Process for the preparation of carbamate derivatives

Abstract

The present disclosure relates to a process for the preparation of 2-methylpyrimidine salts from 4,6-dichloro-2-methylpyrimidine. The present disclosure also relates to compounds prepared by the process, pharmaceutical compositions comprising the compounds, and uses thereof, e.g., for the treatment of disorders (e.g., in which inflammasome activity is implicated).

Description

[0001] Cross-references to related applications This application claims priority and benefit to U.S. Provisional Patent Application No. 63 / 566,096, filed March 15, 2024, the entire contents of which are incorporated herein by reference.

[0002] background Autoimmune diseases are associated with the overproduction of pro-inflammatory factors. One of these 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 a variety of cellular activities, including cell proliferation, differentiation, and apoptosis.

[0003] In humans, 22 NLR proteins are classified 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 pyridine domain. Several NLR family members are associated with 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 sterility risk signals. Many such sterility signals have been elucidated, and their formation is associated with specific disease states. For example, uric acid crystals found in patients with gout are potent triggers for NLRP3 activation. Similarly, cholesterol crystals found in patients with atherosclerosis can also promote NLRP3 activation. The recognition of the role of sterility risk signals as NLRP3 activators has led to the association of IL-1 and IL-18 with a variety of pathophysiological indications, including metabolic disorders, physiological disorders, inflammatory disorders, hematological disorders, and immunological disorders.

[0005] This disclosure stems from the need to provide a novel method for preparing compounds for specifically modulating NLRP3-dependent cellular processes.

[0006] Overview In some respects, this disclosure provides a method for preparing 2-methylpyrimidine salts (compound number 3) from 4,6-dichloro-2-methylpyrimidine (compound number 1) or salts thereof as described herein.

[0007] In some aspects, this disclosure provides methods for preparing 2-methylpyrimidine salts (e.g., compound number 3a) from 4,6-dichloro-2-methylpyrimidine (compound number 1) or salts thereof as described herein.

[0008] In some aspects, this disclosure provides a method for preparing a 2-methylpyrimidine salt (e.g., compound number 3a), the method comprising one or more of steps (i) and (ii): (i) Reacting 4,6-dichloro-2-methylpyrimidine (compound number 1) or a salt thereof with a hydride to form 2-methylpyrimidine (compound number 2); and (ii) React 2-methylpyrimidine (compound number 2) with an acid to form a 2-methylpyrimidine salt (e.g., compound number 3a).

[0009] In some aspects, this disclosure provides a method for preparing a 2-methylpyrimidine salt (e.g., compound number 3a), the method comprising steps (i) and (ii): (i) Reacting 4,6-dichloro-2-methylpyrimidine (compound number 1) or a salt thereof with a hydride to form 2-methylpyrimidine (compound number 2); and (ii) React 2-methylpyrimidine (compound number 2) with an acid to form a 2-methylpyrimidine salt (e.g., compound number 3a).

[0010] In some respects, this disclosure provides a method for preparing compound number 5 or a salt thereof: (Compound No. 5) The method includes one or more of steps (i)-(iii): (i) Reacting 4,6-dichloro-2-methylpyrimidine (compound number 1) or a salt thereof with a hydrogenating agent to form 2-methylpyrimidine (compound number 2); (ii) Reacting 2-methylpyrimidine (compound number 2) with an acid to form a 2-methylpyrimidine salt (e.g., compound number 3a); and (iii) Reacting a 2-methylpyrimidine salt (e.g., compound number 3a) with diisopropyl oxalate (compound number 4) or a salt thereof to form compound number 5 or a salt thereof, wherein the reaction is carried out in the presence of potassium tert-pentoxygenate.

[0011] In some respects, this disclosure provides a method for preparing compound number 5 or a salt thereof: (Compound No. 5) The method includes steps (i)-(iii): (i) Reacting 4,6-dichloro-2-methylpyrimidine (compound number 1) or a salt thereof with a hydrogenating agent to form 2-methylpyrimidine (compound number 2); (ii) Reacting 2-methylpyrimidine (compound number 2) with an acid to form a 2-methylpyrimidine salt (e.g., compound number 3a); and (iii) Reacting a 2-methylpyrimidine salt (e.g., compound number 3a) with diisopropyl oxalate (compound number 4) or a salt thereof to form compound number 5 or a salt thereof, wherein the reaction is carried out in the presence of potassium tert-pentoxygenate.

[0012] In some respects, this disclosure provides a method for preparing compound number 9 or a salt thereof: (Compound No. 9) The method includes one or more of steps (i)-(vii): (i) Reacting 4,6-dichloro-2-methylpyrimidine (compound number 1) or a salt thereof with a hydrogenating agent to form 2-methylpyrimidine (compound number 2); (ii) React 2-methylpyrimidine (compound number 2) with an acid to form a 2-methylpyrimidine salt (e.g., compound number 3a); (iii) Reacting a 2-methylpyrimidine salt (e.g., compound number 3a) with diisopropyl oxalate (compound number 4) or a salt thereof to form compound number 5 or a salt thereof: (Compound No. 5); (iv) React compound number 5 or its salt with a reducing agent to form compound number 6 (e.g., compound number 6a or 6b): (Compound No. 6) or its salt; (v) Number the compound as 7: (Compound No. 7) Or its salt reacts with a CO source to form compound number 8: (Compound No. 8) or its salt; (vi) Reacting compound number 6 (e.g., compound number 6a or 6b) or a salt thereof with compound number 8 or a salt thereof to form compound number 9 (e.g., compound number 9a or 9b) or a salt thereof; and (vii) Purify compound number 9 (e.g., compound number 9a or 9b) or its salt.

[0013] In some respects, this disclosure provides a method for preparing compound number 9 or a salt thereof: (Compound No. 9) The method includes steps (i)-(vii): (i) Reacting 4,6-dichloro-2-methylpyrimidine (compound number 1) or a salt thereof with a hydrogenating agent to form 2-methylpyrimidine (compound number 2); (ii) React 2-methylpyrimidine (compound number 2) with an acid to form a 2-methylpyrimidine salt (e.g., compound number 3a); (iii) Reacting a 2-methylpyrimidine salt (e.g., compound number 3a) with diisopropyl oxalate (compound number 4) or a salt thereof to form compound number 5 or a salt thereof: (Compound No. 5); (iv) React compound number 5 or its salt with a reducing agent to form compound number 6 (e.g., compound number 6a or 6b): (Compound No. 6) or its salt; (v) Number the compound as 7: (Compound No. 7) Or its salt reacts with a CO source to form compound number 8: (Compound No. 8) or its salt; (vi) Reacting compound number 6 (e.g., compound number 6a or 6b) or a salt thereof with compound number 8 or a salt thereof to form compound number 9 (e.g., compound number 9a or 9b) or a salt thereof; and (vii) Purify compound number 9 (e.g., compound number 9a or 9b) or its salt.

[0014] In some aspects, this disclosure provides a method for preparing compound number 6 (e.g., compound number 6a or 6b) or a salt thereof, the method comprising: (iv) React compound number 5 or its salt with a reducing agent to form compound number 6 (e.g., compound number 6a or 6b) or its salt.

[0015] In some respects, this disclosure provides compounds prepared by the methods described herein.

[0016] In some aspects, this disclosure provides a pharmaceutical composition comprising compound number 9 described herein (e.g., compound number 9a or 9b) or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

[0017] 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), the method comprising contacting cells with compound number 9 described herein (e.g., compound number 9a or 9b) or a pharmaceutically acceptable salt thereof (e.g., in an effective amount).

[0018] In some aspects, this disclosure provides a method for treating or preventing a disease or disorder disclosed herein in a subject in need, the method comprising administering to the subject a compound numbered 9 described herein (e.g., compound number 9a or 9b) or a pharmaceutically acceptable salt thereof (e.g., in a therapeutically effective amount).

[0019] In some respects, this disclosure provides compound number 9 (e.g., compound number 9a or 9b) or a pharmaceutically acceptable salt thereof described herein for inhibiting inflammasome (e.g., NLRP3 inflammasome) activity (e.g., in vitro or in vivo).

[0020] In some respects, this disclosure provides compound number 9 (e.g., compound number 9a or 9b) or a pharmaceutically acceptable salt thereof described herein for the treatment or prevention of the diseases or disorders disclosed herein.

[0021] In some respects, this disclosure provides the use of compound number 9 (e.g., compound number 9a or 9b) or a pharmaceutically acceptable salt thereof described herein in the preparation of a medicament for inhibiting the activity of an inflammasome (e.g., NLRP3 inflammasome) in a subject (e.g., in vitro or in vivo).

[0022] In some respects, this disclosure provides for the use of compound number 9 (e.g., compound number 9a or 9b) or a pharmaceutically acceptable salt thereof described herein in the preparation of a medicament for the treatment or prevention of the diseases or disorders disclosed herein.

[0023] In some aspects, this disclosure provides a method for preventing or treating a disease in a subject, the method comprising administering compound number 9 (e.g., compound number 9a or 9b) to the subject.

[0024] In some respects, this disclosure provides compounds numbered 9 (e.g., compounds numbered 9a or 9b) for the prevention or treatment of diseases or for the inhibition of inflammasome activity in subjects.

[0025] In some aspects, this disclosure provides a method for inhibiting inflammasome activity in a subject, the method comprising contacting cells with compound number 9 (e.g., compound number 9a or 9b).

[0026] 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 this specification, singular forms also include plural forms unless the context clearly indicates otherwise. Although methods and materials similar to or equivalent to those described herein may be used in the practice or experimentation of this disclosure, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference. No prior art to the claimed invention is acknowledged in this document. In case of conflict, this specification (including definitions) shall prevail. Furthermore, the materials, methods, and examples described are merely exemplary and not intended to be limiting. In case of conflict between the chemical structures and names of the compounds disclosed herein, the chemical structure shall prevail.

[0027] Other features and advantages of this disclosure will become apparent from the following detailed description and claims.

[0028] Detailed description Autoimmune diseases are associated with the overproduction of pro-inflammatory factors. One of these 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 a variety of cellular activities, including cell proliferation, differentiation, and apoptosis.

[0029] The IL-1 family of cytokines is highly active and serves as an important inflammatory mediator, primarily associated with both acute and chronic inflammation. Overproduction of IL-1 is considered a contributing factor to certain autoimmune and autoinflammatory diseases. Autoinflammatory diseases are characterized by recurrent, unprovoked inflammation in the absence of autoantibodies, infection, or antigen-specific T lymphocytes.

[0030] 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 via the standard cellular secretory apparatus of the endoplasmic reticulum and Golgi apparatus, members of the IL-1 family lack the leader sequence required to enter the endoplasmic reticulum and are therefore retained intracellularly after translation. Furthermore, IL-1β, IL-18, and IL-36α,β,λ are synthesized as procytokines, which require proteolytic activation to become optimal ligands for binding to their homologous receptors on target cells.

[0031] In the case of IL-1α, IL-1β, and IL-18, it is now recognized that a multimeric protein complex called the inflammasome is responsible for activating the precursors of IL-1β and IL-18 and releasing these cytokines extracellularly. The inflammasome complex typically consists of sensor molecules (e.g., NLR (nucleotide-oligomery domain (NOD)-like receptor)), the adaptor molecule ASC (an apoptosis-associated speckle-like protein containing the CARD (aspartate-specific cysteine ​​protease recruitment domain)), and the precursor aspartate-specific cysteine ​​protease-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 may include molecules such as peptidoglycans, viral DNA or RNA, and bacterial DNA or RNA. On the other hand, DAMPs consist of various endogenous or exogenous sterile triggering factors, 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 precursor aspartate-specific cysteine ​​protease-1, leading to the production of highly active cysteine ​​proteases responsible for activating and releasing pre-IL-1β and pre-IL-18. Therefore, the release of these highly inflammatory cytokines only occurs when the inflammasome sensor detects and responds to specific molecular danger signals.

[0032] In humans, 22 NLR proteins are classified 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 pyridine domain. Several NLR family members are associated with inflammasome formation, including NLRP1, NLRP3, NLRP6, NLRP7, NLRP12, and NLRC4 (IPAF).

[0033] Two other structurally distinct inflammasome structures containing the PYHIN domain (proteins containing both pyridine and HIN domains) – namely, the deletion of protein 2 (AIM2) in melanoma and the IFNλ-inducible protein 16 (IFI16) – act as intracellular DNA sensors. Pyridine (encoded by the MEFV gene) represents another class of inflammasome platforms associated with pre-IL-1β activation.

[0034] An inflammasome platform needs to be assembled to enable the activation and release of IL-1β and IL-18 from monocytes and macrophages, ensuring their production is carefully coordinated through a two-step process. First, the cells must encounter a promoter ligand (e.g., TLR4 receptor ligand LPS, or an inflammatory cytokine such as TNFα) that leads to NF-κB-dependent transcription of NLRP3, pre-IL-1β, and pre-IL-18. The newly translated procytokines remain intracellular and inactive until the generating cells encounter a second signal that leads to activation of the inflammasome scaffold and maturation of the precursor aspartate-specific cysteine ​​protease-1.

[0035] In addition to the proteolytic activation of pre-IL-1β and pre-IL-18, active aspartate-specific cysteine ​​protease-1 also triggers a form of inflammatory cell death known as pyroptosis via the cleavage of gasdermin-D. Pyroptosis externalizes the mature forms of IL-1β and IL-18, while simultaneously releasing warning molecules (compounds that promote inflammation and activate innate and adaptive immunity), such as high-mobility group box 1 (HMGB1), IL-33, and IL-1α.

[0036] 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 both endogenous and exogenous sterile danger signals. Many such sterile signals have been elucidated, and their formation is associated with specific disease states. For example, uric acid crystals found in patients with gout are potent triggers for NLRP3 activation. Similarly, cholesterol crystals found in patients with atherosclerosis can also promote NLRP3 activation. The recognition of the role of sterile danger signals as NLRP3 activators has led to the association of IL-1β and IL-18 with a variety of pathophysiological indications, including metabolic disorders, physiological disorders, inflammatory disorders, hematological disorders, and immunological disorders.

[0037] The best example of its association with human diseases is the following finding: mutations in the NLRP3 gene that lead to gain of function trigger a range of autoinflammatory conditions collectively known as cold pyridine-associated periodic syndromes (CAPS, including familial cold autoinflammatory syndrome (FCAS), Muller-Weil syndrome (MWS), and neonatal-onset multisystem inflammatory disease (NOMID) (Hoffman et al., Nat. Genet. 2001, 29(3)). (301-305). Similarly, sterile media-induced NLRP3 activation has been associated with a variety of disorders, including joint degeneration (gout, rheumatoid arthritis, osteoarthritis), cardiovascular and metabolic disorders (type 2 diabetes, atherosclerosis, hypertension), central nervous system disorders (Alzheimer's disease, Parkinson's disease, multiple sclerosis), gastrointestinal disorders (Crohn's disease, ulcerative colitis), pulmonary disorders (chronic obstructive pulmonary disease (COPD), asthma, idiopathic pulmonary fibrosis), and liver disorders (fibrosis, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis (NASH)). Furthermore, NLRP3 activation is believed to promote kidney inflammation and thus contribute to chronic kidney disease (CKD).

[0038] Current treatment options for diseases involving IL-1 as a contributing factor in 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 kanamycin. For example, kanamycin is approved for CAPS, tumor necrosis factor receptor-associated periodic syndrome (TRAPS), hyperimmunoglobulin D syndrome (HIDS) / mevalerate kinase deficiency (MKD), familial Mediterranean fever (FMF), and gout.

[0039] Several small molecules have been reported to inhibit the function of the NLRP3 inflammasome. For example, glibenclamide is a specific inhibitor of NLRP3 activation, although at micromolar concentrations unlikely to be achieved 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 features consisting of olefins activated by electron-withdrawing groups; this can lead to undesirable covalent adducts with proteins containing thiol groups. Many natural products, such as β-hydroxybutyrate, sulforaphane, quercetin, and salvianolic acid, have also been reported to inhibit NLRP3 activation. Similarly, numerous 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 fennalate (NSAID), and the β-adrenergic receptor blocker nebivolol. The efficacy of these molecules as long-term treatments for NLRP3-dependent inflammatory disorders remains to be determined. A series of sulfonylurea-containing molecules have previously been identified as potent and selective inhibitors of pre-IL-1β post-translational processing. The representative molecule from this work, CP-456,773, was recently characterized as a specific inhibitor of NLRP3 activation (Coll et al., Nature Medicine 2015, 21, 248-255).

[0040] 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 that have improved physicochemical, pharmacological, and pharmaceutical properties compared to existing NLRP3-regulating compounds.

[0041] The compounds disclosed herein It should be understood that the structures of compounds numbered 1-3, 3a, 4-6, 6a, 6b, 7-9, 9a and 9b are described in Table I below.

[0042] The method disclosed herein It is not intended to be theoretically constrained, and it should be understood that the methods disclosed herein may have various potential advantages, for example, compared to previously known methods.

[0043] For example, one method of this disclosure may involve the use of catalytic hydrogen transfer (e.g., in step (i)), which is not typically considered a dechlorination method. Such hydrogen transfer conditions can lead to more controlled reduction, and crucially, there are virtually no over-reduction byproducts, resulting in higher yields and cleaner products. As another example, in the method of this disclosure, the preparation of compound number 3 (e.g., compound number 3a) may be novel than previously known methods and can provide a solid-state isolated product with high purity and / or high yield. The synthesized compound number 3 (e.g., compound number 3a) can then be used directly in the next step.

[0044] For example, the method of this disclosure may involve the use of an oxalate (e.g., compound number 3a) in step (iii), and / or the use of potassium tert-pentoxy as a base (e.g., instead of potassium tert-butoxide). This approach avoids the formation of tert-butyl ester impurities, which are known to be difficult to remove and remain in the prepared product (e.g., compound number 9a). Even assuming that tert-pentyl ester impurities may form during step (iii), these impurities are likely to be more lipophilic than tert-butyl ester and therefore may be more easily removed in step (iii) and not remain in the prepared product (e.g., compound number 9a). Therefore, this method can produce products of higher purity in downstream processing, for example, because it indicates that impurities produced by this method are removed more effectively than by other methods.

[0045] In some aspects, this disclosure provides a method for preparing compound number 3 (e.g., compound number 3a) described herein.

[0046] In some implementations, the method includes one or more of steps (i)-(ii): (i) Reacting compound number 1 or its salt with a hydride to form compound number 2; and (ii) React compound number 2 with an acid to form compound number 3 (e.g., compound number 3a).

[0047] In some implementations, the method includes step (i).

[0048] In some implementations, the method includes step (ii).

[0049] In some implementations, the method includes steps (i) and (ii).

[0050] In some implementations, the method includes one or more steps according to scheme A.

[0051] Option A

[0052] In some implementations, the method includes one or more steps according to scheme A-1.

[0053] Option A-1

[0054] In some implementations, the method includes one or more steps according to scheme A-2.

[0055] Option A-2

[0056] In some implementations, the method includes one or more steps according to scheme A-3.

[0057] Option A-3

[0058] In some embodiments, this disclosure provides a method for preparing compound number 5 or a salt thereof described herein.

[0059] In some implementations, the method includes one or more of steps (i)-(iii): (i) Reacting compound number 1 or its salt with a hydride to form compound number 2; and (ii) Reacting compound number 2 with an acid to form compound number 3 (e.g., compound number 3a); and (iii) React compound number 3 (e.g., compound number 3a) with compound number 4 or a salt thereof to form compound number 5 or a salt thereof.

[0060] In some implementations, the method includes step (i).

[0061] In some implementations, the method includes step (ii).

[0062] In some implementations, the method includes step (iii).

[0063] In some implementations, the method includes steps (i)-(iii).

[0064] In some implementations, the method includes one or more steps according to scheme B.

[0065] Option B

[0066] In some implementations, the method includes one or more steps according to scheme B-1.

[0067] Option B-1

[0068] In some implementations, the method includes one or more steps according to scheme B-2.

[0069] Plan B-2

[0070] In some implementations, the method includes one or more steps according to scheme B-3.

[0071] Plan B-3

[0072] In some embodiments, this disclosure provides a method for preparing compound number 6 (e.g., compound number 6a or 6b) or a salt thereof, the method comprising one or more of steps (i)-(iv): (i) Reacting compound number 1 or its salt with a hydride to form compound number 2; and (ii) Reacting compound number 2 with an acid to form compound number 3 (e.g., compound number 3a); and (iii) Reacting compound number 3 (e.g., compound number 3a) with compound number 4 or a salt thereof to form compound number 5 or a salt thereof; and (iv) React compound number 5 or its salt with a reducing agent to form compound number 6 (e.g., compound number 6a or 6b) or its salt.

[0073] In some implementations, the method includes step (i).

[0074] In some implementations, the method includes step (ii).

[0075] In some implementations, the method includes step (iii).

[0076] In some implementations, the method includes step (iv).

[0077] In some implementations, the method includes steps (i)-(iv).

[0078] In some embodiments, this disclosure provides a method for preparing compound number 9 (e.g., compound number 9a or 9b) or a salt thereof described herein.

[0079] In some implementations, the method includes one or more of steps (i)-(vii): (i) React compound number 1 or its salt with a hydride to form compound number 2; (ii) React compound number 2 with an acid to form compound number 3 (e.g., compound number 3a); (iii) Reacting compound number 3 (e.g., compound number 3a) with compound number 4 or a salt thereof to form compound number 5 or a salt thereof; (iv) React compound number 5 or its salt with a reducing agent to form compound number 6 (e.g., compound number 6a or 6b) or its salt; (v) React compound number 7 or its salt with a CO source to form compound number 8 or its salt; (vi) Reacting compound number 6 (e.g., compound number 6a or 6b) or a salt thereof with compound number 8 or a salt thereof to form compound number 9 (e.g., compound number 9a or 9b) or a salt thereof; and (vii) Purify compound number 9 (e.g., compound number 9a or 9b) or its salt.

[0080] In some implementations, the method includes step (i).

[0081] In some implementations, the method includes step (ii).

[0082] In some implementations, the method includes steps (i) and (ii).

[0083] In some implementations, the method includes step (iii).

[0084] In some implementations, the method includes steps (i), (ii), and (iii).

[0085] In some implementations, the method includes step (iv).

[0086] In some implementations, the method includes steps (i), (ii), (iii), and (iv).

[0087] In some implementations, the method includes step (v).

[0088] In some implementations, the method includes steps (i), (ii), (iii), (iv), and (v).

[0089] In some implementations, the method includes step (vi).

[0090] In some implementations, the method includes steps (i), (ii), (iii), (iv), (v), and (vi).

[0091] In some implementations, the method includes step (vii).

[0092] In some implementations, the method includes steps (i), (ii), (iii), (iv), (v), (vi), and (vii).

[0093] In some implementations, the method includes one or more steps according to scheme C.

[0094] In some implementations, the method includes one or more steps according to scheme C-1.

[0095] In some implementations, the method includes one or more steps according to scheme C-2.

[0096] In some implementations, the method includes one or more steps according to scheme C-3.

[0097] Option C

[0098] Option C-1

[0099] Option C-2

[0100] Option C-3

[0101] step （i） In some implementations, in step (i), the hydrogenating agent is hydrogen or ammonium formate.

[0102] In some implementations, in step (i), the hydrogenating agent is hydrogen.

[0103] In some implementations, in step (i), the hydrogenating agent is ammonium formate.

[0104] In some implementations, step (i) is carried out in the presence of a hydrogen transfer catalyst.

[0105] In some embodiments, in step (i), the hydrogen transfer catalyst is a nickel catalyst, a platinum catalyst, a palladium catalyst, a rhodium catalyst, or a ruthenium catalyst.

[0106] In some embodiments, in step (i), the hydrogen transfer catalyst is a nickel catalyst (e.g., Raney nickel).

[0107] In some embodiments, in step (i), the hydrogen transfer catalyst is a platinum catalyst.

[0108] In some embodiments, in step (i), the hydrogen transfer catalyst is a palladium catalyst (e.g., carbon-supported palladium (Pd / C)).

[0109] In some implementations, in step (i), the hydrogen transfer catalyst is a rhodium catalyst.

[0110] In some implementations, in step (i), the hydrogen transfer catalyst is a ruthenium catalyst.

[0111] In some embodiments, in step (i), the reaction is carried out in the presence of a solvent or a mixture of solvents. In some embodiments, the solvent is an organic solvent or a mixture of organic solvents. In some embodiments, the solvent is a polar protic solvent (e.g., methanol, 2-propanol, or a mixture thereof).

[0112] In some embodiments, in step (i), the reaction is carried out at a temperature of 35±15°C, 35±10°C, or 35±5°C (e.g., about 35°C).

[0113] In some embodiments, in step (i), the reaction is carried out at a temperature of 36±15°C, 36±10°C, or 36±5°C (e.g., about 36°C).

[0114] In some embodiments, in step (i), the reaction is carried out at a temperature of 37±15°C, 37±10°C, or 37±5°C (e.g., about 37°C).

[0115] In some embodiments, in step (i), the reaction is carried out at a temperature of 38±15°C, 38±10°C, or 38±5°C (e.g., about 38°C).

[0116] In some embodiments, in step (i), the reaction is carried out at a temperature of 39±15°C, 39±10°C, or 39±5°C (e.g., about 39°C).

[0117] In some embodiments, in step (i), the reaction is carried out at a temperature of 40±15°C, 40±10°C, or 40±5°C (e.g., about 40°C).

[0118] In some implementations, in step (i), the reaction is carried out for 5 ± 10 hours, 5 ± 9 hours, 5 ± 8 hours, 5 ± 7 hours, 5 ± 6 hours, 5 ± 5 hours, 5 ± 4 hours, 5 ± 3 hours, 5 ± 2 hours, or 5 ± 1 hours (e.g., about 5 hours).

[0119] In some implementations, in step (i), the reaction is carried out for 6 ± 10 hours, 6 ± 9 hours, 6 ± 8 hours, 6 ± 7 hours, 6 ± 6 hours, 6 ± 5 hours, 6 ± 4 hours, 6 ± 3 hours, 6 ± 2 hours, or 6 ± 1 hours (e.g., about 6 hours).

[0120] In some implementations, in step (i), the reaction is carried out for 7±10 hours, 7±9 hours, 7±8 hours, 7±7 hours, 7±6 hours, 7±5 hours, 7±4 hours, 7±3 hours, 7±2 hours, or 7±1 hours (e.g., about 7 hours).

[0121] In some implementations, in step (i), the reaction is carried out for 8 ± 10 hours, 8 ± 9 hours, 8 ± 8 hours, 8 ± 7 hours, 8 ± 6 hours, 8 ± 5 hours, 8 ± 4 hours, 8 ± 3 hours, 8 ± 2 hours, or 8 ± 1 hours (e.g., about 8 hours).

[0122] In some embodiments, in step (i), the ratio of the 4,6-dichloro-2-methylpyrimidine (compound number 1) or a salt thereof to the hydrogenating agent is about 5:1 to about 1:5.

[0123] In some embodiments, in step (i), the ratio of the 4,6-dichloro-2-methylpyrimidine (compound number 1) or a salt thereof to the hydrogenating agent is about 4:1 to about 1:4.

[0124] In some embodiments, in step (i), the ratio of the 4,6-dichloro-2-methylpyrimidine (compound number 1) or a salt thereof to the hydrogenating agent is about 3:1 to about 1:3.

[0125] In some embodiments, in step (i), the ratio of the 4,6-dichloro-2-methylpyrimidine (compound number 1) or a salt thereof to the hydrogenating agent is about 2:1 to about 1:2.

[0126] In some embodiments, in step (i), the ratio of the 4,6-dichloro-2-methylpyrimidine (compound number 1) or a salt thereof to the hydrogenating agent is about 1:1 to about 1:4.

[0127] In some embodiments, in step (i), the ratio of the 4,6-dichloro-2-methylpyrimidine (compound number 1) or a salt thereof to the hydrogenating agent is about 1:1.

[0128] In some embodiments, in step (i), the ratio of the 4,6-dichloro-2-methylpyrimidine (compound number 1) or a salt thereof to the hydrogenating agent is about 1:2.

[0129] In some embodiments, in step (i), the ratio of the 4,6-dichloro-2-methylpyrimidine (compound number 1) or a salt thereof to the hydrogenating agent is about 1:3.

[0130] In some embodiments, in step (i), the ratio of the 4,6-dichloro-2-methylpyrimidine (compound number 1) or a salt thereof to the hydrogenating agent is about 1:4.

[0131] In some embodiments, in step (i), 2-methylpyrimidine (compound number 2) is not separated or purified before step (ii) (e.g., before reacting with acid).

[0132] In some embodiments, in step (i), a mixture comprising 2-methylpyrimidine (compound number 2) is formed.

[0133] In some embodiments, in step (i), the mixture containing 2-methylpyrimidine (compound number 2) is acidified (e.g., with an aqueous solution of hydrochloric acid).

[0134] In some embodiments, in step (i), the acidified mixture is washed with an organic solvent (e.g., methyl tert-butyl ether).

[0135] In some embodiments, in step (i), a polar solvent (e.g., dichloromethane) is added to the washed mixture.

[0136] In some implementations, in step (i), the mixture is alkalized (e.g., with an aqueous solution of potassium carbonate).

[0137] In some implementations, in step (i), the mixture is alkalized to a pH of at least about 7.5.

[0138] In some implementations, in step (i), the mixture is alkalized to a pH of at least about 8.

[0139] In some implementations, in step (i), the mixture is alkalized to a pH of at least about 8.5.

[0140] In some implementations, in step (i), the mixture is alkalized to a pH of at least about 9.

[0141] In some embodiments, in step (i), 2-methylpyrimidine (compound number 2) is extracted from the alkalized mixture in a polar solvent (e.g., dichloromethane).

[0142] step (ii) In some embodiments, in step (ii), the acid is an organic acid (e.g., oxalic acid).

[0143] In some implementations, in step (ii), the acid is oxalic acid.

[0144] In some embodiments, in step (ii), the reaction is carried out in the presence of an aprotic solvent (e.g., dichloromethane (DCM), tetrahydrofuran (THF), or a mixture thereof).

[0145] In some embodiments, in step (ii), the reaction is carried out in the presence of tetrahydrofuran (THF).

[0146] In some embodiments, step (ii) is carried out at a temperature of about -20°C to about 60°C to form a second mixture.

[0147] In some embodiments, step (ii) is carried out at a temperature of about 20°C to about 50°C to form a second mixture.

[0148] In some embodiments, step (ii) is carried out at a temperature of about 30°C to about 50°C to form a second mixture.

[0149] In some embodiments, step (ii) is carried out at a temperature of about 40°C to about 50°C to form a second mixture.

[0150] In some embodiments, step (ii) is performed at a temperature of about 20°C to form a second mixture.

[0151] In some embodiments, step (ii) is performed at a temperature of about 25°C to form a second mixture.

[0152] In some embodiments, step (ii) is performed at a temperature of about 30°C to form a second mixture.

[0153] In some embodiments, step (ii) is performed at a temperature of about 35°C to form a second mixture.

[0154] In some embodiments, step (ii) is performed at a temperature of about 40°C to form a second mixture.

[0155] In some embodiments, step (ii) is performed at a temperature of about 45°C to form a second mixture.

[0156] In some embodiments, step (ii) is performed at a temperature of about 50°C to form a second mixture.

[0157] In some implementations, in step (ii), the second mixture is subjected to a temperature cycling procedure.

[0158] In some embodiments, in step (ii), the second mixture is subjected to a temperature cycling procedure comprising the following steps: (a) cooling the second mixture to about 20°C for about 1 hour and stirring for about 15 minutes; (b) heating it back to about 45°C and stirring for at least about 30 minutes; (c) cooling it from about 45°C to about 20°C for about 1 hour and stirring for about 15 minutes; (d) heating it back to about 45°C and stirring for at least about 30 minutes; (e) cooling it from about 45°C to about -10°C for about 4 hours; and (f) stirring it at about -10°C for at least about 13 hours.

[0159] In some embodiments, step (ii) further comprises isolating the 2-methylpyrimidine salt (compound number 3).

[0160] In some embodiments, step (ii) further comprises isolating a 2-methylpyrimidine salt (e.g., compound number 3a).

[0161] In some embodiments, step (ii) further comprises isolating 2-methylpyrimidine oxalate (compound number 3a).

[0162] In some embodiments, step (ii) further comprises drying the 2-methylpyrimidine salt (compound number 3).

[0163] In some embodiments, step (ii) further comprises drying a 2-methylpyrimidine salt (e.g., compound number 3a).

[0164] In some embodiments, step (ii) further comprises drying 2-methylpyrimidine oxalate (compound number 3a).

[0165] In some embodiments, in step (ii), the 2-methylpyrimidine salt (e.g., compound number 3a) has a purity of at least about 98% by area, as determined by HPLC (high performance liquid chromatography).

[0166] In some embodiments, in step (ii), the 2-methylpyrimidine salt (e.g., compound number 3a) has a purity of at least about 98.5% by area, as determined by HPLC.

[0167] In some embodiments, in step (ii), the 2-methylpyrimidine salt (e.g., compound number 3a) has a purity of at least about 99% by area, as determined by HPLC.

[0168] In some embodiments, in step (ii), the 2-methylpyrimidine salt (e.g., compound number 3a) has a purity of at least about 99.1% by area, as determined by HPLC.

[0169] In some embodiments, in step (ii), the 2-methylpyrimidine salt (e.g., compound number 3a) has a purity of at least about 99.2% by area, as determined by HPLC.

[0170] In some embodiments, in step (ii), the 2-methylpyrimidine salt (e.g., compound number 3a) has a purity of at least about 99.3% by area, as determined by HPLC.

[0171] In some embodiments, in step (ii), the 2-methylpyrimidine salt (e.g., compound number 3a) has a purity of at least about 99.4% by area, as determined by HPLC.

[0172] In some embodiments, in step (ii), the 2-methylpyrimidine salt (e.g., compound number 3a) has a purity of at least about 99.5% by area, as determined by HPLC.

[0173] In some embodiments, in step (ii), the 2-methylpyrimidine salt (e.g., compound number 3a) has a purity of at least about 99.6% by area, as determined by HPLC.

[0174] In some embodiments, in step (ii), the 2-methylpyrimidine salt (e.g., compound number 3a) has a purity of at least about 99.7% by area, as determined by HPLC.

[0175] In some embodiments, in step (ii), the 2-methylpyrimidine salt (e.g., compound number 3a) has a purity of at least about 99.8% by area, as determined by HPLC.

[0176] In some embodiments, in step (ii), 2-methylpyrimidine oxalate (compound number 3a) has 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% by area, as determined by HPLC.

[0177] In some embodiments, in step (ii), the yield of the 2-methylpyrimidine salt (e.g., compound number 3a) is at least about 50%.

[0178] In some embodiments, in step (ii), the yield of the 2-methylpyrimidine salt (e.g., compound number 3a) is at least about 55%.

[0179] In some embodiments, in step (ii), the yield of the 2-methylpyrimidine salt (e.g., compound number 3a) is at least about 60%.

[0180] In some embodiments, in step (ii), the yield of the 2-methylpyrimidine salt (e.g., compound number 3a) is at least about 65%.

[0181] In some embodiments, in step (ii), the yield of the 2-methylpyrimidine salt (e.g., compound number 3a) is at least about 69%.

[0182] In some embodiments, in step (ii), the yield of the 2-methylpyrimidine salt (e.g., compound number 3a) is at least about 70%.

[0183] In some embodiments, in step (ii), the yield of the 2-methylpyrimidine salt (e.g., compound number 3a) is at least about 75%.

[0184] In some embodiments, in step (ii), the yield of the 2-methylpyrimidine salt (e.g., compound number 3a) is at least about 80%.

[0185] In some embodiments, in step (ii), the yield of the 2-methylpyrimidine salt (e.g., compound number 3a) is at least about 85%.

[0186] In some embodiments, in step (ii), the yield of 2-methylpyrimidine oxalate (compound number 3a) is at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 69%, at least about 70%, at least about 75%, at least about 80%, or at least about 85%.

[0187] In some embodiments, in step (ii), the 2-methylpyrimidine salt is 2-methylpyrimidine oxalate.

[0188] In some embodiments, in step (ii), the 2-methylpyrimidine salt (e.g., compound number 3a) contains less than about 5% impurities by area, as determined by HPLC.

[0189] In some embodiments, in step (ii), the 2-methylpyrimidine salt (e.g., compound number 3a) contains less than about 4% impurities by area, as determined by HPLC.

[0190] In some embodiments, in step (ii), the 2-methylpyrimidine salt (e.g., compound number 3a) contains less than about 3% impurities by area, as determined by HPLC.

[0191] In some embodiments, in step (ii), the 2-methylpyrimidine salt (e.g., compound number 3a) contains less than about 2% impurities by area, as determined by HPLC.

[0192] In some embodiments, in step (ii), the 2-methylpyrimidine salt (e.g., compound number 3a) contains less than about 1% impurity by area, as determined by HPLC.

[0193] In some embodiments, in step (ii), 2-methylpyrimidine oxalate (compound number 3a) contains less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% by area, as determined by HPLC.

[0194] In some embodiments, in step (ii), the impurity comprises 2-propanol.

[0195] In some embodiments, in step (ii), the impurity comprises 4,6-dichloro-2-methylpyrimidine.

[0196] In some embodiments, in step (ii), the impurity comprises 2-propanol; 4,6-dichloro-2-methylpyrimidine; or a mixture thereof.

[0197] In some embodiments, in step (ii), the impurity comprises less than about 5.5% of 2-propanol.

[0198] In some embodiments, in step (ii), the impurity comprises less than about 0.1% of 4,6-dichloro-2-methylpyrimidine.

[0199] In some embodiments, in step (ii), the impurity comprises about 4.9% 2-propanol; about 0.03% 4,6-dichloro-2-methylpyrimidine; or a mixture thereof.

[0200] step (iii) In some embodiments, in step (iii), the reaction is carried out in the presence of a base. In some embodiments, the base is potassium tert-pentoxygenate.

[0201] In some implementations, step (iii) produces less than about 1.0% tert-amyl ester by area, as determined by HPLC.

[0202] In some implementations, step (iii) produces less than about 0.9% tert-amyl ester by area, as determined by HPLC.

[0203] In some implementations, step (iii) produces less than about 0.8% tert-amyl ester by area, as determined by HPLC.

[0204] In some implementations, step (iii) produces less than about 0.7% tert-amyl ester by area, as determined by HPLC.

[0205] In some implementations, step (iii) produces less than about 0.6% tert-amyl ester by area, as determined by HPLC.

[0206] In some implementations, step (iii) produces less than about 0.5% tert-amyl ester by area, as determined by HPLC.

[0207] In some implementations, step (iii) produces less than about 0.4% tert-amyl ester by area, as determined by HPLC.

[0208] In some implementations, step (iii) produces less than about 0.3% tert-amyl ester by area, as determined by HPLC.

[0209] In some implementations, step (iii) produces less than about 0.2% tert-amyl ester by area, as determined by HPLC.

[0210] In some implementations, step (iii) produces less than about 0.1% tert-amyl ester by area, as determined by HPLC.

[0211] In some embodiments, step (iii) is performed at a temperature of 30±15°C, 30±10°C, or 30±5°C (e.g., about 30°C).

[0212] In some embodiments, step (iii) is performed at a temperature of 40±15°C, 40±10°C, or 40±5°C (e.g., about 40°C).

[0213] In some embodiments, step (iii) is performed at a temperature of 50±15°C, 50±10°C, or 50±5°C (e.g., about 50°C).

[0214] In some implementations, step (iii) is carried out in the presence of a polar solvent.

[0215] In some implementations, step (iii) is performed in the presence of an aprotic solvent.

[0216] In some embodiments, step (iii) is carried out in the presence of a polar solvent, an aprotic solvent, or a mixture thereof. In some embodiments, step (iii) is carried out in the presence of THF, isopropanol (IPA), or a mixture thereof.

[0217] In some embodiments, step (iii) further includes separating compound number 5 or a salt thereof.

[0218] In some embodiments, in step (iii), a mixture comprising compound number 5 or a salt thereof is formed.

[0219] In some embodiments, in step (iii), the mixture containing compound number 5 or its salt is washed with an aqueous solution (e.g., an aqueous solution of potassium bicarbonate).

[0220] In some embodiments, in step (iii), the mixture containing compound number 5 or its salt is further washed with water.

[0221] In some embodiments, in step (iii), an organic solvent (e.g., isopropyl acetate, heptane, or a mixture thereof) is added to the washed mixture to form a suspension.

[0222] In some embodiments, in step (iii), compound number 5 or its salt is separated by filtration.

[0223] In some embodiments, in step (iii), compound number 5 or its salt has a purity of at least about 90% by area, as determined by HPLC.

[0224] In some embodiments, in step (iii), compound number 5 or its salt has a purity of at least about 92% by area, as determined by HPLC.

[0225] In some embodiments, in step (iii), compound number 5 or its salt has a purity of at least about 94% by area, as determined by HPLC.

[0226] In some embodiments, in step (iii), compound number 5 or its salt has a purity of at least about 96% by area, as determined by HPLC.

[0227] In some embodiments, in step (iii), compound number 5 or its salt has a purity of at least about 98% by area, as determined by HPLC.

[0228] In some embodiments, in step (iii), compound number 5 or its salt has a purity of at least about 99% by area, as determined by HPLC.

[0229] In some embodiments, in step (iii), the yield of compound number 5 or its salt is at least about 60%.

[0230] In some embodiments, in step (iii), the yield of compound number 5 or its salt is at least about 65%.

[0231] In some embodiments, in step (iii), the yield of compound number 5 or its salt is at least about 70%.

[0232] In some embodiments, in step (iii), the yield of compound number 5 or its salt is at least about 75%.

[0233] In some embodiments, in step (iii), the yield of compound number 5 or its salt is at least about 80%.

[0234] In some embodiments, in step (iii), the yield of compound number 5 or its salt is at least about 85%.

[0235] In some embodiments, in step (iii), the yield of compound number 5 or its salt is at least about 90%.

[0236] step (iv) In some implementations, in step (iv), the reducing agent is a monosaccharide.

[0237] In some implementations, in step (iv), the reducing agent is glucose monohydrate.

[0238] In some implementations, step (iv) is carried out in the presence of a reduction catalyst.

[0239] In some embodiments, step (iv) is carried out in the presence of a reduction catalyst, wherein the reduction catalyst is an enzyme catalyst.

[0240] In some embodiments, step (iv) is carried out in the presence of a reduction catalyst, wherein the reduction catalyst is a dinucleotide phosphate.

[0241] In some embodiments, step (iv) is carried out in the presence of a reduction catalyst, wherein the reduction catalyst is an enzyme catalyst, a dinucleotide phosphate, or a mixture thereof.

[0242] In some embodiments, in step (iv), the enzyme catalyst is ketone reductase (KRED).

[0243] In some embodiments, in step (iv), the enzyme catalyst is glutamate dehydrogenase (GDH).

[0244] In some embodiments, in step (iv), the enzyme catalyst is ketone reductase (KRED), glutamate dehydrogenase (GDH), or a mixture thereof.

[0245] In some embodiments, in step (iv), the enzyme catalyst is ketone reductase (KRED), glutamate dehydrogenase (GDH), or a mixture thereof, and the dinucleotide phosphate is nicotinamide adenine dinucleotide phosphate (NADP).

[0246] In some embodiments, in step (iv), the molar ratio of the acid to compound number 5 or its salt is about 4:1 to about 1:4.

[0247] In some embodiments, in step (iv), the molar ratio of the acid to compound number 5 or its salt is about 3:1 to about 1:3.

[0248] In some embodiments, in step (iv), the molar ratio of the acid to compound number 5 or its salt is about 2:1 to about 1:2.

[0249] In some embodiments, in step (iv), compound number 6 (e.g., compound number 6a or 6b) or its salt is separated before reacting with compound number 8 or its salt.

[0250] In some embodiments, in step (iv), the reaction is carried out in the presence of a buffer solution. In some embodiments, the buffer solution contains a phosphate (e.g., dipotassium hydrogen phosphate (K₂HPO₄) or potassium dihydrogen phosphate (KH₂PO₄)).

[0251] In some implementations, in step (iv), the reaction is carried out at a pH of about 7.

[0252] In some embodiments, the buffer solution has a pH value of 7.0±2.0, 7.0±1.5, 7.0±1.0, 7.0±0.9, 7.0±0.8, 7.0±0.7, 7.0±0.6, 7.0±0.5, 7.0±0.4, 7.0±0.3, 7.0±0.2 or 7.0±0.1 (e.g., about 7.0).

[0253] In some implementations, contact is carried out in the presence of a polar aprotic solvent (e.g., methyl tert-butyl ether (MTBE)).

[0254] In some embodiments, step (iv) further comprises extracting the formed compound number 6 (e.g., compound number 6a or 6b) or a salt thereof.

[0255] In some embodiments, step (iv) produces a solution of compound number 6 (e.g., compound number 6a or 6b) or a salt thereof.

[0256] step （v） In some implementations, in step (v), the CO source is triphosgene.

[0257] 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)).

[0258] In some embodiments, in step (v), contact is carried out in the presence of a solvent. In some embodiments, the solvent is an aprotic organic solvent (e.g., toluene, dichloromethane (DCM), or a mixture thereof).

[0259] In some embodiments, in step (v), the molar ratio of the base to compound number 8 or its salt is about 3:1 to about 1:3.

[0260] In some embodiments, step (v) comprises filtering a solution of compound number 8 or a salt thereof (e.g., in toluene).

[0261] In some embodiments, step (v) produces a solution of compound number 8 or a salt thereof (e.g., in toluene).

[0262] 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 organic base (e.g., 4-dimethylaminopyridine (DMAP)).

[0263] In some embodiments, in step (vi), the reaction is carried out in the presence of a solvent. In some embodiments, the solvent is an aprotic organic solvent. In some embodiments, the solvent comprises methyltetrahydrofuran (MeTHF).

[0264] In some embodiments, step (vi) is carried out in the presence of an organic base, an aprotic solvent, or a mixture thereof.

[0265] In some embodiments, in step (vi), the molar ratio of compound number 6 (e.g., compound number 6a or 6b) or its salt to compound number 8 or its salt is about 3:1 to about 1:3.

[0266] In some embodiments, in step (vi), compound number 9 (e.g., compound number 9a or 9b) or its salt is separated.

[0267] step (vii) In some embodiments, step (vii) comprises crystallizing compound number 9 (e.g., compound number 9a or 9b) or a salt thereof in the presence of at least one organic solvent. In some embodiments, said at least one organic solvent is isopropyl acetate (IPAc), n-heptane, or a mixture thereof.

[0268] In some embodiments, step (vii) further comprises separating compound number 9 (e.g., compound number 9a or 9b) or its salt.

[0269] In some embodiments, in step (vii), compound number 9 (e.g., compound number 9a or 9b) or a salt thereof has a purity of at least about 99.0% by area, as determined by HPLC.

[0270] In some embodiments, in step (vii), compound number 9 (e.g., compound number 9a or 9b) or a salt thereof has a purity of at least about 99.5% by area, as determined by HPLC.

[0271] Compounds prepared by the method In some embodiments, this disclosure provides compounds prepared by the methods disclosed herein.

[0272] In some embodiments, this disclosure provides compounds prepared on a large scale according to the methods disclosed herein.

[0273] In some embodiments, this disclosure provides a method for preparing compound number 2.

[0274] In some embodiments, this disclosure provides a method for preparing compound number 3.

[0275] In some embodiments, this disclosure provides a method for preparing compound number 3a.

[0276] In some embodiments, this disclosure provides a method for preparing compound number 5 or a salt thereof.

[0277] In some embodiments, this disclosure provides a method for preparing compound number 6 or a salt thereof.

[0278] In some embodiments, this disclosure provides a method for preparing compound number 6a or a salt thereof.

[0279] In some embodiments, this disclosure provides a method for preparing compound number 6b or a salt thereof.

[0280] In some embodiments, this disclosure provides a method for preparing compound number 8 or a salt thereof.

[0281] In some embodiments, this disclosure provides a method for preparing compound number 9 or a salt thereof.

[0282] In some embodiments, this disclosure provides a method for preparing compound number 9a or a salt thereof.

[0283] In some embodiments, this disclosure provides a method for preparing compound number 9b or a salt thereof.

[0284] In some embodiments, this disclosure provides compound number 3.

[0285] In some embodiments, the compound is compound number 3 having an enantiomer excess (ee) of about 90% or greater, about 95% or greater, about 96% or greater, about 97% or greater, about 98% or greater, about 99% or greater, about 99.5% or greater, about 99.6% or greater, about 99.7% or greater, about 99.8% or greater, or about 99.9% or greater.

[0286] In some embodiments, the compound is compound number 3, having a purity of about 90% or greater, about 95% or greater, about 96% or greater, about 97% or greater, about 98% or greater, about 99% or greater, about 99.5% or greater, about 99.6% or greater, about 99.7% or greater, about 99.8% or greater, or about 99.9% or greater.

[0287] In some embodiments, this disclosure provides compound number 3a.

[0288] In some embodiments, the compound is compound number 3a, having an enantiomer excess (ee) of about 90% or greater, about 95% or greater, about 96% or greater, about 97% or greater, about 98% or greater, about 99% or greater, about 99.5% or greater, about 99.6% or greater, about 99.7% or greater, about 99.8% or greater, or about 99.9% or greater.

[0289] In some embodiments, the compound is compound number 3a, having a purity of about 90% or greater, about 95% or greater, about 96% or greater, about 97% or greater, about 98% or greater, about 99% or greater, about 99.5% or greater, about 99.6% or greater, about 99.7% or greater, about 99.8% or greater, or about 99.9% or greater.

[0290] In some embodiments, the compound is: Compound number 3; or Compound number 3a has the following characteristics: (a) an enantiomer excess (ee) of about 90% or greater, about 95% or greater, about 96% or greater, about 97% or greater, about 98% or greater, about 99% or greater, about 99.5% or greater, about 99.6% or greater, about 99.7% or greater, about 99.8% or greater, or about 99.9% or greater; and / or (b) Purity of approximately 90% or greater, approximately 95% or greater, approximately 96% or greater, approximately 97% or greater, approximately 98% or greater, approximately 99% or greater, approximately 99.5% or greater, approximately 99.6% or greater, approximately 99.7% or greater, approximately 99.8% or greater, or approximately 99.9% or greater.

[0291] In some embodiments, this disclosure provides compound number 5 or a salt thereof.

[0292] In some embodiments, the compound is compound number 5 or a salt thereof having an enantiomer excess (ee) of about 90% or greater, about 95% or greater, about 96% or greater, about 97% or greater, about 98% or greater, about 99% or greater, about 99.5% or greater, about 99.6% or greater, about 99.7% or greater, about 99.8% or greater, or about 99.9% or greater.

[0293] In some embodiments, the compound is compound number 5 or a salt thereof having a purity of about 90% or greater, about 95% or greater, about 96% or greater, about 97% or greater, about 98% or greater, about 99% or greater, about 99.5% or greater, about 99.6% or greater, about 99.7% or greater, about 99.8% or greater, or about 99.9% or greater.

[0294] In some embodiments, this disclosure provides compound number 6 or a salt thereof.

[0295] In some embodiments, the compound is compound number 6 or a salt thereof having an enantiomer excess (ee) of about 90% or greater, about 95% or greater, about 96% or greater, about 97% or greater, about 98% or greater, about 99% or greater, about 99.5% or greater, about 99.6% or greater, about 99.7% or greater, about 99.8% or greater, or about 99.9% or greater.

[0296] In some embodiments, the compound is compound number 6 or a salt thereof having a purity of about 90% or greater, about 95% or greater, about 96% or greater, about 97% or greater, about 98% or greater, about 99% or greater, about 99.5% or greater, about 99.6% or greater, about 99.7% or greater, about 99.8% or greater, or about 99.9% or greater.

[0297] In some embodiments, this disclosure provides compound number 6a or a salt thereof.

[0298] In some embodiments, the compound is compound number 6a or a salt thereof having an enantiomer excess (ee) of about 90% or greater, about 95% or greater, about 96% or greater, about 97% or greater, about 98% or greater, about 99% or greater, about 99.5% or greater, about 99.6% or greater, about 99.7% or greater, about 99.8% or greater, or about 99.9% or greater.

[0299] In some embodiments, the compound is compound number 6a or a salt thereof having a purity of about 90% or greater, about 95% or greater, about 96% or greater, about 97% or greater, about 98% or greater, about 99% or greater, about 99.5% or greater, about 99.6% or greater, about 99.7% or greater, about 99.8% or greater, or about 99.9% or greater.

[0300] In some embodiments, this disclosure provides compound number 6b or a salt thereof.

[0301] In some embodiments, the compound is compound number 6b or a salt thereof having an enantiomer excess (ee) of about 90% or greater, about 95% or greater, about 96% or greater, about 97% or greater, about 98% or greater, about 99% or greater, about 99.5% or greater, about 99.6% or greater, about 99.7% or greater, about 99.8% or greater, or about 99.9% or greater.

[0302] In some embodiments, the compound is compound number 6b or a salt thereof having a purity of about 90% or greater, about 95% or greater, about 96% or greater, about 97% or greater, about 98% or greater, about 99% or greater, about 99.5% or greater, about 99.6% or greater, about 99.7% or greater, about 99.8% or greater, or about 99.9% or greater.

[0303] In some embodiments, this disclosure provides compound number 9 or a salt thereof.

[0304] In some embodiments, the compound is compound number 9 or a salt thereof having an enantiomer excess (ee) of about 90% or greater, about 95% or greater, about 96% or greater, about 97% or greater, about 98% or greater, about 99% or greater, about 99.5% or greater, about 99.6% or greater, about 99.7% or greater, about 99.8% or greater, or about 99.9% or greater.

[0305] In some embodiments, the compound is compound number 9 or a salt thereof having a purity of about 90% or greater, about 95% or greater, about 96% or greater, about 97% or greater, about 98% or greater, about 99% or greater, about 99.5% or greater, about 99.6% or greater, about 99.7% or greater, about 99.8% or greater, or about 99.9% or greater.

[0306] In some embodiments, this disclosure provides compound number 9a or a salt thereof.

[0307] In some embodiments, the compound is compound number 9a or a salt thereof having an enantiomer excess (ee) of about 90% or greater, about 95% or greater, about 96% or greater, about 97% or greater, about 98% or greater, about 99% or greater, about 99.5% or greater, about 99.6% or greater, about 99.7% or greater, about 99.8% or greater, or about 99.9% or greater.

[0308] In some embodiments, the compound is compound number 9a or a salt thereof having a purity of about 90% or greater, about 95% or greater, about 96% or greater, about 97% or greater, about 98% or greater, about 99% or greater, about 99.5% or greater, about 99.6% or greater, about 99.7% or greater, about 99.8% or greater, or about 99.9% or greater.

[0309] In some embodiments, this disclosure provides compound number 9b or a salt thereof.

[0310] In some embodiments, the compound is compound number 9b or a salt thereof having an enantiomer excess (ee) of about 90% or greater, about 95% or greater, about 96% or greater, about 97% or greater, about 98% or greater, about 99% or greater, about 99.5% or greater, about 99.6% or greater, about 99.7% or greater, about 99.8% or greater, or about 99.9% or greater.

[0311] In some embodiments, the compound is compound number 9b or a salt thereof having a purity of about 90% or greater, about 95% or greater, about 96% or greater, about 97% or greater, about 98% or greater, about 99% or greater, about 99.5% or greater, about 99.6% or greater, about 99.7% or greater, about 99.8% or greater, or about 99.9% or greater.

[0312] In some embodiments, this disclosure provides compounds prepared by the methods described herein.

[0313] How to use In some embodiments, this disclosure provides a method for preventing or treating a disease in a subject, the method comprising administering to the subject a compound numbered 9 described herein (e.g., compound number 9a or 9b) or a pharmaceutically acceptable salt thereof.

[0314] In some embodiments, this disclosure provides compound number 9 (e.g., compound number 9a or 9b) or a pharmaceutically acceptable salt thereof for the prevention or treatment of disease or for the inhibition of inflammasome activity in a subject.

[0315] In some embodiments, this disclosure provides the use of compound number 9 (e.g., compound number 9a or 9b) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the prevention or treatment of a disease or for the inhibition of inflammasome activity in a subject.

[0316] In some embodiments, this disclosure provides a method for inhibiting inflammasome activity in a subject, the method comprising contacting cells with compound number 9 (e.g., compound number 9a or 9b) or a pharmaceutically acceptable salt thereof.

[0317] In some implementations, the subject is given a therapeutically effective amount of compound number 9 (e.g., compound number 9a or 9b) or a pharmaceutically acceptable salt thereof.

[0318] In some embodiments, this disclosure provides a method for treating a disease in a subject, the method comprising administering to the subject a compound numbered 9 described herein (e.g., compound number 9a or 9b) or a pharmaceutically acceptable salt thereof.

[0319] In some embodiments, this disclosure provides compound number 9 (e.g., compound number 9a or 9b) or a pharmaceutically acceptable salt thereof described herein for the prevention or treatment of a disease in a subject.

[0320] In some embodiments, this disclosure provides the use of compound number 9 (e.g., compound number 9a or 9b) or a pharmaceutically acceptable salt thereof described herein in the preparation of a medicament for the prevention or treatment of a disease in a subject.

[0321] In some embodiments, this disclosure provides the use of compound number 9 (e.g., compound number 9a or 9b) or a pharmaceutically acceptable salt thereof described herein in the preparation of a medicament for treating a disease in a subject.

[0322] In some implementations, the compound or a pharmaceutically acceptable salt thereof is administered in a therapeutically effective amount.

[0323] In some implementations, the disease or disorder is an inflammatory disorder, an autoinflammatory disorder, an autoimmune disorder, a neurodegenerative disease, or cancer.

[0324] In some embodiments, this disclosure provides a method for inhibiting the activity of inflammasomes (e.g., the NLRP3 inflammasome) in a subject, the method comprising contacting cells with compound number 9 described herein (e.g., compound number 9a or 9b) or a pharmaceutically acceptable salt thereof. In some embodiments, this disclosure provides compound number 9 described herein (e.g., compound number 9a or 9b) or a salt thereof for inhibiting the activity of inflammasomes (e.g., the NLRP3 inflammasome) in a subject.

[0325] In some embodiments, this disclosure provides the use of compound number 9 (e.g., compound number 9a or 9b) or a pharmaceutically acceptable salt thereof described herein in the preparation of a medicament for inhibiting the activity of an inflammasome (e.g., NLRP3 inflammasome).

[0326] In some implementations, the subject is an animal.

[0327] In some implementations, the subject is a mammal.

[0328] In some implementations, the subject is a human being.

[0329] In some implementations, the subject is a cell.

[0330] In some implementations, the subjects are a population of cells.

[0331] Pharmaceutical Compositions / Formulations In some embodiments, this disclosure provides pharmaceutical compositions comprising compound number 9 (e.g., compound number 9a or 9b) or a pharmaceutically acceptable salt thereof and excipients, adjuvants, diluents or carriers (e.g., pharmaceutically acceptable excipients, adjuvants, diluents or carriers).

[0332] In some embodiments, this disclosure provides pharmaceutical compositions comprising compound number 9 (e.g., compound number 9a or 9b) or a pharmaceutically acceptable salt thereof, and one or more of a pharmaceutically acceptable carrier, a pharmaceutically acceptable diluent, a pharmaceutically acceptable adjuvant, or a pharmaceutically acceptable excipient.

[0333] Pharmaceutical compositions can be formulated in a conventional manner using one or more physiologically acceptable carriers (including excipients and adjuvants), which facilitate the processing of the active compound into an article that can be used pharmaceutically.

[0334] A suitable formulation depends on the chosen route of administration. Any well-known technology, carrier, and excipient may be used as appropriate and as understood in the art. A summary of the pharmaceutical compositions described herein can be found, for example: Remington: The Science and Practice of Pharmacy, 19th edition (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, 7th edition (Lippincott Williams & Wilkins, 1999), all incorporated herein by reference in their entirety.

[0335] As used herein, a pharmaceutical composition represents compound number 9 (e.g., compound number 9a or 9b) or a pharmaceutically acceptable salt thereof and / or other therapeutic agents and other chemical components, such as carriers, stabilizers, diluents, dispersants, suspending agents, thickeners and / or excipients. As used herein, a pharmaceutical composition represents compound number 9 (e.g., compound number 9a or 9b) or a salt thereof and one or more of the following excipients: microcrystalline cellulose, cropovidone, hydroxypropyl methylcellulose, sodium bicarbonate, hydrophobic colloidal silica and magnesium stearate.

[0336] In practicing the treatments or methods of use provided herein, a therapeutically effective amount of the disclosed compound number 9 (e.g., compound number 9a or 9b) or a pharmaceutically acceptable salt thereof is administered to treat the disease, disorder, or ailment. In some embodiments, the mammal is a human.

[0337] The therapeutically effective amount of the compound can vary depending on the severity of the disease, the age and relative health status of the subject, and other factors.

[0338] Pharmaceutical compositions including compound number 9 (e.g., compound number 9a or 9b) or pharmaceutically acceptable salts thereof described herein can be prepared in a conventional manner, for example, by means of conventional mixing, dissolving, granulation, sugar-coated pelleting, grinding, emulsifying, encapsulation, embedding or compression processes, by way of example only.

[0339] Biological assay Compounds prepared by the methods described herein can be characterized using a variety of assays known to those skilled in the art to determine whether the compounds possess biological activity. For example, the molecules can be characterized by conventional assays, including but not limited to those described below, to determine whether they possess predicted activity, binding activity, and / or binding specificity.

[0340] Furthermore, high-throughput screening can be used to accelerate analyses using such assays. Therefore, it is possible to rapidly screen the activity of 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 can be performed using one or more different assay techniques, including but not limited to those described below.

[0341] Various in vitro or in vivo biological assays can be applied to detect the effects of the compounds disclosed herein. These in vitro or in vivo biological assays may include, but are not limited to, enzyme activity assays, electrophoretic mobility shift assays, reporter gene assays, in vitro cell viability assays, and the assays described herein.

[0342] In some embodiments, the bioassay is a bioassay that tests the inhibitory activity against IL-1β release after NLRP3 activation in peripheral blood mononuclear cells (PBMCs).

[0343] In some implementations, the biological assay is a PBMC IC50 assay.

[0344] In some embodiments, the inhibitory activity of the compound on IL-1β release after NLRP3 activation in blood cells (e.g., peripheral blood mononuclear cells (PBMCs)) is tested.

[0345] In some embodiments, PBMCs are isolated and seeded into wells of a plate and incubated for a period of time (e.g., 3 hours with lipopolysaccharide). After incubation, the culture medium is replaced and a compound (e.g., a compound disclosed herein) is added to the wells, and the cells can be incubated. The cells are then stimulated (e.g., with ATP or nigericin) and the cell culture medium is collected for analysis.

[0346] 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).

[0347] In some implementations, PBMCs are isolated (e.g., from the erythrocyte sedimentation rate (ESR) 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. Subsequently, the cells are stimulated and the culture medium in the wells is collected for analysis.

[0348] In some implementations, the release of IL-1β into the culture medium is determined by quantitative detection (e.g., using HTRF® to quantitatively detect IL-1β in the culture medium).

[0349] definition Unless otherwise stated, the following terms used in this specification and claims shall have the following meanings as set forth below.

[0350] The term "about" is used herein to mean approximately, within a certain range, roughly, or around. When the term "about" is used in conjunction with a range of numbers, it modifies the range by extending the boundaries of the stated value upwards and downwards. Generally, the term "about" is used herein to refer to a variable whose value is modified by 20%, 10%, 5%, 3%, or 1% above or below a specified value.

[0351] As used herein, the term "substantially pure" with respect to a compound indicates that the compound comprises less than 10% by weight, less than 5% by weight, less than 3% by weight, less than 1% by weight, less than 0.5% by weight, less than 0.2% by weight, or less than 0.1% by weight of impurities.

[0352] As used herein, the term "CO source" refers to a reagent capable of becoming a source of carbon monoxide (CO) during a reaction. In some embodiments, the reagent is capable of forming an isocyanate or equivalent after reacting with an amine. In some embodiments, the dissociation reaction of phosgene, the reaction between CO2 and carbon (the Boudouard reaction), the reaction of water vapor with carbon, the high-temperature electrolysis of carbon dioxide using a solid oxide electrolyzer, or the direct oxidation of carbon in the presence of a limited supply of oxygen or air are CO sources. In some embodiments, the CO source is a phosgene derivative. In one specific embodiment, the CO source is triphosgene.

[0353] It should be understood that the compounds described herein include the compounds themselves, as well as their salts and their solvates, where applicable. For example, salts can be formed between an anion and a positively charged group (e.g., an amino group) on the substituted benzene compound. Suitable anions may include chloride, bromide, iodide, sulfate, hydrogen sulfate, aminosulfonate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, glutamate, glucuronate, glutarate, malate, maleate, succinate, fumarate, tartrate, toluenesulfonate, salicylate, lactate, naphthalenesulfonate, and acetate (e.g., trifluoroacetate).

[0354] As used herein, the expressions “one or more of A, B or C”, “one or more A, B or C”, “one or more of A, B and C”, “one or more A, B and C”, “selected from the set consisting of A, B and C”, “selected from A, B and C”, etc., are used interchangeably and all mean selected from: A, B and / or C, that is, one or more A, one or more B, one or more C or any combination thereof, unless otherwise indicated.

[0355] It should be understood that throughout this specification, when a composition is described as having, including, or comprising specific components, it is considered that the composition is also 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 process is also substantially composed of or consisting of the listed processing steps. Furthermore, it should be understood that the order of the steps or the order in which certain actions are performed is not important, as long as the invention remains operable. Moreover, two or more steps or actions may be performed simultaneously.

[0356] It should be understood that the synthetic methods of this disclosure are tolerant of a variety of functional groups, and therefore a wide range of substituted starting materials can be used. The methods typically provide the desired final compound at or near the end of the process, although it may be desirable in some cases to further convert the compound into its pharmaceutically acceptable salt.

[0357] It should be understood that compound number 3 (e.g., compound number 3a) and compound number 9 (e.g., compound number 9a or 9b), or salts thereof, can be prepared in various ways using commercially available starting materials, compounds known in the literature, or prepared from readily prepared intermediates using standard synthetic methods and procedures known to those skilled in the art, or readily apparent to those skilled in the art based on the teachings herein. Standard synthetic methods and procedures for the preparation of organic molecules, as well as for the transformation and manipulation of functional groups, can be obtained from relevant scientific literature or from standard textbooks in the art. While not limited to any one or more sources, classic textbooks, such as those cited in this article by Smith, MB, March, J., are included. March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure , 5th edition, 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 , VCHPublishers (1989); L. Fieser and M. Fieser, Fieser and Fieser’s Reagents for Organic Synthesis John Wiley and Sons (1994); and L. Paquette, eds. Encyclopedia of Reagents for Organic Synthesis John Wiley and Sons (1995) are a useful and well-regarded reference textbook for organic synthesis known to those skilled in the art.

[0358] 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 in the reaction sequences and synthetic schemes described herein. They will also recognize that certain groups may require protection from the effects of reaction conditions by using protecting groups. Protecting groups can also be used to distinguish similar functional groups in a molecule. A list of protecting groups and how to introduce and remove them can be found in Greene, TW, Wuts, PGM, Protective Groups in Organic Synthesis , 3rd ed., John Wiley & Sons: New York, 1999.

[0359] It should be understood that, unless otherwise stated, any description of a treatment or preventative method includes the use of compound number 9 (e.g., compound number 9a or 9b) or a pharmaceutically acceptable salt thereof to provide the treatment or preventative as described herein. It should be further understood that, unless otherwise stated, any description of a treatment or preventative method includes the use of compound number 9 (e.g., compound number 9a or 9b) or a pharmaceutically acceptable salt thereof to prepare a medicament for the treatment or prevention of such a condition. The treatment or prevention includes the treatment or prevention of human or non-human animals, including rodents and other disease models.

[0360] It should be understood that, unless otherwise stated, any description of a treatment method includes the use of compound number 9 (e.g., compound number 9a or 9b) or a pharmaceutically acceptable salt thereof to provide a treatment as described herein. It should be further understood that, unless otherwise stated, any description of a treatment method includes the use of compound number 9 (e.g., compound number 9a or 9b) or a pharmaceutically acceptable salt thereof to prepare a medicament for treating such a condition. The treatment includes treatment of human or non-human animals, including rodents and other disease models.

[0361] In some implementations, the term "filtering" refers to the collection of the desired compound in solid form using a filter medium.

[0362] As used herein, the term "subject" includes humans and non-human animals, as well as cell lines, cell cultures, tissues, and organs. In some embodiments, the subject is a mammal. The mammal may 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 may also be a bird or poultry. In some embodiments, the subject is a human.

[0363] As used herein, the term "subject in need" means a subject who has a disease or an increased risk of developing a disease. A subject in need may be a subject who has been previously diagnosed or identified as having a disease or disorder disclosed herein. A subject in need may also be a subject with 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 predisposed to developing such a disorder relative to the general population). A subject in need may have a treatment-resistant or resistant disease or disorder disclosed herein (i.e., a disease or disorder disclosed herein that does not respond to treatment or has not yet responded to treatment). The subject may be resistant at the start of treatment or may become resistant during treatment. In some embodiments, the subject in need has received all known effective therapies for the disease or disorder disclosed herein and failed. In some embodiments, the subject in need has received at least one prior therapy.

[0364] As used herein, the terms “treatment” or “management” describe the management and care of a patient in order to combat a disease, symptom, or disorder, and include 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, symptom, or disorder. The term “treatment” may also include treatment of in vitro cell or animal models.

[0365] It should be understood that compound number 9 (e.g., compound number 9a or 9b) or its pharmaceutically acceptable salt may or may be used to prevent related diseases, symptoms or disorders, or to identify suitable candidates for such purposes.

[0366] As used in this article, the terms “prevention” or “stopping” describe reducing or eliminating the occurrence of symptoms or complications of such a disease, condition, or disorder.

[0367] 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 textbooks. These textbooks include Ausubel et al. Current Protocols in Molecular Biology John Wiley and Sons, Inc. (2005); Sambrook et al. Molecular Cloning, A Laboratory Manual (3rd ed.), Cold Spring Harbor Press, Cold Spring Harbor, New York (2000); Coligan et al., Current Protocols in Immunology , John Wiley & Sons, NY; Enna et al., Current Protocols in Pharmacology John Wiley & Sons, NY; Fingl et al. The Pharmacological Basis of Therapeutics (1975), Remington's Pharmaceutical Sciences Mack Publishing Co., Easton, PA, 18th edition (1990). Of course, these textbooks may also be consulted when making or using any aspect of this disclosure.

[0368] As used herein, the term "pharmaceutical composition" is a formulation containing compound number 9 (e.g., compound number 9a or 9b) or a pharmaceutically acceptable salt thereof, presented in a form suitable for administration to a subject. In some embodiments, the pharmaceutical composition is in bulk or unit dose form. Unit dose form is any of a variety of forms, including, for example, capsules, intravenous bags, tablets, a single pump or tubular bottle on a nebulizer. The amount of active ingredient (e.g., a formulation of the disclosed compound or its salts, hydrates, solvates, or isomers) in the unit dose composition is an effective amount and varies depending on the specific treatment involved. Those skilled in the art will recognize that, depending on the patient's age and condition, it is sometimes necessary to make routine changes to the dosage. The dosage will also depend on the route of administration. A variety of routes are considered, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalation, sublingual, sublingual, intrapleural, intrathecal, intravitreal, intranasal, etc. Dosage forms for topical or transdermal application of the compounds of this disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. In one embodiment, the active compound is mixed under sterile conditions with one or more pharmaceutically acceptable carriers and with any desired preservatives, buffers, or propellants.

[0369] As used herein, the term “pharmaceutically acceptable” means that compounds, anions, cations, materials, compositions, carriers, and / or dosage forms that, to a reasonable extent of medical judgment, are suitable for contact with human and animal tissues without excessive toxicity, irritation, allergic responses, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0370] As used herein, the term "pharmaceuticalally acceptable excipient" refers to an excipient that can be used to prepare a pharmaceutical composition that is generally safe, non-toxic, and not biologically or otherwise undesirable, and includes excipients acceptable for both veterinary and human pharmaceutical applications. As used in this specification and claims, "pharmaceuticalally acceptable excipient" can include one or more such excipients.

[0371] It should be understood that the pharmaceutical compositions of this disclosure 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 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 (e.g., hydrochloric acid or sodium hydroxide). Parenteral preparations may be encapsulated in ampoules, disposable syringes, or multiple-dose tubular vials made of glass or plastic.

[0372] It should be understood that the compounds or pharmaceutical compositions of this disclosure can be administered to a subject by many well-known methods currently used for chemotherapeutic treatment. For example, the compounds of this disclosure can be injected into the bloodstream or body cavity, administered orally, or applied through the skin as a patch. The selected dose should be sufficient to constitute an effective treatment, but not high enough to cause unacceptable side effects. The status of the disease condition (e.g., the disease or disorder disclosed herein) and the patient's health should preferably be closely monitored during treatment and at a reasonable stage after treatment.

[0373] 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 exhibits a detectable therapeutic or inhibitory effect. This effect can be detected by any assay method known in the art. The precise effective amount for a subject will depend on the subject's weight, size, and health; the nature and severity of the condition; and the therapeutic agent or combination of therapeutic agents chosen for administration. A therapeutically effective amount for a given situation can be determined through routine experiments within the skill and judgment of a clinician.

[0374] As used herein, the term "effective amount" refers to the amount of a pharmaceutical agent used to treat or improve an identified disease or condition, or to exhibit a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. The precise effective amount for a subject will depend on the subject's weight, size, and health; the nature and severity of the condition; and the therapeutic agent or combination of therapeutic agents chosen for administration. A therapeutically effective amount for a given situation can be determined through routine experiments within the skill and judgment of a clinician.

[0375] It should be understood that for any compound, the therapeutically effective dose or effective amount can initially be estimated in cell culture assays (e.g., assays of proliferative cells) or in animal models (typically rats, mice, rabbits, dogs, or pigs). These animal models can also be used to determine appropriate concentration ranges and routes of administration. This information can then be used to determine the useful dose and route of administration in humans. Therapeutic / prophylactic efficacy and toxicity, such as ED, can be determined using standard pharmaceutical procedures in cell cultures or laboratory animals. 50 (The effective dose in 50% of the population) and LD50 50 (The 50% lethal dose for a population). The dose ratio between toxic effects and therapeutic effects is the therapeutic index, and it can be expressed as a ratio, LD50. 50 / ED 50 Pharmaceutical compositions exhibiting a high therapeutic index are preferred. Dosage can vary within this range, depending on the dosage form used, patient sensitivity, and route of administration.

[0376] Adjust the dosage and administration to provide adequate levels of active agent or maintain the desired effect. Factors that may be considered include the severity of the disease state, the subject's general health, the subject's age, weight and sex, diet, timing and frequency of administration, drug combination, sensitivity to response, and tolerance / response to the therapy.

[0377] Pharmaceutical compositions containing compound number 9 (e.g., compound number 9a or 9b) or a pharmaceutically acceptable salt thereof can be prepared in a manner generally known, for example by conventional mixing, dissolving, granulation, pelleting, grinding, emulsification, encapsulation, embedding, or low-pressure lyophilization processes. 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 number 9 (e.g., compound number 9a or 9b) or a pharmaceutically acceptable salt thereof into an article suitable for pharmaceutical use. Appropriate formulations depend on the chosen route of administration.

[0378] In some embodiments, the pharmaceutical compositions disclosed herein further comprise pharmaceutically acceptable excipients, such as diluents, carriers, auxiliaries, binders, lubricants, surfactants, sweeteners, flavoring agents, coating materials, preservatives, dyes, thickeners, or combinations thereof.

[0379] It should be understood that the pharmaceutical composition may be included in a container, package, or dispenser along with the instructions for use.

[0380] It should be understood that all these forms are also considered within the scope of the claimed disclosure for compounds of this disclosure that are capable of further forming salts.

[0381] As used herein, the term "pharmaceutically acceptable salt" refers to a derivative of the compounds disclosed herein, wherein the parent compound is modified by forming its acid salt 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 conventionally nontoxic salts or quaternary ammonium salts of the parent compound, for example, formed from nontoxic inorganic or organic acids. For example, such conventionally nontoxic salts may include, but are not limited to, salts derived from inorganic and organic acids selected from 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edetate, ethanedisulfonic acid, 1,2-ethanesulfonic acid, fumaric acid, glucoheponic acid, gluconic acid, glutamic acid, glycolic acid, p-aminobenzoic acid, hexazorinic acid, hydrabamiic acid. c) Hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxymaleic acid, hydroxynaphthyl carboxylic acid, hydroxyethanesulfonic acid, lactic acid, lactobionic acid, lauryl sulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, oxalic acid, pyric 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.

[0382] In some embodiments, the salt is a sodium salt, potassium salt, calcium salt, magnesium salt, diethylamine salt, choline salt, meglumine salt, dibenzylethylenediamine salt, tromethamine salt, ammonium salt, arginine salt, or lysine salt. In some embodiments, the salt is a sodium salt.

[0383] In some embodiments, the pharmaceutically acceptable salt is a sodium salt, potassium salt, calcium salt, magnesium salt, diethylamine salt, choline salt, meglumine salt, dibenzylethylenediamine 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-en-1-carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, mucoconic acid, etc. This disclosure also covers salts formed when acidic protons present in the parent compound are replaced by metal ions (e.g., alkali metal ions, alkaline earth metal ions, or aluminum ions); or salts formed when coordinated with organic bases such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylreduced glucosamine, etc. In the salt form, it should be understood that the ratio of the compound to the cation or anion of the salt can be 1:1, or any ratio other than 1:1, such as 3:1, 2:1, 1:2, or 1:3.

[0384] It should be understood that all references to pharmaceutically acceptable salts may include the same salt in either a solvation form (solvent) or a crystalline form (polymorph) as defined herein.

[0385] As used herein, the term "inorganic acid" means an acid such as, but not limited to, hydrobromic acid, hydroiodic acid, sulfuric acid, aminosulfonic acid, nitric acid, boric acid, phosphoric acid, and combinations thereof.

[0386] As used herein, the term "organic acid" means acid such as, but not limited to: acetic acid; trifluoroacetic acid; phenylacetic acid; propionic acid; stearic acid; lactic acid; ascorbic acid; maleic acid; hydroxymaleic acid; hydroxyethanesulfonic 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 acid, 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 laurylsulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid or ethanesulfonic acid; cysteine ​​sulfonic acid; and combinations thereof.

[0387] As used herein, the term "inorganic base" means 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.

[0388] As used herein, the term "organic base" refers to an organic compound containing one or more nitrogen atoms and which acts 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), 4-dimethylaminopyridine (DMAP), diisopropylethylamine (DIPEA), triethylamine (TEA), and tert-butoxides (e.g., sodium tert-butoxide, potassium tert-butoxide, calcium tert-butoxide, or magnesium tert-butoxide).

[0389] As used herein, the term "inorganic solvent" means a solvent that does not contain carbon, except as listed 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, chlorofluorosulfonyl, 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.

[0390] As used herein, the term "organic solvent" refers to an organic molecule capable of dissolving at least partially 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.), which also include 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, diphenyl ether, etc.). Organic solvents include: methyl ethers, isopropyl ethers, tert-butyl methyl ethers, tetrahydrofuran, 1,4-dioxane, etc.; amine solvents (e.g., propylamine, diethylamine, triethylamine, aniline, pyridine); alcohol solvents (e.g., methanol, ethanol, isopropanol, 1-propanol, 2-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 organosilicon 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.

[0391] As used herein, unless otherwise indicated, the term "aprotic organic solvent" means any solvent that does not produce protons. Examples of aprotic organic solvents include, but are not limited to, DMF, dioxane, THF, methyltetrahydrofuran, acetonitrile, pyridine, dichloroethane, dichloromethane, MTBE, toluene, etc.

[0392] Techniques for formulating and applying the disclosed compounds can be found in [reference needed]. Remington: the Science and Practice of Pharmacy , 19th edition, Mack Publishing Co., Easton, PA (1995). In some embodiments, compound number 9 (e.g., compound number 9a or 9b) or a pharmaceutically acceptable salt thereof is used in combination with one or more pharmaceutically acceptable carriers, excipients, or diluents in a pharmaceutical article. Suitable pharmaceutically acceptable carriers include, but are not limited to, inert solid fillers or diluents and sterile aqueous or organic solutions. The compound will be present in such a pharmaceutical composition in an amount sufficient to provide the desired dose within the range described herein.

[0393] Unless otherwise stated, all percentages and ratios used herein are by weight. Other features and advantages of this disclosure will become 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 scope of the claimed disclosure. Based on this disclosure, those skilled in the art can identify and employ other components and methods useful for practicing this disclosure.

[0394] In the synthetic schemes described herein, for the sake of brevity, the compounds may be described using a specific configuration. Such a specific configuration should not be construed as limiting this disclosure to one or another isomer, tautomer, positional isomer, or stereoisomer, nor does it exclude mixtures of isomers, tautomers, positional isomers, or stereoisomers; however, it should be understood that a given isomer, tautomer, positional isomer, or stereoisomer may have a higher level of activity than another isomer, tautomer, positional isomer, or stereoisomer.

[0395] All publications and patent documents cited herein are incorporated herein by reference as if each such publication or document were expressly and individually identified as incorporated herein by reference. References to publications and patent documents are not intended to acknowledge that any of them is applicable prior art, nor do they constitute any admission of their content or date. The invention has now been described in writing, and those skilled in the art will recognize that the invention can be practiced in a variety of embodiments, and that the foregoing description and the following examples are for illustrative purposes and not for limiting the purpose of the following claims.

[0396] This disclosure has been described, and the following embodiments are provided by way of illustration rather than limitation.

[0397] Exemplary Implementation Exemplary Implementation 1. A method for preparing 2-methylpyrimidine salts from 4,6-dichloro-2-methylpyrimidine.

[0398] Exemplary Implementation 2. The method of Exemplary Implementation 1, the method comprising steps (i) and (ii): (i) Reacting 4,6-dichloro-2-methylpyrimidine with a hydrogenating agent to form 2-methylpyrimidine; and (ii) React 2-methylpyrimidine with an acid to form a 2-methylpyrimidine salt.

[0399] Exemplary Implementation 3. The method of Exemplary Implementation 2, wherein step (i) is performed in the presence of a hydrogen transfer catalyst.

[0400] Exemplary Implementation 4. The method of Exemplary Implementation 3, wherein the hydrogen transfer catalyst is a nickel catalyst, a platinum catalyst, a palladium catalyst, a rhodium catalyst, or a ruthenium catalyst.

[0401] Exemplary Implementation 5. The method of Exemplary Implementation 2, wherein the hydrogenating agent is ammonium formate.

[0402] Exemplary Implementation 6. The method of Exemplary Implementation 2, wherein the ratio of 4,6-dichloro-2-methylpyrimidine to the hydrogenating agent is about 1:1 to about 1:4.

[0403] Exemplary Implementation 7. The method of Exemplary Implementation 2, wherein step (i) is performed at a temperature of 37±15°C, 37±10°C, or 37±5°C.

[0404] Exemplary Implementation 8. The method of Exemplary Implementation 2, wherein in step (i), a mixture comprising 2-methylpyrimidine is formed.

[0405] Exemplary Implementation 9. The method of Exemplary Implementation 8, wherein prior to the reaction with acid in step (ii), a polar solvent is added to a mixture containing 2-methylpyrimidine to form a first mixture.

[0406] Exemplary Implementation 10. The method of Exemplary Implementation 8, wherein the first mixture is alkalized to a pH of at least about 8.

[0407] Exemplary Implementation 11. The method of Exemplary Implementation 2, wherein in step (ii), the acid is oxalic acid.

[0408] Exemplary Implementation 12. The method of Exemplary Implementation 2, wherein in step (ii), the reaction is carried out in the presence of an aprotic solvent.

[0409] Exemplary Implementation 13. The method of Exemplary Implementation 12, wherein the aprotic solvent is tetrahydrofuran.

[0410] Exemplary Implementation 14. The method of any one of Exemplary Implementations 2 and 11-13, wherein step (ii) is performed at a temperature of about 20°C to about 50°C to form a second mixture.

[0411] Exemplary Implementation 15. The method of Exemplary Implementation 14, wherein the second mixture is subjected to a temperature cycling procedure.

[0412] Exemplary Implementation 16. The method of Exemplary Implementation 15, wherein the temperature cycling procedure comprises the following steps: (a) cooling the second mixture to about 20°C for about 1 hour and stirring for about 15 minutes, (b) heating it back to about 45°C and stirring for at least about 30 minutes, (c) cooling it from about 45°C to about 20°C for about 1 hour and stirring for about 15 minutes, (d) heating it back to about 45°C and stirring for at least about 30 minutes, (e) cooling it from about 45°C to about -10°C for about 4 hours, and (f) stirring it at about -10°C for at least about 13 hours.

[0413] Exemplary Implementation 17. A method of any one of Exemplary Implementations 2 and 11-16, wherein step (ii) further comprises isolating a 2-methylpyrimidine salt.

[0414] Exemplary Implementation 18. A method of any one of Exemplary Implementations 2 and 11-17, wherein step (ii) further comprises drying a 2-methylpyrimidine salt.

[0415] Exemplary Implementation 19. A method of any one of Exemplary Implementations 2 and 11-18, wherein the 2-methylpyrimidine salt has 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% by area, as determined by HPLC.

[0416] Exemplary Implementation 20. The method of any one of Exemplary Implementations 2 and 11-19, wherein the yield of 2-methylpyrimidine salt is at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 69%, at least about 70%, at least about 75%, at least about 80%, or at least about 85%.

[0417] Exemplary Implementation 21. The method of any one of Exemplary Implementations 2 and 17-20, wherein the 2-methylpyrimidine salt is 2-methylpyrimidine oxalate.

[0418] Exemplary Implementation 22. A method of any one of Exemplary Implementations 2 and 17-21, wherein the 2-methylpyrimidine salt contains less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% by area, as determined by HPLC.

[0419] Exemplary Implementation 23. The method of Exemplary Implementation 22, wherein the impurity comprises 2-propanol; 4,6-dichloro-2-methylpyrimidine; or a mixture thereof.

[0420] Exemplary Implementation 24. The method of Exemplary Implementation 22 or Exemplary Implementation 23, wherein the impurity comprises about 4.9% 2-propanol; about 0.03% 4,6-dichloro-2-methylpyrimidine; or a mixture thereof.

[0421] Exemplary Implementation Scheme 25. Method for preparing compound number 5 or a salt thereof: (Compound No. 5) The method includes steps (i)-(iii): (i) Reacting 4,6-dichloro-2-methylpyrimidine with a hydrogenating agent to form 2-methylpyrimidine; (ii) Reacting 2-methylpyrimidine with an acid to form a 2-methylpyrimidine salt; and (iii) Reacting a 2-methylpyrimidine salt with diisopropyl oxalate to form compound number 5 or a salt thereof, wherein the reaction is carried out in the presence of potassium tert-pentoxygenate.

[0422] Exemplary Implementation Scheme 26. Method for preparing compound number 9 or a salt thereof: (Compound No. 9) The method includes one or more of steps (i)-(vii): (i) Reacting 4,6-dichloro-2-methylpyrimidine with a hydrogenating agent to form 2-methylpyrimidine; (ii) Reacting 2-methylpyrimidine with an acid to form a 2-methylpyrimidine salt; (iii) React 2-methylpyrimidine salt with diisopropyl oxalate to form compound number 5: (Compound No. 5), or its salt; (iv) React compound number 5 or its salt with a reducing agent to form compound number 6: (Compound No. 6) or its salt; (v) Number the compound as 7: (Compound No. 7) Or its salt reacts with a CO source to form compound number 8: (Compound No. 8) or its salt; (vi) Reacting compound number 6 or its salt with compound number 8 or its salt to form compound number 9 or its salt; and (vii) Purify compound number 9 or its salt.

[0423] Exemplary Implementation 27. A method for preparing compound number 6 or a salt thereof, the method comprising: (iv) React compound number 5 or its salt with a reducing agent to form compound number 6 or its salt.

[0424] Exemplary Implementation 28. The method of Exemplary Implementation 26, wherein step (i) is performed in the presence of a hydrogen transfer catalyst.

[0425] Exemplary Implementation 29. The method of Exemplary Implementation 26, wherein the hydrogenating agent is ammonium formate.

[0426] Exemplary Implementation 30. The method of Exemplary Implementation 26, wherein the ratio of 4,6-dichloro-2-methylpyrimidine to the hydrogenating agent is about 1:1 to about 1:4.

[0427] Exemplary Implementation 31. The method of Exemplary Implementation 26, wherein in step (ii), 2-methylpyrimidine is dissolved in a polar solvent before reacting with an acid.

[0428] Exemplary Implementation 32. The method of Exemplary Implementation 26 or Exemplary Implementation 31, wherein step (ii) further comprises separating a 2-methylpyrimidine salt.

[0429] Exemplary Implementation 33. The method of Exemplary Implementation 26, wherein step (iii) is performed in the presence of a base.

[0430] Exemplary Implementation 34. The method of Exemplary Implementation 33, wherein the base in step (iii) is potassium tert-pentoxygenate.

[0431] Exemplary Implementation 35. A method of any one of Exemplary Implementations 26, 33 and 34, wherein step (iii) produces less than about 0.3% tert-amyl ester by area, as determined by HPLC.

[0432] Exemplary Implementation 36. The method of any one of Exemplary Implementations 26 and 33-35, wherein step (iii) is performed at a temperature of 40±15°C, 40±10°C or 40±5°C.

[0433] Exemplary Implementation 37. A method of any one of Exemplary Implementations 26 and 33-36, wherein step (iii) is performed in the presence of a polar solvent, an aprotic solvent, or a mixture thereof.

[0434] Exemplary Implementation 38. A method of any one of Exemplary Implementations 26 and 33-37, wherein step (iii) further comprises separating compound number 5 or a salt thereof.

[0435] Exemplary Implementation 39. A method of any one of Exemplary Implementations 26 and 33-38, wherein in step (iii), compound number 5 or a salt thereof has a purity of at least about 90%, at least about 92%, at least about 94%, at least about 96%, at least about 98%, or at least about 99% by area, as determined by HPLC.

[0436] Exemplary Implementation 40. A method of any one of Exemplary Implementations 26-39, wherein in step (iv), the reducing agent is a monosaccharide.

[0437] Exemplary Implementation 41. A method of any one of Exemplary Implementations 26-40, wherein step (iv) is performed in the presence of a reduction catalyst, wherein the reduction catalyst is an enzyme catalyst, a dinucleotide phosphate, or a mixture thereof.

[0438] Exemplary Implementation 42. The method of Exemplary Implementation 41, wherein the enzyme catalyst is ketone reductase (KRED), glutamate dehydrogenase (GDH) or a mixture thereof, and wherein the dinucleotide phosphate is nicotinamide adenine dinucleotide phosphate (NADP).

[0439] Exemplary Implementation 43. The method of any one of Exemplary Implementations 26-42, wherein in step (iv), the molar ratio of the acid to compound number 5 or its salt is about 3:1 to about 1:3.

[0440] Exemplary Implementation 44. A method of any one of Exemplary Implementations 26-43, wherein in step (iv), compound number 6 or a salt thereof is separated prior to reaction with compound number 8 or a salt thereof.

[0441] Exemplary Implementation 45. The method of Exemplary Implementation 26, wherein in step (v), the CO source is triphosgene.

[0442] Exemplary Implementation 46. A method of any one of Exemplary Implementations 26 and 28-45, wherein in step (v), the reaction is carried out in the presence of a base.

[0443] Exemplary Implementation 47. The method of Exemplary Implementation 46, wherein in step (v), the molar ratio of the base to compound number 8 or its salt is about 3:1 to about 1:3.

[0444] Exemplary Implementation 48. A method of any one of Exemplary Implementations 26 and 28-47, wherein step (v) is performed in the presence of toluene, dichloromethane, or a mixture thereof.

[0445] Exemplary Implementation 49. A method of any one of Exemplary Implementations 26 and 28-48, wherein in step (vi), the molar ratio of compound number 6 or a salt thereof to compound number 8 or a salt thereof is about 3:1 to about 1:3.

[0446] Exemplary Implementation 50. The method of Exemplary Implementation 26, wherein step (vii) further comprises crystallizing compound number 9 or a salt thereof in the presence of at least one organic solvent.

[0447] Exemplary Implementation 51. A method of any one of Exemplary Implementations 26 and 28-50, wherein step (vii) further comprises separating compound number 9 or a salt thereof.

[0448] Exemplary Implementation 52. A method of any one of Exemplary Implementations 26 and 28-51, wherein in step (vii), compound number 9 or a salt thereof has a purity of at least about 99.5% by area, as determined by HPLC.

[0449] Exemplary Implementation 53. A compound prepared by any of the methods described in the foregoing exemplary implementations.

[0450] Exemplary Embodiment 54. A pharmaceutical composition comprising compound number 9 or a salt thereof of any one of Exemplary Embodiments 26 and 28-52, and one or more pharmaceutically acceptable carriers, diluents, adjuvants or excipients.

[0451] Exemplary Implementation 55. A method for preventing or treating a disease in a subject, the method comprising administering to the subject a compound numbered 9 or a salt thereof from any one of Exemplary Implementations 26 and 28-52.

[0452] Exemplary Implementation 56. Compound number 9 or a salt thereof of any one of Exemplary Implementations 26 and 28-52, for the prevention or treatment of disease or for the inhibition of inflammasome activity in a subject.

[0453] Exemplary Implementation 57. Use of compound number 9 or a salt thereof of any one of Exemplary Implementations 26 and 28-52 in the preparation of a medicament for the prevention or treatment of a disease or for the inhibition of inflammasome activity in a subject.

[0454] Exemplary Implementation 58. A method for inhibiting inflammasome activity in a subject, the method comprising contacting cells with compound number 9 or a salt thereof from any one of Exemplary Implementations 26 and 28-52.

[0455] Exemplary Implementation 59. The method, compound, or use of any of the foregoing exemplary implementations, wherein the subject is a human. Example

[0456] This disclosure has been described, and the following embodiments are provided by way of illustration rather than limitation.

[0457] It should be understood that all values ​​presented in the examples are approximate and may be affected by instrument and / or experimental variations.

[0458] Example 1. Exemplary synthesis of compound number 9a.

[0459] The exemplary synthesis of compound 9a is performed as shown in Schemes 1, 2, and 3 and the procedures described below. The overall synthetic route is a 7-step process that begins with commercially available or synthetically derived starting materials.

[0460] Scheme 1: Preparation process of compound number 9a

[0461] Example 2. Exemplary synthesis of compound number 3a.

[0462] An exemplary synthesis of compound number 3a is performed as shown in Scheme 2.

[0463] Scheme 2: Preparation process of compound number 3a

[0464] Process Description The carbon-supported palladium catalyst [10% Type 487 paste (10.50 g, 0.1 wt%, based on 47.6% dry basis)] was added to an inert container containing 4,6-dichloro-2-methylpyrimidine (50 g, 307 mmol, 1 equivalent). 2-Propanol (375 mL, 7.5 V / L) was added, and the mixture was stirred at 20–25 °C for 10 min. The mixture was then slowly heated to 35–40 °C over approximately 40 min.

[0465] A solution of ammonium formate (42.6 g, 675 mmol, 2.2 equivalents) in methanol (175 mL, 3.5 V / L) and water (16.65 mL, 0.33 V / L) was carefully added over a period of at least 5 hours. The mixture was then maintained at 35–40 °C and stirred for at least another 2 hours. Process control 1: The end of the reaction was determined by HPLC. The target was a residual amount of 4,6-dichloro-2-methylpyrimidine of less than or equal to 2 area % relative to the product from step 1.

[0466] The catalyst was removed by filtration through a diatomaceous earth mat, and the filter cake was washed with 2-propanol (125 mL, 2.5 volumes). The content of 2-methylpyrimidine products in the 2-propanol solution was determined by NMR spectroscopy. This was used to calculate the subsequent loading of reagents and solvents.

[0467] The resulting solution of 2-methylpyrimidine (24.57 g, 261 mmol, 1 equivalent) was added to a stirred 2M hydrochloric acid aqueous solution (261 mL, 522 mmol, 2 equivalent, 10.5 volumes) at 20–25 °C for at least 30 min. The solution was then concentrated to 10.5 volumes by vacuum distillation, maintaining an internal temperature of approximately 45–60 °C. The mixture was cooled to 20–25 °C. The 2-propanol content (determined by NMR) was target to be less than or equal to 1.22%; the methanol content was target to be less than or equal to 2.30%.

[0468] Add MTBE (171.99 mL, 7 volumes) and stir the mixture at 20–25 °C for at least 15 minutes, then allow sedimentation for at least 30 minutes. Separate the layers and collect the aqueous layer containing the product. Add dichloromethane (171.99 mL, 7 volumes) and stir the mixture for at least 15 minutes. Then slowly alkalize the mixture with a 30% w / w potassium carbonate aqueous solution (103 mL, 287 mmol, 1.1 equivalents, 4.2 volumes), ensuring the internal temperature does not exceed 25 °C. Stir the mixture at 20–25 °C for at least 15 minutes and allow sedimentation for at least 30 minutes. The target alkalinity pH is greater than 8.

[0469] The organic layer containing the product was separated, and the aqueous phase was extracted with dichloromethane (2 x 171.99 mL, 7 volumes). The target was: 3.5% w / w product in the DCM layer - 690 g DCM layer mass - 24.15 g product.

[0470] Oxalic acid (35.3 g, 392 mmol) was dissolved in THF (127.76 mL, 5.2 vol) at 20–25 °C. Then, the combined DCM solution (containing 2-methylpyrimidine) was added under vigorous mixing for at least 2 hours. The mixture was heated to 45 °C and stirred for at least 30 min. Use the following temperature cycle to assist filtration. Cool the reactor contents from 45°C to 20°C over 1 hour, stirring for 15 min. Reheat the reactor contents back to 45°C and stir for at least 30 min. Cool the reactor contents from 45°C to 20°C again over 1 hour, stirring for 15 min. Reheat the reactor contents back to 45°C and stir for at least 30 min. Now cool the reactor contents from 45°C to -10°C over 4 hours. Stir the mixture at -10°C for at least 13 hours.

[0471] The solid (now 1:1.5 oxalate of 2-methylpyrimidine) was removed by filtration, washed with cold DCM (86 mL, 3.5 volumes), and the filter cake was dried for 3 hours. The purity of the wet filter cake was measured by HPLC. The target was at least 99% area%.

[0472] The white solid was dried under vacuum at 25°C for at least 16 hours (47.33 g, 69% yield). Control 4 during the process: moisture content was determined by KF. The target was less than or equal to 5.0% w / w. If the target was not met, drying was continued for up to 24 hours.

[0473] Table 1 provides the results.

[0474] Table 1. Summary of the preparation results of compound number 3a .

[0475] Table 2 provides the results of the process control analysis.

[0476] Table 2. Summary of control results during the preparation of compound 3a .

[0477] Table 3 provides the results of the analysis of isolated intermediates.

[0478] Table 3. Summary of the release results of the isolated intermediate of compound 3a .

[0479] Table 4 provides the results of HPLC purity analysis of the isolated intermediate of synthetic compound number 3a.

[0480] Table 4. Results of HPLC purity for release analysis of synthetic compound number 3a. Example 3. Exemplary synthesis of compound number 5.

[0481] An exemplary synthesis of compound number 5 was performed as shown in scheme 3.

[0482] Scheme 3: Preparation process of compound number 5 A solution of potassium tert-pentoxygenate [2M in THF (7.63 L, 3.5 equivalents)] was added over at least 4 hours to a stirred suspension of 2-methylpyrimidine oxalate (1 kg, 1 equivalent), diisopropyl oxalate (1.25 kg, 1.65 equivalents), and 2-propanol (0.90 L, 2.7 equivalents) in THF (1.0 L, 1 volume), maintaining an internal temperature below 50°C. The reaction mixture was stirred at 40–45°C for at least 2 hours. Process control 1: The end of the reaction was determined by HPLC. The target was a residual 2-methylpyrimidine of less than or equal to 2 area%.

[0483] The suspension was cooled to 0–10 °C and then quenched with a solution of acetic acid (0.90 L, 3.6 equivalents) in water (8.0 L, 8 volumes), maintaining an internal temperature below 30 °C (target: below 25 °C). The temperature was adjusted to 15–25 °C and the mixture was stirred for at least 15 minutes. The resulting two-phase solution was concentrated to 12 volumes, maintaining a temperature <45 °C. Isopropyl acetate (6.0 L, 6 volumes) was added, and the two-phase mixture was again concentrated to 12 volumes, maintaining a temperature below 45 °C. Another 5.0 L, 5 volumes of isopropyl acetate was added, and the two-phase mixture was again concentrated to 12 volumes, maintaining a temperature below 45 °C. Solvent exchange was confirmed by NMR. The target was less than or equal to 2% w / w THF relative to isopropyl acetate.

[0484] Cool the mixture to 20–25 °C and stir for 15 minutes, then separate the layers. Wash the organic layer with 20% w / w potassium bicarbonate aqueous solution (7.0 L, 7 volumes), then with water (5.0 L, 5 volumes). Add another 5.0 L, 5 volumes of isopropyl acetate, then concentrate the solution to 2 volumes under vacuum, keeping the temperature below 40 °C. Add heptane (13.0 L, 13 volumes) and stir the mixture at 35–45 °C for 20 minutes. Slowly cool the resulting suspension to 0–10 °C over 3 hours, then stir at 0–10 °C for another 2 hours. Remove the solids by filtration and wash the filter cake with cold heptane (2 x 2.0 L, 2 volumes). Check 1: Determine the purity of the wet filter cake by HPLC. The target is at least 96% area.

[0485] The filter cake was vacuum-dried for 2 hours, then dried under vacuum at 20-25°C for at least 16 hours. Process control 3: loss on drying. The target is less than 1%.

[0486] Table 5 provides the results.

[0487] Table 5. Summary of the results of preparing compound number 5 .

[0488] Table 6 provides the results of the process control analysis.

[0489] Table 6. Summary of control results during the process for compound number 5 .

[0490] Table 7 provides the results of the analysis of isolated intermediates.

[0491] Table 7. Summary of the release results of the isolated intermediate of compound number 5 .

[0492] Table 8 provides the results of HPLC purity analysis of the isolated intermediate of synthetic compound number 5 (RRT refers to relative retention time).

[0493] Table 8. Results of HPLC analysis of the release of compound No. 5 .

[0494] Equivalent scheme Details of one or more embodiments of this disclosure are set forth in the foregoing description. While any methods and materials similar to or equivalent to those described herein may be used in practice or experimentation with 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 indicators unless the context clearly indicates 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 incorporated herein by reference.

[0495] The foregoing description is for illustrative purposes only and is not intended to limit this disclosure to the precise form disclosed, but is limited by the appended claims.

Claims

1. A method for preparing 2-methylpyrimidine salts from 4,6-dichloro-2-methylpyrimidine.

2. The method according to claim 1, wherein the method comprises steps (i) and (ii): (i) Reacting 4,6-dichloro-2-methylpyrimidine with a hydrogenating agent to form 2-methylpyrimidine; and (ii) React 2-methylpyrimidine with an acid to form a 2-methylpyrimidine salt.

3. The method according to claim 2, wherein step (i) is carried out in the presence of a hydrogen transfer catalyst.

4. The method according to claim 3, wherein the hydrogen transfer catalyst is a nickel catalyst, a platinum catalyst, a palladium catalyst, a rhodium catalyst, or a ruthenium catalyst.

5. The method according to claim 2, wherein the hydrogenating agent is ammonium formate.

6. The method according to claim 2, wherein the ratio of 4,6-dichloro-2-methylpyrimidine to the hydrogenating agent is about 1:1 to about 1:

4.

7. The method according to claim 2, wherein step (i) is performed at a temperature of 37±15°C, 37±10°C or 37±5°C.

8. The method according to claim 2, wherein in step (i), a mixture comprising 2-methylpyrimidine is formed.

9. The method according to claim 8, wherein prior to the reaction with the acid in step (ii), a polar solvent is added to the mixture containing 2-methylpyrimidine to form a first mixture.

10. The method of claim 8, wherein the first mixture is alkalized to a pH of at least about 8.

11. The method according to claim 2, wherein in step (ii), the acid is oxalic acid.

12. The method according to claim 2, wherein in step (ii), the reaction is carried out in the presence of an aprotic solvent.

13. The method of claim 12, wherein the aprotic solvent is tetrahydrofuran.

14. The method according to any one of claims 2 and 11-13, wherein step (ii) is carried out at a temperature of about 20°C to about 50°C to form the second mixture.

15. The method of claim 14, wherein the second mixture is subjected to a temperature cycling procedure.

16. The method of claim 15, wherein the temperature cycling procedure comprises the steps of: (a) cooling the second mixture to about 20°C for about 1 hour and stirring for about 15 minutes; (b) heating it back to about 45°C and stirring for at least about 30 minutes; (c) cooling it from about 45°C to about 20°C for about 1 hour and stirring for about 15 minutes; (d) heating it back to about 45°C and stirring for at least about 30 minutes; (e) cooling it from about 45°C to about -10°C for about 4 hours; and (f) stirring it at about -10°C for at least about 13 hours.

17. The method according to any one of claims 2 and 11-16, wherein step (ii) further comprises isolating the 2-methylpyrimidine salt.

18. The method according to any one of claims 2 and 11-17, wherein step (ii) further comprises drying the 2-methylpyrimidine salt.

19. The method according to any one of claims 2 and 11-18, wherein the 2-methylpyrimidine salt has 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% by area, as determined by HPLC.

20. The method according to any one of claims 2 and 11-19, wherein the yield of the 2-methylpyrimidine salt is at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 69%, at least about 70%, at least about 75%, at least about 80%, or at least about 85%.

21. The method according to any one of claims 2 and 17-20, wherein the 2-methylpyrimidine salt is 2-methylpyrimidine oxalate.

22. The method according to any one of claims 2 and 17-21, wherein the 2-methylpyrimidine salt contains less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% by area, as determined by HPLC.

23. The method of claim 22, wherein the impurity comprises 2-propanol; 4,6-dichloro-2-methylpyrimidine; or a mixture thereof.

24. The method of claim 22 or claim 23, wherein the impurity comprises about 4.9% 2-propanol; about 0.03% 4,6-dichloro-2-methylpyrimidine; or a mixture thereof.

25. Method for preparing compound number 5 or its salt: (Compound No. 5) The method includes steps (i)-(iii): (i) Reacting 4,6-dichloro-2-methylpyrimidine with a hydrogenating agent to form 2-methylpyrimidine; (ii) Reacting 2-methylpyrimidine with an acid to form a 2-methylpyrimidine salt; and (iii) Reaction of a 2-methylpyrimidine salt with diisopropyl oxalate to form compound number 5 or a salt thereof, wherein the reaction is carried out in the presence of potassium tert-pentoxygenate.

26. Method for preparing compound number 9 or its salt: (Compound No. 9) The method includes one or more of steps (i)-(vii): (i) Reacting 4,6-dichloro-2-methylpyrimidine with a hydrogenating agent to form 2-methylpyrimidine; (ii) Reacting 2-methylpyrimidine with an acid to form a 2-methylpyrimidine salt; (iii) React 2-methylpyrimidine salt with diisopropyl oxalate to form compound number 5: (Compound No. 5), or its salt; (iv) React compound number 5 or its salt with a reducing agent to form compound number 6: (Compound No. 6) or its salt; (v) Number the compound as 7: (Compound No. 7) Or its salt reacts with a CO source to form compound number 8: (Compound No. 8) or its salt; (vi) Reacting compound number 6 or its salt with compound number 8 or its salt to form compound number 9 or its salt; and (vii) Purify compound number 9 or its salt.

27. A method for preparing compound number 6 or a salt thereof, said method comprising: (iv) React compound number 5 or its salt with a reducing agent to form compound number 6 or its salt.

28. The method of claim 26, wherein step (i) is carried out in the presence of a hydrogen transfer catalyst.

29. The method of claim 26, wherein the hydrogenating agent is ammonium formate.

30. The method of claim 26, wherein the ratio of 4,6-dichloro-2-methylpyrimidine to the hydrogenating agent is about 1:1 to about 1:

4.

31. The method according to claim 26, wherein in step (ii), 2-methylpyrimidine is dissolved in a polar solvent prior to reacting with the acid.

32. The method according to claim 26 or claim 31, wherein step (ii) further comprises separating the 2-methylpyrimidine salt.

33. The method of claim 26, wherein step (iii) is carried out in the presence of a base.

34. The method according to claim 33, wherein the base in step (iii) is potassium tert-pentoxygenate.

35. The method according to any one of claims 26, 33 and 34, wherein step (iii) produces less than about 0.3% tert-amyl ester by area, as determined by HPLC.

36. The method according to any one of claims 26 and 33-35, wherein step (iii) is carried out at a temperature of 40±15°C, 40±10°C or 40±5°C.

37. The method according to any one of claims 26 and 33-36, wherein step (iii) is carried out in the presence of a polar solvent, an aprotic solvent, or a mixture thereof.

38. The method according to any one of claims 26 and 33-37, wherein step (iii) further comprises separating compound number 5 or a salt thereof.

39. The method according to any one of claims 26 and 33-38, wherein in step (iii), compound number 5 or a salt thereof has a purity of at least about 90%, at least about 92%, at least about 94%, at least about 96%, at least about 98%, or at least about 99% by area, as determined by HPLC.

40. The method according to any one of claims 26-39, wherein in step (iv), the reducing agent is a monosaccharide.

41. The method according to any one of claims 26-40, wherein step (iv) is carried out in the presence of a reduction catalyst, wherein the reduction catalyst is an enzyme catalyst, a dinucleotide phosphate, or a mixture thereof.

42. The method of claim 41, wherein the enzyme catalyst is ketone reductase (KRED), glutamate dehydrogenase (GDH), or a mixture thereof, and wherein the dinucleotide phosphate is nicotinamide adenine dinucleotide phosphate (NADP).

43. The method according to any one of claims 26-42, wherein in step (iv), the molar ratio of the acid to compound number 5 or its salt is about 3:1 to about 1:

3.

44. The method according to any one of claims 26-43, wherein in step (iv), compound number 6 or its salt is separated before reacting with compound number 8 or its salt.

45. The method of claim 26, wherein in step (v), the CO source is triphosgene.

46. ​​The method according to any one of claims 26 and 28-45, wherein in step (v), the reaction is carried out in the presence of a base.

47. The method according to claim 46, wherein in step (v), the molar ratio of the base to compound number 8 or its salt is about 3:1 to about 1:

3.

48. The method according to any one of claims 26 and 28-47, wherein step (v) is carried out in the presence of toluene, dichloromethane or a mixture thereof.

49. The method according to any one of claims 26 and 28-48, wherein in step (vi), the molar ratio of compound number 6 or its salt to compound number 8 or its salt is about 3:1 to about 1:

3.

50. The method of claim 26, wherein step (vii) further comprises crystallizing compound number 9 or a salt thereof in the presence of at least one organic solvent.

51. The method according to any one of claims 26 and 28-50, wherein step (vii) further comprises separating compound number 9 or a salt thereof.

52. The method according to any one of claims 26 and 28-51, wherein in step (vii), compound number 9 or a salt thereof has a purity of at least about 99.5% by area, as determined by HPLC.

53. A compound prepared by the method described in any one of the preceding claims.

54. A pharmaceutical composition comprising compound number 9 or a salt thereof as claimed in any one of claims 26 and 28-52, and one or more pharmaceutically acceptable carriers, diluents, adjuvants or excipients.

55. A method for preventing or treating a disease in a subject, the method comprising administering to the subject a compound numbered 9 or a salt thereof according to any one of claims 26 and 28-52.

56. Compound number 9 or a salt thereof according to any one of claims 26 and 28-52, for the prevention or treatment of disease or for the inhibition of inflammasome activity in a subject.

57. Use of compound number 9 or a salt thereof according to any one of claims 26 and 28-52 in the preparation of a medicament for the prevention or treatment of a disease or for the inhibition of inflammasome activity in a subject.

58. A method for inhibiting inflammasome activity in a subject, the method comprising contacting cells with compound number 9 or a salt thereof according to any one of claims 26 and 28-52.

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

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