Process for the preparation of urea derivatives

Abstract

This disclosure relates to a method for preparing compound No. 10. This disclosure also relates to compounds prepared by said method, pharmaceutical compositions comprising said compounds, and uses thereof, for example, in the treatment of disorders, such as those involving inflammasome activity. (Compound No. 10)

Description

[0001] Related applications This application claims priority and interest in U.S. Provisional Patent Application No. 63 / 600,169, filed November 17, 2023, the entire contents of which are incorporated herein by reference. Background Technology

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

[0003] In humans, 22 NLR proteins are divided into four NLR subfamilies based on their NW-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. Several NLR family members are involved in inflammasome formation.

[0004] Although inflammasome activation appears to have evolved into a crucial component of host immunity against pathogens, the NLRP3 inflammasome is unique in its ability to activate in response to endogenous aseptic danger signals. Many such aseptic 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 understanding of the role of aseptic danger signals as NLRP3 activators has led to the involvement of IL-1 and IL-18 in a wide range of pathophysiological indications, including metabolic disorders, physiological disorders, inflammatory disorders, hematologic disorders, and immune disorders.

[0005] This disclosure stems from the need to provide a novel method for preparing compounds for the specific regulation of NLRP3-dependent cellular processes. Summary of the Invention

[0006] In some respects, this disclosure provides a method for preparing compounds No. 10a or 10b described herein.

[0007] In some respects, this disclosure provides a method for the efficient preparation of compound No. 10a.

[0008] The chemical name of compound No. 10a is 1-(1,2,3,5,6,7-hexahydro-s-benzodiindene-4-yl)-3-[(1-methyl-1H-pyrazol-4-yl)({[(2S)-tetrahydrofuran-2-yl]methyl})aminosulfonyl]urea sodium salt monohydrate: (Compound No. 10a).

[0009] In some aspects, this disclosure provides a method for preparing compound No. 10a or 10b, comprising one or more of steps (iv)-(vii): (iv) Reacting compound No. 5a or 5b or a salt thereof with an acid to form compound No. 6a or 6b or a salt thereof; (v) Reacting compound No. 7 or its salt with a CO source to form compound No. 8 or its salt; (vi) Reacting compound No. 6a or 6b or a salt thereof with compound No. 8 or a salt thereof to form compound No. 9a or 9b; and (vii) Purify compound No. 9a or 9b to isolate compound No. 10a or 10b.

[0010] In some aspects, this disclosure provides a method for preparing compounds No. 10, 10a, or 10b, comprising steps (i)-(vii): (i) Reacting compound No. 1, 1a or 1b with 4-amino-1-methylpyrazole (compound No. 2) or a salt thereof to form compound No. 3, 3a or 3b or a salt thereof; (ii) Reacting compound No. 3, 3a or 3b or a salt thereof with a reducing agent to form compound No. 4, 4a or 4b or a salt thereof; (iii) Reacting compound No. 4, 4a or 4b or a salt thereof with tert-butyl N-chlorosulfonylcarbamate to form compound No. 5, 5a or 5b or a salt thereof; (iv) Reacting compound No. 5, 5a or 5b or a salt thereof with an acid to form compound No. 6, 6a or 6b or a salt thereof; (v) Reacting compound No. 7 or its salt with a CO source to form compound No. 8 or its salt; (vi) Reacting compound No. 6, 6a, or 6b, or a salt thereof, with compound No. 8, or a salt thereof, to form compound No. 9, 9a, or 9b; and (vii) Purify compound No. 9, 9a or 9b to isolate compound No. 10, 10a or 10b.

[0011] In some aspects, this disclosure provides a method for preparing compound No. 10a or 10b, comprising steps (i)-(vii): (i) Reacting compound No. 1, 1a or 1b with 4-amino-1-methylpyrazole (compound No. 2) or a salt thereof to form compound No. 3, 3a or 3b or a salt thereof; (ii) Reacting compound No. 3, 3a or 3b or a salt thereof with a reducing agent to form compound No. 4, 4a or 4b or a salt thereof; (iii) Reacting compound No. 4, 4a or 4b or a salt thereof with tert-butyl N-chlorosulfonylcarbamate to form compound No. 5a or 5b or a salt thereof; (iv) Reacting compound No. 5a or 5b or a salt thereof with an acid to form compound No. 6a or 6b or a salt thereof; (v) Reacting compound No. 7 or its salt with a CO source to form compound No. 8 or its salt; (vi) Reacting compound No. 6a or 6b or a salt thereof with compound No. 8 or a salt thereof to form compound No. 9a or 9b; and (vii) Purify compound No. 9a or 9b to isolate compound No. 10a or 10b.

[0012] In some aspects, this disclosure provides a method for preparing compound No. 10a or 10b, comprising steps (i)-(vii): (i) Reacting compound No. 1, 1a or 1b with 4-amino-1-methylpyrazole (compound No. 2) or a salt thereof to form compound No. 3, 3a or 3b or a salt thereof; (ii) Reacting compound No. 3, 3a or 3b or a salt thereof with a reducing agent to form compound No. 4, 4a or 4b or a salt thereof (e.g., its HCl salt); (iii) Reacting compound No. 4, 4a or 4b or a salt thereof (e.g., its HCl salt) with tert-butyl N-chlorosulfonylcarbamate to form compound No. 5a or 5b or a salt thereof; (iv) Reacting compound No. 5a or 5b or a salt thereof with an acid to form compound No. 6a or 6b or a salt thereof; (v) Reacting compound No. 7 or its salt with a CO source to form compound No. 8 or its salt; (vi) Reacting compound No. 6a or 6b or a salt thereof with compound No. 8 or a salt thereof to form compound No. 9a or 9b; and (vii) Purify compound No. 9a or 9b to isolate compound No. 10a or 10b.

[0013] In some aspects, this disclosure provides a method for preparing compound No. 10, comprising steps (i)-(vii): (i) Reacting tetrahydrofuran-2-carboxylic acid (e.g., (2S)-tetrahydrofuran-2-carboxylic acid or (2R)-tetrahydrofuran-2-carboxylic acid) with 4-amino-1-methylpyrazole or a salt thereof to form N-(1-methyl-1H-pyrazole-4-yl)tetrahydrofuran-2-carboxamide (e.g., (2S)-N-(1-methyl-1H-pyrazole-4-yl)tetrahydrofuran-2-carboxamide or (2R)-N-(1-methyl-1H-pyrazole-4-yl)tetrahydrofuran-2-carboxamide or a salt thereof); (ii) Reacting N-(1-methyl-1H-pyrazol-4-yl)tetrahydrofuran-2-carboxamide (e.g., (2S)-N-(1-methyl-1H-pyrazol-4-yl)tetrahydrofuran-2-carboxamide or (2R)-N-(1-methyl-1H-pyrazol-4-yl)tetrahydrofuran-2-carboxamide) or a salt thereof with a reducing agent to form 1-methyl-N-{[tetrahydrofuran-2-yl]methyl}-1H-pyrazol-4-amine (e.g., 1-methyl-N-{[(2S)-tetrahydrofuran-2-yl]methyl}-1H-pyrazol-4-amine or 1-methyl-N-{[(2R)-tetrahydrofuran-2-yl]methyl}-1H-pyrazol-4-amine) or a salt thereof; (iii) Reacting 1-methyl-N-{[tetrahydrofuran-2-yl]methyl}-1H-pyrazole-4-amine (e.g., 1-methyl-N-{[(2S)-tetrahydrofuran-2-yl]methyl}-1H-pyrazole-4-amine or 1-methyl-N-{[(2R)-tetrahydrofuran-2-yl]methyl}-1H-pyrazole-4-amine) or a salt thereof with tert-butyl N-chlorosulfonylcarbamate to form compound No. 5 or a salt thereof; (iv) Reacting compound No. 5 or its salt with an acid to form compound No. 6 or its salt; (v) Reacting compound No. 7 or its salt with a CO source to form compound No. 8 or its salt; (vi) Reacting compound No. 6 or its salt with compound No. 8 or its salt to form compound No. 9; and (vii) Purify compound No. 9 to separate compound No. 10.

[0014] In some aspects, this disclosure provides a method for preparing compound No. 10a or 10b, comprising steps (i)-(vii): (i) Reacting tetrahydrofuran-2-carboxylic acid (e.g., (2S)-tetrahydrofuran-2-carboxylic acid or (2R)-tetrahydrofuran-2-carboxylic acid) with 4-amino-1-methylpyrazole or a salt thereof to form N-(1-methyl-1H-pyrazole-4-yl)tetrahydrofuran-2-carboxamide (e.g., (2S)-N-(1-methyl-1H-pyrazole-4-yl)tetrahydrofuran-2-carboxamide or (2R)-N-(1-methyl-1H-pyrazole-4-yl)tetrahydrofuran-2-carboxamide or a salt thereof); (ii) Reacting N-(1-methyl-1H-pyrazol-4-yl)tetrahydrofuran-2-carboxamide (e.g., (2S)-N-(1-methyl-1H-pyrazol-4-yl)tetrahydrofuran-2-carboxamide or (2R)-N-(1-methyl-1H-pyrazol-4-yl)tetrahydrofuran-2-carboxamide) or a salt thereof with a reducing agent to form 1-methyl-N-{[tetrahydrofuran-2-yl]methyl}-1H-pyrazol-4-amine (e.g., 1-methyl-N-{[(2S)-tetrahydrofuran-2-yl]methyl}-1H-pyrazol-4-amine or 1-methyl-N-{[(2R)-tetrahydrofuran-2-yl]methyl}-1H-pyrazol-4-amine) or a salt thereof; (iii) Reacting 1-methyl-N-{[tetrahydrofuran-2-yl]methyl}-1H-pyrazole-4-amine (e.g., 1-methyl-N-{[(2S)-tetrahydrofuran-2-yl]methyl}-1H-pyrazole-4-amine or 1-methyl-N-{[(2R)-tetrahydrofuran-2-yl]methyl}-1H-pyrazole-4-amine) or a salt thereof with tert-butyl N-chlorosulfonylcarbamate to form compound No. 5a or 5b or a salt thereof; (iv) Reacting compound No. 5a or 5b or a salt thereof with an acid to form compound No. 6a or 6b or a salt thereof; (v) Reacting compound No. 7 or its salt with a CO source to form compound No. 8 or its salt; (vi) Reacting compound No. 6a or 6b or a salt thereof with compound No. 8 or a salt thereof to form compound No. 9a or 9b; and (vii) Purify compound No. 9a or 9b to isolate compound No. 10a or 10b.

[0015] In some aspects, this disclosure provides a method for preparing compound No. 10a, comprising one or more of steps (iv)-(vii): (iv) Reacting compound No. 5a or its salt with an acid to form compound No. 6a or its salt; (v) Reacting compound No. 7 or its salt with a CO source to form compound No. 8 or its salt; (vi) Reacting compound No. 6a or a salt thereof with compound No. 8 or a salt thereof to form compound No. 9a; and (vii) Purify compound No. 9a to separate compound No. 10a.

[0016] In some aspects, this disclosure provides a method for preparing compound No. 10a, comprising steps (i)-(vii): (i) Reaction of (2S)-tetrahydrofuran-2-carboxylic acid with 4-amino-1-methylpyrazole or a salt thereof to form (2S)-N-(1-methyl-1H-pyrazole-4-yl)tetrahydrofuran-2-carboxamide or a salt thereof; (ii) Reacting (2S)-N-(1-methyl-1H-pyrazol-4-yl)tetrahydrofuran-2-carboxamide or a salt thereof with a reducing agent to form 1-methyl-N-{[(2S)-tetrahydrofuran-2-yl]methyl}-1H-pyrazol-4-amine or a salt thereof; (iii) Reacting 1-methyl-N-{[(2S)-tetrahydrofuran-2-yl]methyl}-1H-pyrazole-4-amine or a salt thereof with tert-butyl N-chlorosulfonylcarbamate to form compound No. 5a or a salt thereof; (iv) Reacting compound No. 5a or its salt with an acid to form compound No. 6a or its salt; (v) Reacting compound No. 7 or its salt with a CO source to form compound No. 8 or its salt; (vi) Reacting compound No. 6a or a salt thereof with compound No. 8 or a salt thereof to form compound No. 9a; and (vii) Purify compound No. 9a to separate compound No. 10a.

[0017] In some aspects, this disclosure provides a method for preparing compound No. 10b, comprising one or more of steps (iv)-(vii): (iv) Reacting compound No. 5b or a salt thereof with an acid to form compound No. 6b or a salt thereof; (v) Reacting compound No. 7 or its salt with a CO source to form compound No. 8 or its salt; (vi) Reacting compound No. 6b or a salt thereof with compound No. 8 or a salt thereof to form compound No. 9b; and (vii) Purify compound No. 9b to isolate compound No. 10b.

[0018] In some aspects, this disclosure provides a method for preparing compound No. 10b, comprising steps (i)-(vii): (i) Reaction of (2R)-tetrahydrofuran-2-carboxylic acid with 4-amino-1-methylpyrazole or a salt thereof to form (2R)-N-(1-methyl-1H-pyrazole-4-yl)tetrahydrofuran-2-carboxamide or a salt thereof; (ii) Reacting (2R)-N-(1-methyl-1H-pyrazol-4-yl)tetrahydrofuran-2-carboxamide or a salt thereof with a reducing agent to form 1-methyl-N-{[(2R)-tetrahydrofuran-2-yl]methyl}-1H-pyrazol-4-amine or a salt thereof; (iii) Reacting 1-methyl-N-{[(2R)-tetrahydrofuran-2-yl]methyl}-1H-pyrazole-4-amine or a salt thereof with tert-butyl N-chlorosulfonylcarbamate to form compound No. 5b or a salt thereof; (iv) Reacting compound No. 5b or a salt thereof with an acid to form compound No. 6b or a salt thereof; (v) Reacting compound No. 7 or its salt with a CO source to form compound No. 8 or its salt; (vi) Reacting compound No. 6b or a salt thereof with compound No. 8 or a salt thereof to form compound No. 9b; and (vii) Purify compound No. 9b to isolate compound No. 10b.

[0019] In some respects, this disclosure provides a compound prepared by the methods described herein.

[0020] In some aspects, this disclosure provides a pharmaceutical composition comprising compound No. 10a or 10b as described herein and one or more pharmaceutically acceptable carriers or excipients.

[0021] In some aspects, this disclosure provides a method for inhibiting the activity of inflammasomes (e.g., NLRP3 inflammasome) (e.g., in vitro or in vivo), which includes contacting cells with compounds No. 10a or 10b as described herein (e.g., in an effective amount).

[0022] In some aspects, this disclosure provides a method for treating or preventing a disease or disorder disclosed herein in a subject in need, comprising administering to the subject a compound No. 10a or 10b as described herein (e.g., in a therapeutically effective amount).

[0023] In some respects, this disclosure provides compounds No. 10a or 10b, as described herein, for inhibiting the activity of inflammasomes (e.g., NLRP3 inflammasome), e.g., in vitro or in vivo.

[0024] In some respects, this disclosure provides compounds No. 10a or 10b as described herein for the treatment or prevention of the diseases or disorders disclosed herein.

[0025] In some respects, this disclosure provides the use of compounds No. 10a or 10b as described herein in the manufacture of pharmaceutical agents for inhibiting the activity of inflammasomes (e.g., NLRP3 inflammasome), e.g., in vitro or in vivo.

[0026] In some respects, this disclosure provides for the use of compounds No. 10a or 10b as described herein in the manufacture of pharmaceutical preparations for the treatment or prevention of the diseases or disorders disclosed herein.

[0027] 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 pertains. In the specification, the singular form also includes the plural unless the context clearly specifies otherwise. Although similar or equivalent methods and materials to those described herein may be used in practice or testing of this disclosure, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated herein by reference. References cited herein are not necessarily prior art to the claimed invention. In case of conflict, this specification, including definitions, shall prevail. Furthermore, materials, methods, and examples are exemplary only and are not intended to constitute limitation. In case of conflict between the chemical structures and names of compounds disclosed herein, the chemical structure shall prevail.

[0028] Other features and advantages of this disclosure will be apparent from the following detailed description and the claims. Detailed Implementation

[0029] Autoimmune diseases are associated with the overproduction of pro-inflammatory factors. One of these pro-inflammatory factors is interleukin-1 (IL-1), produced by activated macrophages, monocytes, fibroblasts, and other components of the innate immune system, such as dendritic cells. IL-1 is involved in various cellular activities, including cell proliferation, differentiation, and apoptosis (Seth L. al. Rev. Immunol. 2009. 27:621–68).

[0030] Cytokines from the IL-1 family are highly active and act as important mediators of inflammation, primarily associated with both acute and chronic inflammation (Sims J. et al., Nature Reviews Immunology 10, 89-102 (February 2010)). Overproduction of IL-1 is considered an initiator of some autoimmune and autoinflammatory diseases. Autoinflammatory diseases are characterized by recurrent and unexplained inflammation in the absence of autoantibodies, infection, or antigen-specific T lymphocytes.

[0031] The IL-1 superfamily of pro-inflammatory cytokines includes IL-1α, IL-1β, IL-18, and IL-36α,β,λ, which are produced as part of the host's innate immune response in response to pathogens and other cellular stressors. Unlike many other secretory cytokines that are processed and released through the standard cellular secretory region composed of the endoplasmic reticulum and Golgi apparatus, IL-1 family members lack the necessary leader sequences for endoplasmic reticulum entry and are therefore retained intracellularly after translation. Furthermore, IL-1β, IL-18, and IL-36α,β,λ are synthesized as procytokines, requiring proteolytic activation to become optimal ligands for binding to their homologous receptors on target cells.

[0032] In the case of IL-1α, IL-1β, and IL-18, it is now recognized that a multi-subunit protein complex called the inflammasome is responsible for activating the proforms of IL-1β and IL-18 and for the extracellular release of these cytokines. The inflammasome complex typically consists of sensor molecules such as NLR (Nucleotide-Oligerimisation Domain (NOD)-like receptors), adaptor molecules ASC (apoptosis-associated speckle-like proteins containing CARD (cysteine ​​recruitment domain),) and procysteine-1. 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 supramolecular structures within the cell. PAMPs can include molecules such as peptidoglycans, viral DNA or RNA, and bacterial DNA or RNA. On the other hand, DAMPs consist of a wide range of endogenous or exogenous sterile triggers, including monosodium urate crystals, silica, alum, asbestos, fatty acids, ceramides, cholesterol crystals, and β-amyloid peptide aggregates. Assembly of the inflammasome platform facilitates the autocatalysis of pro-cysteine ​​protease-1 to produce highly active cysteine ​​proteases responsible for the activation and release of pro-IL-1β and pro-IL-18. Therefore, the release of these highly inflammatory cytokines is achieved solely in response to inflammasome sensors that detect and respond to specific molecular danger signals.

[0033] In humans, 22 NLR proteins are divided into four 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. Several NLR family members are involved in inflammasome formation, including NLRP1, NLRP3, NLRP6, NLRP7, NLRP12, and NLRC4 (IPAF).

[0034] Two other structurally distinct inflammasome structures containing the PYHIN domain (proteins containing both pyrin and HIN domains), namely Absent in Melanoma 2 (AIM2) and IFNλ-induced protein 16 (IFI16) (Latz et al., Nat RevImmunol 2013 13(6) 397-311), act as intracellular DNA sensors. Pyrin (encoded by the MEFV gene) represents another type of inflammasome platform associated with pro-IL-1β activation (Chae et al., Immunity 34, 755-768, 2011).

[0035] The requirement to assemble an inflammasome platform to achieve the activation and release of IL-1β and IL-18 from monocytes and macrophages ensures that their generation is carefully planned through a two-step process. First, the cell must encounter a promoter ligand (such as the TLR4 receptor ligand LPS or an inflammatory cytokine such as TNFα), which leads to NFkB-dependent transcription of NLRP3, pro-IL-1β, and pro-IL-18. The newly translated procytokines remain intracellular and inactive unless the generating cell encounters a second signal leading to the activation of the inflammasome scaffold and the maturation of proceaspase-1.

[0036] In addition to proteolytic activation of pro-IL-1β and pro-IL-18, active caspase-1 also triggers a form of inflammatory cell death known as pyroptosis via the cleavage of gasdermin-D. Pyroptosis enables the externalization of mature forms of IL-1β and IL-18 along with the release of 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.

[0037] Although inflammasome activation appears to have evolved into a crucial component of host immunity against pathogens, the NLRP3 inflammasome is unique in its ability to activate in response to endogenous aseptic danger signals. Many such aseptic 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 understanding of the role of aseptic danger signals as NLRP3 activators has led to the involvement of IL-1 and IL-18 in a wide range of pathophysiological indications, including metabolic disorders, physiological disorders, inflammatory disorders, hematologic disorders, and immune disorders.

[0038] The best example of its association with human diseases is the following finding: mutations in the NLRP3 gene that lead to gain of function cause a series of autoinflammatory conditions collectively known as cryopyrin-associated periodic syndromes (CAPS), including familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal onset multisystem inflammatory disease (NOMID) (Hoffman et al., Nat Genet. 29(3) (2001) 301-305). Similarly, sterile mediator-induced NLRP3 activation has been linked to a wide range of disorders, including joint degeneration (gout, rheumatoid arthritis, osteoarthritis), cardiovascular metabolism (type 2 diabetes, atherosclerosis, hypertension), central nervous system disorders (Alzheimer's disease, Parkinson's disease, multiple sclerosis), gastrointestinal disorders (Crohn's disease, ulcerative colitis), lung disorders (chronic obstructive pulmonary disease (COPD), asthma, idiopathic pulmonary fibrosis), and liver disorders (fibrosis, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis (NASH)). Furthermore, it is believed that NLRP3 activation promotes kidney inflammation and thus contributes to chronic kidney disease (CKD).

[0039] Current treatment options for diseases in which IL-1 contributes to pathogenesis include the IL-1 receptor antagonist anakinin, an Fc-containing fusion construct of the extracellular domain of the IL-1 receptor and IL-1 receptor accessory protein (linasip), and the anti-IL-1β monoclonal antibody canakinumab. For example, canakinumab is licensed for CAPS, tumor necrosis factor receptor-associated periodic syndrome (TRAPS), hyperimmunoglobulin D syndrome (HIDS) / mevalerate kinase deficiency (MKD), familial Mediterranean fever (FMF), and gout.

[0040] Several small molecules have been reported to inhibit the function of the NLRP3 inflammasome. Glibenclamide, for example, is a specific inhibitor of NLRP3 activation, although at micromolar concentrations that are impossible to achieve in vivo. Non-specific agents, such as parthenolide, Bay 11-7082, and 3,4-methylenedioxy-β-nitrostyrene, have been reported to impair NLRP3 activation, but are expected to have limited therapeutic efficacy due to their shared structural characteristics (composed of olefins activated by substitution with electron-withdrawing groups); this can lead to the undesirable formation of covalent adducts with thiol groups attached to proteins. Many natural products, such as β-hydroxybutyrate, sulforaphane, quercetin, and salvianolic acid, have also been reported to inhibit NLRP3 activation. Similarly, many effectors / modulators of other molecular targets have been reported to impair NLRP3 activation, including agonists of the G-protein-coupled receptor TGR5, epigliflozin (an inhibitor of sodium-glucose cotransport), the dopamine receptor antagonist A-68930, the serotonin reuptake inhibitor fluoxetine, the nonsteroidal anti-inflammatory drug fenamate, and the β-adrenergic receptor blocker nebivolol. The efficacy of these molecules as therapeutic agents for the chronic treatment of NLRP3-dependent inflammatory disorders remains to be established. A series of sulfonylurea-containing molecules have previously been identified as potent and selective inhibitors of pro-IL-1β post-translational processing (Perregaux et al., J Pharmacol. Exp. Ther. 299, 187-197, 2001). The example molecule CP-456,773 from this work was recently characterized as a specific inhibitor of NLRP3 activation (Coll et al., Nat Med 21.3 (2015): 248-255).

[0041] This disclosure relates to methods for preparing compounds that can be used to regulate NLRP3-dependent cellular processes. In some embodiments, there is a need for methods for preparing compounds with improved physicochemical, pharmacological, and pharmaceutical properties compared to existing NLRP3-regulating compounds.

[0042] The compounds disclosed herein It is important to understand that the structures of compounds No. 1, 1a, 1b, 2, 3, 3a, 3b, 4, 4a, 4b, 5, 5a, 5b, 6, 6a, 6b, 7, 8, 9, 9a, 9b, 9', 9a', 9b', 10, 10a, 10b, 10', 10a' and 10b' are as described in Table 1.

[0043] In some embodiments, the salt contains alkali metal ions (e.g., Li+, Na+, or K+).

[0044] In some embodiments, the salt is a sodium salt.

[0045] In some embodiments, the salt contains alkaline earth metal ions (e.g., Mg2+ or Ca2+).

[0046] The method disclosed herein In some respects, this disclosure provides a method for preparing compounds No. 10a or 10b described herein.

[0047] In some aspects, this disclosure provides a method for preparing compound No. 10a or 10b according to the following scheme: .

[0048] In some aspects, this disclosure provides a method for preparing compounds No. 10, 10a, or 10b, comprising steps (i)-(vii): (i) Reacting compound No. 1, 1a or 1b with 4-amino-1-methylpyrazole (compound No. 2) or a salt thereof to form compound No. 3, 3a or 3b or a salt thereof; (ii) Reacting compound No. 3, 3a or 3b or a salt thereof with a reducing agent to form compound No. 4, 4a or 4b or a salt thereof; (iii) Reacting compound No. 4, 4a or 4b or a salt thereof with tert-butyl N-chlorosulfonylcarbamate to form compound No. 5, 5a or 5b or a salt thereof; (iv) Reacting compound No. 5, 5a or 5b or a salt thereof with an acid to form compound No. 6, 6a or 6b or a salt thereof; (v) Reacting compound No. 7 or its salt with a CO source to form compound No. 8 or its salt; (vi) Reacting compound No. 6, 6a, or 6b, or a salt thereof, with compound No. 8, or a salt thereof, to form compound No. 9, 9a, or 9b; and (vii) Purify compound No. 9, 9a or 9b to isolate compound No. 10, 10a or 10b.

[0049] In some aspects, this disclosure provides a method for preparing compound No. 10a or 10b, comprising one or more of steps (iv)-(vii): (iv) Reacting compound No. 5a or 5b or a salt thereof with an acid to form compound No. 6a or 6b or a salt thereof; (v) Reacting compound No. 7 or its salt with a CO source to form compound No. 8 or its salt; (vi) Reacting compound No. 6a or 6b or a salt thereof with compound No. 8 or a salt thereof to form compound No. 9a or 9b; and (vii) Purify compound No. 9a or 9b to isolate compound No. 10a or 10b.

[0050] In some embodiments, the method for preparing compound No. 10a or 10b includes one or more of steps (iv), (v), (vi), and (vii).

[0051] In some embodiments, the method for preparing compound No. 10a or 10b includes step (iv).

[0052] In some embodiments, the method for preparing compound No. 10a or 10b includes step (v).

[0053] In some embodiments, the method for preparing compound No. 10a or 10b includes steps (iv) and (v).

[0054] In some embodiments, the method for preparing compound No. 10a or 10b includes step (vi).

[0055] In some embodiments, the method for preparing compound No. 10a or 10b includes steps (iv), (v) and (vi).

[0056] In some embodiments, the method for preparing compound No. 10a or 10b includes one or more of steps (iv), (v), (vi), and (vii).

[0057] In some implementations, the method includes steps (iv), (v), (vi), and (vii).

[0058] In some aspects, this disclosure provides a method for preparing compound No. 10a or 10b, comprising steps (i)-(vii): (i) Reacting tetrahydrofuran-2-carboxylic acid (e.g., (2S)-tetrahydrofuran-2-carboxylic acid or (2R)-tetrahydrofuran-2-carboxylic acid) with 4-amino-1-methylpyrazole or a salt thereof to form N-(1-methyl-1H-pyrazole-4-yl)tetrahydrofuran-2-carboxamide (e.g., (2S)-N-(1-methyl-1H-pyrazole-4-yl)tetrahydrofuran-2-carboxamide or (2R)-N-(1-methyl-1H-pyrazole-4-yl)tetrahydrofuran-2-carboxamide or a salt thereof); (ii) Reacting N-(1-methyl-1H-pyrazol-4-yl)tetrahydrofuran-2-carboxamide (e.g., (2S)-N-(1-methyl-1H-pyrazol-4-yl)tetrahydrofuran-2-carboxamide or (2R)-N-(1-methyl-1H-pyrazol-4-yl)tetrahydrofuran-2-carboxamide) or a salt thereof with a reducing agent to form 1-methyl-N-{[tetrahydrofuran-2-yl]methyl}-1H-pyrazol-4-amine (e.g., 1-methyl-N-{[(2S)-tetrahydrofuran-2-yl]methyl}-1H-pyrazol-4-amine or 1-methyl-N-{[(2R)-tetrahydrofuran-2-yl]methyl}-1H-pyrazol-4-amine) or a salt thereof; (iii) Reacting 1-methyl-N-{[tetrahydrofuran-2-yl]methyl}-1H-pyrazole-4-amine (e.g., 1-methyl-N-{[(2S)-tetrahydrofuran-2-yl]methyl}-1H-pyrazole-4-amine or 1-methyl-N-{[(2R)-tetrahydrofuran-2-yl]methyl}-1H-pyrazole-4-amine) or a salt thereof with tert-butyl N-chlorosulfonylcarbamate to form compound No. 5a or 5b or a salt thereof; (iv) Reacting compound No. 5a or 5b or a salt thereof with an acid to form compound No. 6a or 6b or a salt thereof; (v) Reacting compound No. 7 or its salt with a CO source to form compound No. 8 or its salt; (vi) Reacting compound No. 6a or 6b or a salt thereof with compound No. 8 or a salt thereof to form compound No. 9a or 9b; and (vii) Purify compound No. 9a or 9b to isolate compound No. 10a or 10b.

[0059] In some embodiments, the method for preparing compound No. 10a or 10b includes one or more of steps (i), (ii), (iii), (iv), (v), (vi), and (vii).

[0060] In some embodiments, the method for preparing compound No. 10a or 10b includes step (i).

[0061] In some embodiments, the method for preparing compound No. 10a or 10b includes step (ii).

[0062] In some embodiments, the method for preparing compound No. 10a or 10b includes steps (i) and (ii).

[0063] In some embodiments, the method for preparing compound No. 10a or 10b includes step (iii).

[0064] In some embodiments, the method for preparing compound No. 10a or 10b includes steps (i), (ii) and (iii).

[0065] In some embodiments, the method for preparing compound No. 10a or 10b includes step (iv).

[0066] In some embodiments, the method for preparing compound No. 10a or 10b includes steps (i), (ii), (iii) and (iv).

[0067] In some embodiments, the method for preparing compound No. 10a or 10b includes step (v).

[0068] In some embodiments, the method for preparing compound No. 10a or 10b includes steps (i), (ii), (iii), (iv), and (v).

[0069] In some embodiments, the method for preparing compound No. 10a or 10b includes step (vi).

[0070] In some embodiments, the method for preparing compound No. 10a or 10b includes steps (i), (ii), (iii), (iv), (v) and (vi).

[0071] In some embodiments, the method for preparing compound No. 10a or 10b includes step (vii).

[0072] In some embodiments, the method for preparing compound No. 10a or 10b includes steps (i), (ii), (iii), (iv), (v), (vi), and (vii).

[0073] In some embodiments, the method for preparing compound No. 10a or 10b includes one or more of steps (i), (ii), (iii), (iv), (v), (vi), and (vii).

[0074] In some respects, this disclosure provides a method for preparing compound No. 10a.

[0075] In some aspects, this disclosure provides a method for preparing compound No. 10a, comprising one or more of steps (iv)-(vii): (iv) Reacting compound No. 5a or its salt with an acid to form compound No. 6a or its salt; (v) Reacting compound No. 7 or its salt with a CO source to form compound No. 8 or its salt; (vi) Reacting compound No. 6a or a salt thereof with compound No. 8 or a salt thereof to form compound No. 9a; and (vii) Purify compound No. 9a to separate compound No. 10a.

[0076] In some embodiments, the method for preparing compound No. 10a includes one or more of steps (iv), (v), (vi), and (vii).

[0077] In some embodiments, the method for preparing compound No. 10a includes step (iv).

[0078] In some embodiments, the method for preparing compound No. 10a includes steps (iv) and (v).

[0079] In some embodiments, the method for preparing compound No. 10a includes step (v).

[0080] In some embodiments, the method for preparing compound No. 10a includes step (vi).

[0081] In some embodiments, the method for preparing compound No. 10a includes steps (iv), (v) and (vi).

[0082] In some embodiments, the method for preparing compound No. 10a includes one or more of steps (iv), (v), (vi), and (vii).

[0083] In some aspects, this disclosure provides a method for preparing compound No. 10a, comprising steps (i)-(vii): (i) Reaction of (2S)-tetrahydrofuran-2-carboxylic acid with 4-amino-1-methylpyrazole or a salt thereof to form (2S)-N-(1-methyl-1H-pyrazole-4-yl)tetrahydrofuran-2-carboxamide or a salt thereof; (ii) Reacting (2S)-N-(1-methyl-1H-pyrazol-4-yl)tetrahydrofuran-2-carboxamide or a salt thereof with a reducing agent to form 1-methyl-N-{[(2S)-tetrahydrofuran-2-yl]methyl}-1H-pyrazol-4-amine or a salt thereof; (iii) Reacting 1-methyl-N-{[(2S)-tetrahydrofuran-2-yl]methyl}-1H-pyrazole-4-amine or a salt thereof with tert-butyl N-chlorosulfonylcarbamate to form compound No. 5a or a salt thereof; (iv) Reacting compound No. 5a or its salt with an acid to form compound No. 6a or its salt; (v) Reacting compound No. 7 or its salt with a CO source to form compound No. 8 or its salt; (vi) Reacting compound No. 6a or a salt thereof with compound No. 8 or a salt thereof to form compound No. 9a; and (vii) Purify compound No. 9a to separate compound No. 10a.

[0084] In some embodiments, the method for preparing compound No. 10a includes one or more of steps (i), (ii), (iii), (iv), (v), (vi), and (vii).

[0085] In some embodiments, the method for preparing compound No. 10a includes step (i).

[0086] In some embodiments, the method for preparing compound No. 10a includes step (ii).

[0087] In some embodiments, the method for preparing compound No. 10a includes steps (i) and (ii).

[0088] In some embodiments, the method for preparing compound No. 10a includes step (iii).

[0089] In some embodiments, the method for preparing compound No. 10a includes steps (i), (ii) and (iii).

[0090] In some embodiments, the method for preparing compound No. 10a includes steps (i), (ii), (iii) and (iv).

[0091] In some embodiments, the method for preparing compound No. 10a includes steps (i), (ii), (iii), (iv), and (v).

[0092] In some embodiments, the method for preparing compound No. 10a includes steps (i), (ii), (iii), (iv), (v), and (vi).

[0093] In some embodiments, the method for preparing compound No. 10a includes step (vii).

[0094] In some embodiments, the method for preparing compound No. 10a includes steps (i), (ii), (iii), (iv), (v), (vi), and (vii).

[0095] In some aspects, this disclosure provides a method for preparing compound No. 10b, comprising one or more of steps (iv)-(vii): (iv) Reacting compound No. 5b or a salt thereof with an acid to form compound No. 6b or a salt thereof; (v) Reacting compound No. 7 or its salt with a CO source to form compound No. 8 or its salt; (vi) Reacting compound No. 6b or a salt thereof with compound No. 8 or a salt thereof to form compound No. 9b; and (vii) Purify compound No. 9b to isolate compound No. 10b.

[0096] In some embodiments, the method for preparing compound No. 10b includes one or more of steps (iv), (v), (vi), and (vii).

[0097] In some embodiments, the method for preparing compound No. 10b includes step (iv).

[0098] In some embodiments, the method for preparing compound No. 10b includes steps (iv) and (v).

[0099] In some embodiments, the method for preparing compound No. 10b includes step (v).

[0100] In some embodiments, the method for preparing compound No. 10b includes step (vi).

[0101] In some embodiments, the method for preparing compound No. 10b includes steps (iv), (v) and (vi).

[0102] In some embodiments, the method for preparing compound No. 10b includes one or more of steps (iv), (v), (vi), and (vii).

[0103] In some aspects, this disclosure provides a method for preparing compound No. 10b, comprising steps (i)-(vii): (i) Reaction of (2R)-tetrahydrofuran-2-carboxylic acid with 4-amino-1-methylpyrazole or a salt thereof to form (2R)-N-(1-methyl-1H-pyrazole-4-yl)tetrahydrofuran-2-carboxamide or a salt thereof; (ii) Reacting (2R)-N-(1-methyl-1H-pyrazol-4-yl)tetrahydrofuran-2-carboxamide or a salt thereof with a reducing agent to form 1-methyl-N-{[(2R)-tetrahydrofuran-2-yl]methyl}-1H-pyrazol-4-amine or a salt thereof; (iii) Reacting 1-methyl-N-{[(2R)-tetrahydrofuran-2-yl]methyl}-1H-pyrazole-4-amine or a salt thereof with tert-butyl N-chlorosulfonylcarbamate to form compound No. 5b or a salt thereof; (iv) Reacting compound No. 5b or a salt thereof with an acid to form compound No. 6b or a salt thereof; (v) Reacting compound No. 7 or its salt with a CO source to form compound No. 8 or its salt; (vi) Reacting compound No. 6b or a salt thereof with compound No. 8 or a salt thereof to form compound No. 9b; and (vii) Purify compound No. 9b to isolate compound No. 10b.

[0104] In some embodiments, the method for preparing compound No. 10b includes one or more of steps (i), (ii), (iii), (iv), (v), (vi), and (vii).

[0105] In some embodiments, the method for preparing compound No. 10b includes step (i).

[0106] In some embodiments, the method for preparing compound No. 10b includes step (ii).

[0107] In some embodiments, the method for preparing compound No. 10b includes steps (i) and (ii).

[0108] In some embodiments, the method for preparing compound No. 10b includes step (iii).

[0109] In some embodiments, the method for preparing compound No. 10b includes steps (i), (ii) and (iii).

[0110] In some embodiments, the method for preparing compound No. 10b includes steps (i), (ii), (iii), and (iv).

[0111] In some embodiments, the method for preparing compound No. 10b includes steps (i), (ii), (iii), (iv), and (v).

[0112] In some embodiments, the method for preparing compound No. 10b includes steps (i), (ii), (iii), (iv), (v), and (vi).

[0113] In some embodiments, the method for preparing compound No. 10b includes step (vii).

[0114] In some embodiments, the method for preparing compound No. 10b includes steps (i), (ii), (iii), (iv), (v), (vi), and (vii).

[0115] In some aspects, this disclosure provides a method for preparing compound No. 10a' or 10b', comprising one or more of steps (iv)-(vii): (iv) Reacting compound No. 5a or 5b or a salt thereof with an acid to form compound No. 6a or 6b or a salt thereof; (v) Reacting compound No. 7 or its salt with a CO source to form compound No. 8 or its salt; (vi) Reacting compound No. 6a or 6b or a salt thereof with compound No. 8 or a salt thereof to form compound No. 9a' or 9b'; and (vii) Purify compound No. 9a' or 9b' to isolate compound No. 10a' or 10b'.

[0116] In some embodiments, the method for preparing compound No. 10a' or 10b' includes one or more of steps (iv), (v), (vi), and (vii).

[0117] In some embodiments, the method for preparing compound No. 10a' or 10b' includes step (iv).

[0118] In some embodiments, the method for preparing compound No. 10a' or 10b' includes step (v).

[0119] In some embodiments, the method for preparing compound No. 10a' or 10b' includes steps (iv) and (v).

[0120] In some embodiments, the method for preparing compound No. 10a' or 10b' includes step (vi).

[0121] In some embodiments, the method for preparing compound No. 10a' or 10b' includes steps (iv), (v) and (vi).

[0122] In some embodiments, the method for preparing compound No. 10a' or 10b' includes one or more of steps (iv), (v), (vi), and (vii).

[0123] In some implementations, the method includes steps (iv), (v), (vi), and (vii).

[0124] In some aspects, this disclosure provides a method for preparing compound No. 10a' or 10b', comprising steps (i)-(vii): (i) Reacting tetrahydrofuran-2-carboxylic acid (e.g., (2S)-tetrahydrofuran-2-carboxylic acid or (2R)-tetrahydrofuran-2-carboxylic acid) with 4-amino-1-methylpyrazole or a salt thereof to form N-(1-methyl-1H-pyrazole-4-yl)tetrahydrofuran-2-carboxamide (e.g., (2S)-N-(1-methyl-1H-pyrazole-4-yl)tetrahydrofuran-2-carboxamide or (2R)-N-(1-methyl-1H-pyrazole-4-yl)tetrahydrofuran-2-carboxamide or a salt thereof); (ii) Reacting N-(1-methyl-1H-pyrazol-4-yl)tetrahydrofuran-2-carboxamide (e.g., (2S)-N-(1-methyl-1H-pyrazol-4-yl)tetrahydrofuran-2-carboxamide or (2R)-N-(1-methyl-1H-pyrazol-4-yl)tetrahydrofuran-2-carboxamide) or a salt thereof with a reducing agent to form 1-methyl-N-{[tetrahydrofuran-2-yl]methyl}-1H-pyrazol-4-amine (e.g., 1-methyl-N-{[(2S)-tetrahydrofuran-2-yl]methyl}-1H-pyrazol-4-amine or 1-methyl-N-{[(2R)-tetrahydrofuran-2-yl]methyl}-1H-pyrazol-4-amine) or a salt thereof; (iii) Reacting 1-methyl-N-{[tetrahydrofuran-2-yl]methyl}-1H-pyrazole-4-amine (e.g., 1-methyl-N-{[(2S)-tetrahydrofuran-2-yl]methyl}-1H-pyrazole-4-amine or 1-methyl-N-{[(2R)-tetrahydrofuran-2-yl]methyl}-1H-pyrazole-4-amine) or a salt thereof with tert-butyl N-chlorosulfonylcarbamate to form compound No. 5a or 5b or a salt thereof; (iv) Reacting compound No. 5a or 5b or a salt thereof with an acid to form compound No. 6a or 6b or a salt thereof; (v) Reacting compound No. 7 or its salt with a CO source to form compound No. 8 or its salt; (vi) Reacting compound No. 6a or 6b or a salt thereof with compound No. 8 or a salt thereof to form compound No. 9a' or 9b'; and (vii) Purify compound No. 9a' or 9b' to isolate compound No. 10a' or 10b'.

[0125] In some embodiments, the method for preparing compound No. 10a' or 10b' includes one or more of steps (i), (ii), (iii), (iv), (v), (vi), and (vii).

[0126] In some embodiments, the method for preparing compound No. 10a' or 10b' includes step (i).

[0127] In some embodiments, the method for preparing compound No. 10a' or 10b' includes step (ii).

[0128] In some embodiments, the method for preparing compound No. 10a' or 10b' includes steps (i) and (ii).

[0129] In some embodiments, the method for preparing compound No. 10a' or 10b' includes step (iii).

[0130] In some embodiments, the method for preparing compound No. 10a' or 10b' includes steps (i), (ii) and (iii).

[0131] In some embodiments, the method for preparing compound No. 10a' or 10b' includes steps (i), (ii), (iii), and (iv).

[0132] In some embodiments, the method for preparing compound No. 10a' or 10b' includes steps (i), (ii), (iii), (iv), and (v).

[0133] In some embodiments, the method for preparing compound No. 10a' or 10b' includes steps (i), (ii), (iii), (iv), (v) and (vi).

[0134] In some embodiments, the method for preparing compound No. 10a' or 10b' includes step (vii).

[0135] In some embodiments, the method for preparing compound No. 10a' or 10b' includes steps (i), (ii), (iii), (iv), (v), (vi), and (vii).

[0136] In some embodiments, the method for preparing compound No. 10a' or 10b' includes one or more of steps (i), (ii), (iii), (iv), (v), (vi), and (vii).

[0137] In some respects, this disclosure provides a method for preparing compound No. 10a'.

[0138] In some aspects, this disclosure provides a method for preparing compound No. 10a', comprising one or more of steps (iv)-(vii): (iv) Reacting compound No. 5a or its salt with an acid to form compound No. 6a or its salt; (v) Reacting compound No. 7 or its salt with a CO source to form compound No. 8 or its salt; (vi) Reacting compound No. 6a or a salt thereof with compound No. 8 or a salt thereof to form compound No. 9a'; and (vii) Purify compound No. 9a' to separate compound No. 10a'.

[0139] In some embodiments, the method for preparing compound No. 10a' includes one or more of steps (iv), (v), (vi), and (vii).

[0140] In some embodiments, the method for preparing compound No. 10a' includes step (iv).

[0141] In some embodiments, the method for preparing compound No. 10a' includes step (v).

[0142] In some embodiments, the method for preparing compound No. 10a' includes steps (iv) and (v).

[0143] In some embodiments, the method for preparing compound No. 10a' includes step (vi).

[0144] In some embodiments, the method for preparing compound No. 10a' includes steps (iv), (v) and (vi).

[0145] In some embodiments, the method for preparing compound No. 10a' includes one or more of steps (iv), (v), (vi), and (vii).

[0146] In some aspects, this disclosure provides a method for preparing compound No. 10a', comprising steps (i)-(vii): (i) Reaction of (2S)-tetrahydrofuran-2-carboxylic acid with 4-amino-1-methylpyrazole or a salt thereof to form (2S)-N-(1-methyl-1H-pyrazole-4-yl)tetrahydrofuran-2-carboxamide or a salt thereof; (ii) Reacting (2S)-N-(1-methyl-1H-pyrazol-4-yl)tetrahydrofuran-2-carboxamide or a salt thereof with a reducing agent to form 1-methyl-N-{[(2S)-tetrahydrofuran-2-yl]methyl}-1H-pyrazol-4-amine or a salt thereof; (iii) Reacting 1-methyl-N-{[(2S)-tetrahydrofuran-2-yl]methyl}-1H-pyrazole-4-amine or a salt thereof with tert-butyl N-chlorosulfonylcarbamate to form compound No. 5a or a salt thereof; (iv) Reacting compound No. 5a or its salt with an acid to form compound No. 6a or its salt; (v) Reacting compound No. 7 or its salt with a CO source to form compound No. 8 or its salt; (vi) Reacting compound No. 6a or a salt thereof with compound No. 8 or a salt thereof to form compound No. 9a'; and (vii) Purify compound No. 9a' to separate compound No. 10a'.

[0147] In some embodiments, the method for preparing compound No. 10a' includes one or more of steps (i), (ii), (iii), (iv), (v), (vi), and (vii).

[0148] In some embodiments, the method for preparing compound No. 10a' includes step (i).

[0149] In some embodiments, the method for preparing compound No. 10a' includes step (ii).

[0150] In some embodiments, the method for preparing compound No. 10a' includes steps (i) and (ii).

[0151] In some embodiments, the method for preparing compound No. 10a' includes step (iii).

[0152] In some embodiments, the method for preparing compound No. 10a' includes steps (i), (ii) and (iii).

[0153] In some embodiments, the method for preparing compound No. 10a' includes steps (i), (ii), (iii) and (iv).

[0154] In some embodiments, the method for preparing compound No. 10a' includes steps (i), (ii), (iii), (iv), and (v).

[0155] In some embodiments, the method for preparing compound No. 10a' includes steps (i), (ii), (iii), (iv), (v) and (vi).

[0156] In some embodiments, the method for preparing compound No. 10a' includes step (vii).

[0157] In some embodiments, the method for preparing compound No. 10a' includes steps (i), (ii), (iii), (iv), (v), (vi), and (vii).

[0158] In some aspects, this disclosure provides a method for preparing compound No. 10b', comprising one or more of steps (iv)-(vii): (iv) Reacting compound No. 5b or a salt thereof with an acid to form compound No. 6b or a salt thereof; (v) Reacting compound No. 7 or its salt with a CO source to form compound No. 8 or its salt; (vi) Reacting compound No. 6b or a salt thereof with compound No. 8 or a salt thereof to form compound No. 9b'; and (vii) Purify compound No. 9b' to isolate compound No. 10b'.

[0159] In some embodiments, the method for preparing compound No. 10b' includes one or more of steps (iv), (v), (vi), and (vii).

[0160] In some embodiments, the method for preparing compound No. 10b' includes step (iv).

[0161] In some embodiments, the method for preparing compound No. 10b' includes step (v).

[0162] In some embodiments, the method for preparing compound No. 10b' includes steps (iv) and (v).

[0163] In some embodiments, the method for preparing compound No. 10b' includes step (vi).

[0164] In some embodiments, the method for preparing compound No. 10b' includes steps (iv), (v) and (vi).

[0165] In some embodiments, the method for preparing compound No. 10b' includes one or more of steps (iv), (v), (vi), and (vii).

[0166] In some aspects, this disclosure provides a method for preparing compound No. 10b', comprising steps (i)-(vii): (i) Reaction of (2R)-tetrahydrofuran-2-carboxylic acid with 4-amino-1-methylpyrazole or a salt thereof to form (2R)-N-(1-methyl-1H-pyrazole-4-yl)tetrahydrofuran-2-carboxamide or a salt thereof; (ii) Reacting (2R)-N-(1-methyl-1H-pyrazol-4-yl)tetrahydrofuran-2-carboxamide or a salt thereof with a reducing agent to form 1-methyl-N-{[(2R)-tetrahydrofuran-2-yl]methyl}-1H-pyrazol-4-amine or a salt thereof; (iii) Reacting 1-methyl-N-{[(2R)-tetrahydrofuran-2-yl]methyl}-1H-pyrazole-4-amine or a salt thereof with tert-butyl N-chlorosulfonylcarbamate to form compound No. 5b or a salt thereof; (iv) Reacting compound No. 5b or a salt thereof with an acid to form compound No. 6b or a salt thereof; (v) Reacting compound No. 7 or its salt with a CO source to form compound No. 8 or its salt; (vi) Reacting compound No. 6b or a salt thereof with compound No. 8 or a salt thereof to form compound No. 9b'; and (vii) Purify compound No. 9b' to isolate compound No. 10b'.

[0167] In some embodiments, the method for preparing compound No. 10b' includes one or more of steps (i), (ii), (iii), (iv), (v), (vi), and (vii).

[0168] In some embodiments, the method for preparing compound No. 10b' includes step (i).

[0169] In some embodiments, the method for preparing compound No. 10b' includes step (ii).

[0170] In some embodiments, the method for preparing compound No. 10b' includes steps (i) and (ii).

[0171] In some embodiments, the method for preparing compound No. 10b' includes step (iii).

[0172] In some embodiments, the method for preparing compound No. 10b' includes steps (i), (ii) and (iii).

[0173] In some embodiments, the method for preparing compound No. 10b' includes step (iv).

[0174] In some embodiments, the method for preparing compound No. 10b' includes steps (i), (ii), (iii) and (iv).

[0175] In some embodiments, the method for preparing compound No. 10b' includes step (v).

[0176] In some embodiments, the method for preparing compound No. 10b' includes steps (i), (ii), (iii), (iv), and (v).

[0177] In some embodiments, the method for preparing compound No. 10b' includes step (vi).

[0178] In some embodiments, the method for preparing compound No. 10b' includes steps (i), (ii), (iii), (iv), (v) and (vi).

[0179] In some embodiments, the method for preparing compound No. 10b' includes step (vii).

[0180] In some embodiments, the method for preparing compound No. 10b' includes steps (i), (ii), (iii), (iv), (v), (vi), and (vii).

[0181] In some implementations, separation is performed after purification.

[0182] In some embodiments, compound No. 4 or a salt thereof is compound No. 4a or a salt thereof.

[0183] In some embodiments, compound No. 4 or a salt thereof is compound No. 4b or a salt thereof.

[0184] In some embodiments, compound No. 5 or a salt thereof is compound No. 5a or a salt thereof.

[0185] In some embodiments, compound No. 5 or a salt thereof is compound No. 5b or a salt thereof.

[0186] In some embodiments, compound No. 6 or a salt thereof is compound No. 6a or a salt thereof.

[0187] In some embodiments, compound No. 6 or a salt thereof is compound No. 6b or a salt thereof.

[0188] In some implementations, compound No. 9 is compound No. 9a.

[0189] In some implementations, compound No. 9 is compound No. 9b.

[0190] In some implementations, compound No. 9' is compound No. 9a'.

[0191] In some implementations, compound No. 9' is compound No. 9b'.

[0192] In some implementations, compound No. 10 is compound No. 10a.

[0193] In some implementations, compound No. 10 is compound No. 10b.

[0194] In some implementations, compound No. 10' is compound No. 10a'.

[0195] In some implementations, compound No. 10' is compound No. 10b'.

[0196] Step (iv) In some implementations, in step (iv), the acid is an inorganic acid.

[0197] In some embodiments, in step (iv), the acid is hydrochloric acid.

[0198] In some embodiments, in step (iv), the molar ratio of the acid to compound No. 5a or 5b or a salt thereof is about 5:1 to about 1:1.

[0199] In some embodiments, in step (iv), the molar ratio of the acid to compound No. 5a or 5b or a salt thereof is about 4:1 to about 1:1.

[0200] In some embodiments, in step (iv), the molar ratio of the acid to compound No. 5a or 5b or a salt thereof is about 3:1 to about 1:1.

[0201] In some embodiments, in step (iv), the molar ratio of the acid to compound No. 5a or 5b or a salt thereof is about 2:1 to about 1:1.

[0202] In some embodiments, in step (iv), the molar ratio of the acid to compound No. 5a or 5b or a salt thereof is about 5:1.

[0203] In some embodiments, in step (iv), the molar ratio of the acid to compound No. 5a or 5b or a salt thereof is about 4:1.

[0204] In some embodiments, in step (iv), the molar ratio of the acid to compound No. 5a or 5b or a salt thereof is about 3:1.

[0205] In some embodiments, in step (iv), the molar ratio of the acid to compound No. 5a or 5b or a salt thereof is about 2.5:1.

[0206] In some embodiments, in step (iv), the molar ratio of the acid to compound No. 5a or 5b or a salt thereof is about 2:1.

[0207] In some embodiments, in step (iv), the molar ratio of the acid to compound No. 5a or 5b or a salt thereof is about 1.5:1.

[0208] In some embodiments, in step (iv), the molar ratio of the acid to compound No. 5a or 5b or a salt thereof is about 1.1:1.

[0209] In some embodiments, in step (iv), the molar ratio of the acid to compound No. 5a or 5b or a salt thereof is about 1:1.

[0210] In some embodiments, in step (iv), the reaction is carried out in the presence of a first solvent to form a first mixture. In some embodiments, the first solvent is an inorganic solvent. In some embodiments, the first solvent is a polar protic solvent (e.g., water). In some embodiments, the first solvent is water.

[0211] In some embodiments, in step (iv), the reaction is carried out at a first temperature of 25±15°C, 25±10°C, or 25±5°C (e.g., about 25°C).

[0212] In some embodiments, in step (iv), the reaction is carried out at a first temperature of about 25 ± 15 °C, about 25 ± 10 °C, or about 25 ± 5 °C (e.g., about 25 °C).

[0213] In some implementations, in step (iv), the reaction is carried out at a first temperature of about 25°C.

[0214] In some implementations, in step (iv), the reaction is carried out for 26 ± 20 hours, 26 ± 15 hours, 26 ± 10 hours, 26 ± 5 hours, 26 ± 4 hours, 26 ± 3 hours, 26 ± 2 hours, or 26 ± 1 hour (e.g., about 26 hours).

[0215] In some implementations, in step (iv), the reaction is carried out for about 26 ± 20 hours, about 26 ± 15 hours, about 26 ± 10 hours, about 26 ± 5 hours, about 26 ± 4 hours, about 26 ± 3 hours, about 26 ± 2 hours, or about 26 ± 1 hour (e.g., about 26 hours).

[0216] In some embodiments, in step (iv), the first mixture is cooled to a second temperature of 0±15°C, 0±10°C, or 0±5°C (e.g., about 0°C).

[0217] In some embodiments, in step (iv), the first mixture is cooled to a second temperature of about 0±15°C, about 0±10°C, or about 0±5°C (e.g., about 0°C).

[0218] In some embodiments, in step (iv), the first mixture is cooled to a second temperature of approximately 0°C.

[0219] In some embodiments, in step (iv), the first mixture is cooled to a second temperature of 0±15°C, 0±10°C, or 0±5°C (e.g., about 0°C), and a second solvent is added to form a second mixture. In some embodiments, the second solvent is an organic solvent. In some embodiments, the second solvent is dichloromethane.

[0220] In some embodiments, in step (iv), an alkali is added to the second mixture. In some embodiments, the alkali is sodium hydroxide. In some embodiments, the alkali is potassium hydroxide.

[0221] In some embodiments, in step (iv), an alkali is added to the second mixture and the pH is adjusted.

[0222] In some implementations, in step (iv), a buffer is added to the second mixture and the pH is adjusted.

[0223] In some embodiments, step (iv) further includes adding a base to the first mixture to form compound No. 6a or 6b or a salt thereof.

[0224] In some embodiments, step (iv) further includes adding a base to the second mixture to form compound No. 6a or 6b or a salt thereof.

[0225] In some embodiments, step (iv) further includes adding an alkali or buffer to the second mixture and adjusting the pH to 8.0 ± 2.0.

[0226] In some embodiments, step (iv) further includes adding an alkali or buffer to the second mixture and adjusting the pH to approximately 8.0 ± 2.0.

[0227] In some embodiments, step (iv) further includes adding an alkali or buffer to the second mixture and adjusting the pH to approximately 8.0.

[0228] In some embodiments, step (iv) further includes adding an alkali or buffer to the second mixture and adjusting the pH to approximately 9.0.

[0229] In some embodiments, step (iv) further comprises adding a base to the first mixture and adjusting the pH to 8.0±2.0, 8.0±1.5, 8.0±1.0, 8.0±0.9, 8.0±0.8, 8.0±0.7, 8.0±0.6, 8.0±0.5, 8.0±0.4, 8.0±0.3, 8.0±0.2 or 8.0±0.1 (e.g., about 8.0), thereby forming compound No. 6a or 6b or a salt thereof.

[0230] In some embodiments, step (iv) further includes adding a base to the first mixture and adjusting the pH to about 8.0±2.0, about 8.0±1.5, about 8.0±1.0, about 8.0±0.9, about 8.0±0.8, about 8.0±0.7, about 8.0±0.6, about 8.0±0.5, about 8.0±0.4, about 8.0±0.3, about 8.0±0.2, or about 8.0±0.1 (e.g., about 8.0), thereby forming compound No. 6a or 6b or a salt thereof.

[0231] In some embodiments, step (iv) further comprises adding a base to the first mixture and adjusting the pH to 9.0±2.0, 9.0±1.5, 9.0±1.0, 9.0±0.9, 9.0±0.8, 9.0±0.7, 9.0±0.6, 9.0±0.5, 9.0±0.4, 9.0±0.3, 9.0±0.2 or 9.0±0.1 (e.g., about 9.0), thereby forming compound No. 6a or 6b or a salt thereof.

[0232] In some embodiments, step (iv) further includes adding a base to the first mixture and adjusting the pH to about 9.0 ± 2.0, about 9.0 ± 1.5, about 9.0 ± 1.0, about 9.0 ± 0.9, about 9.0 ± 0.8, about 9.0 ± 0.7, about 9.0 ± 0.6, about 9.0 ± 0.5, about 9.0 ± 0.4, about 9.0 ± 0.3, about 9.0 ± 0.2, or about 9.0 ± 0.1 (e.g., about 9.0), thereby forming compound No. 6a or 6b or a salt thereof.

[0233] In some embodiments, step (iv) further comprises adding a base to the second mixture and adjusting the pH to 8.0±2.0, 8.0±1.5, 8.0±1.0, 8.0±0.9, 8.0±0.8, 8.0±0.7, 8.0±0.6, 8.0±0.5, 8.0±0.4, 8.0±0.3, 8.0±0.2 or 8.0±0.1 (e.g., about 8.0), thereby forming compound No. 6a or 6b or a salt thereof.

[0234] In some embodiments, step (iv) further includes adding a base to the second mixture and adjusting the pH to about 8.0±2.0, about 8.0±1.5, about 8.0±1.0, about 8.0±0.9, about 8.0±0.8, about 8.0±0.7, about 8.0±0.6, about 8.0±0.5, about 8.0±0.4, about 8.0±0.3, about 8.0±0.2 or about 8.0±0.1 (e.g., about 8.0), thereby forming compound No. 6a or 6b or a salt thereof.

[0235] In some embodiments, step (iv) further comprises adding a base to the second mixture and adjusting the pH to 9.0±2.0, 9.0±1.5, 9.0±1.0, 9.0±0.9, 9.0±0.8, 9.0±0.7, 9.0±0.6, 9.0±0.5, 9.0±0.4, 9.0±0.3, 9.0±0.2 or 9.0±0.1 (e.g., about 9.0), thereby forming compound No. 6a or 6b or a salt thereof.

[0236] In some embodiments, step (iv) further includes adding a base to the second mixture and adjusting the pH to about 9.0±2.0, about 9.0±1.5, about 9.0±1.0, about 9.0±0.9, about 9.0±0.8, about 9.0±0.7, about 9.0±0.6, about 9.0±0.5, about 9.0±0.4, about 9.0±0.3, about 9.0±0.2, or about 9.0±0.1 (e.g., about 9.0), thereby forming compound No. 6a or 6b or a salt thereof.

[0237] In some embodiments, step (iv) further includes adding an inorganic or organic base to the formed compound No. 6a or 6b or a salt thereof, thereby adjusting the pH value to a value of about 8.0 to about 9.0.

[0238] In some embodiments, step (iv) further includes adding a K2CO3 solution to the formed compound No. 6a or 6b or its salt to adjust the pH value to a value of about 8.0 to about 9.0.

[0239] In step (iv) of some embodiments, compound No. 6a or 6b or its salts are isolated and / or purified prior to reaction with compound No. 8.

[0240] In step (iv) of some embodiments, compounds No. 6a or 6b or their salts are not isolated or purified prior to reaction with compound No. 8.

[0241] In some embodiments, step (iv) produces compound No. 6a or 6b or a salt thereof with a purity of at least about 95%, as determined by high performance liquid chromatography (HPLC).

[0242] In some embodiments, step (iv) produces compound No. 6a or 6b or a salt thereof with a purity of at least about 96%, as determined by HPLC.

[0243] In some embodiments, step (iv) produces compound No. 6a or 6b or a salt thereof with a purity of at least about 97%, as determined by HPLC.

[0244] In some embodiments, step (iv) produces compound No. 6a or 6b or a salt thereof with a purity of at least about 98%, as determined by HPLC.

[0245] In some embodiments, step (iv) produces compound No. 6a or 6b or a salt thereof with a purity of at least about 99%, as determined by HPLC.

[0246] Step (v) In some implementations, step (v) involves the dissociation of phosgene, the reaction between CO2 and carbon (the Boudouard reaction), the reaction between steam and carbon, the high-temperature electrolysis of carbon dioxide using a solid oxide electrolyzer, or the direct oxidation of carbon to a CO source under limited oxygen or air supply.

[0247] In some implementations, in step (v), the phosgene derivative is a CO source.

[0248] In some implementations, in step (v), triphosgene is the CO source.

[0249] In some embodiments, in step (v), the reaction is carried out in the presence of a base. In some embodiments, the base is an organic base (e.g., triethylamine (TEA)).

[0250] In some implementations, in step (v), the reaction is carried out in the presence of triethylamine (TEA).

[0251] In some embodiments, in step (v), the molar ratio of the base to compound No. 8 or its salt is about 3:1 to about 1:1.

[0252] In some embodiments, in step (v), the molar ratio of the base to compound No. 8 or its salt is about 2:1 to about 1:1.

[0253] In some embodiments, in step (v), the molar ratio of the base to compound No. 8 or its salt is about 3:1.

[0254] In some embodiments, in step (v), the molar ratio of the base to compound No. 8 or its salt is about 2.5:1.

[0255] In some embodiments, in step (v), the molar ratio of the base to compound No. 8 or its salt is about 2.1:1.

[0256] In some embodiments, in step (v), the molar ratio of the base to compound No. 8 or its salt is about 2.0:1.

[0257] In some embodiments, in step (v), the reaction is carried out in the presence of a solvent. In some embodiments, the solvent is an aprotic organic solvent (e.g., toluene). In some embodiments, in step (v), the reaction is carried out in the presence of toluene.

[0258] In some embodiments, step (v) includes filtering a solution of compound No. 8 or its salt (e.g., in toluene).

[0259] In step (v) of some embodiments, compound No. 8 or its salt is isolated and / or purified prior to reaction with compound No. 6a or 6b or a salt thereof.

[0260] In step (v) of some embodiments, compound No. 8 or its salt is not isolated and / or purified before reacting with compound No. 6a or 6b or its salt.

[0261] In some embodiments, step (v) produces a solution of compound No. 8 or a salt thereof (e.g., in toluene).

[0262] In some embodiments, step (v) produces compound No. 8 or its salt with a purity of at least about 95%, as determined by HPLC.

[0263] In some embodiments, step (v) produces compound No. 8 or a salt thereof with a purity of at least about 96%, as determined by HPLC.

[0264] In some embodiments, step (v) produces compound No. 8 or a salt thereof with a purity of at least about 97%, as determined by HPLC.

[0265] In some embodiments, step (v) produces compound No. 8 or a salt thereof with a purity of at least about 98%, as determined by HPLC.

[0266] In some embodiments, step (v) produces compound No. 8 or a salt thereof with a purity of at least about 99%, as determined by HPLC.

[0267] Step (vi) In some embodiments, in step (vi), the reaction is carried out in the presence of a base. In some embodiments, the base is an inorganic base (e.g., NaOH).

[0268] In some implementations, in step (vi), the reaction is carried out in the presence of NaOH.

[0269] In some embodiments, in step (vi), the reaction is carried out in the presence of a first solvent. In some embodiments, the first solvent is an organic solvent. In some embodiments, the first solvent is an aprotic solvent (e.g., tetrahydrofuran (THF)).

[0270] In some embodiments, in step (vi), the reaction is carried out in the presence of tetrahydrofuran (THF).

[0271] In some embodiments, in step (vi), the molar ratio of compound No. 6a or 6b or a salt thereof to compound No. 8 or a salt thereof is about 2:1 to about 1:2.

[0272] In some embodiments, in step (vi), the molar ratio of compound No. 6a or 6b or a salt thereof to compound No. 8 or a salt thereof is about 1.5:1 to about 1:1.5.

[0273] In some embodiments, in step (vi), the molar ratio of compound No. 6a or 6b or a salt thereof to compound No. 8 or a salt thereof is about 1:1.

[0274] In some embodiments, in step (vi), the reaction is carried out in the presence of an organic solvent.

[0275] In some embodiments, in step (vi), the reaction is carried out in the presence of toluene.

[0276] In some implementations, in step (vi), the reaction includes removing the first solvent.

[0277] In some implementations, in step (vi), the reaction includes partial removal of the first solvent.

[0278] In some embodiments, in step (vi), the reaction is carried out in the presence of a second solvent. In some embodiments, in step (vi), the second solvent is an alcohol. In some embodiments, in step (vi), the second solvent is methanol, ethanol, or isopropanol. In some embodiments, in step (vi), the second solvent is isopropanol (IPA).

[0279] In some embodiments, in step (vi), the reaction includes extracting compound No. 9a or 9b using an ether.

[0280] In some embodiments, in step (vi), the reaction includes extracting compound No. 9a or 9b using methyl tert-butyl ether (MTBE).

[0281] In some embodiments, in step (vi), the reaction includes filtering out compound No. 9a or 9b.

[0282] In some embodiments, in step (vi), the reaction includes filtering out compound No. 9a or 9b and washing compound No. 9a or 9b with an organic solvent.

[0283] In some embodiments, in step (vi), the reaction includes filtering out compound No. 9a or 9b and washing compound No. 9a or 9b with a mixture of organic solvents.

[0284] In some embodiments, in step (vi), the reaction includes filtering out compound No. 9a or 9b and washing compound No. 9a or 9b with a mixture of alcohol and ether.

[0285] In some embodiments, in step (vi), the reaction includes filtering out compound No. 9a or 9b and washing compound No. 9a or 9b with IPA-MTBE.

[0286] In some embodiments, in step (vi), the reaction is carried out at a first temperature of 25±15°C, 25±10°C, or 25±5°C (e.g., about 25°C).

[0287] In some embodiments, in step (vi), the reaction is carried out at a first temperature of about 25 ± 15 °C, about 25 ± 10 °C, or about 25 ± 5 °C (e.g., about 25 °C).

[0288] In some embodiments, in step (iv), the reaction is carried out for 25 ± 20 hours, 5 ± 2 hours, 5 ± 4 hours, 5 ± 3 hours, 5 ± 2 hours or 5 ± 1 hours (e.g., about 5 hours, about 4 hours, about 3 hours, about 2 hours or about 1 hour).

[0289] In some embodiments, in step (iv), the reaction is carried out for about 25 ± 20 hours, about 5 ± 2 hours, about 5 ± 4 hours, about 5 ± 3 hours, about 5 ± 2 hours, or about 5 ± 1 hours (e.g., about 5 hours, about 4 hours, about 3 hours, about 2 hours, or about 1 hour).

[0290] In some implementations, step (vi) includes filtering compound No. 9a or 9b.

[0291] In some implementations, in step (vi), compound No. 9a or 9b is isolated and / or purified.

[0292] In some implementations, in step (vi), compound No. 9a or 9b is not isolated and / or purified.

[0293] In some embodiments, step (vi) produces compound No. 9a or 9b with a purity of at least about 95%, as determined by HPLC.

[0294] In some embodiments, step (vi) produces compound No. 9a or 9b with a purity of at least about 96%, as determined by HPLC.

[0295] In some embodiments, step (vi) produces compound No. 9a or 9b with a purity of at least about 97%, as determined by HPLC.

[0296] In some embodiments, step (vi) produces compound No. 9a or 9b with a purity of at least about 98%, as determined by HPLC.

[0297] In some embodiments, step (vi) produces compound No. 9a or 9b with a purity of at least about 99%, as determined by HPLC.

[0298] Step (vii) In some embodiments, step (vii) includes recrystallizing compound No. 9a or 9b in the presence of an organic solvent. In some embodiments, the organic solvent comprises n-heptane.

[0299] In some embodiments, step (vii) includes recrystallizing compound No. 9a or 9b from tetrahydrofuran, water, and ethyl acetate in the presence of an organic solvent. In some embodiments, the organic solvent comprises n-heptane.

[0300] In some embodiments, in step (vii), compound No. 9a or 9b is dissolved in tetrahydrofuran.

[0301] In some embodiments, in step (vii), compound No. 9a or 9b is dissolved in tetrahydrofuran and filtered.

[0302] In some embodiments, in step (vii), compound No. 9a or 9b is dissolved in about 4 volumes of tetrahydrofuran and filtered.

[0303] In some embodiments, in step (vii), compound No. 9a or 9b is dissolved in tetrahydrofuran, filtered, and washed with tetrahydrofuran to form a first mixture.

[0304] In some embodiments, in step (vii), compound No. 9a or 9b is dissolved in about 4 volumes of tetrahydrofuran, filtered, and washed with 2 × 1 volumes of tetrahydrofuran to form a first mixture.

[0305] In some implementations, the first mixture is concentrated in step (vii).

[0306] In some implementations, the first mixture in step (vii) is concentrated to approximately 3 volumes.

[0307] In some embodiments, the first mixture of the concentration step (vii) is added with ethyl acetate to form a second mixture.

[0308] In some embodiments, the first mixture of step (vii) is concentrated to about 3 volumes and ethyl acetate is added to form a second mixture.

[0309] In some embodiments, the first mixture of step (vii) is concentrated to about 3 volumes and about 15 volumes of ethyl acetate is added to form a second mixture.

[0310] In some implementations, the second mixture is concentrated in step (vii).

[0311] In some embodiments, the second mixture of the concentration step (vii) is combined with ethyl acetate and water to form a third mixture.

[0312] In some embodiments, the second mixture of step (vii) is concentrated to about 10 volumes.

[0313] In some embodiments, the second mixture from step (vii) is concentrated to about 10 volumes and ethyl acetate and water are added to form a third mixture.

[0314] In some embodiments, the second mixture from step (vii) is concentrated to about 10 volumes and about 10 volumes of ethyl acetate and about 0.2 volumes of water are added to form a third mixture.

[0315] In some embodiments, the third mixture in step (vii) is heated and then inoculated to form an inoculated third mixture.

[0316] In some embodiments, the third mixture of step (vii) is heated to a first temperature of 45±20°C, 45±15°C, 45±10°C, 45±5°C, 45±4°C, 45±3°C, 45±2°C or 45±1°C (e.g., about 45°C) and then inoculated to form an inoculated third mixture.

[0317] In some embodiments, the third mixture of step (vii) is heated to a first temperature of about 45±20°C, about 45±15°C, about 45±10°C, about 45±5°C, about 45±4°C, about 45±3°C, about 45±2°C, or about 45±1°C (e.g., about 45°C), and then inoculated to form the inoculated third mixture.

[0318] In some embodiments, after heating to the first temperature, the third mixture of inoculation in step (vii) is aged for 1 ± 2 hours or 1 ± 1 hour (e.g., about 0.5 hours or about 1 hour).

[0319] In some embodiments, after heating to the first temperature, the third mixture of inoculation in step (vii) is aged for about 1 ± 2 hours or about 1 ± 1 hour (e.g., about 0.5 hours or about 1 hour).

[0320] In some embodiments, in step (vii), after aging the inoculated third mixture, the inoculated third mixture is cooled to a second temperature of 30±20°C, 30±15°C, 30±10°C, 30±5°C, 30±4°C, 30±3°C, 30±2°C, or 30±1°C (e.g., about 30°C).

[0321] In some embodiments, in step (vii), after aging the inoculated third mixture, the inoculated third mixture is cooled to a second temperature of about 30±20°C, about 30±15°C, about 30±10°C, about 30±5°C, about 30±4°C, about 30±3°C, about 30±2°C, or about 30±1°C (e.g., about 30°C).

[0322] In some embodiments, in step (vii), after aging the inoculated third mixture, the inoculated third mixture is cooled to a second temperature of 30±20°C, 30±15°C, 30±10°C, 30±5°C, 30±4°C, 30±3°C, 30±2°C, or 30±1°C (e.g., about 30°C) and aged for about 1 hour to about 12 hours, about 2 hours to about 10 hours, or about 3 hours to about 6 hours to form a mixture containing compound No. 10.

[0323] In some embodiments, in step (vii), after aging the inoculated third mixture, the inoculated third mixture is cooled to a second temperature of about 30±20°C, about 30±15°C, about 30±10°C, about 30±5°C, about 30±4°C, about 30±3°C, about 30±2°C, or about 30±1°C (e.g., about 30°C), and aged for about 1 hour to about 12 hours, about 2 hours to about 10 hours, or about 3 hours to about 6 hours to form a mixture containing compound No. 10.

[0324] In some embodiments, in step (vii), after aging the inoculated third mixture, the inoculated third mixture is cooled to a second temperature of 30±20°C, 30±15°C, 30±10°C, 30±5°C, 30±4°C, 30±3°C, 30±2°C, or 30±1°C (e.g., about 30°C) and aged for about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, or about 12 hours to form a mixture containing compound No. 10a or 10b.

[0325] In some embodiments, in step (vii), after aging the inoculated third mixture, the inoculated third mixture is cooled to a second temperature of about 30±20°C, about 30±15°C, about 30±10°C, about 30±5°C, about 30±4°C, about 30±3°C, about 30±2°C, or about 30±1°C (e.g., about 30°C), and aged for about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, or about 12 hours to form a mixture containing compound No. 10a or 10b.

[0326] In some embodiments, in step (vii), n-heptane is added to the mixture containing compound No. 10a or 10b to form compound No. 10a or 10b in solid form.

[0327] In some embodiments, in step (vii), about 5 volumes of n-heptane are added to the mixture containing compound No. 10a or 10b to form compound No. 10a or 10b in solid form.

[0328] In some embodiments, in step (vii), the solid form of compound No. 10a or 10b is filtered out and washed to form a substantially pure solid form of compound No. 10a or 10b.

[0329] In some embodiments, in step (vii), the solid form of compound No. 10a or 10b is filtered out and washed with a mixture containing ethyl acetate, heptane and water to form a substantially pure solid form of compound No. 10a or 10b.

[0330] In some embodiments, in step (vii), the solid form of compound No. 10a or 10b is filtered out, thereby separating the substantially pure solid form of compound No. 10a or 10b.

[0331] In some embodiments, in step (vii), the solid form of compound No. 10a or 10b is filtered out and washed with ethyl acetate-heptane to separate the substantially pure solid form of compound No. 10a or 10b.

[0332] In some embodiments, in step (vii), the solid form of compound No. 10a or 10b is filtered out and washed with aqueous ethyl acetate-heptane to separate substantially pure solid form of compound No. 10a or 10b.

[0333] In some embodiments, in step (vii), the solid form of compound No. 10a or 10b is filtered out and washed with 4:1 ethyl acetate-heptane (4 volumes) containing 1% v / v water (relative to ethyl acetate) to form a substantially pure solid form of compound No. 10a or 10b.

[0334] In some embodiments, in step (vii), the solid form of compound No. 10a or 10b is dried.

[0335] In some implementations, step (vii) produces the polymorphic form of compound No. 10a or 10b.

[0336] In some embodiments, the polymorphic form is a monohydrate of compound No. 10a or 10b.

[0337] In some embodiments, step (vii) produces a polymorphic form of compound No. 10a (e.g., form 3).

[0338] In some implementations, form 3 is the monohydrate of compound No. 10a.

[0339] In some implementations, step (vii) produces the polymorphic form (form 3) of compound No. 10 monohydrate.

[0340] In some implementations, form 3 exhibits high solubility in water, for example, high water solubility.

[0341] In some implementations, compound No. 10a has a water solubility of about 24 μg / mL in simulated gastric juice (FaSSGF; pH about 1.6) under fasting conditions.

[0342] In some implementations, compound No. 10a has a water solubility of about 169 μg / mL in a simulated intestinal fluid (FeSSIF; pH about 5.0) under feeding conditions.

[0343] In some implementations, compound No. 10a has a water solubility of about 126 μg / mL in fasting simulated intestinal fluid (FaSSIF; pH about 6.5).

[0344] In some embodiments, compound No. 10a has a water solubility of more than 300 mg / mL in tris(hydroxymethyl)aminomethane (Tris; pH about 8.0).

[0345] In some embodiments, compound No. 10a (form 3) exhibits good solubility in methanol, ethanol, acetone, methyl ethyl ketone (MEK), and tetrahydrofuran.

[0346] In some embodiments, compound No. 10a (form 3) exhibits poor solubility in ethyl acetate, isopropyl acetate, methyl isobutyl ketone (MIBK), isopropanol, and n-heptane.

[0347] In some embodiments, step (vii) produces compound No. 10a or 10b in solid form with a purity of at least about 98%, as determined by HPLC.

[0348] In some embodiments, step (vii) produces compound No. 10a or 10b in solid form with a purity of at least about 98.5%, as determined by HPLC.

[0349] In some embodiments, step (vii) produces compound No. 10a or 10b in solid form with a purity of at least about 99%, as determined by HPLC.

[0350] In some embodiments, step (vii) produces compound No. 10a or 10b in solid form with a purity of at least about 99.1%, as determined by HPLC.

[0351] In some embodiments, step (vii) produces compound No. 10a or 10b in solid form with a purity of at least about 99.2%, as determined by HPLC.

[0352] In some embodiments, step (vii) produces compound No. 10a or 10b in solid form with a purity of at least about 99.3%, as determined by HPLC.

[0353] In some embodiments, step (vii) produces compound No. 10a or 10b in solid form with a purity of at least about 99.4%, as determined by HPLC.

[0354] In some embodiments, step (vii) produces compound No. 10a or 10b in solid form with a purity of at least about 99.5%, as determined by HPLC.

[0355] In some embodiments, step (vii) produces compound No. 10a or 10b in solid form with a purity of at least about 99.6%, as determined by HPLC.

[0356] In some embodiments, step (vii) produces compound No. 10a or 10b in solid form with a purity of at least about 99.7%, as determined by HPLC.

[0357] In some embodiments, step (vii) produces compound No. 10a or 10b in solid form with a purity of at least about 99.8%, as determined by HPLC.

[0358] In some implementations, step (vii) produces substantially pure compound No. 10.

[0359] In some implementations, step (vii) produces a substantially pure polymorphic form (form 3) of compound No. 10a.

[0360] In some embodiments, step (vii) produces compound No. 10a in solid form with a purity of at least about 98%, as determined by HPLC.

[0361] In some embodiments, step (vii) produces compound No. 10a in solid form with a purity of at least about 98.5%, as determined by HPLC.

[0362] In some embodiments, step (vii) produces compound No. 10a in solid form with a purity of at least about 99%, as determined by HPLC.

[0363] In some embodiments, step (vii) produces compound No. 10a in solid form with a purity of at least about 99.1%, as determined by HPLC.

[0364] In some embodiments, step (vii) produces compound No. 10a in solid form with a purity of at least about 99.2%, as determined by HPLC.

[0365] In some embodiments, step (vii) produces compound No. 10a in solid form with a purity of at least about 99.3%, as determined by HPLC.

[0366] In some embodiments, step (vii) produces compound No. 10a in solid form with a purity of at least about 99.4%, as determined by HPLC.

[0367] In some embodiments, step (vii) produces compound No. 10a in solid form with a purity of at least about 99.5%, as determined by HPLC.

[0368] In some embodiments, step (vii) produces compound No. 10a in solid form with a purity of at least about 99.6%, as determined by HPLC.

[0369] In some embodiments, step (vii) produces compound No. 10a in solid form with a purity of at least about 99.7%, as determined by HPLC.

[0370] In some embodiments, step (vii) produces compound No. 10a in solid form with a purity of at least about 99.8%, as determined by HPLC.

[0371] In some implementations, step (vii) produces substantially pure compound No. 10a.

[0372] In some implementations, step (vii) produces a substantially pure polymorphic form (form 3) of compound No. 10a.

[0373] In some embodiments, step (vii) produces compound No. 10b in solid form with a purity of at least about 98%, as determined by HPLC.

[0374] In some embodiments, step (vii) produces compound No. 10b in solid form with a purity of at least about 98.5%, as determined by HPLC.

[0375] In some embodiments, step (vii) produces compound No. 10b in solid form with a purity of at least about 99%, as determined by HPLC.

[0376] In some embodiments, step (vii) produces compound No. 10b in solid form with a purity of at least about 99.1%, as determined by HPLC.

[0377] In some embodiments, step (vii) produces compound No. 10b in solid form with a purity of at least about 99.2%, as determined by HPLC.

[0378] In some embodiments, step (vii) produces compound No. 10b in solid form with a purity of at least about 99.3%, as determined by HPLC.

[0379] In some embodiments, step (vii) produces compound No. 10b in solid form with a purity of at least about 99.4%, as determined by HPLC.

[0380] In some embodiments, step (vii) produces compound No. 10b in solid form with a purity of at least about 99.5%, as determined by HPLC.

[0381] In some embodiments, step (vii) produces compound No. 10b in solid form with a purity of at least about 99.6%, as determined by HPLC.

[0382] In some embodiments, step (vii) produces compound No. 10b in solid form with a purity of at least about 99.7%, as determined by HPLC.

[0383] In some embodiments, step (vii) produces compound No. 10b in solid form with a purity of at least about 99.8%, as determined by HPLC.

[0384] In some implementations, step (vii) produces substantially pure compound No. 10b.

[0385] In some embodiments, in-process testing is performed during the synthesis of compound No. 10a to monitor the completion of conversion or drying at each step.

[0386] In some embodiments, step (vii) produces at least one solid form of compound No. 10a or 10b with a purity of at least about 98%, as determined by HPLC.

[0387] In some embodiments, step (vii) produces at least one solid form of compound No. 10a or 10b with a purity of at least about 98.5%, as determined by HPLC.

[0388] In some embodiments, step (vii) produces at least one solid form of compound No. 10a or 10b with a purity of at least about 99%, as determined by HPLC.

[0389] In some embodiments, step (vii) produces at least one solid form of compound No. 10a or 10b with a purity of at least about 99.1%, as determined by HPLC.

[0390] In some embodiments, step (vii) produces at least one solid form of compound No. 10a or 10b with a purity of at least about 99.2%, as determined by HPLC.

[0391] In some embodiments, step (vii) produces at least one solid form of compound No. 10a or 10b with a purity of at least about 99.3%, as determined by HPLC.

[0392] In some embodiments, step (vii) produces at least one solid form of compound No. 10a or 10b with a purity of at least about 99.4%, as determined by HPLC.

[0393] In some embodiments, step (vii) produces at least one solid form of compound No. 10a or 10b with a purity of at least about 99.5%, as determined by HPLC.

[0394] In some embodiments, step (vii) produces at least one solid form of compound No. 10a or 10b with a purity of at least about 99.6%, as determined by HPLC.

[0395] In some embodiments, step (vii) produces at least one solid form of compound No. 10a or 10b with a purity of at least about 99.7%, as determined by HPLC.

[0396] In some embodiments, step (vii) produces at least one solid form of compound No. 10a or 10b with a purity of at least about 99.8%, as determined by HPLC.

[0397] In some embodiments, step (vii) produces at least one solid form of compound No. 10a with a purity of at least about 98%, as determined by HPLC.

[0398] In some embodiments, step (vii) produces at least one solid form of compound No. 10a with a purity of at least about 98.5%, as determined by HPLC.

[0399] In some embodiments, step (vii) produces at least one solid form of compound No. 10a with a purity of at least about 99%, as determined by HPLC.

[0400] In some embodiments, step (vii) produces at least one solid form of compound No. 10a with a purity of at least about 99.1%, as determined by HPLC.

[0401] In some embodiments, step (vii) produces at least one solid form of compound No. 10a with a purity of at least about 99.2%, as determined by HPLC.

[0402] In some embodiments, step (vii) produces at least one solid form of compound No. 10a with a purity of at least about 99.3%, as determined by HPLC.

[0403] In some embodiments, step (vii) produces at least one solid form of compound No. 10a with a purity of at least about 99.4%, as determined by HPLC.

[0404] In some embodiments, step (vii) produces at least one solid form of compound No. 10a with a purity of at least about 99.5%, as determined by HPLC.

[0405] In some embodiments, step (vii) produces at least one solid form of compound No. 10a with a purity of at least about 99.6%, as determined by HPLC.

[0406] In some embodiments, step (vii) produces at least one solid form of compound No. 10a with a purity of at least about 99.7%, as determined by HPLC.

[0407] In some embodiments, step (vii) produces at least one solid form of compound No. 10a with a purity of at least about 99.8%, as determined by HPLC.

[0408] In some embodiments, step (vii) produces at least one solid form of compound No. 10b with a purity of at least about 98%, as determined by HPLC.

[0409] In some embodiments, step (vii) produces at least one solid form of compound No. 10b with a purity of at least about 98.5%, as determined by HPLC.

[0410] In some embodiments, step (vii) produces at least one solid form of compound No. 10b with a purity of at least about 99%, as determined by HPLC.

[0411] In some embodiments, step (vii) produces at least one solid form of compound No. 10b with a purity of at least about 99.1%, as determined by HPLC.

[0412] In some embodiments, step (vii) produces at least one solid form of compound No. 10b with a purity of at least about 99.2%, as determined by HPLC.

[0413] In some embodiments, step (vii) produces at least one solid form of compound No. 10b with a purity of at least about 99.3%, as determined by HPLC.

[0414] In some embodiments, step (vii) produces at least one solid form of compound No. 10b with a purity of at least about 99.4%, as determined by HPLC.

[0415] In some embodiments, step (vii) produces at least one solid form of compound No. 10b with a purity of at least about 99.5%, as determined by HPLC.

[0416] In some embodiments, step (vii) produces at least one solid form of compound No. 10b with a purity of at least about 99.6%, as determined by HPLC.

[0417] In some embodiments, step (vii) produces at least one solid form of compound No. 10b with a purity of at least about 99.7%, as determined by HPLC.

[0418] In some embodiments, step (vii) produces at least one solid form of compound No. 10b with a purity of at least about 99.8%, as determined by HPLC.

[0419] In some embodiments, in-process testing is performed during the synthesis of compound No. 10a to monitor the completion of conversion or drying at each step. The testing methods for process control (IPC) are shown in Table 2.

[0420] Table 2: Test methods used in the preparation of compound No. 10a .

[0421] Compounds prepared by the method In some respects, this disclosure provides a compound prepared by the methods disclosed herein.

[0422] In some respects, this disclosure provides a compound that can be prepared on a large scale according to the methods disclosed herein.

[0423] In some respects, this disclosure provides a method for preparing compound No. 5.

[0424] In some respects, this disclosure provides a method for preparing compound No. 5a.

[0425] In some respects, this disclosure provides a method for preparing compound No. 5b.

[0426] In some respects, this disclosure provides a method for preparing compound No. 6.

[0427] In some respects, this disclosure provides a method for preparing compound No. 6a.

[0428] In some respects, this disclosure provides a method for preparing compound No. 6b.

[0429] In some respects, this disclosure provides a method for preparing compound No. 8.

[0430] In some respects, this disclosure provides a method for preparing compound No. 9.

[0431] In some respects, this disclosure provides a method for preparing compound No. 9a.

[0432] In some respects, this disclosure provides a method for preparing compound No. 9b.

[0433] In some respects, this disclosure provides a method for preparing compound No. 9'.

[0434] In some respects, this disclosure provides a method for preparing compound No. 9a'.

[0435] In some respects, this disclosure provides a method for preparing compound No. 9b'.

[0436] In some respects, this disclosure provides a method for preparing compound No. 10.

[0437] In some respects, this disclosure provides a method for preparing compound No. 10a.

[0438] In some respects, this disclosure provides a method for preparing compound No. 10b.

[0439] In some respects, this disclosure provides a method for preparing compound No. 10'.

[0440] In some respects, this disclosure provides a method for preparing compound No. 10a'.

[0441] In some respects, this disclosure provides a method for preparing compound No. 10b'.

[0442] In some respects, this disclosure provides compound No. 3 or a salt thereof.

[0443] In some respects, this disclosure provides compound No. 3a or a salt thereof.

[0444] In some embodiments, the compound is compound No. 3a or a salt thereof, having an enantiomeric excess (ee) 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.

[0445] In some embodiments, the compound is compound No. 3a 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.

[0446] In some respects, this disclosure provides compound No. 3b or a salt thereof.

[0447] In some embodiments, the compound is compound No. 3b or a salt thereof, having an enantiomeric excess (ee) 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.

[0448] In some embodiments, the compound is compound No. 3b 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.

[0449] In some respects, this disclosure provides compound No. 4 or a salt thereof.

[0450] In some respects, this disclosure provides compound No. 4a or a salt thereof.

[0451] In some embodiments, the compound is compound No. 4a or a salt thereof, having an enantiomeric excess (ee) 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.

[0452] In some embodiments, the compound is compound No. 4a 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.

[0453] In some respects, this disclosure provides compound No. 4b or a salt thereof.

[0454] In some embodiments, the compound is compound No. 4b or a salt thereof, having an enantiomeric excess (ee) 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.

[0455] In some embodiments, the compound is compound No. 4b 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.

[0456] In some respects, this disclosure provides compound No. 5 or a salt thereof.

[0457] In some respects, this disclosure provides compound No. 5a or a salt thereof.

[0458] In some embodiments, the compound is compound No. 5a or a salt thereof, having an enantiomeric excess (ee) 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.

[0459] In some embodiments, the compound is compound No. 5a 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.

[0460] In some respects, this disclosure provides compound No. 5b or a salt thereof.

[0461] In some embodiments, the compound is compound No. 5b or a salt thereof, having an enantiomeric excess (ee) 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.

[0462] In some embodiments, the compound is compound No. 5b 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.

[0463] In some respects, this disclosure provides compound No. 6 or a salt thereof.

[0464] In some respects, this disclosure provides compound No. 6a or a salt thereof.

[0465] In some embodiments, the compound is compound No. 6a or a salt thereof, having an enantiomeric excess (ee) 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.

[0466] In some embodiments, the compound is compound No. 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.

[0467] In some respects, this disclosure provides compound No. 6b or a salt thereof.

[0468] In some embodiments, the compound is compound No. 6b or a salt thereof, having an enantiomeric excess (ee) 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.

[0469] In some embodiments, the compound is compound No. 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.

[0470] In some respects, this disclosure provides compound No. 8 or a salt thereof.

[0471] In some embodiments, the compound is compound No. 8 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.

[0472] In some respects, this disclosure provides for compound No. 9.

[0473] In some respects, this disclosure provides for compound No. 9a.

[0474] In some embodiments, the compound is compound No. 9a, having an enantiomeric excess (ee) 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.

[0475] In some embodiments, the compound is compound No. 9a, 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.

[0476] In some respects, this disclosure provides for compound No. 9b.

[0477] In some embodiments, the compound is compound No. 9b, having an enantiomeric excess (ee) 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.

[0478] In some embodiments, the compound is compound No. 9b, 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.

[0479] In some embodiments, the compound is: Compound No. 9; Compound No. 9a; or Compound No. 9b has the following properties: (a) an enantiomeric excess of approximately 90% or higher, approximately 95% or higher, approximately 96% or higher, approximately 97% or higher, approximately 98% or higher, approximately 99% or higher, approximately 99.5% or higher, approximately 99.6% or higher, approximately 99.7% or higher, approximately 99.8% or higher, or approximately 99.9% or higher (ee); and / or (b) Purity of approximately 90% or higher, approximately 95% or higher, approximately 96% or higher, approximately 97% or higher, approximately 98% or higher, approximately 99% or higher, approximately 99.5% or higher, approximately 99.6% or higher, approximately 99.7% or higher, approximately 99.8% or higher, or approximately 99.9% or higher.

[0480] In some respects, this disclosure provides for compound No. 9'.

[0481] In some respects, this disclosure provides for compound No. 9a'.

[0482] In some embodiments, the compound is compound No. 9a', having an enantiomeric excess (ee) 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.

[0483] In some embodiments, the compound is compound No. 9a', 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.

[0484] In some respects, this disclosure provides for compound No. 9b'.

[0485] In some embodiments, the compound is compound No. 9b', having an enantiomeric excess (ee) 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.

[0486] In some embodiments, the compound is compound No. 9b', 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.

[0487] In some embodiments, the compound is: Compound No. 9'; Compound No. 9a'; or Compound No. 9b' has the following properties: (a) an enantiomeric excess of approximately 90% or higher, approximately 95% or higher, approximately 96% or higher, approximately 97% or higher, approximately 98% or higher, approximately 99% or higher, approximately 99.5% or higher, approximately 99.6% or higher, approximately 99.7% or higher, approximately 99.8% or higher, or approximately 99.9% or higher (ee); and / or (b) Purity of approximately 90% or higher, approximately 95% or higher, approximately 96% or higher, approximately 97% or higher, approximately 98% or higher, approximately 99% or higher, approximately 99.5% or higher, approximately 99.6% or higher, approximately 99.7% or higher, approximately 99.8% or higher, or approximately 99.9% or higher.

[0488] In some respects, this disclosure provides for compound No. 10.

[0489] In some respects, this disclosure provides for compound No. 10a.

[0490] In some embodiments, the compound is compound No. 10a, having an enantiomeric excess (ee) 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.

[0491] In some embodiments, the compound is compound No. 10a, 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.

[0492] In some respects, this disclosure provides for compound No. 10b.

[0493] In some embodiments, the compound is compound No. 10b, having an enantiomeric excess (ee) 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.

[0494] In some embodiments, the compound is compound No. 10b, 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.

[0495] In some embodiments, the compound is: Compound No. 10; Compound No. 10a; or Compound No. 10b has the following properties: (a) an enantiomeric excess of approximately 90% or higher, approximately 95% or higher, approximately 96% or higher, approximately 97% or higher, approximately 98% or higher, approximately 99% or higher, approximately 99.5% or higher, approximately 99.6% or higher, approximately 99.7% or higher, approximately 99.8% or higher, or approximately 99.9% or higher (ee); and / or (b) Purity of approximately 90% or higher, approximately 95% or higher, approximately 96% or higher, approximately 97% or higher, approximately 98% or higher, approximately 99% or higher, approximately 99.5% or higher, approximately 99.6% or higher, approximately 99.7% or higher, approximately 99.8% or higher, or approximately 99.9% or higher.

[0496] In some respects, this disclosure provides for compound No. 10'.

[0497] In some respects, this disclosure provides for compound No. 10a'.

[0498] In some embodiments, the compound is compound No. 10a', having an enantiomeric excess (ee) 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.

[0499] In some embodiments, the compound is compound No. 10a', 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.

[0500] In some respects, this disclosure provides for compound No. 10b'.

[0501] In some embodiments, the compound is compound No. 10b', having an enantiomeric excess (ee) 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.

[0502] In some embodiments, the compound is compound No. 10b', 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.

[0503] In some embodiments, the compound is: Compound No. 10'; Compound No. 10a'; or Compound No. 10b' has the following properties: (a) an enantiomeric excess of approximately 90% or higher, approximately 95% or higher, approximately 96% or higher, approximately 97% or higher, approximately 98% or higher, approximately 99% or higher, approximately 99.5% or higher, approximately 99.6% or higher, approximately 99.7% or higher, approximately 99.8% or higher, or approximately 99.9% or higher (ee); and / or (b) Purity of approximately 90% or higher, approximately 95% or higher, approximately 96% or higher, approximately 97% or higher, approximately 98% or higher, approximately 99% or higher, approximately 99.5% or higher, approximately 99.6% or higher, approximately 99.7% or higher, approximately 99.8% or higher, or approximately 99.9% or higher.

[0504] How to use In some aspects, this disclosure provides a method for preventing or treating a disease in a subject, comprising administering to the subject a compound No. 10 as described herein (e.g., compound No. 10a or 10b).

[0505] In some implementations, a therapeutically effective dose is administered to the subject.

[0506] In some aspects, this disclosure provides a method of treating a subject’s disease, comprising administering to the subject a compound No. 10 as described herein (e.g., compound No. 10a or 10b).

[0507] In some respects, this disclosure provides compounds No. 10 (e.g., compounds No. 10a or 10b) as described herein for the prevention or treatment of a disease in a subject.

[0508] In some respects, this disclosure provides the use of compound No. 10 (e.g., compound No. 10a or 10b) as described herein in the manufacture of a pharmaceutical preparation for the prevention or treatment of a disease in a subject.

[0509] In some respects, this disclosure provides the use of compound No. 10 (e.g., compound No. 10a or 10b) as described herein in the manufacture of a pharmaceutical preparation for treating a disease of a subject.

[0510] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is administered in a therapeutically effective amount.

[0511] In some implementations, the disease or disorder is an inflammatory disorder, an autoinflammatory disorder, an autoimmune disorder, a neurodegenerative disease, or cancer.

[0512] In some aspects, this disclosure provides a method for inhibiting the activity of a subject inflammasome (e.g., the NLRP3 inflammasome), which includes contacting cells with a compound No. 10 as described herein (e.g., compound No. 10a or 10b).

[0513] In some respects, this disclosure provides compounds No. 10 (e.g., compounds No. 10a or 10b) as described herein, which are used to inhibit the activity of inflammasomes (e.g., NLRP3 inflammasomes) in a subject.

[0514] In some respects, this disclosure provides the use of compound No. 10 (e.g., compound No. 10a or 10b) as described herein in the manufacture of pharmaceutical agents for inhibiting the activity of inflammasomes (e.g., NLRP3 inflammasome).

[0515] In some implementations, the subject is an animal.

[0516] In some implementations, the subject is a mammal.

[0517] In some implementations, the subject is a human being.

[0518] In some implementations, the subject is a cell.

[0519] In some implementations, the subjects are a population of cells.

[0520] Pharmaceutical Compositions / Formulations In some embodiments, this disclosure provides pharmaceutical compositions comprising compound No. 10 (e.g., compound No. 10a or 10b) and excipients, adjuvants, diluents, or carriers (e.g., pharmaceutically acceptable excipients, adjuvants, diluents, or carriers).

[0521] Pharmaceutical compositions can be formulated in a conventional manner using one or more physiologically acceptable carriers, including excipients and adjuvants that facilitate the processing of active compounds into pharmaceutically acceptable formulations.

[0522] Appropriate formulation depends on the chosen route of administration. Any known techniques, carriers, and excipients suitable and understood in the art may be used. An overview of the pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins, 1999), the entire contents of which are incorporated herein by reference.

[0523] As used herein, a pharmaceutical composition refers to compound No. 10 (e.g., compound No. 10a or 10b) and / or other therapeutic agents with other chemical components such as carriers, stabilizers, diluents, dispersants, suspending agents, thickeners, and / or excipients. As used herein, a pharmaceutical composition refers to compound No. 10 (e.g., compound No. 10a or 10b) with one or more of the following excipients: microcrystalline cellulose, cropovidone, hydroxypropyl methylcellulose, sodium bicarbonate, hydrophobic colloidal silica, and magnesium stearate.

[0524] When implementing the treatment methods or uses provided herein, a therapeutically effective amount of the disclosed compound No. 10 (e.g., compound No. 10a or 10b) is administered to a subject suffering from a disease, disorder, or condition to be treated. In some embodiments, the mammal is a human. The therapeutically effective amount of the compound may vary depending on the severity of the disease, the age and relative health status of the subject, and other factors.

[0525] Pharmaceutical compositions containing compound No. 10 described herein (e.g., compound No. 10a or 10b) can be manufactured in conventional ways, such as by means of conventional mixing, dissolving, granulation, making sugar-coated pills, grinding, emulsifying, encapsulating, embedding, or compression.

[0526] Bioassay Compounds prepared by the methods described herein can be characterized using various assays known to those skilled in the art to determine whether the compound possesses biological activity. For example, the molecule can be characterized by conventional assays, including but not limited to those described below, to determine whether it possesses predicted activity, binding activity, and / or binding specificity.

[0527] Furthermore, high-throughput screening can be used to accelerate analyses using these assays. Therefore, it is possible to rapidly screen the activity of the molecules described herein using techniques known in the art. General methods for performing high-throughput screening are described, for example, in Devlin (1998) High Throughput Screening, Marcel Dekker; and U.S. Patent No. 5,763,263. High-throughput assays may use one or more different assay techniques, including but not limited to those described below.

[0528] Various in vitro or in vivo bioassays may be suitable for detecting the effects of the compounds disclosed herein. These in vitro or in vivo bioassays may include, but are not limited to, enzyme activity assays, electrophoretic mobility variation assays, reporter gene assays, in vitro cell viability assays, and the assays described herein.

[0529] In some implementations, the bioassay is a bioassay that tests the inhibitory activity against the release of IL-1β following NLRP3 activation in peripheral blood mononuclear cells (PBMCs).

[0530] In some implementations, the bioassay is a PBMC IC50 assay.

[0531] In some implementations, the compound is tested for its inhibitory activity against the release of IL-1β following NLRP3 activation in blood cells (e.g., peripheral blood mononuclear cells (PBMCs)).

[0532] In some embodiments, PBMCs are isolated and seeded into wells and incubated for a period of time (e.g., 3 hours with lipopolysaccharide). After incubation, the culture medium is changed and a compound (e.g., the compound disclosed herein) is added to the wells, and the cells can be incubated again. Next, the cells are stimulated (e.g., with ATP or nigericin) and the cell culture medium is collected for analysis.

[0533] In some implementations, the release of IL-1β into the culture medium is determined by quantitatively detecting IL-1β in the culture medium (e.g., using ELISA).

[0534] In some implementations, PBMCs are isolated (e.g., from the erythrocyte sedimentation rate (ESR) amber layer). The isolated cells are seeded into wells and incubated (e.g., with lipopolysaccharide for 3 hours). The compound is then added and the cells are incubated again. Next, the cells are stimulated and the culture medium from the wells is collected for analysis.

[0535] In some implementations, IL-1β released into the culture medium is determined by quantitative detection (e.g., using HTRF® to quantitatively detect IL-1β in the culture medium).

[0536] definition Unless otherwise stated, the following terms used in the specification and claims have the meanings given below.

[0537] As used herein, the term “about” means approximately, within a range, roughly, or around. When the term “about” is used with a numerical range, it modifies the range by expanding the upper and lower limits of the value. Generally, the term “about” is used herein to modify a value that is 20%, 10%, 5%, 3%, or 1% higher or lower than the value.

[0538] As used herein, the term “substantially pure” for a compound means that the compound contains less than 10%, less than 5%, less than 3%, less than 1%, less than 0.5%, less than 0.2%, or less than 0.1% by weight of impurities.

[0539] As used herein, the term "CO source" refers to a reagent that can act as a source of carbon monoxide (CO) during a reaction. In some embodiments, the reagent is capable of forming an isocyanate or equivalent upon reaction with an amine. In some embodiments, the dissociation reaction of phosgene, the reaction between CO2 and carbon (the Boudouard reaction), the reaction of vapor with carbon, the high-temperature electrolysis of carbon dioxide using a solid oxide electrolyzer, or the direct oxidation of carbon under limited oxygen or air supply are CO sources. In some embodiments, phosgene derivatives are CO sources. In one specific embodiment, triphosgene is the CO source.

[0540] It should be understood that the compounds described herein include the compounds themselves and their salts and solvates (if applicable). For example, salts can be formed between an anion and a positively charged group (e.g., an amino group) on a substituted benzene compound. Suitable anions may include chloride, bromide, iodide, sulfate, hydrogen sulfate, aminosulfonate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, glutamate, glucuronide, glutarate, malate, maleate, succinate, fumarate, tartrate, toluenesulfonate, salicylate, lactate, naphthalenesulfonate, and acetate (e.g., trifluoroacetate). Unless otherwise stated, the expressions “one or more of A, B, or C,” “one or more of A, B, or C,” “one or more of A, B, and C,” “one or more of A, B, and C,” “selected from the group consisting of A, B, and C,” “selected from A, B, and C,” etc., used herein are used interchangeably and all refer to the group consisting of A, B, and / or C, i.e., one or more A, one or more B, one or more C, or any combination thereof.

[0541] It should be understood that throughout the specification, when a composition is described as having, including, or comprising specific components, it is also contemplated that the composition is substantially composed of or consisting of the listed components. Similarly, when a method or process is described as having, including, or comprising specific process steps, the method is also substantially composed of or consisting of the listed process steps. Furthermore, it should be understood that the order of the steps or the sequence in which certain operations are performed is not important, as long as the invention remains practicable. Moreover, two or more steps or operations may be performed simultaneously.

[0542] It should be understood that the synthetic methods disclosed herein are accommodating to a wide variety of functional groups, and therefore allow for the use of a variety of substituted raw materials. The methods typically provide the desired final compound at or near the end of the overall process, although in some cases it may be desirable to further convert the compound into its pharmaceutically acceptable salt.

[0543] It should be understood that compounds No. 10a or 10b can be prepared in various ways using commercially available raw materials, compounds known in the literature, or readily prepared intermediates, using standard synthetic methods and procedures known to those skilled in the art or obvious to those skilled in the art based on the teachings herein. Standard synthetic methods and procedures for the preparation of organic molecules and for the transformation and manipulation of functional groups are available from relevant scientific literature or standard textbooks in the field. Although not limited to any one or a few sources, classic textbooks such as Smith, MB, March, J., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th ed., John Wiley & Sons: New York, 2001; Greene, TW, Wuts, PGM, Protective Groups in Organic Synthesis, 3rd ed., John Wiley & Sons: New York, 1999; R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette (ed.), Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) (which are cited here and incorporated herein by reference) are known and widely accepted reference textbooks for organic synthesis in the art.

[0544] Those skilled in the art will notice that the order of certain steps, such as the introduction and removal of protecting groups, can be altered during the reaction sequences and synthetic schemes described herein. They will also recognize that certain groups may require protecting with protecting groups to prevent them from being affected by reaction conditions. Protecting groups can also be used to distinguish similar functional groups within a molecule. A list of protecting groups and how to introduce and remove them can be found in Greene, TW, Wuts, PGM, Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons: New York, 1999.

[0545] It should be understood that, unless otherwise stated, any description of a treatment or prevention method includes the use of compound No. 10a or 10b to provide the treatment or prevention as described herein. It should be further understood that, unless otherwise stated, any description of a treatment or prevention method includes the preparation of an agent for the treatment or prevention of such conditions using compound No. 10a or 10b. Treatment or prevention includes treatment or prevention in humans or non-human animals, including rodents and other disease models.

[0546] It should be understood that, unless otherwise stated, any description of a treatment method includes the use of compound No. 10a or 10b to provide the treatment as described herein. It should be further understood that, unless otherwise stated, any description of a treatment method includes the preparation of an agent for treating such conditions using compound No. 10a or 10b. Treatment includes treatment in humans or non-human animals, including rodents and other disease models.

[0547] In some implementations, the term "filtered out" refers to the collection of the desired compound in solid form using a filter medium.

[0548] As used herein, the term "subject" includes human or non-human animals, as well as cell lines, cell cultures, tissues, and organs. In some embodiments, the subject is a mammal. A 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 avian. In some embodiments, the subject is a human.

[0549] As used herein, the term "subject in need" means a subject who has a disease or has an increased risk of developing such a disease. A subject in need may be a subject who has been previously diagnosed or confirmed to have a disease or disorder disclosed herein. A subject in need may also be a subject suffering from a disease or disorder disclosed herein. Alternatively, a subject in need may be a subject with an increased risk of developing such a disease or disorder relative to the general population (i.e., a subject who is predisposed to such a disorder relative to the general population). A subject in need may suffer from a treatment-resistant or drug-resistant disease or disorder disclosed herein (i.e., a disease or disorder disclosed herein that is unresponsive or has not yet responded to treatment). The subject may be drug-resistant at the start of treatment or may become drug-resistant during treatment. In some embodiments, the subject in need has received all known effective therapies for the disease or disorder disclosed herein and these have failed. In some embodiments, the subject in need has received at least one prior therapy.

[0550] As used herein, the term "treating / treat" describes the management and care of a patient in order to combat a disease, condition, or disorder, and includes the administration of compounds of this disclosure or their pharmaceutically acceptable salts, polymorphs, or solvates to alleviate or eliminate symptoms or complications of the disease, condition, or disorder. The term "treating" may also include treatment in in vitro cell or animal models.

[0551] It should be understood that compounds No. 10a or 10b may or may also be used to prevent related diseases, conditions or disorders, or to identify suitable candidates for these purposes.

[0552] As used in this article, the term "preventing" describes reducing or eliminating the onset of symptoms or complications of such a disease, condition, or disorder.

[0553] It should be understood that for a detailed description of the known or equivalent techniques discussed herein, those skilled in the art may refer to general reference texts. 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 Edition), Cold Spring Harbor Press, Cold Spring Harbor, New York (2000); Coligan et al., Current Protocols in Immunology, John Wiley & Sons, NY; Enna et al., Current Protocols in Pharmacology, John Wiley & Sons, NY; Fingle et al., The Pharmacological Basis of Therapeutics (1975), Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 18th Edition (1990). These texts may also be referenced when making or using any aspect of this disclosure.

[0554] As used herein, the term "pharmaceutical composition" is a formulation containing compound No. 10a or 10b in a form suitable for administration to a subject. In some embodiments, the pharmaceutical composition is in bulk or unit dosage form. Unit dosage form is any of a variety of forms, including, for example, capsules, IV bags, tablets, single pumps or tubing bottles on aerosol inhalers. The amount of active ingredient (e.g., a formulation of the disclosed compound or its salts, hydrates, solvates or isomers) in a unit dose composition is an effective amount and varies depending on the specific treatment involved. Those skilled in the art will recognize that doses must sometimes be routinely varied according to the patient's age and condition. Dosage also depends on the route of administration. Various routes are considered, including oral, pulmonary, rectal, parenteral, percutaneous, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalation, buccal, sublingual, intrapleural, intrathecal, intravitreal, intranasal, etc. Dosage forms for topical or percutaneous administration of the compounds of this disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalers. In one embodiment, the active compound is mixed under sterile conditions with one or more pharmaceutically acceptable carriers, and with any necessary preservatives, buffers, or propellants. As used herein, the term "pharmaceutically acceptable" means those compounds, anionic, cationic, materials, compositions, carriers, and / or dosage forms that are suitable for use in human and animal tissues to the extent of reasonable medical judgment without excessive toxicity, irritation, allergic reactions, or other problems or complications, and that are commensurate with a reasonable benefit / risk ratio.

[0555] As used herein, the term "pharmaceuticalally acceptable excipient" means an excipient that can be used to prepare pharmaceutical compositions that are generally safe, non-toxic, and not biologically or otherwise undesirable, and includes excipients acceptable for veterinary use as well as for human pharmaceutical use. "Pharmaceuticalally acceptable excipient" as used in the specification and claims may include one or more such excipients.

[0556] It is to be understood that the pharmaceutical compositions disclosed herein are formulated to be compatible with their intended route of administration. Examples of routes of administration include parenteral, such as intravenous, intradermal, subcutaneous, intravitreal, oral (e.g., ingestion), inhalation, transdermal (topical), and transmucosal administration. Solutions or suspensions intended for parenteral, intradermal, or subcutaneous application may include the following components: sterile diluents, such as water for injection, saline solution, non-volatile oils, polyethylene glycol, glycerol, propylene glycol, or other synthetic solvents; antibacterial agents, such as benzyl alcohol or methylparaben; antioxidants, such as ascorbic acid or sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid; buffers, such as acetates, citrates, or phosphates; and agents for adjusting the pH, such as sodium chloride or dextran. The pH may be adjusted with an acid or base, such as hydrochloric acid or sodium hydroxide. Parenteral formulations may be packaged in ampoules, disposable syringes, or multi-dose vials made of glass or plastic.

[0557] It is to be understood that the compounds or pharmaceutical compositions disclosed herein can be administered to a subject in many well-known methods currently used for chemotherapy. For example, the compounds disclosed herein can be injected into the bloodstream or body cavity, or administered orally or transdermally as a patch. The selected dose should be sufficient to constitute an effective treatment, but not high enough to cause unacceptable side effects. Close monitoring of the disease status (e.g., the disease or disorder disclosed herein) and the patient's health should preferably be conducted during treatment and for a reasonable period after treatment.

[0558] As used herein, the term "therapeutic effective amount" refers to the amount of a pharmaceutical agent that treats, improves, or prevents an identified disease or condition, or that 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 depends on the subject's weight, body type, and health; the nature and extent of the condition; and the chosen therapeutic agent or combination of therapeutic agents. The therapeutic effective amount for a given condition can be determined through routine laboratory testing within the technical and judgmental capabilities of a clinician.

[0559] As used herein, the term "effective amount" refers to the amount of a drug that treats or improves an identified disease or condition 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 depends on the subject's weight, body type, and health; the nature and extent of the condition; and the chosen therapeutic agent or combination of therapeutic agents. The therapeutically effective amount for a given condition can be determined through routine laboratory testing within the technical and judgmental capabilities of a clinician.

[0560] It is important to understand that for any compound, a therapeutically effective dose or effective amount can initially be evaluated in cell culture assays, such as tumor cell culture assays, or in animal models, typically 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 the dose and route of administration that will be useful in humans. Therapeutic / prophylactic efficacy and toxicity can be determined in cell cultures or laboratory animals using standard pharmaceutical procedures, such as ED. 50 (The effective dose in 50% of the population) and LD50 50 (The dose that is lethal to 50% of the population). The dose ratio between toxicity and therapeutic effect is the therapeutic index, which can be expressed as the ratio LD50. 50 / ED 50 Pharmaceutical compositions exhibiting a high therapeutic index are preferred. Dosage may vary within this range, depending on the dosage form used, patient sensitivity, and route of administration.

[0561] Adjust the dosage and administration to provide adequate levels of the active agent or maintain the desired effect. Factors that may be taken into consideration include the severity of the disease state, the subject's general health condition, the subject's age, weight and sex, diet, timing and frequency of administration, drug combination, responsiveness, and tolerance / response to treatment.

[0562] Pharmaceutical compositions containing compounds No. 10a or 10b can be manufactured in a manner commonly known, such as by conventional mixing, dissolving, granulation, pelleting, grinding, emulsification, encapsulation, entrapping, or lyophilization. The pharmaceutical compositions can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers containing excipients and / or adjuvants that facilitate the processing of compound No. 10a or 10b into a pharmaceutically acceptable formulation. Appropriate formulations depend on the chosen route of administration.

[0563] In some embodiments, the pharmaceutical compositions disclosed herein further comprise pharmaceutically acceptable excipients, such as diluents, carriers, adjuvants, binders, lubricants, surfactants, sweeteners, flavorings, coating materials, preservatives, dyes, thickeners, or combinations thereof.

[0564] It should be understood that the pharmaceutical composition may be included in a container, package, or dispenser along with the instructions for use.

[0565] It should be understood that all these forms are also within the scope of the claimed disclosure for compounds of this disclosure that are capable of further forming salts.

[0566] As used herein, the term "pharmaceutically acceptable salt" refers to a derivative of a compound disclosed herein, wherein the parent compound is modified by preparing its acid or base salt. Examples of pharmaceutically acceptable salts may include, but are not limited to, inorganic or organic acid salts of basic residues such as amines, and alkali metal or organic salts of acidic residues such as carboxylic acids. Pharmaceutically acceptable salts may include those formed from the parent compound, such as conventional non-toxic salts or quaternary ammonium salts formed from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts may include, but are not limited to, salts derived from the following inorganic and organic acids: 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edemanic acid, ethanedisulfonic acid, 1,2-ethanesulfonic acid, fumaric acid, glucoheponic acid, gluconic acid, glutamic acid, glycolic acid, arsanilic acid, hexylresorcinol, hyaluronic 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, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, succinic acid, aminosulfonic acid, p-aminobenzenesulfonic acid, sulfuric acid, tannic acid, tartaric acid, toluenesulfonic acid, and common amino acids such as glycine, alanine, phenylalanine, and arginine.

[0567] In some embodiments, the salt is a sodium salt, potassium salt, calcium salt, magnesium salt, diethylamine salt, choline salt, meglumine salt, benzyl benzoate salt, tromethamine salt, ammonium salt, arginine salt, or lysine salt. In some embodiments, the salt is a sodium salt.

[0568] In some embodiments, the pharmaceutically acceptable salt is a sodium salt, potassium salt, calcium salt, magnesium salt, diethylamine salt, choline salt, meglumine salt, benzylamine salt, tromethamine salt, ammonium salt, arginine salt, or lysine salt. In some embodiments, the pharmaceutically acceptable salt is a sodium salt. Other examples of pharmaceutically acceptable salts may include hexanoic acid, cyclopentanepropionic acid, pyruvic acid, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo-[2.2.2]-oct-2-ene-1-carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, mucoconic acid, etc. This disclosure also covers salts formed when an acidic proton present in the parent compound is replaced by a metal ion (e.g., an alkali metal ion, an alkaline earth metal ion, or an aluminum ion); or when coordinated with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucosamine, etc. In the salt form, it is to be understood that the ratio of the cation or anion of the compound to the salt can be 1:1, or any ratio other than 1:1, such as 3:1, 2:1, 1:2, or 1:3.

[0569] It should be understood that all references to pharmaceutically acceptable salts may include the same salt in its solvation form (solvent) or crystalline form (polymorph) as defined herein.

[0570] As used herein, form 2 of compound No. 10a corresponds to form 2 disclosed in U.S. Provisional Patent Application No. 63 / 600,104, filed November 17, 2023.

[0571] In some embodiments, form 2 of compound No. 10a is characterized by XRPD plots using Cu Kα radiation containing signals at 4.2±0.5, 16.7±0.5, and 16.8±0.5 °2θ (e.g., 4.2±0.2, 16.7±0.2, and 16.8±0.2 °2θ using Cu Kα radiation; e.g., 4.2±0.1, 16.7±0.1, and 16.8±0.1 °2θ using Cu Kα radiation; e.g., 4.2, 16.7, and 16.8 °2θ using Cu Kα radiation)).

[0572] In some embodiments, compound No. 10a, form 2, is characterized by XRPD patterns obtained using Cu Kα radiation at values ​​of 4.2±0.5, 8.4±0.5, 10.2±0.5, 10.4±0.5, 13.1±0.5, 13.5±0.5, 16.3±0.5, 16.7±0.5, 16.8±0.5, 18.2±0.5, 18.6±0.5, 19.3±0.5, 20.8±0.5, 21.1±0.5, 23.0±0.5, 23.3±0.5, and 23.5±0. 5, 24.3±0.5, 24.7±0.5, 25.2±0.5, 25.3±0.5, 25.6±0.5, 26.1±0.5, 26.6±0.5, 27.1±0.5, 28.3±0.5, 28.9±0.5, 29.1±0.5, 29.5±0.5, 29.8±0.5, 30.0±0.5, 30.3±0.5, 30.7±0.5, 31.1±0.5 and 31.7±0.5 °2θ (e.g. using Cu) The values ​​of Kα radiation are 4.2±0.2, 8.4±0.2, 10.2±0.2, 10.4±0.2, 13.1±0.2, 13.5±0.2, 16.3±0.2, 16.7±0.2, 16.8±0.2, 18.2±0.2, 18.6±0.2, 19.3±0.2, 20.8±0.2, 21.1±0.2, 23.0±0.2, 23.3±0.2, 23.5±0.2, and 24. 0.3±0.2, 24.7±0.2, 25.2±0.2, 25.3±0.2, 25.6±0.2, 26.1±0.2, 26.6±0.2, 27.1±0.2, 28.3±0.2, 28.9±0.2, 29.1±0.2, 29.5±0.2, 29.8±0.2, 30.0±0.2, 30.3±0.2, 30.7±0.2, 31.1±0.2 and 31.7±0.2 °2θ (e.g. using Cu) The values ​​of Kα radiation are 4.2±0.1, 8.4±0.1, 10.2±0.1, 10.4±0.1, 13.1±0.1, 13.5±0.1, 16.3±0.1, 16.7±0.1, 16.8±0.1, 18.2±0.1, 18.6±0.1, 19.3±0.1, 20.8±0.1, 21.1±0.1, 23.0±0.1, 23.3±0.1, 23 0.5±0.1, 24.3±0.1, 24.7±0.1, 25.2±0.1, 25.3±0.1, 25.6±0.1, 26.1±0.1, 26.6±0.1, 27.1±0.1, 28.3±0.1, 28.9±0.1, 29.1±0.1, 29.5±0.1, 29.8±0.1, 30.0±0.1, 30.3±0.1, 30.7±0.1. Signals at 31.1±0.1 and 31.7±0.1 °2θ (e.g., signals using Cu Kα radiation at 4.2, 8.4, 10.2, 10.4, 13.1, 13.5, 16.3, 16.7, 16.8, 18.2, 18.6, 19.3, 20.8, 21.1, 23.0, 23.3, 23.5, 24.3, 24.7, 25.2, 25.3, 25.6, 26.1, 26.6, 27.1, 28.3, 28.9, 29.1, 29.5, 29.8, 30.0, 30.3, 30.7, 31.1, and 31.7 °2θ).

[0573] In some embodiments, compound No. 10a in form 2 is characterized by an endothermic event that begins at 50 ± 20 °C, 50 ± 15 °C, 50 ± 10 °C or 50 ± 5 °C (e.g., about 50 °C), as measured by DSC.

[0574] In some embodiments, compound No. 10a in form 2 is characterized by an endothermic event that begins at 144±20°C, 144±15°C, 144±10°C or 144±5°C (e.g., about 144°C), as measured by DSC.

[0575] In some embodiments, compound No. 10a, form 2, is characterized by a water absorption of 9.1 ± 0.5%, 9.1 ± 0.4%, 9.1 ± 0.3%, 9.1 ± 0.2%, 9.1 ± 0.1%, or 9.1 ± 0.05% (e.g., about 9.1%) as measured by GVS.

[0576] In some embodiments, compound No. 10a, form 2, is characterized by an absorbance of 2.2 ± 0.05%, 2.2 ± 0.04%, 2.2 ± 0.03%, 2.2 ± 0.02%, or 2.2 ± 0.01% (e.g., about 2.2%) as measured by GVS (e.g., from 40% to 70% RH).

[0577] In some embodiments, compound No. 10a, form 2, is characterized by an absorbance of 6.1 ± 0.05%, 6.1 ± 0.04%, 6.1 ± 0.03%, 6.1 ± 0.02%, or 6.1 ± 0.01% (e.g., about 6.1%) as measured by GVS (e.g., from 40% to 70% RH).

[0578] In some embodiments, compound No. 10a in form 2 is characterized by a reversible hysteresis (e.g., from 70% to 10% RH) as measured by GVS.

[0579] As used herein, form 3 of compound No. 10a corresponds to form 3 disclosed in U.S. Provisional Patent Application No. 63 / 600,104, filed November 17, 2023.

[0580] In some embodiments, form 3 of compound No. 10a is characterized by XRPD plots using Cu Kα radiation containing signals at 4.4 ± 0.5, 8.4 ± 0.5, and 17.8 ± 0.5 °2θ (e.g., 4.4 ± 0.2, 8.4 ± 0.2, and 17.8 ± 0.2 °2θ using Cu Kα radiation; e.g., 4.4 ± 0.1, 8.4 ± 0.1, and 17.8 ± 0.1 °2θ using Cu Kα radiation; e.g., 4.4, 8.4, and 17.8 °2θ using Cu Kα radiation)).

[0581] In some embodiments, compound No. 10a, form 3, is characterized by XRPD patterns obtained using Cu Kα radiation at values ​​of 4.4±0.5, 8.4±0.5, 8.9±0.5, 11.1±0.5, 11.4±0.5, 12.0±0.5, 14.2±0.5, 14.3±0.5, 15.1±0.5, 16.8±0.5, 17.3±0.5, 17.8±0.5, 19.0±0.5, 19.2±0.5, 19.6±0.5, 20.6±0.5, 20.9±0.5, and 21.3±0.5. 21.5±0.5, 21.9±0.5, 22.3±0.5, 22.4±0.5, 22.9±0.5, 23.2±0.5, 23.6±0.5, 24.4±0.5, 24.8±0.5, 25.2±0.5, 26.8±0.5, 27.4±0.5, 27.8±0.5, 29.1±0.5, 29.4±0.5, 29.8±0.5, 30.1±0.5, 31.0±0.5 and 31.4±0.5 °2θ (e.g. using Cu) The values ​​of Kα radiation are 4.4±0.2, 8.4±0.2, 8.9±0.2, 11.1±0.2, 11.4±0.2, 12.0±0.2, 14.2±0.2, 14.3±0.2, 15.1±0.2, 16.8±0.2, 17.3±0.2, 17.8±0.2, 19.0±0.2, 19.2±0.2, 19.6±0.2, 20.6±0.2, 20.9±0.2, 21.3±0.2, and 21. 5±0.2, 21.9±0.2, 22.3±0.2, 22.4±0.2, 22.9±0.2, 23.2±0.2, 23.6±0.2, 24.4±0.2, 24.8±0.2, 25.2±0.2, 26.8±0.2, 27.4±0.2, 27.8±0.2, 29.1±0.2, 29.4±0.2, 29.8±0.2, 30.1±0.2, 31.0±0.2 and 31.4±0.2 °2θ (e.g. using Cu) The values ​​of Kα radiation were 4.4±0.1, 8.4±0.1, 8.9±0.1, 11.1±0.1, 11.4±0.1, 12.0±0.1, 14.2±0.1, 14.3±0.1, 15.1±0.1, 16.8±0.1, 17.3±0.1, 17.8±0.1, 19.0±0.1, 19.2±0.1, and 19.6± 0.1, 20.6±0.1, 20.9±0.1, 21.3±0.1, 21.5±0.1, 21.9±0.1, 22.3±0.1, 22.4±0.1, 22.9±0.1, 23.2±0.1, 23.6±0.1, 24.4±0.1, 24.8±0.1, 25.2±0.1, 26.8±0.1, 27.4±0.1, 27.8±0.1, 29.1±0.1, 29.4±0.1, 29.8±0.1, 30.1±0.1, 31.0±0.1 and 31.4±0.1 °2θ (e.g. using Cu) Signals of Kα radiation at 4.4, 8.4, 8.9, 11.1, 11.4, 12.0, 14.2, 14.3, 15.1, 16.8, 17.3, 17.8, 19.0, 19.2, 19.6, 20.6, 20.9, 21.3, 21.5, 21.9, 22.3, 22.4, 22.9, 23.2, 23.6, 24.4, 24.8, 25.2, 26.8, 27.4, 27.8, 29.1, 29.4, 29.8, 30.1, 31.0, and 31.4 °2θ.

[0582] In some embodiments, compound No. 10a, form 3, is characterized by degradation events up to 85±40°C, 85±30°C, 85±20°C, 85±15°C, 85±10°C, or 85±5°C (e.g., up to about 85°C), as measured by TGA.

[0583] In some embodiments, compound No. 10a, form 3, is characterized by degradation events that begin at 85±40°C, 85±30°C, 85±20°C, 85±15°C, 85±10°C, or 85±5°C (e.g., about 85°C), as measured by TGA.

[0584] In some embodiments, compound No. 10a in form 3 is characterized by an endothermic event that begins at 34 ± 20 °C, 34 ± 15 °C, 34 ± 10 °C or 34 ± 5 ​​°C (e.g., about 34 °C), as measured by DSC.

[0585] In some embodiments, compound No. 10a in form 3 is characterized by an endothermic event that begins at 102 ± 20 °C, 102 ± 15 °C, 102 ± 10 °C or 102 ± 5 °C (e.g., about 102 °C), as measured by DSC.

[0586] In some embodiments, compound No. 10a in form 3 is characterized by an endothermic event that begins at 152 ± 20 °C, 152 ± 15 °C, 152 ± 10 °C or 152 ± 5 °C (e.g., about 152 °C), as measured by DSC.

[0587] In some embodiments, compound No. 10a in form 3 is characterized by an absorbance of 2.3 ± 0.5%, 2.3 ± 0.4%, 2.3 ± 0.3%, 2.3 ± 0.2%, 2.3 ± 0.1% or 2.3 ± 0.05% (e.g., about 2.3%) as measured by GVS.

[0588] In some embodiments, compound No. 10a, form 3, is characterized by an absorbance of 8.9 ± 0.5%, 8.9 ± 0.4%, 8.9 ± 0.3%, 8.9 ± 0.2%, 8.9 ± 0.1%, or 8.9 ± 0.05% (e.g., about 8.9%) as measured by GVS.

[0589] In some embodiments, compound No. 10a, form 3, is characterized by an absorbance of 5.1 ± 0.5%, 5.1 ± 0.4%, 5.1 ± 0.3%, 5.1 ± 0.2%, 5.1 ± 0.1%, or 5.1 ± 0.05% (e.g., about 5.1%) as measured by GVS.

[0590] In some embodiments, compound No. 10a in form 3 is characterized by a reversible hysteresis (e.g., from 70% to 10% RH) as measured by GVS.

[0591] In some embodiments, compound No. 10a, form 3, is a crystalline solid having one or more of the following characteristics: a) Crystal size of 0.300 x 0.250 x 0.200 mm; b) Colorless, cut rod-shaped crystal habit; c) Monoclinic system; d) The space group of P21; e) The cell size; f) 2457.54(4) Å 3 Volume; g) 1.350 Mg / m 3 Density (calculated); h) 1.708 mm -1 The absorption coefficient; and / or i) 1056 F (000).

[0592] As used herein, the term "inorganic acid" refers to acids such as, but not limited to, hydrobromic acid, hydroiodic acid, sulfuric acid, aminosulfonic acid, nitric acid, boric acid, phosphoric acid, and combinations thereof.

[0593] As used herein, the term "organic acid" refers to acids such as, but not limited to: acetic acid; trifluoroacetic acid; phenylacetic acid; propionic acid; stearic acid; lactic acid; ascorbic acid; maleic acid; hydroxymaleic acid; ethanesulfonic acid; succinic acid; valeric acid; fumaric acid; malonic acid; pyruvic acid; oxalic acid; glycolic acid; salicylic acid; oleic acid; palmitic acid; lauric acid; pyranoside, such as glucuronic acid or galacturonic acid; α-hydroxy acids, such as mandelic acid, citric acid or tartaric acid; cysteine ​​sulfinic acid; amino acids, such as aspartic acid, glutaric acid or glutamic acid; aromatic acids, such as benzoic acid, 2-acetoxybenzoic acid, naphtholic acid or cinnamic acid; sulfonic acids, such as lauryl sulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid or ethanesulfonic acid; cysteine ​​sulfonic acid; and combinations thereof.

[0594] As used herein, the term "inorganic base" refers to bases such as, but not limited to, sodium hydroxide, potassium hydroxide, lithium hydroxide, ammonium hydroxide, magnesium hydroxide, sodium carbonate, potassium carbonate, barium hydroxide, calcium hydroxide, ammonia, and combinations thereof.

[0595] As used herein, the term "organic base" refers to an organic compound containing one or more nitrogen atoms and acting as a base. Examples of organic bases include, but are not limited to, tertiary amine bases. Examples of organic bases include, but are not limited to, 1,8-diazabicyclo[5.4.0]undec-7-ene ("DBU"), N-methylmorpholine (NMM), diisopropylethylamine (DIPEA), triethylamine (TEA), and tert-butoxides (e.g., sodium tert-butoxide, potassium tert-butoxide, calcium tert-butoxide, or magnesium tert-butoxide).

[0596] As used herein, the term "inorganic solvent" refers to a solvent that does not contain carbon, except as otherwise specified below. In one embodiment, the inorganic solvent may contain or be composed of water. In another embodiment, the inorganic solvent may contain a non-aqueous solvent. For example, and not limited to, inorganic non-aqueous solvents may include ammonia, sulfur dioxide, sulfuryl chloride, sulfuryl chloride fluoride, phosphoryl chloride, nitrogen tetroxide, antimony trichloride, bromine pentafluoride, sulfuric acid, nitric acid, phosphorus tribromide, hydrogen fluoride, supercritical carbon dioxide, carbon dioxide, carbon disulfide, various molten salts, etc.

[0597] As used herein, the term "organic solvent" refers to an organic molecule capable of at least partially dissolving another substance (i.e., a solute). Examples of organic solvents that can be used in this invention include, but are not limited to: hydrocarbon solvents (e.g., n-pentane, n-hexane, n-heptane, n-octane, paraffin, cyclohexane, methylcyclohexane, decahydronaphthalene, mineral oil, crude oil, etc.), including aromatic solvents (e.g., benzene, toluene, o-xylene, m-xylene, and p-xylene), halogenated hydrocarbon solvents (e.g., carbon tetrachloride, 1,2-dichloroethane, dichloromethane, chloroform, etc.), ester solvents (e.g., ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, ethyl malonate, etc.), ketone solvents (e.g., acetone, methyl ethyl ketone or 2-butanone, methyl isobutyl ketone, cyclohexanone, cyclopentanone, 3-pentanone, etc.), and ether solvents (e.g., diethyl ether, dipropyl ether, diethyl ... Organic solvents include: phenyl ether, isopropyl ether, tert-butyl methyl ether, tetrahydrofuran, 1,4-dioxane, etc.; amine solvents (e.g., propylamine, diethylamine, triethylamine, aniline, pyridine); alcohol solvents (e.g., methanol, ethanol, isopropanol, 1-propanol, 2-methyl-1-propanol, 1-butanol, 2-butanol, 1-pentanol, 3-methyl-1-butanol, tert-butanol, 1-octanol, benzyl alcohol, phenol, trifluoroethanol, glycerol, ethylene glycol, propylene glycol, m-cresol, etc.); acid solvents (e.g., acetic acid, hexanoic acid, etc.); carbon disulfide; nitrobenzene; N,N-dimethylformamide; N,N-dimethylacetamide; dimethyl sulfoxide; N-methyl-2-pyrrolidone; acetonitrile; and siloxane solvents (e.g., silicone oil, polysiloxane, cyclosiloxane). In some embodiments, the organic solvent may be formed from a combination of two or more organic solvents.

[0598] As used herein, unless otherwise stated, the term "aprotic organic solvent" means any solvent that does not release protons. Examples of aprotic organic solvents include, but are not limited to, DMF, dioxane, THF, acetonitrile, pyridine, dichloroethane, dichloromethane, MTBE, toluene, etc.

[0599] The formulation and administration techniques of the compounds disclosed herein can be found in Remington: the Science and Practice of Pharmacy, 19th edition, Mack Publishing Co., Easton, PA (1995). In some embodiments, compound No. 10a or 10b is used in combination with one or more pharmaceutically acceptable carriers, excipients, or diluents for pharmaceutical formulations. Suitable pharmaceutically acceptable carriers include, but are not limited to, inert solid fillers or diluents and sterile aqueous or organic solutions. The compound is present in such pharmaceutical compositions in an amount sufficient to provide the desired dose within the range described herein.

[0600] Unless otherwise stated, all percentages and ratios used herein are by weight. Other features and advantages of this disclosure will be apparent from the various embodiments. The provided embodiments illustrate different components and methods that can be used to practice this disclosure. The embodiments do not limit the claimed disclosure. Based on this disclosure, those skilled in the art can identify and use other components and methods that can be used to practice this disclosure.

[0601] In the synthetic diagrams described herein, compounds may be drawn in a particular configuration for simplicity. Such a particular configuration should not be construed as limiting this disclosure to one or another isomer, tautomer, regio isomer, or stereoisomer, nor does it exclude mixtures of isomers, tautomers, regio isomers, or stereoisomers; however, it is to be understood that a given isomer, tautomer, regio isomer, or stereoisomer may have a higher level of activity than another isomer, tautomer, regio isomer, or stereoisomer.

[0602] All publications and patent documents cited herein are incorporated herein by reference, as if each such publication or document were expressly and individually indicated to be incorporated herein by reference. References to publications and patent documents are not intended as an admission that they are relevant prior art, nor do they constitute any admission of their contents or dates. The invention has now been described in writing, and those skilled in the art will recognize that the invention can be practiced in various embodiments, and that the foregoing description and the following examples are illustrative and not limiting of the subsequent claims.

[0603] This disclosure has been described, and the following embodiments are provided as illustrative rather than limiting.

[0604] Exemplary Implementation Exemplary Implementation 1. A method for preparing compound No. 10, comprising one or more of steps (iv)-(vii): (iv) Reacting compound No. 5 or its salt with an acid to form compound No. 6 or its salt; (v) Reacting compound No. 7 or its salt with a CO source to form compound No. 8 or its salt; (vi) To react compound No. 6 or its salt with compound No. 8 or its salt to form compound No. 9; or (vii) Purify compound No. 9 to separate compound No. 10.

[0605] Exemplary Implementation Scheme 2. A method for preparing compound No. 5 or a salt thereof, comprising: (iii) Reacting compound No. 5 or its salt with an acid to form compound No. 6 or its salt.

[0606] Exemplary Implementation 3. A method for preparing compound No. 9, comprising: (iv) React compound No. 6 or its salt with compound No. 8 or its salt to form compound No. 9.

[0607] Exemplary Implementation 4. A method for preparing compound No. 10, comprising: (vii) Purify compound No. 9 to separate compound No. 10.

[0608] Exemplary Implementation 5. The method as described in Exemplary Implementation 1, further comprising steps (i)-(iv): (i) Reacting tetrahydrofuran-2-carboxylic acid with 4-amino-1-methylpyrazole or a salt thereof to form N-(1-methyl-1H-pyrazole-4-yl)tetrahydrofuran-2-carboxamide or a salt thereof; (ii) Reacting N-(1-methyl-1H-pyrazol-4-yl)tetrahydrofuran-2-carboxamide or a salt thereof with a reducing agent to form 1-methyl-N-{[tetrahydrofuran-2-yl]methyl}-1H-pyrazol-4-amine or a salt thereof; (iii) Reacting 1-methyl-N-{[tetrahydrofuran-2-yl]methyl}-1H-pyrazole-4-amine or a salt thereof with tert-butyl N-chlorosulfonylcarbamate to form compound No. 5 or a salt thereof; and (iv) React compound No. 5 or its salt with an acid to form compound No. 6 or its salt.

[0609] Exemplary Implementation 6. The method as described in any of the foregoing exemplary implementations, wherein compound No. 9 is compound No. 9a.

[0610] Exemplary Implementation 7. The method as described in any of the foregoing exemplary implementations, wherein compound No. 10 is compound No. 10a.

[0611] Exemplary Implementation 8. The method as described in any of the foregoing exemplary implementations, wherein compound No. 9 is compound No. 9b.

[0612] Exemplary Implementation 9. The method as described in any of the foregoing exemplary implementations, wherein in step (iv), the acid is hydrochloric acid.

[0613] Exemplary Implementation 10. The method as described in any of the foregoing exemplary implementations, wherein in step (iv), the molar ratio of the acid to compound No. 5 or its salt is about 3:1 to about 1:1.

[0614] Exemplary Implementation 11. The method as described in any of the foregoing exemplary implementations, wherein in step (iv), the reaction is carried out in the presence of a first solvent to form a first mixture.

[0615] Exemplary Implementation 12. The method as described in any of the foregoing exemplary implementations, wherein in step (iv), the reaction is carried out at a first temperature of about 25 ± 15 °C, about 25 ± 10 °C, or about 25 ± 5 °C.

[0616] Exemplary Implementation 13. The method as described in any of the foregoing exemplary implementations, wherein in step (iv), the reaction is carried out for about 26 ± 20 hours, about 26 ± 15 hours, about 26 ± 10 hours, about 26 ± 5 hours, about 26 ± 4 hours, about 26 ± 3 hours, about 26 ± 2 hours, or about 26 ± 1 hour.

[0617] Exemplary Implementation 14. The method as described in Exemplary Implementation 11, wherein the first mixture is cooled to a second temperature of about 0±15°C, about 0±10°C, or about 0±5°C.

[0618] Exemplary Embodiment 15. The method as described in Exemplary Embodiment 11, wherein the first mixture is cooled to a second temperature of about 0±15°C, about 0±10°C, or about 0±5°C, and a second solvent is added to form a second mixture.

[0619] Exemplary Implementation 16. The method as described in Exemplary Implementation 15, wherein an alkali or buffer is added to the second mixture.

[0620] Exemplary Implementation 17. The method as described in any of the foregoing exemplary implementations, wherein in step (iv), compound No. 6 or its salt is isolated and / or purified prior to reaction with compound No. 8.

[0621] Exemplary Implementation 18. The method as described in Exemplary Implementation 17, wherein in step (iv), the purity of compound No. 6 or its salt is at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99%, as determined by HPLC.

[0622] Exemplary Implementation 19. The method as described in Exemplary Implementation 1, wherein in step (v), triphosgene is a CO source.

[0623] Exemplary Implementation 20. The method as described in Exemplary Implementation 1, wherein in step (v), the reaction is carried out in the presence of a base.

[0624] Exemplary Implementation 21. The method as described in Exemplary Implementation 20, wherein in step (v), the molar ratio of the base to compound No. 8 or a salt thereof is about 3:1 to about 1:1.

[0625] Exemplary Implementation 22. The method as described in Exemplary Implementation 1, wherein in step (v), the reaction is carried out in the presence of a solvent.

[0626] Exemplary Implementation 23. The method as described in Exemplary Implementation 1, wherein step (v) includes filtering a solution of compound No. 8 or a salt thereof.

[0627] Exemplary Implementation 24. The method as described in Exemplary Implementation 1, wherein in step (v), compound No. 8 or its salt is isolated and / or purified prior to reaction with compound No. 6 or its salt.

[0628] Exemplary Implementation 25. The method as described in Exemplary Implementation 1, wherein in step (v), compound No. 8 or its salt is not isolated and / or purified prior to reaction with compound No. 6 or its salt.

[0629] Exemplary Implementation 26. The method as described in Exemplary Implementation 1, wherein step (v) produces a solution of compound No. 8 or a salt thereof.

[0630] Exemplary Implementation 27. The method as described in Exemplary Implementation 1, wherein step (v) produces compound No. 8 or a salt thereof with a purity of at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99%, as determined by HPLC.

[0631] Exemplary Implementation 28. The method as described in Exemplary Implementation 1, wherein in step (vi), the reaction is carried out in the presence of a base.

[0632] Exemplary Implementation 29. The method as described in Exemplary Implementation 1, wherein in step (vi), the reaction is carried out in the presence of a first solvent.

[0633] Exemplary Implementation 30. The method as described in Exemplary Implementation 1, wherein in step (vi), the molar ratio of compound No. 6 or a salt thereof to compound No. 8 or a salt thereof is about 2:1 to about 1:2.

[0634] Exemplary Implementation 31. The method as described in Exemplary Implementation 1, wherein in step (vi), the reaction includes partial removal of the first solvent.

[0635] Exemplary Implementation 32. The method as described in Exemplary Implementation 1, wherein in step (vi), the reaction is carried out in the presence of a second solvent.

[0636] Exemplary Implementation 33. The method as described in Exemplary Implementation 1, wherein in step (vi), the reaction includes extracting compound No. 9 using an ether.

[0637] Exemplary Implementation 34. The method as described in Exemplary Implementation 1, wherein in step (vi), the reaction includes filtering out compound No. 9, washing compound No. 9 or a combination thereof with IPA-MTBE.

[0638] Exemplary Implementation 35. The method as described in Exemplary Implementation 1, wherein in step (vi), the reaction is carried out at a first temperature of about 25 ± 15°C, about 25 ± 10°C, or about 25 ± 5°C.

[0639] Exemplary Implementation 36. The method as described in Exemplary Implementation 1, wherein step (vi) includes filtering compound No. 9.

[0640] Exemplary Implementation 37. The method as described in Exemplary Implementation 1, wherein in step (vi), compound No. 9a or 9b is isolated and / or purified.

[0641] Exemplary Implementation 38. The method as described in Exemplary Implementation 1, wherein step (vi) produces compound No. 9 with a purity of at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99%, as determined by HPLC.

[0642] Exemplary Implementation 39. The method as described in Exemplary Implementation 1, wherein step (vii) includes recrystallizing compound No. 9 in the presence of an organic solvent.

[0643] Exemplary Implementation 40. The method as described in Exemplary Implementation 1, wherein in step (vii), compound No. 9 is dissolved in tetrahydrofuran, filtered, and washed with tetrahydrofuran to form a first mixture.

[0644] Exemplary Implementation 41. The method as described in Exemplary Implementation 40, wherein the first mixture of the concentration step (vii) is followed by the addition of ethyl acetate to form a second mixture.

[0645] Exemplary Implementation 42. The method as described in Exemplary Implementation 41, wherein the second mixture of the concentration step (vii) is followed by the addition of ethyl acetate and water to form a third mixture.

[0646] Exemplary Implementation 43. The method as described in Exemplary Implementation 42, wherein the third mixture of step (vii) is heated and then inoculated to form an inoculated third mixture.

[0647] Exemplary Implementation 44. The method as described in Exemplary Implementation 42, wherein the third mixture of step (vii) is heated to a first temperature of about 45±20°C, about 45±15°C, about 45±10°C, about 45±5°C, about 45±4°C, about 45±3°C, about 45±2°C, or about 45±1°C, and then inoculated to form an inoculated third mixture.

[0648] Exemplary Implementation 45. The method as described in Exemplary Implementation 44, wherein after heating to a first temperature, the third mixture inoculated in step (vii) is aged for about 1 ± 2 hours or 1 ± 1 hour.

[0649] Exemplary Implementation 46. The method as described in Exemplary Implementation 45, wherein in step (vii), after aging the inoculated third mixture, the inoculated third mixture is cooled to a second temperature of about 30±20°C, about 30±15°C, about 30±10°C, about 30±5°C, about 30±4°C, about 30±3°C, about 30±2°C, or about 30±1°C.

[0650] Exemplary Implementation 47. The method as described in Exemplary Implementation 45, wherein in step (vii), after aging the inoculated third mixture, the inoculated third mixture is cooled to a second temperature of about 30±20°C, about 30±15°C, about 30±10°C, about 30±5°C, about 30±4°C, about 30±3°C, about 30±2°C, or about 30±1°C (e.g., about 30°C), and aged for about 1 hour to about 12 hours, about 2 hours to about 10 hours, or about 3 hours to about 6 hours to form a mixture comprising compound No. 10.

[0651] Exemplary Implementation 48. The method as described in Exemplary Implementation 47, wherein in step (vii), n-heptane is added to the mixture containing compound No. 10 to form a solid form of compound No. 10.

[0652] Exemplary Implementation 49. The method as described in Exemplary Implementation 48, wherein in step (vii), the solid form of compound No. 10 is filtered out and washed to form a substantially pure solid form of compound No. 10.

[0653] Exemplary Implementation 50. The method as described in Exemplary Implementation 49, wherein step (vii) produces a specific polymorphic form of compound No. 10.

[0654] Exemplary Implementation 51. The method as described in Exemplary Implementation 49, wherein step (vii) produces a polymorphic form (form 3) of compound No. 10a.

[0655] Exemplary Implementation 52. The method as described in Exemplary Implementation 49, wherein step (vii) produces compound No. 10 in solid form with a purity of at least about 98%, at least about 98.5%, at least about 99%, at least about 99.1%, at least about 99.2%, at least about 99.3%, at least about 99.4%, at least about 99.5%, at least about 99.6%, at least about 99.7%, or at least about 99.8%, as determined by HPLC.

[0656] Exemplary Implementation 53. The method as described in Exemplary Implementation 49, wherein step (vii) produces a substantially pure polymorphic form (form 3) of compound No. 10a.

[0657] Exemplary Implementation 54. A compound prepared by the method of any one of the foregoing exemplary implementations.

[0658] Exemplary Embodiment 55. A pharmaceutical composition comprising compound No. 10 as described in any of the preceding exemplary embodiments, and one or more pharmaceutically acceptable carriers or excipients.

[0659] Exemplary Implementation 56. A method for preventing or treating a disease in a subject, comprising administering to the subject compound No. 10 of any one of the exemplary implementations.

[0660] Exemplary Implementation 57. Compound No. 10 of any of the foregoing exemplary implementations, used for the prevention or treatment of a subject's disease.

[0661] Exemplary Embodiment 58. Use of Compound No. 10 of any of the foregoing exemplary embodiments in the manufacture of a pharmaceutical preparation for the prevention or treatment of a subject’s disease.

[0662] Exemplary Implementation 59. A method for inhibiting the activity of inflammasomes in a subject, comprising contacting cells with compound No. 10 as described in any of the preceding exemplary implementations.

[0663] Exemplary Implementation 60. Compound No. 10 of any one of the foregoing exemplary implementations, used to inhibit the activity of inflammasomes in a subject.

[0664] Exemplary Embodiment 61. Use of compound No. 10 from any of the foregoing exemplary embodiments in the manufacture of a pharmaceutical agent for inhibiting inflammasome activity.

[0665] Exemplary Implementation 62. The method, compound, or use as described in any of the foregoing exemplary implementations, wherein the subject is a human. Example

[0666] The following embodiments are provided as illustrative purposes and not as limiting, given that this disclosure has already been described.

[0667] It should be understood that all values ​​presented in the examples are approximate and are subject to instrument and / or experimental variations.

[0668] Example 1. Exemplary synthesis of compound No. 10a The exemplary synthesis of compound No. 10a was carried out as shown in Schemes 1 and 2 and the following procedures. The overall synthetic route is a 7-step method, starting from commercially available or synthetically available starting materials. Scheme 1 details four steps of the preparation method. Compound No. 5a was prepared using the method described in Scheme 2.

[0669] Scheme 1: Synthetic route for the preparation of compound No. 10a Scheme 2: Synthetic route for the preparation of compound No. 5a (starting material) A. Materials Control Starting materials Two characterized starting materials were used in the preparation of compound No. 10a. 1,2,3,5,6,7-hexahydro-s-benzodiindene-4-amine (compound No. 7; CAS 63089-56-5) was a commercially available substance prepared to high specifications. The second starting material, compound No. 5a, was also prepared using the method described in Scheme 2. The starting materials (S)-tetrahydrofuran-2-carboxylic acid and 4-amino-1-methylpyrazole hydrochloride used to prepare compound No. 5a were commercially available substances.

[0670] All starting materials were fully synthetic, non-animal derived, and certified TSE-free. Starting materials were provided with the analytical certificate. All starting materials were validated and tested for use before proceeding to any step of the method.

[0671] Compound No. 5a (the starting material for step 4 of the preparation method) was prepared with very high purity (e.g., >99% as determined by HPLC). One parameter in the specification of Compound No. 5a is chiral purity. Due to toxicological issues related to the (R)-isomer, the specification for the enantiomer in Compound No. 5a was set at <100 ppm. This was achieved in part by using enantiomerically pure (S)-tetrahydrofuran-2-carboxylic acid, but during the preparation of Compound No. 5a, enantiomer excess was monitored at each stage, and both intermediates were recrystallized to ensure continuous chiral enrichment throughout the synthesis. The batches of Compound No. 5a conformed to this specification limit. The analysis of the batches of Compound No. 5a used in the preparation method is shown in Table A.

[0672] Table A: Analysis of Compound No. 5a Note: The identification of compound No. 5a in batches 1 and 2 was performed using... 1 H NMR, 13 Verification was performed using C NMR and mass spectrometry.

[0673] 1,2,3,5,6,7-Hexahydro-s-benzodiindene-4-amine (compound No. 7), the starting material for step 5 of the preparation method, was prepared with high purity (e.g., >98% as determined by HPLC). The analysis of compound No. 7 used in the preparation method is shown in Table B.

[0674] Table B: Analysis of Compound No. 7 Note: The identification of compound No. 7 in batch 1 was performed using... 1 Verification was performed using H NMR and mass spectrometry.

[0675] B. Control of steps and intermediates The yield and analytical results of the prepared intermediates are shown in Table CE.

[0676] Table C: Analysis of Compound No. 6a ND = Not detected Note: This method was used for the identification of compound 6a in batches 1 and 2. 1 H NMR verification.

[0677] Compound No. 8 was prepared in the form of a toluene solution and used directly in step 6. The analysis is shown in Table D.

[0678] Table D: Analysis of Compound No. 8 Note: Compound 8 in batches 1 and 2 was used for identification. 1 H NMR verification.

[0679] Table E: Analysis of crude compound No. 9a Note: This method was used for the identification of compound 9a in batches 1 and 2. 1 H NMR verification.

[0680] In-process tests were performed during the synthesis of compound No. 10a to monitor the completion of conversion or drying at each step. The progress of each reaction was monitored using analytical techniques known in the art, such as HPLC, GC, GC-HS, MS, NMR, XRPD, and KF.

[0681] Step 4: Preparation of 1-(1-methyl-1H-pyrazol-4-yl)-1-[{(2S)-tetrahydrofuran-2-yl}methyl]sulfonylurea (compound No. 6a) Step 4 involves deprotecting the starting material (compound No. 5a) from its BOC using an aqueous hydrochloric acid solution. The reaction conditions for step 4 are as shown in Scheme 3.

[0682] Scheme 3: Step 4 - Preparation of compound No. 6a An aqueous solution of hydrochloric acid was prepared using water (1.1 v / v) and concentrated hydrochloric acid (5.0 equivalents, 1.1 v / v). Compound No. 5a (1 equivalent) was added in portions over approximately 2 hours. The mixture was stirred at room temperature for approximately 24 hours. After the reaction was complete, the mixture was cooled to 0 °C. Dichloromethane (2 v / v) was added, and the mixture was then alkalized by adding dropwise 46% sodium hydroxide solution (4.5 equivalents) over approximately 1 hour while maintaining the temperature at approximately 0 °C. The mixture was warmed to room temperature, and the pH was finely adjusted to pH 8 / 9 using 30% K₂CO₃ solution. The layers were separated, and the aqueous layer was extracted with dichloromethane (2 × 1 v / v) [water loss: ~0.5 mg / mL, 0.2% loss]. The combined dichloromethane extracts were washed with water (2 × 1 v / v), and the combined washes were further extracted with dichloromethane (1 × 2 v / v) [water loss: ~8.0 mg / mL, 2.3% loss]. The dichloromethane solution was concentrated to approximately 4 volumes (relative to compound No. 6). Heptane (6 volumes) was added dropwise, and the resulting slurry was aged at room temperature for approximately 1 hour. The solids were removed by filtration, and the filter cake was washed with heptane (1 × 1 volume) [mother liquor loss: ~2.6 mg / mL, 2.1% loss]. The collected solids were vacuum dried at 20°C for approximately 20 hours.

[0683] The exemplary yield of step 4 is 90%, with a purity of >98% as determined by HPLC.

[0684] Step 5: Preparation of 1,2,3,5,6,7-hexahydro-s-benzodiindene-4-isocyanate (compound No. 8) Step 5 involves treating 1,2,3,5,6,7-hexahydro-s-benzodiindene-4-amine (compound No. 7) with triphosgene to form the corresponding isocyanate, a toluene solution of 1,2,3,5,6,7-hexahydro-s-benzodiindene-4-isocyanate (compound No. 8). A concentrated solution of compound No. 8 (approximately 30% by weight) is used directly in step 6. The reaction conditions for step 5 are as shown in Scheme 5.

[0685] Scheme 5: Preparation of step 5-1,2,3,5,6,7-hexahydro-s-benzodiindene-4-isocyanate (compound No. 8) A solution of 1,2,3,5,6,7-hexahydro-s-benzodiindene-4-amine (compound No. 7; 1 equivalent) and triethylamine (2.05 equivalents) in toluene (6 volumes) was batch-treated over approximately 1 hour with a solution of cooled (0°C) triphosgene (0.34 equivalents) in toluene (21 volumes) while maintaining the temperature below 10°C. The mixture was then heated to room temperature. After confirming the reaction was complete, the mixture (which is a very thick slurry of triethylamine hydrochloride in toluene) was aged at room temperature for up to 24 hours. The slurry was filtered and the filtrate was collected. The reaction vessel was rinsed with toluene (8 volumes), and the filter cake was washed with the rinsing solution. The combined filtrate was then concentrated to ~4.5 volumes (relative to the input of compound No. 7). This solution can be stored at ambient temperature before use in step 6.

[0686] An exemplary weight-corrected yield of 1,2,3,5,6,7-hexahydro-s-benzodiindene-4-isocyanate (compound No. 8) was approximately 85%, with a purity of >98% as determined by HPLC.

[0687] Step 6: Preparation of 1-(1,2,3,5,6,7-hexahydro-s-benzodiindene-4-yl)-3-[(1-methyl-1H-pyrazol-4-yl)({[(2S)-tetrahydrofuran-2-yl]methyl})aminosulfonyl]urea sodium salt IPA solvate (compound No. 9a) Step 6 is the final synthetic step in preparing compound No. 9a prior to final recrystallization to prepare the desired polymorphic form. This reaction is a sulfonylurea formation reaction involving the treatment of a tetrahydrofuran solution of 1-(1-methyl-1H-pyrazol-4-yl)-1-[{(2S)-tetrahydrofuran-2-yl}methyl]sulfonylurea (compound No. 6a) with a toluene solution of 1,2,3,5,6,7-hexahydro-s-benzodiindene-4-isocyanate (compound No. 8) in the presence of sodium hydroxide. The crude compound No. 9a is isolated as an IPA solvate of the monosodium salt. The reaction conditions for step 6 are as shown in Scheme 6.

[0688] Scheme 6: Step 6 - Preparation of crude compound No. 9a While maintaining room temperature, a tetrahydrofuran solution (10 volumes) of compound No. 6a (1.0 equivalent) was treated dropwise with concentrated NaOH (46.7 wt%, 1.01 equivalent). The solution was aged at room temperature for approximately 0.5 hours. Then, a toluene solution (1.01 equivalent) of compound No. 8 was added over approximately 0.5 hours. After the reaction was complete, the mixture was concentrated to remove the tetrahydrofuran (approximately 8 volumes of solvent). Isopropanol (IPA; 10 volumes) was added, and the mixture was aged for approximately 0.5 hours. Then, methyl tert-butyl ether (MTBE; 5 volumes) was added, and the mixture was aged for approximately 0.5 hours. After confirming satisfactory conversion, the solid was removed by filtration, and the filter cake was washed with 2:1 IPA-MTBE (6 volumes). The resulting solid was dried under vacuum at 20–40 °C.

[0689] The exemplary weight-corrected yield of crude compound No. 9a is approximately 90%, with a purity of >99% as determined by HPLC.

[0690] Step 7: Preparation of 1-(1,2,3,5,6,7-hexahydro-s-benzodiindene-4-yl)-3-[(1-methyl-1H-pyrazol-4-yl)({[(2S)-tetrahydrofuran-2-yl]methyl})aminosulfonyl]urea sodium salt monohydrate (compound No. 10a) The final step in the preparation of compound No. 10a is the recrystallization of crude compound No. 9a from tetrahydrofuran / water / ethyl acetate using n-heptane as the antisolvent. This recrystallization method can be used to improve the purity of compound No. 10a, but the primary purpose is to control the polymorphic form (form 3) of compound No. 10a used in clinical trials to be a monohydrate. The reaction conditions for step 7 are shown in Scheme 7.

[0691] Scheme 7: Step-by-step preparation of purified compound No. 10a The crude compound No. 9a was dissolved in tetrahydrofuran (THF; 4 volumes relative to the content). The solution was filtered through diatomaceous earth and washed with THF (2 × 1 volume). This solution was then subjected to final fine filtration and concentrated to 3 volumes. Ethyl acetate (15 volumes) was added and the mixture was concentrated to 10 volumes. Ethyl acetate (10 volumes) and water (0.2 volumes) were then added, and the mixture was heated to 45°C, then inoculated (1% seed crystals relative to the content) and aged for up to 1 hour. The mixture was then cooled to 30°C over 0.5–1 hour. Heptane (5 volumes) was added. The resulting solid was collected by filtration and washed with 4:1 ethyl acetate-heptane (4 volumes) containing 1% v / v water (relative to ethyl acetate). The solid was dried in a vacuum oven at 20°C by purging with N2.

[0692] The exemplary weight-corrected recovery of compound No. 10a is approximately 90%, and the purity is >99% as determined by HPLC.

[0693] Example 2. Properties of compound No. 10a Compound No. 10a is a white to off-white crystalline powder. It has a single stereocenter. Compound No. 10a is a confirmed single enantiomer with the (S)-configuration.

[0694] Polymorphism: Polymorphism screening of compound No. 10a revealed one hygroscopic amorphous form and three polymorphic forms. During characterization, a metastable anhydrous form 1 was recovered from GVS analysis. Furthermore, a dihydrate form 2 was prepared from the amorphous compound at 25°C / 97% RH and 40°C / 75% RH. After storage at 60°C / 75% RH, the amorphous compound converted to a monohydrate form 3. A new metastable anhydrous form 9 was identified upon dehydration of form 3. Compound No. 10a forms solvates with certain alcohol solvents, most notably the IPA solvate, which was separated as an intermediate during preparation and then further processed into the final form.

[0695] Form 2 (dihydrate) and Form 3 (monohydrate) have comparable solid-state properties. The monohydrate (form 3) was prepared as described in Example 1. It exhibits a single crystalline / polycrystalline form, namely the sodium salt monohydrate (form 3).

[0696] In some embodiments, form 2 of compound No. 10a is characterized by XRPD plots using Cu Kα radiation containing signals at 4.2±0.5, 16.7±0.5, and 16.8±0.5 °2θ (e.g., 4.2±0.2, 16.7±0.2, and 16.8±0.2 °2θ using Cu Kα radiation; e.g., 4.2±0.1, 16.7±0.1, and 16.8±0.1 °2θ using Cu Kα radiation; e.g., 4.2, 16.7, and 16.8 °2θ using Cu Kα radiation)).

[0697] In some embodiments, compound No. 10a, form 2, is characterized by XRPD patterns obtained using Cu Kα radiation at values ​​of 4.2±0.5, 8.4±0.5, 10.2±0.5, 10.4±0.5, 13.1±0.5, 13.5±0.5, 16.3±0.5, 16.7±0.5, 16.8±0.5, 18.2±0.5, 18.6±0.5, 19.3±0.5, 20.8±0.5, 21.1±0.5, 23.0±0.5, 23.3±0.5, and 23.5±0. 5, 24.3±0.5, 24.7±0.5, 25.2±0.5, 25.3±0.5, 25.6±0.5, 26.1±0.5, 26.6±0.5, 27.1±0.5, 28.3±0.5, 28.9±0.5, 29.1±0.5, 29.5±0.5, 29.8±0.5, 30.0±0.5, 30.3±0.5, 30.7±0.5, 31.1±0.5 and 31.7±0.5 °2θ (e.g. using Cu) The values ​​of Kα radiation are 4.2±0.2, 8.4±0.2, 10.2±0.2, 10.4±0.2, 13.1±0.2, 13.5±0.2, 16.3±0.2, 16.7±0.2, 16.8±0.2, 18.2±0.2, 18.6±0.2, 19.3±0.2, 20.8±0.2, 21.1±0.2, 23.0±0.2, 23.3±0.2, 23.5±0.2, and 24. 0.3±0.2, 24.7±0.2, 25.2±0.2, 25.3±0.2, 25.6±0.2, 26.1±0.2, 26.6±0.2, 27.1±0.2, 28.3±0.2, 28.9±0.2, 29.1±0.2, 29.5±0.2, 29.8±0.2, 30.0±0.2, 30.3±0.2, 30.7±0.2, 31.1±0.2 and 31.7±0.2 °2θ (e.g. using Cu) The values ​​of Kα radiation are 4.2±0.1, 8.4±0.1, 10.2±0.1, 10.4±0.1, 13.1±0.1, 13.5±0.1, 16.3±0.1, 16.7±0.1, 16.8±0.1, 18.2±0.1, 18.6±0.1, 19.3±0.1, 20.8±0.1, 21.1±0.1, 23.0±0.1, 23.3±0.1, 23 0.5±0.1, 24.3±0.1, 24.7±0.1, 25.2±0.1, 25.3±0.1, 25.6±0.1, 26.1±0.1, 26.6±0.1, 27.1±0.1, 28.3±0.1, 28.9±0.1, 29.1±0.1, 29.5±0.1, 29.8±0.1, 30.0±0.1, 30.3±0.1, 30.7±0.1. Signals at 31.1±0.1 and 31.7±0.1 °2θ (e.g., signals using Cu Kα radiation at 4.2, 8.4, 10.2, 10.4, 13.1, 13.5, 16.3, 16.7, 16.8, 18.2, 18.6, 19.3, 20.8, 21.1, 23.0, 23.3, 23.5, 24.3, 24.7, 25.2, 25.3, 25.6, 26.1, 26.6, 27.1, 28.3, 28.9, 29.1, 29.5, 29.8, 30.0, 30.3, 30.7, 31.1, and 31.7 °2θ).

[0698] In some embodiments, compound No. 10a in form 2 is characterized by an endothermic event that begins at 50 ± 20 °C, 50 ± 15 °C, 50 ± 10 °C or 50 ± 5 °C (e.g., about 50 °C), as measured by DSC.

[0699] In some embodiments, compound No. 10a in form 2 is characterized by an endothermic event that begins at 144±20°C, 144±15°C, 144±10°C or 144±5°C (e.g., about 144°C), as measured by DSC.

[0700] In some embodiments, compound No. 10a, form 2, is characterized by a water absorption of 9.1 ± 0.5%, 9.1 ± 0.4%, 9.1 ± 0.3%, 9.1 ± 0.2%, 9.1 ± 0.1%, or 9.1 ± 0.05% (e.g., about 9.1%) as measured by GVS.

[0701] In some embodiments, compound No. 10a, form 2, is characterized by an absorbance of 2.2 ± 0.05%, 2.2 ± 0.04%, 2.2 ± 0.03%, 2.2 ± 0.02%, or 2.2 ± 0.01% (e.g., about 2.2%) as measured by GVS (e.g., from 40% to 70% RH).

[0702] In some embodiments, compound No. 10a, form 2, is characterized by an absorbance of 6.1 ± 0.05%, 6.1 ± 0.04%, 6.1 ± 0.03%, 6.1 ± 0.02%, or 6.1 ± 0.01% (e.g., about 6.1%) as measured by GVS (e.g., from 40% to 70% RH).

[0703] In some embodiments, compound No. 10a in form 2 is characterized by a reversible hysteresis (e.g., from 70% to 10% RH) as measured by GVS.

[0704] In some embodiments, form 3 of compound No. 10a is characterized by XRPD plots using Cu Kα radiation containing signals at 4.4 ± 0.5, 8.4 ± 0.5, and 17.8 ± 0.5 °2θ (e.g., 4.4 ± 0.2, 8.4 ± 0.2, and 17.8 ± 0.2 °2θ using Cu Kα radiation; e.g., 4.4 ± 0.1, 8.4 ± 0.1, and 17.8 ± 0.1 °2θ using Cu Kα radiation; e.g., 4.4, 8.4, and 17.8 °2θ using Cu Kα radiation)).

[0705] In some embodiments, compound No. 10a, form 3, is characterized by XRPD patterns obtained using Cu Kα radiation at values ​​of 4.4±0.5, 8.4±0.5, 8.9±0.5, 11.1±0.5, 11.4±0.5, 12.0±0.5, 14.2±0.5, 14.3±0.5, 15.1±0.5, 16.8±0.5, 17.3±0.5, 17.8±0.5, 19.0±0.5, 19.2±0.5, 19.6±0.5, 20.6±0.5, 20.9±0.5, and 21.3±0.5. 21.5±0.5, 21.9±0.5, 22.3±0.5, 22.4±0.5, 22.9±0.5, 23.2±0.5, 23.6±0.5, 24.4±0.5, 24.8±0.5, 25.2±0.5, 26.8±0.5, 27.4±0.5, 27.8±0.5, 29.1±0.5, 29.4±0.5, 29.8±0.5, 30.1±0.5, 31.0±0.5 and 31.4±0.5 °2θ (e.g. using Cu) The values ​​of Kα radiation are 4.4±0.2, 8.4±0.2, 8.9±0.2, 11.1±0.2, 11.4±0.2, 12.0±0.2, 14.2±0.2, 14.3±0.2, 15.1±0.2, 16.8±0.2, 17.3±0.2, 17.8±0.2, 19.0±0.2, 19.2±0.2, 19.6±0.2, 20.6±0.2, 20.9±0.2, 21.3±0.2, and 21. 5±0.2, 21.9±0.2, 22.3±0.2, 22.4±0.2, 22.9±0.2, 23.2±0.2, 23.6±0.2, 24.4±0.2, 24.8±0.2, 25.2±0.2, 26.8±0.2, 27.4±0.2, 27.8±0.2, 29.1±0.2, 29.4±0.2, 29.8±0.2, 30.1±0.2, 31.0±0.2 and 31.4±0.2 °2θ (e.g. using Cu) The values ​​of Kα radiation were 4.4±0.1, 8.4±0.1, 8.9±0.1, 11.1±0.1, 11.4±0.1, 12.0±0.1, 14.2±0.1, 14.3±0.1, 15.1±0.1, 16.8±0.1, 17.3±0.1, 17.8±0.1, 19.0±0.1, 19.2±0.1, and 19.6± 0.1, 20.6±0.1, 20.9±0.1, 21.3±0.1, 21.5±0.1, 21.9±0.1, 22.3±0.1, 22.4±0.1, 22.9±0.1, 23.2±0.1, 23.6±0.1, 24.4±0.1, 24.8±0.1, 25.2±0.1, 26.8±0.1, 27.4±0.1, 27.8±0.1, 29.1±0.1, 29.4±0.1, 29.8±0.1, 30.1±0.1, 31.0±0.1 and 31.4±0.1 °2θ (e.g. using Cu) Signals of Kα radiation at 4.4, 8.4, 8.9, 11.1, 11.4, 12.0, 14.2, 14.3, 15.1, 16.8, 17.3, 17.8, 19.0, 19.2, 19.6, 20.6, 20.9, 21.3, 21.5, 21.9, 22.3, 22.4, 22.9, 23.2, 23.6, 24.4, 24.8, 25.2, 26.8, 27.4, 27.8, 29.1, 29.4, 29.8, 30.1, 31.0, and 31.4 °2θ.

[0706] In some embodiments, compound No. 10a, form 3, is characterized by degradation events up to 85±40°C, 85±30°C, 85±20°C, 85±15°C, 85±10°C, or 85±5°C (e.g., up to about 85°C), as measured by TGA.

[0707] In some embodiments, compound No. 10a, form 3, is characterized by degradation events that begin at 85±40°C, 85±30°C, 85±20°C, 85±15°C, 85±10°C, or 85±5°C (e.g., about 85°C), as measured by TGA.

[0708] In some embodiments, compound No. 10a in form 3 is characterized by an endothermic event that begins at 34 ± 20 °C, 34 ± 15 °C, 34 ± 10 °C or 34 ± 5 ​​°C (e.g., about 34 °C), as measured by DSC.

[0709] In some embodiments, compound No. 10a in form 3 is characterized by an endothermic event that begins at 102 ± 20 °C, 102 ± 15 °C, 102 ± 10 °C or 102 ± 5 °C (e.g., about 102 °C), as measured by DSC.

[0710] In some embodiments, compound No. 10a in form 3 is characterized by an endothermic event that begins at 152 ± 20 °C, 152 ± 15 °C, 152 ± 10 °C or 152 ± 5 °C (e.g., about 152 °C), as measured by DSC.

[0711] In some embodiments, compound No. 10a in form 3 is characterized by an absorbance of 2.3 ± 0.5%, 2.3 ± 0.4%, 2.3 ± 0.3%, 2.3 ± 0.2%, 2.3 ± 0.1% or 2.3 ± 0.05% (e.g., about 2.3%) as measured by GVS.

[0712] In some embodiments, compound No. 10a, form 3, is characterized by an absorbance of 8.9 ± 0.5%, 8.9 ± 0.4%, 8.9 ± 0.3%, 8.9 ± 0.2%, 8.9 ± 0.1%, or 8.9 ± 0.05% (e.g., about 8.9%) as measured by GVS.

[0713] In some embodiments, compound No. 10a, form 3, is characterized by an absorbance of 5.1 ± 0.5%, 5.1 ± 0.4%, 5.1 ± 0.3%, 5.1 ± 0.2%, 5.1 ± 0.1%, or 5.1 ± 0.05% (e.g., about 5.1%) as measured by GVS.

[0714] In some embodiments, compound No. 10a in form 3 is characterized by a reversible hysteresis (e.g., from 70% to 10% RH) as measured by GVS.

[0715] In some embodiments, compound No. 10a, form 3, is a crystalline solid having one or more of the following characteristics: a) Crystal size of 0.300 x 0.250 x 0.200 mm; b) Colorless, cut rod-shaped crystal habit; c) Monoclinic system; d) The space group of P21; e) The cell size; f) 2457.54(4) Å 3 Volume; g) 1.350 Mg / m 3 Density (calculated); h) 1.708 mm -1 The absorption coefficient; and / or i) 1056 F (000).

[0716] Melting point: By DSC, compound No. 10a showed a broad endothermic temperature at 113.7 °C, starting at 70.6 °C with an enthalpy of 99.0 J / g, followed by melting endothermic temperature at 163.2 °C, starting at 148.0 °C with an enthalpy of 40.1 J / g.

[0717] Hygroscopicity: Compound No. 10a is a monohydrate and has been identified as slightly hygroscopic, absorbing water at RH greater than 95%.

[0718] pKa: 5.7 LogD 7.4 1.04 (LogD) 2.0 = 3.11; LogD 11.0 = 0.26) Solubility: Compound No. 10a (form 3) is highly soluble in water (>300 mg / mL); the water solubility of compound No. 10a varies in the pH range of 1.6-8.5 [FaSSGF (pH 1.6) = 24 μg / mL; FeSSIF (pH 5.0) = 169 μg / mL; FaSSIF (pH 6.5) = 126 μg / mL; Tris (pH 8.0) >300 mg / mL].

[0719] Form 3 exhibits good solubility in methanol, ethanol, acetone, MEK, and tetrahydrofuran, but poor solubility in ethyl acetate, isopropyl acetate, MIBK, isopropanol, and n-heptane.

[0720] Principle of Equivalence Details of one or more embodiments of this disclosure are set forth in the appended specification. Although any methods and materials similar to or equivalent to those described herein may be used in the practice or testing of this disclosure, preferred methods and materials are now described. Other features, objects, and advantages of this disclosure will be apparent from the specification and claims. In the specification and appended claims, the singular form may include plural objects unless the context clearly specifies otherwise. 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 pertains. All patents and publications referenced in this specification are hereby incorporated herein by reference.

[0721] The foregoing description is for illustrative purposes only and is not intended to limit this disclosure to the exact form disclosed, but is subject to the appended claims.

Claims

1. A method for preparing compound No. 10, comprising one or more of steps (iv)-(vii): (iv) Reacting compound No. 5 or its salt with an acid to form compound No. 6 or its salt; (v) Reacting compound No. 7 or its salt with a CO source to form compound No. 8 or its salt; (vi) To react compound No. 6 or its salt with compound No. 8 or its salt to form compound No. 9; or (vii) Purify compound No. 9 to separate compound No.

10.

2. A method for preparing compound No. 5 or a salt thereof, comprising: (iii) Reacting compound No. 5 or its salt with an acid to form compound No. 6 or its salt.

3. A method for preparing compound No. 9, comprising: (iv) React compound No. 6 or its salt with compound No. 8 or its salt to form compound No.

9.

4. A method for preparing compound No. 10, comprising: (vii) Purify compound No. 9 to separate compound No.

10.

5. The method according to claim 1, further comprising steps (i)-(iv): (i) Reacting tetrahydrofuran-2-carboxylic acid with 4-amino-1-methylpyrazole or a salt thereof to form N-(1-methyl-1H-pyrazole-4-yl)tetrahydrofuran-2-carboxamide or a salt thereof; (ii) Reacting N-(1-methyl-1H-pyrazol-4-yl)tetrahydrofuran-2-carboxamide or a salt thereof with a reducing agent to form 1-methyl-N-{[tetrahydrofuran-2-yl]methyl}-1H-pyrazol-4-amine or a salt thereof; (iii) Reacting 1-methyl-N-{[tetrahydrofuran-2-yl]methyl}-1H-pyrazole-4-amine or a salt thereof with tert-butyl N-chlorosulfonylcarbamate to form compound No. 5 or a salt thereof; and (iv) React compound No. 5 or its salt with an acid to form compound No. 6 or its salt.

6. The method as described in any of the preceding claims, wherein compound No. 9 is compound No. 9a.

7. The method as described in any of the preceding claims, wherein compound No. 10 is compound No. 10a.

8. The method as described in any of the preceding claims, wherein compound No. 9 is compound No. 9b.

9. The method as claimed in any of the preceding claims, wherein in step (iv), the acid is hydrochloric acid.

10. The method as claimed in any of the preceding claims, wherein in step (iv), the molar ratio of the acid to compound No. 5 or a salt thereof is about 3:1 to about 1:

1.

11. The method as claimed in any of the preceding claims, wherein in step (iv), the reaction is carried out in the presence of a first solvent to form a first mixture.

12. The method as claimed in any of the preceding claims, wherein in step (iv), the reaction is carried out at a first temperature of about 25 ± 15 °C, about 25 ± 10 °C, or about 25 ± 5 °C.

13. The method as claimed in any of the preceding claims, wherein in step (iv), the reaction is carried out for about 26 ± 20 hours, about 26 ± 15 hours, about 26 ± 10 hours, about 26 ± 5 hours, about 26 ± 4 hours, about 26 ± 3 hours, about 26 ± 2 hours, or about 26 ± 1 hour.

14. The method of claim 11, wherein the first mixture is cooled to a second temperature of about 0±15°C, about 0±10°C, or about 0±5°C.

15. The method of claim 11, wherein the first mixture is cooled to a second temperature of about 0±15°C, about 0±10°C, or about 0±5°C, and a second solvent is added to form a second mixture.

16. The method of claim 15, wherein an alkali or a buffer is added to the second mixture.

17. The method of any of the preceding claims, wherein in step (iv), compound No. 6 or its salt is isolated and / or purified prior to reaction with compound No.

8.

18. The method of claim 17, wherein in step (iv), the purity of compound No. 6 or a salt thereof is at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99%, as determined by HPLC.

19. The method according to claim 1, wherein in step (v), triphosgene is a CO source.

20. The method according to claim 1, wherein in step (v), the reaction is carried out in the presence of a base.

21. The method of claim 20, wherein in step (v), the molar ratio of the base to compound No. 8 or a salt thereof is about 3:1 to about 1:

1.

22. The method of claim 1, wherein in step (v), the reaction is carried out in the presence of a solvent.

23. The method of claim 1, wherein step (v) comprises filtering a solution of compound No. 8 or a salt thereof.

24. The method of claim 1, wherein in step (v), compound No. 8 or its salt is isolated and / or purified prior to reaction with compound No. 6 or its salt.

25. The method of claim 1, wherein in step (v), compound No. 8 or its salt is not isolated and / or purified prior to reaction with compound No. 6 or its salt.

26. The method of claim 1, wherein step (v) produces a solution of compound No. 8 or a salt thereof.

27. The method of claim 1, wherein step (v) produces compound No. 8 or a salt thereof with a purity of at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99%, as determined by HPLC.

28. The method according to claim 1, wherein in step (vi), the reaction is carried out in the presence of a base.

29. The method according to claim 1, wherein in step (vi), the reaction is carried out in the presence of a first solvent.

30. The method according to claim 1, wherein in step (vi), the molar ratio of compound No. 6 or a salt thereof to compound No. 8 or a salt thereof is about 2:1 to about 1:

2.

31. The method of claim 1, wherein in step (vi), the reaction comprises partially removing the first solvent.

32. The method according to claim 1, wherein in step (vi), the reaction is carried out in the presence of a second solvent.

33. The method of claim 1, wherein in step (vi), the reaction comprises extracting compound No. 9 using an ether.

34. The method of claim 1, wherein in step (vi), the reaction comprises filtering out compound No. 9, washing compound No. 9 or a combination thereof with IPA-MTBE.

35. The method according to claim 1, wherein in step (vi), the reaction is carried out at a first temperature of about 25 ± 15 °C, about 25 ± 10 °C, or about 25 ± 5 °C.

36. The method of claim 1, wherein step (vi) comprises filtering compound No.

9.

37. The method according to claim 1, wherein in step (vi), compound No. 9a or 9b is isolated and / or purified.

38. The method of claim 1, wherein step (vi) produces compound No. 9 with a purity of at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99%, as determined by HPLC.

39. The method of claim 1, wherein step (vii) comprises recrystallizing compound No. 9 in the presence of an organic solvent.

40. The method of claim 1, wherein in step (vii), compound No. 9 is dissolved in tetrahydrofuran, filtered, and washed with tetrahydrofuran to form a first mixture.

41. The method of claim 40, wherein the first mixture of the concentration step (vii) is followed by the addition of ethyl acetate to form a second mixture.

42. The method according to claim 41, wherein the second mixture of the concentration step (vii) is followed by the addition of ethyl acetate and water to form a third mixture.

43. The method of claim 42, wherein the third mixture of step (vii) is heated and then inoculated to form an inoculated third mixture.

44. The method of claim 42, wherein the third mixture of step (vii) is heated to a first temperature of about 45±20°C, about 45±15°C, about 45±10°C, about 45±5°C, about 45±4°C, about 45±3°C, about 45±2°C, or about 45±1°C, and then inoculated to form an inoculated third mixture.

45. The method of claim 44, wherein after heating to the first temperature, the third mixture of inoculation in step (vii) is aged for about 1 ± 2 hours or 1 ± 1 hour.

46. ​​The method of claim 45, wherein in step (vii), after aging the inoculated third mixture, the inoculated third mixture is cooled to a second temperature of about 30±20°C, about 30±15°C, about 30±10°C, about 30±5°C, about 30±4°C, about 30±3°C, about 30±2°C, or about 30±1°C.

47. The method of claim 45, wherein in step (vii), after aging the inoculated third mixture, the inoculated third mixture is cooled to a second temperature of about 30±20°C, about 30±15°C, about 30±10°C, about 30±5°C, about 30±4°C, about 30±3°C, about 30±2°C, or about 30±1°C (e.g., about 30°C), and aged for about 1 hour to about 12 hours, about 2 hours to about 10 hours, or about 3 hours to about 6 hours to form a mixture comprising compound No.

10.

48. The method of claim 47, wherein in step (vii), n-heptane is added to the mixture containing compound No. 10 to form compound No. 10 in solid form.

49. The method of claim 48, wherein in step (vii), the solid form of compound No. 10 is filtered out and washed to form a substantially pure solid form of compound No.

10.

50. The method of claim 49, wherein step (vii) produces a specific polymorphic form of compound No.

10.

51. The method of claim 49, wherein step (vii) produces the polymorphic form (form 3) of compound No. 10a.

52. The method of claim 49, wherein step (vii) produces compound No. 10 in solid form with a purity of at least about 98%, at least about 98.5%, at least about 99%, at least about 99.1%, at least about 99.2%, at least about 99.3%, at least about 99.4%, at least about 99.5%, at least about 99.6%, at least about 99.7%, or at least about 99.8%, as determined by HPLC.

53. The method of claim 49, wherein step (vii) produces a substantially pure polymorphic form (form 3) of compound No. 10a.

54. A compound prepared by the method of any one of the preceding claims.

55. A pharmaceutical composition comprising compound No. 10 according to any one of the preceding claims and one or more pharmaceutically acceptable carriers or excipients.

56. A method for preventing or treating a disease in a subject, comprising administering to the subject compound No. 10 according to any one of the preceding claims.

57. Compound No. 10 according to any one of the preceding claims, used for the prevention or treatment of a disease in a subject.

58. Use of compound No. 10 according to any one of the preceding claims in the manufacture of a pharmaceutical preparation for the prevention or treatment of a disease in a subject.

59. A method for inhibiting the activity of inflammasomes in a subject, comprising contacting cells with compound No. 10 according to any one of the preceding claims.

60. Compound No. 10 according to any one of the preceding claims, used to inhibit inflammasome activity in a subject.

61. Use of compound No. 10 according to any one of the preceding claims in the manufacture of a pharmaceutical agent for inhibiting inflammasome activity.

62. The method, compound, or use according to any one of the preceding claims, wherein the subject is a human.

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