b) or a pharmaceutically acceptable salt thereof into a medicinally administrable preparation. The appropriate formulation depends on the chosen route of administration.

[0267] The compound of formula (IX) (such as compound 9a or 9b) or a pharmaceutically acceptable salt thereof can be prepared with one or more pharmaceutically acceptable carriers that will protect the compound from rapid elimination from the body, such as controlled release formulations, including implants and microencapsulation delivery systems.

[0268] It should be understood that the pharmaceutical composition can be included in a container, package or dispenser together with instructions for administration.

[0269] It should be understood that for the compounds of the present disclosure that are capable of further forming salts, all such forms are also covered within the scope of the claimed disclosure.

[0270] As used herein, the term "pharmaceutically acceptable salt" refers to derivatives of the compounds of the present disclosure in which the parent compound is modified by preparing its acid or base salts. Examples of pharmaceutically acceptable salts can include, but are not limited to, mineral or organic salts of basic residues such as amines, alkali metal salts or organic salts of acidic residues such as carboxylic acids, etc. Pharmaceutically acceptable salts can include, for example, conventional non-toxic salts or quaternary ammonium salts of the parent compound formed from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts can include, but are not limited to, those salts derived from inorganic acids and organic acids selected from the following: 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonic acid, carbonic acid, citric acid, ethylenediaminetetraacetic acid, ethanedisulfonic acid, 1,2-ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, glycollanilidearsonic acid, hexylresorcinol, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxymaleic acid, hydroxynaphthoic acid, hydroxyethanesulfonic acid, lactic acid, lactobionic acid, laurylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, napsylic, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, subacetic, succinic acid, sulfamic acid, p-aminobenzenesulfonic acid, sulfuric acid, tannic acid, tartaric acid, toluenesulfonic acid, and common amino acids, such as glycine, alanine, phenylalanine, arginine, etc.

[0271] In some embodiments, the pharmaceutically acceptable salts are sodium salts, potassium salts, calcium salts, magnesium salts, diethylamine salts, choline salts, meglumine salts, benzathine salts, tromethamine salts, ammonium salts, arginine salts or lysine salts. In some embodiments, the pharmaceutically acceptable salt is a sodium salt.

[0272] Other examples of pharmaceutically acceptable salts can include caproic 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, etc. The present disclosure also encompasses salts formed when the acidic protons present in the parent compound are replaced by metal ions (such as alkali metal ions, alkaline earth ions or aluminum ions); or salts formed when coordinated with organic bases (such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, etc.). In salt form, it should be understood that the ratio of the compound to the cation or anion of the salt can be 1:1, or can be any ratio other than 1:1, such as 3:1, 2:1, 1:2 or 1:3.

[0273] It should be understood that all references to pharmaceutically acceptable salts can include solvate addition forms (solvates) or crystal forms (polymorphs) of the same salt as defined herein.

[0274] Techniques for formulating and administering the compounds disclosed in the present disclosure can be found in Remington: the Science and Practice of Pharmacy, 19th Edition, Mack Publishing Co., Easton, PA (1995). In some embodiments, the compound of formula (IX) (such as compound 9a or 9b) or its pharmaceutically acceptable salt is combined with one or more pharmaceutically acceptable carriers or diluents for use in pharmaceutical formulations. Suitable pharmaceutically acceptable carriers include, but are not limited to, inert solid fillers or diluents and sterile aqueous or organic solutions. The amount of the compound present in such pharmaceutical compositions is sufficient to provide the desired dose within the range described herein.

[0275] Unless otherwise indicated, all percentages and ratios used herein are by weight. Other features and advantages of the present disclosure will be apparent from the different examples. The examples provided illustrate different components and methods useful in practicing the present disclosure. These examples do not limit the claimed disclosure. Based on the present disclosure, those skilled in the art can identify and employ other components and methods that can be used to practice the present disclosure.

[0276] In the synthetic schemes described herein, for simplicity, compounds may be drawn in a specific configuration. Such a specific configuration should not be construed as limiting the disclosure to one or another isomer, tautomer, regioisomer, or stereoisomer, nor does it exclude mixtures of isomers, tautomers, regioisomers, or stereoisomers; however, it should be understood that a given isomer, tautomer, regioisomer, or stereoisomer may have a higher level of activity than another isomer, tautomer, regioisomer, or stereoisomer.

[0277] All publications and patent documents cited herein are incorporated herein by reference as if each such publication or document was specifically and individually indicated to be incorporated by reference. Citing publications and patent documents does not imply any admission as to what is relevant prior art, nor does it constitute any admission as to the content or date thereof. The invention has now been described by way of written description, and those skilled in the art will recognize that the invention can be practiced in a variety of embodiments, and the foregoing description and the following examples are for purposes of illustration and not for limitation of the claims that follow.

[0278] The present disclosure has been described, and the following examples are provided by way of illustration and not limitation.

[0279] Exemplary Embodiment

[0280] Exemplary Embodiment 1. A method for preparing a compound of formula (IX) (such as compound 9a or 9b) or a salt thereof, comprising one or more of steps (i)-(vii):

[0281] (i) contacting compound 1 or a salt thereof with a hydrogenating agent to form compound 2 or a salt thereof;

[0282] (ii) contacting compound 3 with an esterifying agent to form a compound of formula (IV);

[0283] (iii) contacting compound 2 or a salt thereof with a compound of formula (IV) to form a compound of formula (V) or a salt thereof;

[0284] (iv) contacting a compound of formula (V) or a salt thereof with a reducing agent to form a compound of formula (VI) or a salt thereof;

[0285] (v) contacting compound 7 or a salt thereof with a CO generating agent to form compound 8 or a salt thereof;

[0286] (vi) contacting a compound of formula (VI) or a salt thereof with compound 8 or a salt thereof to form a compound of formula (IX) (such as compound 9a or 9b) or a salt thereof; or

[0287] (vii) purifying the compound of formula (IX) or a salt thereof.

[0288] Exemplary Embodiment 2. A method for preparing a compound of formula (V) or a salt thereof, comprising:

[0289] (iii) contacting Compound 2 or a salt thereof with a compound of formula (IV) to form a compound of formula (V) or a salt thereof.

[0290] Exemplary Embodiment 3. A method for preparing a compound of formula (VI) or a salt thereof, comprising:

[0291] (iv) contacting a compound of formula (V) or a salt thereof with a reducing agent to form a compound of formula (VI) or a salt thereof.

[0292] Exemplary Embodiment 4. The method according to any one of the foregoing exemplary embodiments, wherein the compound of formula (IV) is Compound 4.

[0293] Exemplary Embodiment 5. The method according to any one of the foregoing exemplary embodiments, wherein the compound of formula (V) or a salt thereof is Compound 5 or a salt thereof.

[0294] Exemplary Embodiment 6. The method according to any one of the foregoing exemplary embodiments, wherein the compound of formula (VI) or a salt thereof is Compound 6 or a salt thereof.

[0295] Exemplary Embodiment 7. The method according to any one of the foregoing exemplary embodiments, wherein the compound of formula (VI) or a salt thereof is a compound of formula (VI-a) or a salt thereof;

[0296] Optionally, wherein the compound of formula (VI) or a salt thereof is Compound 6a or a salt thereof.

[0297] Exemplary Embodiment 8. The method according to any one of the foregoing exemplary embodiments, wherein the compound of formula (VI) or a salt thereof is a compound of formula (VI-b) or a salt thereof;

[0298] Optionally, wherein the compound of formula (VI) or a salt thereof is Compound 6b or a salt thereof.

[0299] Exemplary Embodiment 9. The method according to any one of the foregoing exemplary embodiments, wherein the compound of formula (IX) or a salt thereof is Compound 9.

[0300] Exemplary Embodiment 10. The method according to any one of the foregoing exemplary embodiments, wherein the compound of formula (IX) or a salt thereof is a compound of formula (IX-a) or a salt thereof;

[0301] Optionally, wherein the compound of formula (IX) or a salt thereof is Compound 9a or a salt thereof.

[0302] Exemplary Embodiment 11. The method according to any one of the foregoing exemplary embodiments, wherein the compound of formula (IX) or a salt thereof is a compound of formula (IX-b) or a salt thereof;

[0303] Optionally, the compound of formula (IX) or a salt thereof is compound 9b or a salt thereof.

[0304] Exemplary embodiment 12. The method of any one of the foregoing exemplary embodiments, wherein in step (i), the hydrogenating agent is hydrogen.

[0305] Exemplary embodiment 13. The method of any one of the foregoing exemplary embodiments, wherein in step (i), the contacting is carried out in the presence of a hydrogenation catalyst;

[0306] Optionally, the hydrogenation catalyst is Raney nickel.

[0307] Exemplary embodiment 14. The method of any one of the foregoing exemplary embodiments, wherein in step (i), the contacting is carried out in the presence of a base;

[0308] Optionally, the base is potassium carbonate (K2CO3).

[0309] Exemplary embodiment 15. The method of any one of the foregoing exemplary embodiments, wherein compound 2 or a salt thereof is separated and / or purified before contacting with the compound of formula (IV).

[0310] Exemplary embodiment 16. The method of any one of the foregoing exemplary embodiments, wherein compound 2 or a salt thereof is not separated or purified before contacting with the compound of formula (IV).

[0311] Exemplary embodiment 17. The method of any one of the foregoing exemplary embodiments, wherein in step (ii), the esterifying agent is an alcohol;

[0312] Optionally, the esterifying agent is isopropyl alcohol (iPrOH; propan-2-ol).

[0313] Exemplary embodiment 18. The method of any one of the foregoing exemplary embodiments, wherein in step (ii), the contacting is carried out in the presence of an esterification catalyst;

[0314] Optionally, the esterification catalyst is 4-dimethylaminopyridine (DMAP).

[0315] Exemplary embodiment 19. The method of any one of the foregoing exemplary embodiments, wherein in step (ii), the contacting is carried out in the presence of a base;

[0316] Optionally, the base is pyridine.

[0317] Exemplary embodiment 20. The method of any one of the foregoing exemplary embodiments, wherein in step (iii), the contacting is carried out in the presence of a salt;

[0318] Optionally, wherein the salt is potassium tert-butoxide (tBuOK).

[0319] Exemplary embodiment 21. The method according to any one of the foregoing exemplary embodiments, wherein in step (iii), the contacting is carried out in the presence of an alcohol;

[0320] Optionally, wherein the alcohol is isopropyl alcohol (iPrOH; propan-2-ol).

[0321] Exemplary embodiment 22. The method according to any one of the foregoing exemplary embodiments, wherein in step (iv), the reducing agent is a monosaccharide;

[0322] Optionally, wherein the reducing agent is glucose; and

[0323] Optionally, wherein the reducing agent is D-glucose.

[0324] Exemplary embodiment 23. The method according to any one of the foregoing exemplary embodiments, wherein in step (iv), the contacting is carried out in the presence of a reduction catalyst;

[0325] Optionally, wherein the reduction catalyst comprises ketoreductase (KRED), glutamate dehydrogenase (GDH) and nicotinamide adenine dinucleotide phosphate (NADP).

[0326] Exemplary embodiment 24. The method according to any one of the foregoing exemplary embodiments, wherein in step (v), the CO generator is triphosgene.

[0327] Exemplary embodiment 25. The method according to any one of the foregoing exemplary embodiments, wherein in step (v), the contacting is carried out in the presence of a base;

[0328] Optionally, wherein the base is triethylamine (TEA).

[0329] Exemplary embodiment 26. The method according to any one of the foregoing exemplary embodiments, wherein in step (vi), the contacting is carried out in the presence of a base;

[0330] Optionally, wherein the base is 4-dimethylaminopyridine (DMAP).

[0331] Exemplary embodiment 27. The method according to any one of the foregoing exemplary embodiments, wherein step (vii) comprises crystallizing the compound of formula (IX) or a salt thereof in the presence of an organic solvent;

[0332] Optionally, wherein the organic solvent comprises isopropyl acetate and n-heptane; and

[0333] Optionally, the proportion of isopropyl acetate and n-heptane present is about 1:1, about 1:2, about 1:3, about 1:4, or about 1:5.

[0334] Exemplary embodiment 28. A compound prepared by the method of any of the foregoing exemplary embodiments.

[0335] Exemplary embodiment 29. A compound of formula (V) or a salt thereof;

[0336] Optionally, the compound is compound 5 or a salt thereof; and

[0337] Optionally, the compound is compound 5 or a salt thereof with a purity of about 90% or higher, about 95% or higher, about 96% or higher, about 97% or higher, about 98% or higher, about 99% or higher, about 99.5% or higher, about 99.6% or higher, about 99.7% or higher, about 99.8% or higher, or about 99.9% or higher.

[0338] Exemplary embodiment 30. A compound of formula (VI) or a salt thereof;

[0339] Optionally, the compound is compound 6 or a salt thereof;

[0340] Optionally, the compound is compound 6a or a salt thereof; and

[0341] Optionally, the compound is compound 6a or a salt thereof having:

[0342] (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

[0343] (b) A purity of about 90% or higher, about 95% or higher, about 96% or higher, about 97% or higher, about 98% or higher, about 99% or higher, about 99.5% or higher, about 99.6% or higher, about 99.7% or higher, about 99.8% or higher, or about 99.9% or higher.

[0344] Exemplary embodiment 31. A compound of formula (IX) or a salt thereof;

[0345] Optionally, the compound is compound 9 or a salt thereof;

[0346] Optionally, the compound is compound 9a or a salt thereof; and

[0347] Optionally, wherein the compound is compound 9a having the following or a salt thereof:

[0348] (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

[0349] (b) a purity of about 90% or higher, about 95% or higher, about 96% or higher, about 97% or higher, about 98% or higher, about 99% or higher, about 99.5% or higher, about 99.6% or higher, about 99.7% or higher, about 99.8% or higher, or about 99.9% or higher.

[0350] Exemplary Embodiment 32. A pharmaceutical composition comprising a compound of formula (IX) or a pharmaceutically acceptable salt thereof according to any one of the foregoing exemplary embodiments, and one or more pharmaceutically acceptable carriers or excipients.

[0351] Exemplary Embodiment 33. A method of 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 foregoing exemplary embodiments.

[0352] Exemplary Embodiment 34. A compound of formula (IX) or a pharmaceutically acceptable salt thereof according to any one of the foregoing exemplary embodiments, for preventing or treating a disease in a subject.

[0353] Exemplary Embodiment 35. Use of a compound of formula (IX) or a pharmaceutically acceptable salt thereof according to any one of the foregoing exemplary embodiments in the manufacture of a medicament for preventing or treating a disease in a subject.

[0354] Exemplary Embodiment 36. A method of inhibiting inflammasome activity in a subject, comprising contacting cells with a compound of formula (IX) or a pharmaceutically acceptable salt thereof according to any one of the foregoing exemplary embodiments.

[0355] Exemplary Embodiment 37. A compound of formula (IX) or a pharmaceutically acceptable salt thereof according to any one of the foregoing exemplary embodiments, for inhibiting inflammasome activity in a subject.

[0356] Exemplary Embodiment 38. Use of a compound of formula (IX) or a pharmaceutically acceptable salt thereof according to any one of the foregoing exemplary embodiments in the manufacture of a medicament for inhibiting inflammasome activity.

[0357] Exemplary Embodiment 39. The method, compound or use of any of the foregoing exemplary embodiments, wherein the subject is a human.

[0358] Examples

[0359] The present disclosure has been described, and the following examples are provided by way of illustration and not limitation.

[0360] It should be understood that all values given in the examples are approximate and are subject to instrument and / or experimental variations.

[0361] Example 1. Exemplary synthesis of compound 9a.

[0362] The exemplary synthesis of compound 9a was carried out according to the following synthetic scheme and procedures.

[0363] Scheme 1

[0364]

[0365] Step 1

[0366] Step 1 was carried out using the equipment described in Table 1A and according to the procedures described in Table 1B.

[0367] Table 1A. Equipment used in Step 1.

[0368]

[0369]

[0370] Table 1B. Exemplary procedures for Step 1.

[0371]

[0372]

[0373] The product of this step was evaluated using the chromatographic conditions shown in Table 1C, and the results are summarized in Table 1D.

[0374] Table 1C. Chromatographic conditions for evaluating the product of Step 1.

[0375]

[0376] Table 1D. Evaluation of the product of Step 1.

[0377]

[0378]

[0379] Step 2

[0380] Step 2 is carried out using the equipment described in Table 2A and following the procedure described in Table 2B.

[0381] Table 2A. Equipment used in Step 2.

[0382]

[0383] Table 2B. Exemplary procedure for Step 2.

[0384]

[0385]

[0386]

[0387] The product of this step is evaluated using the chromatographic conditions shown in Table 2C, and the results are summarized in Table 2D.

[0388] Table 2C. Chromatographic conditions for evaluating the product of Step 2.

[0389]

[0390]

[0391] Table 2D. Evaluation of the product of Step 2.

[0392]

[0393] Step 3

[0394] Step 3 is carried out using the equipment described in Table 3A and following the procedure described in Table 3B.

[0395] Table 3A. Equipment used in Step 3.

[0396]

[0397] Table 3B. Exemplary procedure for Step 3.

[0398]

[0399]

[0400]

[0401]

[0402] The product of this step is evaluated using the chromatographic conditions shown in Table 3C, and the results are summarized in Table 3D.

[0403] Table 3C. Chromatographic conditions for evaluating the product of Step 3.

[0404]

[0405]

[0406] Table 3D. Evaluation of the product of Step 3.

[0407]

[0408] Step 4

[0409] Step 4 is carried out using the equipment described in Table 4A and according to the procedure described in Table 4B.

[0410] Table 4A. Equipment used in Step 4.

[0411]

[0412]

[0413] Table 4B. Exemplary procedure for Step 4.

[0414]

[0415]

[0416]

[0417] The product of this step is evaluated using the chromatographic conditions shown in Table 4C, and the results are summarized in Table 4D.

[0418] Table 4C. Chromatographic conditions for evaluating the product of Step 4.

[0419]

[0420]

[0421] Table 4D. Evaluation of the product of Step 4.

[0422]

[0423] Step 5

[0424] Step 5 is carried out using the equipment described in Table 5A and according to the procedure described in Table 5B. The product of this step is evaluated, and the results are summarized in Table 5C.

[0425] Table 5A. Equipment used in Step 5.

[0426]

[0427] Table 5B. Exemplary procedure for Step 5.

[0428]

[0429]

[0430] Table 5C. Evaluation of the product of Step 5.

[0431]

[0432] Step 6

[0433] Step 6 is carried out using the equipment described in Table 6A and according to the procedure described in Table 6B.

[0434] Table 6A. Equipment used in Step 6.

[0435]

[0436]

[0437] Table 6B. Exemplary procedure for Step 6.

[0438]

[0439]

[0440]

[0441] The product of this step is evaluated using the chromatographic conditions shown in Table 6C, and the results are summarized in Table 6D.

[0442] Table 6C. Chromatographic conditions for evaluating the product of Step 6.

[0443]

[0444]

[0445] Table 6D. Evaluation of the product of Step 6.

[0446]

[0447] Step 7

[0448] Step 7 is carried out using the equipment described in Table 7A and according to the procedure described in Table 7B.

[0449] Table 7A. Equipment used in Step 7.

[0450]

[0451] Table 7B. Exemplary procedure for Step 7.

[0452]

[0453]

[0454] Evaluate the product of this step using the chromatographic conditions shown in Table 7C, and summarize the results in Table 7D.

[0455] Table 7C. Chromatographic conditions for evaluating the product of Step 7.

[0456]

[0457] Table 7D. Evaluation of the product of Step 7.

[0458]

[0459] Equivalents

[0460] Details of one or more embodiments of the present disclosure are set forth in the description above. Preferred methods and materials are now described, however, any methods and materials similar or equivalent to those described herein may be used in the practice or testing of the present disclosure. Other features, objects, and advantages of the present disclosure will be apparent from the specification and claims. In the specification and the appended claims, the singular forms may include plural referents unless the context clearly dictates otherwise. All technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs, unless otherwise defined. All patents and publications cited in this specification are incorporated by reference.

[0461] The foregoing description is presented for illustrative purposes only and is not intended to limit the present disclosure to the precise form disclosed, but is limited by the appended claims.

Claims

1. A method for preparing a compound of formula (IX) (such as compound 9a or 9b) or a salt thereof, comprising one or more of steps (i)-(vii): (i) contacting a compound 1 or a salt thereof with a hydrogenating agent to form a compound 2 or a salt thereof; (ii) contacting a compound 3 with an esterifying agent to form a compound of formula (IV); (iii) contacting a compound 2 or a salt thereof with a compound of formula (IV) to form a compound of formula (V) or a salt thereof; (iv) contacting a compound of formula (V) or a salt thereof with a reducing agent to form a compound of formula (VI) or a salt thereof; (v) contacting a compound 7 or a salt thereof with a CO-generating agent to form a compound 8 or a salt thereof; (vi) contacting a compound of formula (VI) or a salt thereof with a compound 8 or a salt thereof to form a compound of formula (IX) (such as compound 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 a compound 2 or a salt thereof with a compound of formula (IV) to form a compound of formula (V) or a salt thereof.

3. A method for preparing a compound of formula (VI) or a salt thereof, comprising: (iv) contacting a compound of formula (V) or a salt thereof with a reducing agent to form a compound of formula (VI) or a salt thereof.

4. The method according to any one of the preceding claims, wherein the compound of formula (IX) or a salt thereof is (a) compound 9; (b) a compound of formula (IX-a) or a salt thereof; optionally, wherein the compound of formula (IX) or a salt thereof is compound 9a or a salt thereof; or (c) a compound of formula (IX-b) or a salt thereof; optionally, wherein the compound of formula (IX) or a salt thereof is compound 9b or a salt thereof.

5. The method according to any one of the preceding claims, wherein in step (i), the contacting is carried out in the presence of a hydrogenation catalyst; optionally, wherein the hydrogenation catalyst is Raney nickel.

6. The method according to any one of the preceding claims, wherein in step (i), the contacting is carried out in the presence of a base; optionally, wherein the base is potassium carbonate (K2CO3).

7. The method according to any one of the preceding claims, wherein in step (ii), the esterifying agent is an alcohol; optionally, wherein the esterifying agent is isopropyl alcohol (iPrOH; propan-2-ol).

8. The method according to any one of the preceding claims, wherein in step (ii), the contacting is carried out in the presence of an esterification catalyst; optionally, wherein the esterification catalyst is 4-dimethylaminopyridine (DMAP).

9. The method according to any one of the preceding claims, wherein in step (ii), the contacting is carried out in the presence of a base; optionally, wherein the base is pyridine.

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

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

12. The method according to any one of the preceding claims, wherein in step (iv), the reducing agent is a monosaccharide; Optionally, the reducing agent is glucose; and Optionally, the reducing agent is D-glucose.

13. The method according to any one of the preceding claims, wherein in step (iv), the contacting is carried out in the presence of a reduction catalyst; Optionally, the reduction catalyst comprises ketoreductase (KRED), glutamate dehydrogenase (GDH), and nicotinamide adenine dinucleotide phosphate (NADP).

14. The method according to any one of the preceding claims, wherein in step (v), the CO generator is triphosgene, and the contacting is carried out in the presence of a base; Optionally, the base is triethylamine (TEA).

15. The method according to any one of the preceding claims, wherein in step (vi), the contacting is carried out in the presence of a base; Optionally, the base is 4-dimethylaminopyridine (DMAP).

16. The method according to any one of the preceding claims, wherein 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 Optionally, the ratio of isopropyl acetate to n-heptane is about 1:1, about 1:2, about 1:3, about 1:4, or about 1:

5.

17. The compound of formula (IX) or a salt thereof; Optionally, the compound is compound 9 or a salt thereof; Optionally, the compound is compound 9a or a salt thereof; and Optionally, the compound is compound 9a or a salt thereof having: (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 higher, about 95% or higher, about 96% or higher, about 97% or higher, about 98% or higher, about 99% or higher, about 99.5% or higher, about 99.6% or higher, about 99.7% or higher, about 99.8% or higher, or about 99.9% or higher.

18. A pharmaceutical composition comprising the compound of formula (IX) or a pharmaceutically acceptable salt thereof according to any one of the preceding claims, and one or more pharmaceutically acceptable carriers or excipients.

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

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

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