Forms of carbamate derivatives and related uses

Abstract

The present disclosure relates to morphic forms of Compound A. The present disclosure also relates to processes for preparing the morphic forms of Compound A, pharmaceutical compositions comprising the morphic forms, and their uses, for example, in the treatment of disorders, such as disorders involving inflammasome activity. TIFF2025533089000019.tif25128

Description

[Technical Field]

[0001] Related Applications This application claims priority to U.S. Patent No. 63 / 414,036, filed October 4, 2022, the entire contents of which are incorporated herein by reference. [Background technology]

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

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

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

[0005] The present disclosure arises from the need to provide additional compounds for the specific modulation of NLRP3-dependent cellular processes, particularly compounds that have improved physicochemical, pharmacological, and pharmaceutical properties over existing compounds. [Prior art documents] [Non-patent literature]

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

[0007] overview In some aspects, the present disclosure provides morphic forms of Compound A.

[0008] In some aspects, the present disclosure provides methods of preparing the crystalline forms of Compound A described herein.

[0009] In some aspects, the present disclosure provides pharmaceutical compositions comprising a morphic form of Compound A described herein and one or more pharmaceutically acceptable carrier or excipient materials.

[0010] In some aspects, the present disclosure provides a method of inhibiting inflammasome (e.g., NLRP3 inflammasome) activity (e.g., in vitro or in vivo), comprising contacting a cell with an effective amount of a morphic form of Compound A.

[0011] In some aspects, the present disclosure provides a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject an effective amount of a morphic form of Compound A.

[0012] In some aspects, the present disclosure provides morphic forms of Compound A for use in inhibiting inflammasome (e.g., NLRP3 inflammasome) activity (e.g., in vitro or in vivo).

[0013] In some aspects, the present disclosure provides morphic forms of Compound A for use in treating or preventing a disease or disorder disclosed herein.

[0014] In some aspects, the present disclosure provides the use of a morphic form of Compound A in the manufacture of a medicament for inhibiting inflammasome (e.g., NLRP3 inflammasome) activity (e.g., in vitro or in vivo).

[0015] In some aspects, the present disclosure provides for the use of a morphic form of Compound A in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0016] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs.In this specification, the singular form "a," "an," or "the" includes the plural unless the context clearly dictates otherwise.Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below.All publications, patent applications, patents, and other references mentioned herein are incorporated by reference.The references cited herein are not admitted to be prior art to the claimed invention.In case of conflict, the present specification, including definitions, will prevail.In addition, the materials, methods, and examples are merely illustrative and are not intended to be limiting.In the event of a conflict between the chemical structure and name of a compound disclosed herein, the chemical structure will prevail.

[0017] Other features and advantages of the present disclosure will become apparent from the following detailed description and claims. [Brief explanation of the drawings]

[0018] [Figure 1] 1 is a graph showing the H-NMR of Form 1. The H-NMR spectrum was collected using the conditions described in the Examples. [Figure 2] 1 is a graph showing the XRPD of Form 1. [Figure 3] 1 is a graph showing TGA of Form 1. [Figure 4] 4A and 4B are a set of photographs showing SEM images of Form 1. [Figure 5] 1 is a graph showing the Raman spectrum of Form 1. [Figure 6A] 6A and 6B are a set of graphs showing the GVS isotherm and kinetic plots of Form 1. [Figure 6B] See legend to Figure 6A. [Figure 7]1 is a graph showing the 1H-NMR of Form 2. The 1H-NMR spectrum was collected using the conditions described in the Examples. [Figure 8] 1 is a graph showing the XRPD of Form 2. [Figure 9] 1 is a graph showing TGA of Form 2. [Figure 10-1] 10A-10C are a set of photographs showing PLM images of Form 2. [Figure 10-2] See the description of Figure 10-1. [Figure 11A] 11A and 11B are a set of graphs showing the GVS isotherm and kinetic plots of Form 2. [Figure 11B] See the legend to Figure 11A. DETAILED DESCRIPTION OF THE INVENTION

[0019] Detailed Description Autoimmune diseases are associated with the overproduction of proinflammatory factors, one of which is interleukin-1 (IL-1), which is produced by activated macrophages, monocytes, fibroblasts, and other components of the innate immune system, such as dendritic cells, and is involved in diverse cellular activities, including cell proliferation, differentiation, and apoptosis (Masters, SL, et al. Annu. Rev. Immunol. 2009. 27:621-68).

[0020] Cytokines from the IL-1 family are highly active and are primarily associated with acute and chronic inflammation as key mediators of inflammation (Sims J. et al. Nature Reviews Immunology 10, 89-102 (February 2010)). Excessive production of IL-1 is thought to be a mediator of several autoimmune and autoinflammatory diseases. Autoinflammatory diseases are characterized by recurrent and unprovoked inflammation in the absence of autoantibodies, infections, or antigen-specific T lymphocytes.

[0021] Proinflammatory cytokines of the IL-1 superfamily, including IL-1α, IL-1β, IL-18, and IL-36α, β, and λ, are produced in response to pathogens and other cellular stressors as part of the host innate immune response. Unlike many other secreted cytokines, which are processed and released through the standard cellular secretory apparatus consisting of the endoplasmic reticulum and Golgi apparatus, IL-1 family members lack the leader sequence required for endoplasmic reticulum translocation and are therefore retained intracellularly after translation. In addition, IL-1β, IL-18, and IL-36α, β, and λ are synthesized as procytokines that require proteolytic activation to become optimal ligands for binding to their corresponding receptors on target cells.

[0022] In the cases of IL-1α, IL-1β, and IL-18, multimeric protein complexes known as inflammasomes are now known to be responsible for the activation of IL-1β and IL-18 proforms and the extracellular release of these cytokines. Inflammasome complexes typically consist of sensor molecules such as NLRs (nucleotide-oligomeric domain (NOD)-like receptors), the adaptor molecule ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain (CARD)), and procaspase-1. In response to diverse "danger signals," including pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs), inflammasome subunits oligomerize to form intracellular supramolecular structures. PAMPs include molecules such as peptidoglycan, viral DNA or RNA, and bacterial DNA or RNA. On the other hand, DAMPs consist of a wide range of endogenous and exogenous sterile triggers, including monosodium urate crystals, silica, alum, asbestos, fatty acids, ceramides, cholesterol crystals, and beta-amyloid peptide aggregates. Assembly of the inflammasome platform drives the autocatalytic activity of procaspase-1, generating a highly active cysteine ​​protease responsible for the activation and release of pro-IL-1β and pro-IL-18. Thus, the release of these pro-inflammatory cytokines is achieved only in response to inflammasome sensors that detect and respond to specific molecular danger signals.

[0023] In humans, 22 NLR proteins are classified into four NLR subfamilies according to their N-terminal domains: NLRA contains a CARD-AT domain, NLRB (NAIP) contains a BIR domain, NLRC (including NOD1 and NOD2) contains a CARD domain, and NLRP contains a pyrin domain. Many NLR family members, including NLRP1, NLRP3, NLRP6, NLRP7, NLRP12, and NLRC4 (IPAF), are involved in inflammasome formation.

[0024] Two other structurally distinct inflammasome structures containing PYHIN domains (pyrin and HIN domain-containing proteins), namely, Absent in Melanoma 2 (AIM2) and IFNλ-inducible protein 16 (IFI16) (Latz et al., Nat Rev Immunol 2013 13(6) 397-311), function as intracellular DNA sensors. Pyrin (encoded by the MEFV gene) represents another type of inflammasome platform associated with pro-IL-1β activation (Chae et al., Immunity 34, 755-768, 2011).

[0025] The activation and release of IL-1β and IL-18 from monocytes and macrophages requires the assembly of an inflammasome platform, ensuring that their production is carefully orchestrated as a whole through a two-step process. First, cells must encounter a priming ligand (e.g., the TLR4 receptor ligand LPS or a proinflammatory cytokine such as TNFα) that leads to NFkB-dependent transcription of NLRP3, pro-IL-1β, and pro-IL-18. The newly translated pro-cytokine remains intracellular and inactive unless the producing cell encounters a second signal that leads to activation of the inflammasome scaffold and maturation of pro-caspase-1.

[0026] In addition to the proteolytic activation of pro-IL-1β and pro-IL-18, active caspase-1 also triggers a form of inflammatory cell death known as pyroptosis through cleavage of gasdermin-D. Pyroptosis allows the mature forms of IL-1β and IL-18 to be externalized along with the release of alarmin molecules (compounds that promote inflammation and activate innate and adaptive immunity), such as high-mobility group box 1 protein (HMGB1), IL-33, and IL-1α.

[0027] Although inflammasome activation appears to have evolved as a critical component of host immunity against pathogens, the NLRP3 inflammasome is unique in its ability to activate in response to endogenous and exogenous sterile danger signals. Many such sterile signals have been elucidated, and their formation has been linked to specific disease states. For example, uric acid crystals found in patients with gout are potent triggers of NLRP3 activation. Similarly, cholesterol crystals found in patients with atherosclerosis may also promote NLRP3 activation. Recognition of the role of sterile danger signals as NLRP3 activators has led to the implication of IL-1β and IL-18 in a wide range of pathophysiological indications, including metabolic, physiological, inflammatory, hematological, and immunological disorders.

[0028] The association with human disease is best exemplified by the discovery that mutations in the NLRP3 gene leading to gain of function confer a variety of autoinflammatory conditions collectively known as cryopyrin-associated periodic syndromes (CAPS), including familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease (NOMID) (Hoffman et al., Nat Genet. 29(3) (2001) 301-305). Similarly, sterile mediator-induced activation of NLRP3 has been implicated in a wide range of disorders, including joint degeneration (gout, rheumatoid arthritis, osteoarthritis), cardiometabolic disorders (type 2 diabetes, atherosclerosis, hypertension), central nervous system disorders (Alzheimer's disease, Parkinson's disease, multiple sclerosis), gastrointestinal disorders (Crohn's disease, ulcerative colitis), pulmonary disorders (chronic obstructive pulmonary disease (COPD), asthma, idiopathic pulmonary fibrosis), and liver disorders (fibrosis, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis (NASH)). Furthermore, NLRP3 activation is thought to promote renal inflammation and thus contribute to chronic kidney disease (CKD).

[0029] Current treatment options for diseases involving IL-1 as a contributing factor in the pathogenesis include the IL-1 receptor antagonist anakinra, an Fc-containing fusion construct of the extracellular domain of the IL-1 receptor and IL-1 receptor accessory protein (rilonacept), and the anti-IL-1β monoclonal antibody canakinumab. For example, canakinumab is approved for CAPS, tumor necrosis factor receptor-associated periodic syndrome (TRAPS), hyperimmunoglobulin D syndrome (HIDS) / mevalonate kinase deficiency (MKD), familial Mediterranean fever (FMF), and gout.

[0030] Several small molecules have been reported to inhibit the function of the NLRP3 inflammasome. For example, glyburide is a specific inhibitor of NLRP3 activation, albeit at micromolar concentrations that are unlikely to be reached in vivo. Nonspecific agents such as parthenolide, Bay 11-7082, and 3,4-methylenedioxy-β-nitrostyrene have been reported to reduce NLRP3 activation, but are expected to have limited therapeutic utility due to the fact that they share a common structural feature consisting of an olefin that is activated by substitution with an electron-withdrawing group; this structural feature may lead to the undesired formation of covalent adducts with protein-borne thiol groups. Some natural products, such as β-hydroxybutyrate, sulforaphane, quercetin, and salvianolic acid, have also been reported to suppress NLRP3 activation. Similarly, numerous effectors / modulators of other molecular targets have been reported to attenuate NLRP3 activation, including agonists of the G protein-coupled receptor TGR5, the sodium-glucose cotransporter inhibitor epigliflozin, the dopamine receptor antagonist A-68930, the serotonin reuptake inhibitor fluoxetine, the fenamic acid nonsteroidal anti-inflammatory drugs, and the β-adrenergic receptor blocker nebivolol. The utility of these molecules as therapeutic agents for the chronic treatment of NLRP3-dependent inflammatory disorders remains to be established.

[0031] The present disclosure relates to compounds useful for specifically modulating NLRP3-dependent cellular processes. In particular, compounds that have improved physicochemical, pharmacological, and pharmaceutical properties relative to existing NLRP3-modulating compounds are desirable.

[0032] Morphic Forms of the Present Disclosure "Compound A" as used herein refers to the following: It is understood that this refers to a compound having the structure shown in TIFF2025533089000002.tif36128.

[0033] It is understood that the chemical name of Compound A is propan-2-yl(2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl]oxy}-3-(pyrimidin-2-yl)propanoate. It is understood that Compound A can be prepared as described in Example 101 of WO 2019 / 025467 (incorporated herein by reference).

[0034] In some aspects, the present disclosure provides morphic forms of Compound A.

[0035] In some embodiments, the morphic form is a crystalline form of Compound A.

[0036] In some embodiments, the morphic form is Form 1 of Compound A.

[0037] In some embodiments, the morphic form is Form 2 of Compound A.

[0038] Form 1 In some embodiments, the morphic form of Compound A is Form 1 described herein.

[0039] Characterization by X-ray powder diffraction (XRPD) In some embodiments, a morphic form of Compound A (e.g., Form 1) is characterized by an XRPD pattern comprising signals (e.g., peaks) at 8.7±0.5, 15.3±0.5, and 15.9±0.5 degrees 2θ (e.g., 8.7±0.2, 15.3±0.2, and 15.9±0.2 degrees 2θ using Cu Kα radiation (e.g., 8.7±0.1, 15.3±0.1, and 15.9±0.1 degrees 2θ using Cu Kα radiation (e.g., 8.7, 15.3, and 15.9 degrees 2θ using Cu Kα radiation)).

[0040] In some embodiments, a morphic form of Compound A (e.g., Form 1) is characterized by an XRPD pattern comprising signals (e.g., peaks) at 7.9±0.5, 8.7±0.5, 15.3±0.5, and 15.9±0.5 degrees two-theta (e.g., 7.9±0.2, 8.7±0.2, 15.3±0.2, and 15.9±0.2 degrees two-theta using Cu Kα radiation (e.g., 7.9±0.1, 8.7±0.1, 15.3±0.1, and 15.9±0.1 degrees two-theta using Cu Kα radiation (e.g., 7.9, 8.7, 15.3, and 15.9 degrees two-theta) using Cu Kα radiation)).

[0041] In some embodiments, a morphic form of Compound A (e.g., Form 1) is characterized by an XRPD pattern comprising signals (e.g., peaks) at 7.9±0.5, 8.7±0.5, 15.3±0.5, 15.9±0.5, and 24.4±0.5 degrees two-theta (e.g., 7.9±0.2, 8.7±0.2, 15.3±0.2, 15.9±0.2, and 24.4±0.2 degrees two-theta using Cu Kα radiation (e.g., 7.9±0.1, 8.7±0.1, 15.3±0.1, 15.9±0.1, and 24.4±0.1 degrees two-theta using Cu Kα radiation (e.g., 7.9, 8.7, 15.3, 15.9, and 24.4 degrees two-theta) using Cu Kα radiation)).

[0042] In some embodiments, the morphic forms of Compound A (e.g., Form 1) have chromatic angles of 7.9±0.5, 8.7±0.5, 15.3±0.5, 15.9±0.5, 22.3±0.5, and 24.4±0.5 degrees two-theta (e.g., 7.9±0.2, 8.7±0.2, 15.3±0.2, 15.9±0.2, 22.3±0.2, and 24.4±0.2 degrees two-theta using Cu Kα radiation (e.g., 7.9±0.1, 8.7±0.1, 15.3±0.1, 15.9±0.1, 22.3±0.1, and 24.4±0.1 degrees two-theta using Cu Kα radiation (e.g., It is characterized by an XRPD pattern including signals (e.g., peaks) at 7.9, 8.7, 15.3, 15.9, 22.3, and 24.4 degrees 2θ))) using Kα radiation.

[0043] In some embodiments, the morphic forms of Compound A (e.g., Form 1) have chromatic angles of 7.9±0.5, 8.7±0.5, 15.3±0.5, 15.9±0.5, 22.3±0.5, 23.9±0.5, and 24.4±0.5 degrees two-theta (e.g., 7.9±0.2, 8.7±0.2, 15.3±0.2, 15.9±0.2, 22.3±0.2, 23.9±0.2, and 24.4±0.2 degrees two-theta using Cu Kα radiation (e.g., 7.9±0.1, 8.7±0.1, 15.3±0.1, 15.9±0.1, 22.3±0.1, 23.9±0.1, and 24.4±0.1 degrees two-theta using Cu Kα radiation (e.g., It is characterized by an XRPD pattern including signals (e.g., peaks) at 7.9, 8.7, 15.3, 15.9, 22.3, 23.9, and 24.4 degrees 2θ))) using Kα radiation.

[0044] In some embodiments, the morphic forms of Compound A (e.g., Form 1) have peaks of 5.9±0.5, 7.9±0.5, 8.7±0.5, 15.3±0.5, 15.9±0.5, 22.3±0.5, 23.9±0.5, and 24.4±0.5 degrees two-theta (e.g., using Cu Kα radiation) and 5.9±0.2, 7.9±0.2, 8.7±0.2, 15.3±0.2, 15.9±0.2, 22.3±0.2, 23.9±0.2, and 24.4±0.2 degrees two-theta (e.g., using Cu Kα radiation). It is characterized by an XRPD pattern including signals (e.g., peaks) at 5.9±0.1, 7.9±0.1, 8.7±0.1, 15.3±0.1, 15.9±0.1, 22.3±0.1, 23.9±0.1, and 24.4±0.1 degrees 2θ using Kα radiation (e.g., 5.9, 7.9, 8.7, 15.3, 15.9, 22.3, 23.9, and 24.4 degrees 2θ using Cu Kα radiation).

[0045] In some embodiments, a morphic form of Compound A (eg, Form 1) is characterized by an XRPD pattern comprising one or more signals (eg, peaks) set forth in Table 1 below.

[0046] [Table 1] *The values ​​shown in the table above are approximate and subject to instrument variance and standard error.

[0047] In some embodiments, a morphic form of Compound A (eg, Form 1) is characterized by an XRPD pattern substantially similar to that depicted in FIG.

[0048] Other characterizations In some embodiments, a morphic form of Compound A (e.g., Form 1) is substantially similar to that depicted in FIG. 1 Characterized by H-NMR spectrum.

[0049] In some embodiments, a morphic form of Compound A (e.g., Form 1) is characterized by a decomposition event at 220±40°C, 220±30°C, 220±20°C, 220±15°C, 220±10°C, or 220±5°C (e.g., about 220°C) as measured by thermogravimetric analysis (TGA).

[0050] In some embodiments, a morphic form of Compound A (e.g., Form 1) is characterized by a TGA thermogram substantially similar to that depicted in Figure 3. In some embodiments, a morphic form of Compound A (e.g., Form 1) is characterized by a Raman spectrum substantially similar to that depicted in Figure 5.

[0051] In some embodiments, a morphic form of Compound A (e.g., Form 1) is characterized by an endothermic event with an onset at 129±20°C, 129±15°C, 129±10°C, or 129±5°C (e.g., about 129°C) as measured by differential scanning calorimetry (DSC).

[0052] In some embodiments, a morphic form of Compound A (e.g., Form 1) is characterized by a water uptake (e.g., at 0%-90% RH) of less than about 1%, less than about 0.9%, less than about 0.7%, less than about 0.6%, less than about 0.5%, less than about 0.4%, less than about 0.3%, less than about 0.2%, or less than about 0.1% as measured by gravimetric vapor sorption (GVS).

[0053] In some embodiments, a morphic form of Compound A (eg, Form 1) is characterized by a GVS isotherm plot and kinetics plot substantially similar to those depicted in Figures 6A and 6B.

[0054] In some embodiments, the morphic form of Compound A (eg, Form 1) is a crystalline solid, eg, a needle-like crystalline form.

[0055] In some embodiments, the morphic form of Compound A (e.g., Form 1) is a crystalline solid having an average size of 150±30 μm, 150±20 μm, 150±15 μm, 150±10 μm, or 150±5 μm (e.g., 150 μm).

[0056] Form 2 In some embodiments, the morphic form of Compound A is Form 2 described herein.

[0057] Characterization by X-ray powder diffraction (XRPD) In some embodiments, a morphic form of Compound A (e.g., Form 2) is characterized by an XRPD pattern comprising signals (e.g., peaks) at 7.6±0.5, 9.4±0.5, and 15.9±0.5 degrees two-theta (e.g., 7.6±0.2, 9.4±0.2, and 15.9±0.2 degrees two-theta using Cu Kα radiation (e.g., 7.6±0.1, 9.4±0.1, and 15.9±0.1 degrees two-theta using Cu Kα radiation (e.g., 7.6, 9.4, and 15.9 degrees two-theta using Cu Kα radiation)).

[0058] In some embodiments, a morphic form of Compound A (e.g., Form 2) is characterized by an XRPD pattern comprising signals (e.g., peaks) at 7.6±0.5, 9.4±0.5, 15.2±0.5, and 15.9±0.5 degrees two-theta (e.g., 7.6±0.2, 9.4±0.2, 15.2±0.2, and 15.9±0.2 degrees two-theta using Cu Kα radiation (e.g., 7.6±0.1, 9.4±0.1, 15.2±0.1, and 15.9±0.1 degrees two-theta using Cu Kα radiation (e.g., 7.6, 9.4, 15.2, and 15.9 degrees two-theta) using Cu Kα radiation)).

[0059] In some embodiments, a morphic form of Compound A (e.g., Form 2) is characterized by an XRPD pattern comprising signals (e.g., peaks) at 6.0±0.5, 7.6±0.5, 9.4±0.5, 15.2±0.5, and 15.9±0.5 degrees two-theta (e.g., 6.0±0.2, 7.6±0.2, 9.4±0.2, 15.2±0.2, and 15.9±0.2 degrees two-theta using Cu Kα radiation (e.g., 6.0±0.1, 7.6±0.1, 9.4±0.1, 15.2±0.1, and 15.9±0.1 degrees two-theta using Cu Kα radiation (e.g., 6.0, 7.6, 9.4, 15.2, and 15.9 degrees two-theta) using Cu Kα radiation)).

[0060] In some embodiments, the morphic forms of Compound A (e.g., Form 2) have chromatic angles of 6.0±0.5, 7.6±0.5, 9.4±0.5, 15.2±0.5, 15.9±0.5, and 21.5±0.5 degrees two-theta (e.g., using Cu Kα radiation) or 6.0±0.2, 7.6±0.2, 9.4±0.2, 15.2±0.2, 15.9±0.2, and 21.5±0.2 degrees two-theta (e.g., using Cu Kα radiation) or 6.0±0.1, 7.6±0.1, 9.4±0.1, 15.2±0.1, 15.9±0.1, and 21.5±0.1 degrees two-theta (e.g., using Cu Kα radiation). It is characterized by an XRPD pattern containing signals (e.g., peaks) at 6.0, 7.6, 9.4, 15.2, 15.9, and 21.5 degrees 2θ))) using Kα radiation.

[0061] In some embodiments, the morphic forms of Compound A (e.g., Form 2) have chromatic angles of 6.0±0.5, 7.6±0.5, 9.4±0.5, 15.2±0.5, 15.9±0.5, 21.5±0.5, and 23.9±0.5 degrees two-theta (e.g., 6.0±0.2, 7.6±0.2, 9.4±0.2, 15.2±0.2, 15.9±0.2, 21.5±0.2, and 23.9±0.2 degrees two-theta using Cu Kα radiation (e.g., 6.0±0.1, 7.6±0.1, 9.4±0.1, 15.2±0.1, 15.9±0.1, 21.5±0.1, and 23.9±0.1 degrees two-theta using Cu Kα radiation (e.g., It is characterized by an XRPD pattern including signals (e.g., peaks) at 6.0, 7.6, 9.4, 15.2, 15.9, 21.5, and 23.9 degrees 2θ))) using Kα radiation.

[0062] In some embodiments, the morphic forms of Compound A (e.g., Form 2) have peaks of 6.0±0.5, 7.6±0.5, 9.4±0.5, 15.2±0.5, 15.9±0.5, 21.2±0.5, 21.5±0.5, and 23.9±0.5 degrees two-theta (e.g., using Cu Kα radiation) and 6.0±0.2, 7.6±0.2, 9.4±0.2, 15.2±0.2, 15.9±0.2, 21.2±0.2, 21.5±0.2, and 23.9±0.2 degrees two-theta (e.g., using Cu Kα radiation). It is characterized by an XRPD pattern including signals (e.g., peaks) at 6.0±0.1, 7.6±0.1, 9.4±0.1, 15.2±0.1, 15.9±0.1, 21.2±0.1, 21.5±0.1, and 23.9±0.1 degrees 2θ using Kα radiation (e.g., 6.0, 7.6, 9.4, 15.2, 15.9, 21.2, 21.5, and 23.9 degrees 2θ using Cu Kα radiation).

[0063] In some embodiments, a morphic form of Compound A (eg, Form 2) is characterized by an XRPD pattern comprising one or more signals (eg, peaks) set forth in Table 2 below.

[0064] [Table 2] *The values ​​shown in the table above are approximate and subject to instrument variance and standard error.

[0065] In some embodiments, a morphic form of Compound A (eg, Form 2) is characterized by an XRPD pattern substantially similar to that depicted in FIG.

[0066] Other characterizations In some embodiments, a morphic form of Compound A (e.g., Form 2) is substantially similar to that depicted in FIG. 1 Characterized by H-NMR spectrum.

[0067] In some embodiments, a morphic form of Compound A (e.g., Form 2) is characterized by a decomposition event at 200±40°C, 200±30°C, 200±20°C, 200±15°C, 200±10°C, or 200±5°C (e.g., about 200°C) as measured by thermogravimetric analysis (TGA).

[0068] In some embodiments, a morphic form of Compound A (eg, Form 2) is characterized by a TGA thermogram substantially similar to that depicted in FIG.

[0069] In some embodiments, a morphic form of Compound A (e.g., Form 2) is characterized by an endothermic event with an onset at 129±20°C, 129±15°C, 129±10°C, or 129±5°C (e.g., about 129°C) as measured by differential scanning calorimetry (DSC).

[0070] In some embodiments, a morphic form of Compound A (e.g., Form 2) is characterized by a water uptake (e.g., at 0%-90% RH) of 0.15±0.5%, 0.15±0.4%, 0.15±0.3%, 0.15±0.2%, 0.15±0.1%, or 0.15±0.05% (e.g., about 0.15%) as measured by gravimetric vapor sorption (GVS).

[0071] In some embodiments, a morphic form of Compound A (e.g., Form 2) is characterized by a water uptake (e.g., at 40%-90% RH) of 0.09±0.05%, 0.09±0.04%, 0.09±0.03%, 0.09±0.02%, or 0.09±0.01% (e.g., about 0.09%) as measured by gravimetric vapor sorption (GVS).

[0072] In some embodiments, a morphic form of Compound A (eg, Form 2) is characterized by a GVS isotherm plot and kinetic plot substantially similar to those depicted in Figures 11A and 11B.

[0073] In some embodiments, the morphic form of Compound A (eg, Form 2) is a crystalline solid, eg, a needle-like crystalline form.

[0074] In some embodiments, the morphic form of Compound A (eg, Form 2) is a crystalline solid having an average size ranging from about 50 μm to about 75 μm.

[0075] In some embodiments, the morphic form of Compound A (e.g., Form 2) is a crystalline solid having an average size of 68±30 μm, 68±20 μm, 68±15 μm, 68±10 μm, or 68±5 μm (e.g., 68 μm).

[0076] Other properties of the crystalline form In some embodiments, the morphic form of Compound A has a purity of about 80% or greater, about 85% or greater, about 90% or greater, about 91% or greater, about 92% or greater, about 93% or greater, about 94% or greater, about 95% or greater, about 96% or greater, about 97% or greater, about 98% or greater, about 99% or greater, about 99.1% or greater, about 99.2% or greater, about 99.3% or greater, about 99.4% 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.

[0077] In some embodiments, Form 1 of Compound A has a purity of about 80% or greater, about 85% or greater, about 90% or greater, about 91% or greater, about 92% or greater, about 93% or greater, about 94% or greater, about 95% or greater, about 96% or greater, about 97% or greater, about 98% or greater, about 99% or greater, about 99.1% or greater, about 99.2% or greater, about 99.3% or greater, about 99.4% 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 as measured by HPLC.

[0078] In some embodiments, Compound A Form 2 has a purity of about 80% or greater, about 85% or greater, about 90% or greater, about 91% or greater, about 92% or greater, about 93% or greater, about 94% or greater, about 95% or greater, about 96% or greater, about 97% or greater, about 98% or greater, about 99% or greater, about 99.1% or greater, about 99.2% or greater, about 99.3% or greater, about 99.4% 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 as measured by HPLC.

[0079] In some embodiments, the morphic form of Compound A has a morphic purity of about 80% or more, about 85% or more, about 90% or more, about 91% or more, about 92% or more, about 93% or more, about 94% or more, about 95% or more, about 96% or more, about 97% or more, about 98% or more, about 99% or more, about 99.1% or more, about 99.2% or more, about 99.3% or more, about 99.4% or more, about 99.5% or more, about 99.6% or more, about 99.7% or more, about 99.8% or more, or about 99.9% or more.

[0080] In some embodiments, Form 1 of Compound A has a morphic purity of about 80% or greater, about 85% or greater, about 90% or greater, about 91% or greater, about 92% or greater, about 93% or greater, about 94% or greater, about 95% or greater, about 96% or greater, about 97% or greater, about 98% or greater, about 99% or greater, about 99.1% or greater, about 99.2% or greater, about 99.3% or greater, about 99.4% 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 as measured by HPLC.

[0081] In some embodiments, Compound A Form 2 has a morphic purity of about 80% or greater, about 85% or greater, about 90% or greater, about 91% or greater, about 92% or greater, about 93% or greater, about 94% or greater, about 95% or greater, about 96% or greater, about 97% or greater, about 98% or greater, about 99% or greater, about 99.1% or greater, about 99.2% or greater, about 99.3% or greater, about 99.4% 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 as measured by HPLC.

[0082] In some embodiments, the morphic form of Compound A exhibits less than about 10%, less than about 9%, less than about 8%, less than about 7%, less than about 6%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, less than about 1%, less than about 0.9%, less than about 0.8%, less than about 0.7%, less than about 0.6%, less than about 0.5%, less than about 0.4%, less than about 0.3%, less than about 0.2%, or less than about 0.1% impurities over 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, or 4 months at 25° C. and 97% relative humidity (RH).

[0083] In some embodiments, Compound A Form 1 exhibits less than about 10%, less than about 9%, less than about 8%, less than about 7%, less than about 6%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, less than about 1%, less than about 0.9%, less than about 0.8%, less than about 0.7%, less than about 0.6%, less than about 0.5%, less than about 0.4%, less than about 0.3%, less than about 0.2%, or less than about 0.1% impurities as measured by HPLC at 25° C. and 97% relative humidity (RH) over 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, or 4 months.

[0084] In some embodiments, Compound A Form 2 exhibits less than about 10%, less than about 9%, less than about 8%, less than about 7%, less than about 6%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, less than about 1%, less than about 0.9%, less than about 0.8%, less than about 0.7%, less than about 0.6%, less than about 0.5%, less than about 0.4%, less than about 0.3%, less than about 0.2%, or less than about 0.1% impurities as measured by HPLC at 25° C. and 97% relative humidity (RH) over 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, or 4 months.

[0085] In some embodiments, the morphic form of Compound A exhibits less than about 10%, less than about 9%, less than about 8%, less than about 7%, less than about 6%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, less than about 1%, less than about 0.9%, less than about 0.8%, less than about 0.7%, less than about 0.6%, less than about 0.5%, less than about 0.4%, less than about 0.3%, less than about 0.2%, or less than about 0.1% impurities over 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, or 4 months at 40° C. and 75% relative humidity (RH).

[0086] In some embodiments, Compound A Form 1 exhibits less than about 10%, less than about 9%, less than about 8%, less than about 7%, less than about 6%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, less than about 1%, less than about 0.9%, less than about 0.8%, less than about 0.7%, less than about 0.6%, less than about 0.5%, less than about 0.4%, less than about 0.3%, less than about 0.2%, or less than about 0.1% impurities as measured by HPLC at 40° C. and 75% relative humidity (RH) over 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, or 4 months.

[0087] In some embodiments, Compound A Form 2 exhibits less than about 10%, less than about 9%, less than about 8%, less than about 7%, less than about 6%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, less than about 1%, less than about 0.9%, less than about 0.8%, less than about 0.7%, less than about 0.6%, less than about 0.5%, less than about 0.4%, less than about 0.3%, less than about 0.2%, or less than about 0.1% impurities as measured by HPLC at 40° C. and 75% relative humidity (RH) over 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, or 4 months.

[0088] Methods for preparing crystalline forms In some aspects, the present disclosure provides methods of preparing the crystalline forms of Compound A described herein.

[0089] In some aspects, the present disclosure provides methods of preparing a crystalline form of Compound A, comprising one or more of the steps described herein.

[0090] In some aspects, the present disclosure provides compounds obtainable by, obtained by, or directly obtained from the methods for preparing crystalline forms of Compound A described herein.

[0091] In some embodiments, the prepared crystalline form of Compound A has a higher purity (e.g., 1% or more, 2% or more, 3% or more, 4% or more, 5% or more, 10% or more, 15% or more, 20% or more, 25% or more, 30% or more, 35% or more, 40% or more, 45% or more, or 50% or more) than Compound A prepared by a comparable method.

[0092] In some embodiments, the prepared crystalline Form 1 of Compound A has a higher purity (e.g., 1% or more, 2% or more, 3% or more, 4% or more, 5% or more, 10% or more, 15% or more, 20% or more, 25% or more, 30% or more, 35% or more, 40% or more, 45% or more, or 50% or more as measured by HPLC) compared to Compound A prepared by a comparable method.

[0093] In some embodiments, the prepared crystalline Form 2 of Compound A has a higher purity (e.g., 1% or more, 2% or more, 3% or more, 4% or more, 5% or more, 10% or more, 15% or more, 20% or more, 25% or more, 30% or more, 35% or more, 40% or more, 45% or more, or 50% or more as measured by HPLC) compared to Compound A prepared by a comparable method.

[0094] In some embodiments, the prepared crystalline form of Compound A (e.g., Form 1 or Form 2) has a morphic purity that is greater (e.g., 1% or more, 2% or more, 3% or more, 4% or more, 5% or more, 10% or more, 15% or more, 20% or more, 25% or more, 30% or more, 35% or more, 40% or more, 45% or more, or 50% or more) than Compound A prepared by a comparable method.

[0095] In some embodiments, the prepared crystalline Form 1 of Compound A has a higher morphic purity (e.g., 1% or more, 2% or more, 3% or more, 4% or more, 5% or more, 10% or more, 15% or more, 20% or more, 25% or more, 30% or more, 35% or more, 40% or more, 45% or more, or 50% or more as measured by HPLC) compared to Compound A prepared by a comparable method.

[0096] In some embodiments, the prepared crystalline Form 2 of Compound A has a higher morphic purity (e.g., 1% or more, 2% or more, 3% or more, 4% or more, 5% or more, 10% or more, 15% or more, 20% or more, 25% or more, 30% or more, 35% or more, 40% or more, 45% or more, or 50% or more as measured by HPLC) compared to Compound A prepared by a comparable method.

[0097] In some embodiments, the morphic form of Compound A exhibits less impurities (e.g., about 1%, about 2%, about 3%, about 4%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50%) than Compound A prepared by a comparable method over a period of 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, or 4 months at 25°C and 97% relative humidity (RH).

[0098] In some embodiments, Form 1 of Compound A exhibits less impurities (e.g., about 1%, about 2%, about 3%, about 4%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50%) as measured by HPLC at 25° C. and 97% relative humidity (RH) over 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, or 4 months compared to Compound A prepared by a comparable method.

[0099] In some embodiments, Form 2 of Compound A exhibits less impurities (e.g., about 1%, about 2%, about 3%, about 4%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50%) as measured by HPLC at 25° C. and 97% relative humidity (RH) over 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, or 4 months compared to Compound A prepared by a comparable method.

[0100] In some embodiments, the morphic form of Compound A exhibits less impurities (e.g., about 1%, about 2%, about 3%, about 4%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50%) than Compound A prepared by a comparable method over 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, or 4 months at 40°C and 75% relative humidity (RH).

[0101] In some embodiments, Form 1 of Compound A exhibits less impurities (e.g., about 1%, about 2%, about 3%, about 4%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50%) as measured by HPLC over 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, or 4 months at 40°C and 75% relative humidity (RH) compared to Compound A prepared by a comparable method.

[0102] In some embodiments, Form 2 of Compound A exhibits less impurities (e.g., about 1%, about 2%, about 3%, about 4%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50%) as measured by HPLC over 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, or 4 months at 40°C and 75% relative humidity (RH) compared to Compound A prepared by a comparable method.

[0103] Crystalline forms of Compound A can be prepared by any suitable technique known in the art. Specific processes for preparing these compounds are further described in the accompanying Examples.

[0104] In some embodiments, the reaction of the compounds is carried out in the presence of a suitable solvent, preferably inert under the respective reaction conditions. Examples of suitable solvents include hydrocarbons such as hexane, petroleum ether, benzene, toluene, or xylene; chlorinated hydrocarbons such as trichloroethylene, 1,2-dichloroethane, tetrachloromethane, chloroform, or dichloromethane; alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol, or tert-butanol; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, cyclopentyl methyl ether (CPME), methyl tert-butyl ether (MTBE), or dioxane; ethylene glycol monomethyl ether; ether or glycol ethers such as ethylene glycol monoethyl ether or ethylene glycol dimethyl ether (diglyme); ketones such as acetone, methyl isobutyl ketone (MIBK), or butanone; amides such as acetamide, dimethylacetamide, dimethylformamide (DMF), or N-methylpyrrolidinone (NMP); nitriles such as acetonitrile; sulfoxides such as dimethyl sulfoxide (DMSO); nitro compounds such as nitromethane or nitrobenzene; esters such as ethyl acetate or methyl acetate, or mixtures of said solvents, or mixtures with water.

[0105] The reaction time generally ranges from less than a minute to several days, depending on the reactivity of each compound and the reaction conditions. Suitable reaction times can be easily determined by methods known in the art, such as reaction monitoring. Based on the reaction temperatures described above, suitable reaction times generally range from about 5 minutes to about 48 hours.

[0106] Biological assays The compounds described herein can be characterized using a variety of assays known to those skilled in the art to determine whether the compounds have biological activity. For example, molecules can be characterized by conventional assays, including but not limited to the assays described below, to determine whether they have the expected activity, binding activity, and / or binding specificity.

[0107] Furthermore, high-throughput screening can be used to speed up the analysis using such assay.As a result, it may be possible to use techniques known in the art to rapidly screen the molecules described herein for activity.The general methodology for carrying out high-throughput screening is described, for example, in Devlin (1998) High Throughput Screening, Marcel Dekker; and U.S. Patent No. 5,763,263.High-throughput assay can use one or more different assay techniques, including but not limited to:

[0108] Various in vitro or in vivo biological assays may be suitable for detecting the effects of the compounds of the present disclosure, including, but not limited to, enzyme activity assays, electrophoretic mobility shift assays, reporter gene assays, in vitro cell viability assays, and assays described herein.

[0109] In some embodiments, the biological away is a biological away that tests inhibitory activity against IL-1β release upon NLRP3 activation in peripheral blood mononuclear cells (PBMCs).

[0110] In some embodiments, the biological assay is a PBMC IC50 determination assay.

[0111] In some embodiments, compounds are tested for their inhibitory activity on IL-1β release upon NLRP3 activation in blood cells (e.g., peripheral blood mononuclear cells (PBMCs)).

[0112] In some embodiments, PBMCs are isolated, seeded into wells of a plate, and incubated for a period of time (e.g., 3 hours with lipopolysaccharide). After incubation, the medium is replaced, a compound (e.g., a compound of the present disclosure) is added to the well, and the cells can be incubated. The cells are then stimulated (e.g., with ATP or nigericin), and the cell culture medium is collected for analysis.

[0113] In some embodiments, release of IL-1β into the medium is determined by quantitative detection of IL-1β in the medium (eg, using ELISA).

[0114] In some embodiments, PBMCs are isolated (e.g., from buffy coats). The isolated cells are seeded into wells and incubated (e.g., with lipopolysaccharide for 3 hours). Compounds are then added and the cells are incubated. The cells are then stimulated, and the medium is collected from the wells for analysis.

[0115] In some embodiments, release of IL-1β into the medium is determined by quantitative detection (eg, of IL-1β in the medium using HTRF®).

[0116] Pharmaceutical Compositions In some aspects, the present disclosure provides pharmaceutical compositions comprising a crystalline form of Compound A described herein and one or more pharmaceutically acceptable carrier or excipient materials.

[0117] The pharmaceutical composition containing the active compound of the present disclosure can be prepared in a generally known manner, for example, by conventional mixing, dissolving, granulating, sugar-coating, wet grinding, emulsifying, encapsulating, encapsulating or lyophilizing process.Pharmaceutical composition can be prepared in a conventional manner using one or more pharmaceutically acceptable carriers, comprising one or more excipients and / or auxiliary substances that facilitate the processing of active compound into pharmaceutically usable preparations.Those skilled in the art will understand that suitable formulation can depend on the selected route of administration.

[0118] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions, and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers may include physiological saline, bacteriostatic water, Cremophor EL (BASF, Parsippany, NJ), or phosphate-buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringability exists. The composition must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. Prevention of microbial action can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal and the like.In many cases, it is preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol and sorbitol, and sodium chloride in the composition.Prolonged absorption of injection compositions can be achieved by including agents that delay absorption, for example, aluminum monostearate and gelatin in the composition.

[0119] Sterile injectable solution can be prepared by incorporating active compound into appropriate solvent with one or combination of above-listed components as needed in required amount, and then sterilize by filtering.Generally, dispersion is prepared by incorporating active compound into sterile vehicle that contains basic dispersion medium and other components that are required from above-listed components.In the case of sterile powder that is used to prepare sterile injectable solution, the preparation method is vacuum drying and freeze-drying, which produces powder of active compound and any additional required components from the solution that is previously sterilized and filtered.

[0120] Oral compositions can contain one or more inert diluents or one or more pharmaceutically acceptable edible carriers.They can be enclosed in gelatin capsules or compressed into tablets.For the purpose of oral therapeutic administration, active compounds can be incorporated with excipients and can be used in the form of tablets, lozenges or capsules.Oral compositions can also be prepared using fluid carriers for use as mouthwash, and the compound in the fluid carrier is applied to the oral cavity, swished, and expectorated or swallowed.Pharmaceutically compatible binding agents and / or auxiliary materials can be included as part of the composition. Tablets, pills, capsules, troches, and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth, or gelatin; a filler such as starch or lactose; a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricating agent such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

[0121] For administration by inhalation, the compounds are delivered in the form of an aerosol spray from a pressured container or dispenser which contains a suitable propellant, eg, a gas such as carbon dioxide, or a nebulizer.

[0122] Systemic administration can also be by transmucosal or transdermal means.For transmucosal or transdermal administration, a penetrant suitable for the barrier to be permeated is used in the formulation.Such penetrants are generally known in the art, and for example, for transmucosal administration, include surfactants, bile salts, and fusidic acid derivatives.Transmucosal administration can be achieved through the use of nasal sprays or suppositories.For transdermal administration, active compounds are formulated into ointments, salves, gels, or creams as are generally known in the art.

[0123] The active compound can be prepared with one or more pharmaceutically acceptable carriers that can protect the compound against rapid elimination from the body, such as controlled-release formulations, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparing such formulations will be apparent to those skilled in the art.

[0124] For the sake of ease of administration and uniformity of dosage, it can be particularly advantageous to prepare oral or parenteral compositions in dosage unit form.Dosage unit form used herein refers to a physically separate unit that is suitable as a unitary dosage for the object to be treated; each unit contains a predetermined amount of active compound that is calculated to produce desired therapeutic effect together with required pharmaceutical carrier.The specification of dosage unit form of the present disclosure is determined by and directly depends on the unique characteristics of active compound and the specific therapeutic effect that should be achieved.

[0125] In therapeutic applications, dosages of pharmaceutical compositions used in accordance with the present disclosure will vary depending on the agent, the age, weight, and clinical condition of the recipient patient, and the experience and judgment of the clinician or practitioner administering the treatment, among other factors influencing the selected dosage. Generally, the dose should be sufficient to result in a slowing, and preferably regression, of disease symptoms, and preferably complete regression of the disease.

[0126] It will be appreciated that the pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

[0127] How to use In some aspects, the present disclosure provides a method of preventing or treating a disease or disorder in a subject, the method comprising administering to the subject a pharmaceutically effective amount of a morphic form of Compound A described herein.

[0128] In some aspects, the present disclosure provides a method of treating a disease or disorder in a subject, the method comprising administering to the subject a pharmaceutically effective amount of a morphic form of Compound A described herein.

[0129] In some aspects, the present disclosure provides a morphic form of Compound A described herein for use in preventing or treating a disease or disorder in a subject.

[0130] In some aspects, the present disclosure provides a morphic form of Compound A described herein for use in treating a disease or disorder in a subject.

[0131] In some aspects, the present disclosure provides for the use of a morphic form of Compound A described herein in the manufacture of a medicament for preventing or treating a disease or disorder in a subject.

[0132] In some aspects, the present disclosure provides for the use of a morphic form of Compound A described herein in the manufacture of a medicament for treating a disease or disorder in a subject.

[0133] In some aspects, the present disclosure provides for the use of a morphic form of Compound A described herein to prevent or treat a disease or disorder in a subject.

[0134] In some aspects, the present disclosure provides for the use of a morphic form of Compound A described herein to treat a disease or disorder in a subject.

[0135] In some embodiments, the disease or disorder is associated with associated inflammasome activity. In some embodiments, the disease or disorder is a disease or disorder in which inflammasome activity is implicated.

[0136] In some embodiments, the disease or disorder is an inflammatory disorder, an autoinflammatory disorder, an autoimmune disorder, a neurodegenerative disease, or cancer.

[0137] In some embodiments, the disease or disorder is an inflammatory disorder, an autoinflammatory disorder, and / or an autoimmune disorder.

[0138] In some embodiments, the disease or disorder is selected from cryopyrin-associated autoinflammatory syndromes (CAPS; e.g., familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurological, cutaneous, and articular (CINCA) syndrome / neonatal-onset multisystem inflammatory disease (NOMID)), familial Mediterranean fever (FMF), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), gout, rheumatoid arthritis, osteoarthritis, Crohn's disease, chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD), fibrosis, obesity, type 2 diabetes, multiple sclerosis, dermatological diseases (e.g., acne), and neuroinflammation manifested in protein misfolding diseases (e.g., prion diseases).

[0139] In some embodiments, the disease or disorder is a neurodegenerative disease.

[0140] In some embodiments, the disease or disorder is Parkinson's disease or Alzheimer's disease.

[0141] In some embodiments, the disease or disorder is a dermatological disease.

[0142] In some embodiments, the dermatological condition is acne.

[0143] In some embodiments, the disease or disorder is cancer.

[0144] In some embodiments, the cancer is metastatic cancer, gastrointestinal cancer, skin cancer, non-small cell lung carcinoma, brain cancer (eg, glioblastoma), or colorectal adenocarcinoma.

[0145] In some aspects, the present disclosure provides a method for inhibiting inflammasome (e.g., NLRP3 inflammasome) activity in a subject (e.g., in vitro or in vivo), the method comprising contacting a cell with an effective amount of a crystalline form of Compound A.

[0146] In some aspects, the present disclosure provides a crystalline form of Compound A described herein for use in inhibiting inflammasome (e.g., NLRP3 inflammasome) activity in a subject (e.g., in vitro or in vivo).

[0147] In some aspects, the present disclosure provides for the use of a crystalline form of Compound A described herein in the manufacture of a medicament for inhibiting inflammasome (e.g., NLRP3 inflammasome) activity (e.g., in vitro or in vivo).

[0148] In some embodiments, the inflammasome is the NLRP3 inflammasome.

[0149] In some embodiments, the subject is an animal.

[0150] In some embodiments, the subject is a mammal.

[0151] In some embodiments, the subject is a human.

[0152] In some embodiments, the subject is a cell.

[0153] In some embodiments, the subject is a cell population.

[0154] definition Unless otherwise stated, the following terms used in the specification and claims have the following meanings specified below.

[0155] As used herein, the term "about" means approximately, in the vicinity, roughly, or around.When the term "about" is used in conjunction with a numerical range, the term modifies the range by extending the boundaries above and below the stated numerical value.In general, the term "about" is used herein to modify numerical values ​​above and below the stated value by 20%, 10%, 5%, 3%, or 1% variation.

[0156] It is understood that the compounds disclosed in the present invention can exist in either hydrated or non-hydrated (anhydrous) form, or as solvates with other solvent molecules.Non-limiting examples of hydrates can include monohydrates and dihydrates.Non-limiting examples of solvates can include ethanol solvates and acetone solvates.

[0157] As used herein, the phrases "one or more of A, B, or C," "one or more of A, B, or C," "one or more of A, B, and C," "one or more of A, B, and C," "selected from the group consisting of A, B, and C," "selected from A, B, and C," and the like, are used interchangeably and all refer to a selection from the group consisting of A, B, and / or C, i.e., one or more A, one or more B, one or more C, or any combination thereof, unless otherwise indicated.

[0158] It is to be understood that the present disclosure provides methods for synthesizing crystalline forms of Compound A.

[0159] It should be understood that throughout the description where a composition is described as having, including, or comprising specified components, it is contemplated that the composition also consists essentially of or consists of the listed components. Similarly, where a method or process is described as having, including, or comprising specified process steps, the process also consists essentially of or consists of the listed processing steps. Furthermore, it should be understood that the order of steps or the order for performing certain actions is immaterial so long as the invention remains operable. Furthermore, two or more steps or actions can be performed simultaneously.

[0160] It is understood that the synthetic processes of the present disclosure can accommodate a wide variety of functional groups and therefore variously substituted starting materials can be used.

[0161] It should be understood that the crystalline forms of Compound A can be prepared in a variety of ways using commercially available starting materials, compounds known in the literature, or from readily prepared intermediates by employing standard synthetic methods and procedures that are either known to those skilled in the art or will be apparent to those skilled in the art in light of the teachings herein. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be obtained from the relevant scientific literature or standard textbooks in the field. Examples include, but are not limited to, any one or several sources, Smith, MB, March, J., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5, incorporated herein by reference. th edition, John Wiley & Sons: New York, 2001;Greene, TW, Wuts, PGM, Protective Groups in Organic Synthesis, 3 rd edition, John Wiley & Sons: New York, 1999; R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), are useful and recognized reference texts of organic synthesis known to those skilled in the art.

[0162] Those skilled in the art will note that the order of certain steps, such as the introduction and removal of protecting groups, may be varied during the reaction sequences and synthetic schemes. Those skilled in the art will recognize that certain groups may need to be protected from reaction conditions through the use of protecting groups. Protecting groups may also be used to distinguish similar functional groups in a molecule. For a list of protecting groups and how to introduce and remove these groups, see Greene, TW, Wuts, PGM, Protective Groups in Organic Synthesis, 3 rd edition, John Wiley & Sons: New York, 1999.

[0163] Unless otherwise stated, any description of a method of treatment or prevention should be understood to include the use of a crystalline form of Compound A to provide treatment or prevention as described herein. Unless otherwise stated, any description of a method of treatment or prevention should be understood to include the use of a crystalline form of Compound A to prepare a medicament for treating or preventing such a condition. Treatment or prevention includes treatment or prevention of humans or non-human animals, including rodents and other disease models.

[0164] Unless otherwise stated, any description of a method of treatment is understood to include the use of a crystalline form of Compound A to provide treatment as described herein. Unless otherwise stated, any description of a method of treatment is further understood to include the use of a crystalline form of Compound A to prepare a medicament for treating such a condition. Treatment includes treatment of humans or non-human animals, including rodents and other disease models.

[0165] As used herein, the term "subject" includes human and non-human animals, as well as cell lines, cell cultures, tissues, and organs. In some embodiments, the subject is a mammal. The mammal can be, for example, a human or a suitable non-human mammal, such as a primate, mouse, rat, dog, cat, cow, horse, goat, camel, sheep, or pig. The subject can also be a bird or poultry. In some embodiments, the subject is a human.

[0166] As used herein, the term "subject in need thereof" refers to a subject who has a disease or is at increased risk of developing a disease. A subject in need thereof can be a subject who has previously been diagnosed or identified as having a disease or disorder disclosed herein. A subject in need thereof can also be a subject suffering from a disease or disorder disclosed herein. Alternatively, a subject in need thereof can be a subject who is at increased risk of developing such a disease or disorder compared to the population as a whole (i.e., a subject who is more susceptible to developing such a disorder compared to the population as a whole). A subject in need thereof can have a refractory or resistant disease or disorder disclosed herein (i.e., a disease or disorder disclosed herein that does not respond or has not yet responded to treatment). A subject can be resistant at the start of treatment or can become resistant during treatment. In some embodiments, a subject in need thereof has tried and failed all known effective treatments for a disease or disorder disclosed herein. In some embodiments, a subject in need thereof has previously undergone at least one treatment.

[0167] As used herein, the term "treating" or "treat" refers to the management and care of a patient for the purpose of combating a disease, condition, or disorder, and includes the administration of a compound of the present disclosure, a polymorph, or a solvate thereof, to alleviate the symptoms or complications of the disease, condition, or disorder, or to eliminate the disease, condition, or disorder. The term "treat" can also include treatment of a cell in vitro or treatment of an animal model.

[0168] It is understood that morphic forms of Compound A can also be used or can be used to prevent related diseases, conditions, or disorders, or to identify suitable candidates for such purposes.

[0169] As used herein, the terms "preventing," "prevent," or "protecting against" refer to reducing or eliminating the onset of symptoms or complications of such disease, condition, or disorder.

[0170] It should be understood that "solubility" or "solubility rating" refers to the property of a polymorph disclosed herein to dissolve in a liquid solvent and form a homogeneous solution. In some embodiments, solubility is expressed as a concentration by mass of solute per unit volume of solvent (e.g., g of solute per kg of solvent, g per dL (100 mL), mg / mL, etc.), molality, molality, mole fraction, or other similar concentration description. One of skill in the art will understand that the maximum equilibrium amount of solute that can be dissolved per volume of solvent is the solubility of that solute in that solvent under specified conditions, including temperature, pressure, pH, and solvent properties. In some embodiments, solubility is measured at physiological or non-physiological pH, e.g., about pH 5.0, about pH 6.0, about pH 7.0, about pH 7.4, about pH 7.6, about pH 7.8, or about pH 8.0 (e.g., about pH 5-8). In some embodiments, solubility is measured in water or a physiological buffer, such as PBS, NaCl (with or without NaPO), or FaSSIF. In some embodiments, solubility is measured in a biological fluid (solvent) (e.g., blood or serum). In some embodiments, the temperature is near room temperature (e.g., about 20, about 21, about 22, about 23, about 24, or about 25°C) or near body temperature (about 37°C). In some embodiments, the agent has a solubility rating of at least about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 25, about 30, about 40, about 50, about 60, about 70, about 80, about 90, or about 100 mg / ml at room temperature or 37°C.

[0171] As used herein, "stable" refers to a polymorph that maintains purity, appearance, and / or analytical parameters over a defined time and temperature range compared to the polymorph when isolated. In some embodiments, a "stable" polymorph exhibits less than about 10%, less than about 9%, less than about 8%, less than about 7%, less than about 6%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, less than about 1%, less than about 0.9%, less than about 0.8%, less than about 0.7%, less than about 0.6%, less than about 0.5%, less than about 0.4%, less than about 0.3%, less than about 0.2%, or less than about 0.1% impurities over a defined period of time (e.g., 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, or 4 months). For example, if after two weeks at room temperature the DSC and TGA profiles are consistent with the originally isolated polymorph, the polymorph is stable.

[0172] It should be understood that one skilled in the art can refer to general reference texts for detailed descriptions of the known techniques discussed herein or equivalent techniques. These texts include Ausubel et al., Current Protocols in Molecular Biology, John Wiley and Sons, Inc. (2005); Sambrook et al., Molecular Cloning, A Laboratory Manual (3 rdedition), Cold Spring Harbor Press, Cold Spring Harbor, New York (2000);Coligan et al., Current Protocols in Immunology, John Wiley & Sons, NY;Enna et al., Current Protocols in Pharmacology, John Wiley & Sons, NY;Fingl et al., The Pharmacological Basis of Therapeutics (1975), Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 18 th Of course, these texts can also be referenced when making or using aspects of the present disclosure.

[0173] It should be understood that the present disclosure also provides pharmaceutical compositions comprising a crystalline form of Compound A in combination with at least one pharmaceutically acceptable excipient or carrier.

[0174] As used herein, the term "pharmaceutical composition" refers to a formulation containing a crystalline form of Compound A in a form suitable for administration to a subject. In some embodiments, the pharmaceutical composition is in bulk or unit dosage form. The unit dosage form may be in any of a variety of forms, including, for example, a capsule, an IV bag, a tablet, a single pump on an aerosol inhaler, or a vial. The amount of active ingredient (e.g., a formulation of the disclosed compound or its salt, hydrate, solvate, or isomer) in a unit dose of the composition is an effective amount and varies depending on the specific treatment involved. Those skilled in the art will recognize that routine variations in dosage may sometimes be necessary depending on the age and condition of the patient. The dosage also depends on the route of administration. Various routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalation, buccal, sublingual, intrapleural, intrathecal, intranasal, and the like. Dosage forms for topical or transdermal administration of the compounds of the present 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 any required preservatives, buffers, or propellants.

[0175] As used herein, the term "pharmaceutically acceptable" refers to compounds, anions, cations, materials, compositions, carriers, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0176] As used herein, the term "pharmaceutically acceptable excipient" means an excipient that is generally safe, non-toxic, and not biologically or otherwise undesirable and is useful in preparing pharmaceutical compositions, and includes excipients that are acceptable for veterinary and human pharmaceutical use. As used in the specification and claims, "pharmaceutically acceptable excipient" can include both one such excipient and more than one such excipient.

[0177] It should be understood that the pharmaceutical compositions of the present disclosure are formulated to be compatible with their intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., ingestion), inhalation, transdermal (topical), and transmucosal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can contain the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycol, glycerin, propylene glycol, or other synthetic solvents; an antibacterial agent such as benzyl alcohol or methylparaben; an antioxidant such as ascorbic acid or sodium bisulfite; a chelating agent such as ethylenediaminetetraacetic acid; a buffer such as acetate, citrate, or phosphate, and an agent for adjusting osmolality such as sodium chloride or dextrose. pH can be adjusted with acids or bases such as hydrochloric acid or sodium hydroxide. Parenteral preparations can be enclosed in ampoules, disposable syringes, or multiple-dose vials made of glass or plastic.

[0178] It should be understood that the compound or pharmaceutical composition of the present disclosure can be administered to a subject by many well-known methods currently used for chemotherapy treatment.For example, the compound of the present disclosure can be injected into the bloodstream or body cavity, or can be taken orally, or can be applied through the skin using a patch.The selected dose should be sufficient to constitute effective treatment, but should not be so high as to cause unacceptable side effects.The status of disease state (for example, disease or disorder disclosed herein) and the health condition of the patient should preferably be carefully monitored during treatment and for a reasonable period after treatment.

[0179] As used herein, the term "therapeutically effective amount" refers to the amount of a pharmaceutical agent to treat, alleviate, or prevent a identified disease or condition, or to exhibit a detectable therapeutic or inhibitory effect.The effect can be detected by any assay method known in the art.The exact effective amount for a subject depends on the subject's weight, size, and health; the nature and extent of the condition; and the therapeutic agent or combination of therapeutic agents selected for administration.The therapeutically effective amount for a given situation can be determined by routine experimentation, which is within the skill and judgment of the clinician.

[0180] As used herein, the term "effective amount" refers to the amount of a pharmaceutical agent to treat or alleviate a identified disease or condition, or to exhibit a detectable therapeutic or inhibitory effect.The effect can be detected by any assay method known in the art.The exact effective amount for a subject depends on the subject's weight, size, and health; the nature and extent of the condition; and the therapeutic agent or combination of therapeutic agents selected for administration.The therapeutically effective amount for a given situation can be determined by routine experimentation, which is within the skill and judgment of the clinician.

[0181] It is understood that for any compound, the therapeutically effective amount or effective dose can be estimated first either in cell culture assays, for example, cell culture assays of neoplastic cells, or in animal models, usually rats, mice, rabbits, dogs, or pigs. Animal models can also be used to determine appropriate concentration ranges and administration routes. Such information can then be used to determine useful doses and routes for administration in humans. Therapeutic / prophylactic efficacy and toxicity can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, for example, ED 50 (the dose that is therapeutically effective in 50% of the population) and LD 50 (the dose lethal to 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, which is the LD 50 / ED 50 Pharmaceutical compositions that exhibit large therapeutic indices are preferred. The dosage can vary within this range depending on the dosage form employed, sensitivity of the patient, and the route of administration.

[0182] Dosage and administration are adjusted to provide a sufficient level of the active agent or to maintain the desired effect.Factors that can be taken into consideration include the severity of the disease state, the subject's general health condition, the subject's age, weight, and sex, diet, administration time and frequency, drug combinations, reaction sensitivity, and treatment tolerance / response.

[0183] Pharmaceutical compositions containing the crystalline form of Compound A can be prepared in a generally known manner, for example, by conventional mixing, dissolving, granulating, dragee-making, wet-grinding, emulsifying, encapsulating, encapsulating, or lyophilizing processes. Pharmaceutical compositions can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers, including excipients and / or auxiliary substances that facilitate the processing of the crystalline form of Compound A into a pharmaceutically usable preparation. The appropriate formulation depends on the selected route of administration.

[0184] The crystalline forms of Compound A can be prepared with one or more pharmaceutically acceptable carriers that protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems.

[0185] It will be appreciated that the pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

[0186] Techniques for formulation and administration of the disclosed compounds of this disclosure are described in Remington: The Science and Practice of Pharmacy, 1999. th It can be found in the "Chemical Forms of Compound A" (1995), Mack Publishing Co., Easton, PA edition. In some embodiments, the crystalline form of Compound A is used in pharmaceutical preparations in combination with one or more pharmaceutically acceptable carriers or diluents. Suitable pharmaceutically acceptable carriers include, but are not limited to, inert solid fillers or inert diluents, and sterile aqueous or organic solutions. The compound is present in such pharmaceutical compositions in an amount sufficient to provide the desired dosage within the range described herein.

[0187] All percentages and ratios used herein are by weight unless otherwise indicated. Other features and advantages of the present disclosure will become apparent from the various examples. The examples provided illustrate various components and methodologies useful in practicing the present disclosure. The examples do not limit the claimed disclosure. Based on the present disclosure, one skilled in the art can identify and adopt other components and methodologies useful in practicing the present disclosure.

[0188] In the synthetic schemes, compounds may be depicted in one particular configuration for simplicity. Such a particular configuration should not be construed as limiting the 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 will be understood that a given isomer, tautomer, positional isomer, or stereoisomer may have a higher level of activity than another isomer, tautomer, positional isomer, or stereoisomer.

[0189] All publications and patent documents cited in this specification are incorporated herein by reference as if each such publication or document was specifically and individually indicated to be incorporated herein by reference. Citation of publications and patent documents is not intended as an admission that any is pertinent prior art, nor does it constitute any admission as to the contents or date thereof. Having now described the invention by written description, those skilled in the art will recognize that the invention can be practiced in a variety of embodiments, and that the foregoing description and the following examples are intended to be illustrative and not limiting of the scope of the claims which follow.

[0190] Having described the present disclosure, the following examples are offered by way of illustration and not by way of limitation.

[0191] Exemplary Embodiments Exemplary Embodiment 1. Compound A: Morphic form of TIFF2025533089000005.tif36128.

[0192] Exemplary Embodiment 2. A morphic form according to exemplary embodiment 1, which is a crystalline form of Compound A.

[0193] Exemplary Embodiment 3. The morphic form of any one of the preceding exemplary embodiments, which is Form 1 of Compound A.

[0194] Exemplary Embodiment 4. The morphic form of any one of the preceding exemplary embodiments, characterized by an XRPD pattern comprising signals at 8.7±0.5, 15.3±0.5, and 15.9±0.5 degrees 2θ using Cu Kα radiation.

[0195] Exemplary Embodiment 5. The morphic form of any one of the preceding exemplary embodiments, characterized by an XRPD pattern comprising signals at 7.9±0.5, 8.7±0.5, 15.3±0.5, and 15.9±0.5 degrees 2θ using Cu Kα radiation.

[0196] Exemplary Embodiment 6. The morphic form of any one of the preceding exemplary embodiments, characterized by an XRPD pattern comprising signals at 7.9±0.5, 8.7±0.5, 15.3±0.5, 15.9±0.5, and 24.4±0.5 degrees 2θ using Cu Kα radiation.

[0197] Exemplary Embodiment 7. The morphic form of any one of the preceding exemplary embodiments, characterized by an XRPD pattern comprising signals at 7.9±0.5, 8.7±0.5, 15.3±0.5, 15.9±0.5, 22.3±0.5, and 24.4±0.5 degrees 2θ using Cu Kα radiation.

[0198] Exemplary Embodiment 8. The morphic form of any one of the preceding exemplary embodiments, characterized by an XRPD pattern comprising signals at 7.9±0.5, 8.7±0.5, 15.3±0.5, 15.9±0.5, 22.3±0.5, 23.9±0.5, and 24.4±0.5 degrees 2θ using Cu Kα radiation.

[0199] Exemplary Embodiment 9. The morphic form of any one of the preceding exemplary embodiments, characterized by an XRPD pattern comprising signals at 5.9±0.5, 7.9±0.5, 8.7±0.5, 15.3±0.5, 15.9±0.5, 22.3±0.5, 23.9±0.5, and 24.4±0.5 degrees 2θ using Cu Kα radiation.

[0200] Exemplary Embodiment 10. The morphic form of any one of the preceding exemplary embodiments, characterized by an XRPD pattern comprising one or more signals set forth in Table 1.

[0201] Exemplary Embodiment 11. The morphic form of any one of the preceding exemplary embodiments, characterized by an XRPD pattern substantially similar to that depicted in FIG.

[0202] Exemplary Embodiment 12. The morphic form of any one of Exemplary Embodiments 1-2, which is Form 2 of Compound A.

[0203] Exemplary Embodiment 13. The morphic form of any one of Exemplary Embodiments 1-2 and 12, characterized by an XRPD pattern comprising signals at 7.6±0.5, 9.4±0.5, and 15.9±0.5 degrees 2θ using Cu Kα radiation.

[0204] Exemplary Embodiment 14. The morphic form of any one of Exemplary Embodiments 1-2 and 12-13, characterized by an XRPD pattern comprising signals at 7.6±0.5, 9.4±0.5, 15.2±0.5, and 15.9±0.5 degrees 2θ using Cu Kα radiation.

[0205] Exemplary Embodiment 15. The morphic form of any one of Exemplary Embodiments 1-2 and 12-14, characterized by an XRPD pattern comprising signals at 6.0±0.5, 7.6±0.5, 9.4±0.5, 15.2±0.5, and 15.9±0.5 degrees 2θ using Cu Kα radiation.

[0206] Exemplary Embodiment 16. The morphic form of any one of Exemplary Embodiments 1-2 and 12-15, characterized by an XRPD pattern comprising signals at 6.0±0.5, 7.6±0.5, 9.4±0.5, 15.2±0.5, 15.9±0.5, and 21.5±0.5 degrees 2θ using Cu Kα radiation.

[0207] Exemplary Embodiment 17. The morphic form of any one of Exemplary Embodiments 1-2 and 12-16, characterized by an XRPD pattern comprising signals at 6.0±0.5, 7.6±0.5, 9.4±0.5, 15.2±0.5, 15.9±0.5, 21.5±0.5, and 23.9±0.5 degrees 2θ using Cu Kα radiation.

[0208] Exemplary Embodiment 18. The morphic form of any one of Exemplary Embodiments 1-2 and 12-17, characterized by an XRPD pattern comprising signals at 6.0±0.5, 7.6±0.5, 9.4±0.5, 15.2±0.5, 15.9±0.5, 21.2±0.5, 21.5±0.5, and 23.9±0.5 degrees 2θ using Cu Kα radiation.

[0209] Exemplary Embodiment 19. The morphic form of any one of Exemplary Embodiments 1-2 and 12-18, characterized by an XRPD pattern comprising one or more signals set forth in Table 2.

[0210] Exemplary Embodiment 20. The morphic form of any one of Exemplary Embodiments 1-2 and 12-19, characterized by an XRPD pattern substantially similar to that depicted in FIG.

[0211] Exemplary Embodiment 21. The morphic form of any one of the preceding exemplary embodiments, having a purity of about 80% or more, about 85% or more, about 90% or more, about 91% or more, about 92% or more, about 93% or more, about 94% or more, about 95% or more, about 96% or more, about 97% or more, about 98% or more, about 99% or more, about 99.1% or more, about 99.2% or more, about 99.3% or more, about 99.4% or more, about 99.5% or more, about 99.6% or more, about 99.7% or more, about 99.8% or more, or about 99.9% or more.

[0212] Exemplary Embodiment 22. The morphic form of any one of the preceding exemplary embodiments, having a morphic purity of about 80% or more, about 85% or more, about 90% or more, about 91% or more, about 92% or more, about 93% or more, about 94% or more, about 95% or more, about 96% or more, about 97% or more, about 98% or more, about 99% or more, about 99.1% or more, about 99.2% or more, about 99.3% or more, about 99.4% or more, about 99.5% or more, about 99.6% or more, about 99.7% or more, about 99.8% or more, or about 99.9% or more.

[0213] Exemplary Embodiment 23. The morphic form of any one of the preceding exemplary embodiments, exhibiting less than about 10%, less than about 9%, less than about 8%, less than about 7%, less than about 6%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, less than about 1%, less than about 0.9%, less than about 0.8%, less than about 0.7%, less than about 0.6%, less than about 0.5%, less than about 0.4%, less than about 0.3%, less than about 0.2%, or less than about 0.1% impurities over 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, or 4 months at 25° C. and 97% relative humidity (RH).

[0214] Exemplary Embodiment 24. The morphic form of any one of the preceding exemplary embodiments, exhibiting less than about 10%, less than about 9%, less than about 8%, less than about 7%, less than about 6%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, less than about 1%, less than about 0.9%, less than about 0.8%, less than about 0.7%, less than about 0.6%, less than about 0.5%, less than about 0.4%, less than about 0.3%, less than about 0.2%, or less than about 0.1% impurities over 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, or 4 months at 40° C. and 75% relative humidity (RH).

[0215] Exemplary Embodiment 25. A method of preparing a morphic form of compound A according to any one of the preceding exemplary embodiments.

[0216] Exemplary Embodiment 26. A pharmaceutical composition comprising a morphic form of Compound A according to any one of the preceding exemplary embodiments, and one or more pharmaceutically acceptable carriers or excipients.

[0217] Exemplary Embodiment 27. A method for preventing or treating a disease or disorder in a subject, comprising administering to the subject a morphic form of compound A described in any one of Exemplary Embodiments 1-24 or a pharmaceutical composition described in Exemplary Embodiment 26.

[0218] Exemplary Embodiment 28. A morphic form of compound A according to any one of exemplary embodiments 1-24 or a pharmaceutical composition according to exemplary embodiment 26, for use in preventing or treating a disease or disorder in a subject.

[0219] Exemplary Embodiment 29. Use of a morphic form of compound A according to any one of exemplary embodiments 1-24 or a pharmaceutical composition according to exemplary embodiment 26 in the manufacture of a medicament for preventing or treating a disease or disorder in a subject.

[0220] Exemplary Embodiment 30. A method for inhibiting inflammasome activity in a subject, comprising contacting a cell with a morphic form of compound A described in any one of Exemplary Embodiments 1-24 or a pharmaceutical composition described in Exemplary Embodiment 26.

[0221] Exemplary Embodiment 31. A morphic form of compound A according to any one of exemplary embodiments 1-24 or a pharmaceutical composition according to exemplary embodiment 26 for use in inhibiting inflammasome activity in a subject.

[0222] Exemplary Embodiment 32. Use of a morphic form of Compound A in the manufacture of a medicament for inhibiting inflammasome activity in a subject.

[0223] Exemplary Embodiment 33. The method, morphic form, pharmaceutical composition, or use of any one of the preceding exemplary embodiments, wherein the subject is a human. [Example]

[0224] Equipment and methodology details Details of the equipment and methodology of the experiments carried out in the Examples are provided herein.

[0225] X-ray powder diffraction (XRPD) Bruker AXS C2 GADDS XRPD diffractograms were collected on a Bruker AXS C2 GADDS diffractometer using Cu Kα radiation (40 kV, 40 mA), an automated XYZ stage, a laser video microscope for automated sample positioning, and a Vantec-500 2D area detector. The X-ray optics consisted of a single Goebel multilayer mirror coupled with a 0.3 mm pinhole collimator. The beam divergence angle, i.e., the effective size of the X-ray beam on the sample, was approximately 4 mm. The θ-θ continuous scan mode was employed with a sample-to-detector distance of 20 cm, giving an effective 2θ range of 1.5° to 32.5°. Typically, the sample was exposed to the X-ray beam for 120 s. The software used for data collection and analysis was GADDS and Diffrac Plus EVA for Windows 7 / XP, respectively.

[0226] Ambient Conditions: Samples run under ambient conditions were prepared as flat specimens using the as-received powder without grinding. Samples were prepared and analyzed on glass slides by lightly pressing the powder to provide a flat surface for analysis.

[0227] For non-ambient: variable temperature (VT-XRPD) experiments, samples were mounted on an Anton Paar DHS 900 hot stage at ambient conditions. The sample was then heated at 20°C / min to the appropriate temperature, followed by an isothermal hold for 1 minute before data collection. Samples were prepared and analyzed on silicon wafers mounted to the hot stage using thermal paste.

[0228] Bruker AXS D8 Advance XRPD diffractograms were collected on a Bruker D8 diffractometer using Cu Kα radiation (40 kV, 40 mA) and a θ-2θ goniometer equipped with a Ge monochromator. The incident beam passed through a 2.0 mm divergence slit, then a 0.2 mm anti-scatter slit and a knife edge. The diffracted beam passed through an 8.0 mm receiving slit with a 2.5° Soller slit, then a Lynxeye detector. The software used for data collection and analysis was Diffrac Plus XRD Commander and Diffrac Plus EVA, respectively.

[0229] Using the as-received powder, samples were run under ambient conditions as flat specimens. Samples were prepared on polished, zero-background (510) silicon wafers by gently pressing onto a flat surface or packing into a cut recess. The sample was rotated in its own plane.

[0230] Details of the standard Pharmorphix data collection method are below. Angle range: 2~42°2θ Step size: 0.05° 2θ Acquisition time: 0.5 seconds / step (total acquisition time: 6.40 minutes)

[0231] When required, other methods for data collection will be used with the following details: TIFF2025533089000006.tif22128

[0232] PANalytical Empyrean XRPD diffractograms were collected on a PANalytical Empyrean diffractometer using Cu Kα radiation (45 kV, 40 mA) in transmission geometry. A 0.04 rad Soller slit with a 0.5° slit, a 4 mm mask, and a focusing mirror was used for the incident beam. A PIXcel was positioned for the diffracted beam. 3DThe detector was fitted with a receiving slit and a 0.04 rad Soller slit. The software used for data collection was X'Pert Data Collector with the X'Pert Operator Interface. Data were analyzed and presented using Diffrac Plus EVA or HighScore Plus. Samples were prepared and analyzed in transmission mode in either metal 96-well plates or Millipore 96-well plates. X-ray transparent film was used between metal sheets on the metal well plates, and powders (approximately 1-2 mg) were used as received. Millipore plates were used to isolate and analyze solids from suspensions by adding a small amount of suspension directly to the plate before filtering under light vacuum.

[0233] The scanning mode for the metal plates used the gonioscan axis, whereas the Millipore plates utilized 2θ scanning.

[0234] Details of standard screening data collection methods are provided below. Angle range: 2.5 to 32.0° 2θ Step size: 0.0130°2θ Acquisition time: 12.75 seconds / step (total acquisition time: 2.07 minutes)

[0235] nuclear magnetic resonance (NMR) A Bruker 400MHz instrument equipped with an autosampler and controlled by a DRX400 console 1 H NMR spectra were collected. Samples were prepared in DMSO-d6 solvent unless otherwise stated. The automated experiments were performed using standard experimental equipment provided by Bruker ( 1 H) were acquired using the ICON-NMR configuration within Topspin software. Offline analysis was performed using an ACD Spectrus Processor.

[0236] Differential scanning calorimetry (DSC) TA Instruments Q2000: DSC data were collected on a TA Instruments Q2000 equipped with a 50-position autosampler. Typically, 0.5–3 mg of each sample was heated from 25°C to 260°C at 10°C / min in a pinhole-open aluminum pan. A dry nitrogen purge at 50 ml / min was maintained over the sample. Temperature-modulated DSC was performed using a base heating rate of 2°C / min and temperature modulation parameters of ±0.636°C (amplitude) every 60 seconds (cycle). The instrument control software was Advantage for Q Series and Thermal Advantage, and data were analyzed using Universal Analysis or TRIOS.

[0237] Thermogravimetric analysis (TGA) TA Instruments Q500: TGA data were collected on a TA Instruments Q500 TGA equipped with a 16-position autosampler. Typically, 5–10 mg of each sample was placed in a pre-tared aluminum DSC pan and heated from ambient to 350°C at 10°C / min. A 60 ml / min nitrogen purge was maintained over the sample. The instrument control software was Advantage for Q Series and Thermal Advantage, and data were analyzed using Universal Analysis or TRIOS.

[0238] Polarized Light Microscopy (PLM) Leica LM / DM Polarized Light Microscope: Samples were analyzed with a Leica LM / DM Polarized Light Microscope equipped with a digital video camera for image capture. A small amount of each sample was placed on a glass slide with or without immersion oil and covered with a coverslip. Samples were viewed under appropriate magnification and with partially polarized light in combination with a λ false color filter. Images were captured using StudioCapture or Image ProPlus software.

[0239] Scanning Electron Microscopy (SEM) Data were collected on a Phenom Pro scanning electron microscope. A small sample was mounted on an aluminum stub using conductive double-sided adhesive tape. A thin layer of gold was applied using a sputter coater (20 mA, 120 seconds).

[0240] Gravimetric Vapor Sorption (GVS) Sorption isotherms were obtained using an SMS DVS Intrinsic moisture sorption analyzer controlled by DVS Intrinsic Control software. Sample temperature was maintained at 25°C by the instrument control. Humidity was controlled by mixing dry and humid nitrogen streams at a total flow rate of 200 ml / min. Relative humidity was measured by a calibrated Rotronic probe (dynamic range 1.0-100% RH) placed near the sample. Sample weight change (mass relaxation) as a function of % RH was continuously monitored by a microbalance (accuracy ±0.005 mg).

[0241] Typically, 5-30 mg of sample was placed under ambient conditions in a tared stainless steel mesh basket. Samples were loaded and removed at 40% RH and 25°C (typical room conditions). Moisture sorption isotherms were performed as outlined below (two scans per complete cycle). Standard isotherms were performed at 10% RH intervals at 25°C over the range of 0-90% RH. Typically, duplicate cycles (four scans) were performed. Data analysis was performed in Microsoft Excel using the DVS Analysis Suite. TIFF2025533089000007.tif50128

[0242] Samples were withdrawn after completion of the isotherm and reanalyzed by XRPD.

[0243] Chemical purity determination by high performance liquid chromatography (HPLC) Purity analysis was performed on an Agilent HP1100 / Infinity II 1260 series system equipped with a diode array detector and using OpenLAB software. Full details of the method are provided below. HPLC Method No. 1 TIFF2025533089000008.tif79144 HPLC Method No. 2 TIFF2025533089000009.tif94144

[0244] Unless otherwise stated within the data tables, all HPLC purity data reported was run using HPLC Method No. 2.

[0245] Single Crystal X-ray Diffraction (SCXRD) Data were collected on a Rigaku Oxford Diffraction XtaLAB Synergy-S diffractometer equipped with a dualflex source (Cu at Zero), a HyPix-6000HE detector, and an Oxford Cryosystems Cobra cooling device. Data were collected using Cu Kα radiation as described in the experimental table. Structures were solved and refined using the Shelx suite of programs, and OLEX was used as the interface for viewing structures and generating diagrams. Unless otherwise stated, hydrogen atoms attached to carbon were geometrically positioned to allow for their refinement using riding isotropic displacement parameters. Reference diffractograms for the crystal structures were generated using Mercury.

[0246] Example 1. Exemplary Preparation of Form 1 Compound A was dissolved in IPA (8.6x) and the temperature was raised to 50°C. Seeds (0.01x) were added to the reaction at 40°C. The reaction was kept at 40°C for 2 hours, then at 30°C for 2 hours. n-Heptane was slowly added (21x) and the mixture was stirred at 30°C for an additional 9 hours. The reaction was then cooled (5°C) and filtered. The cake was washed with n-heptane to give Form 1 (90% yield).

[0247] To investigate its solid-state morphology and chemical properties, Form 1 was characterized using a wide range of techniques (Figures 1-6B). A summary of the results is provided below.

[0248] [Table A]

[0249] Form 1 is anhydrous and thermally stable, as shown by thermal analysis. TGA showed no weight loss before decomposition, which began approximately at 220 °C, and DSC showed a melting endotherm beginning at 128.7 °C. Form 1 is non-hygroscopic; GVS showed a <0.1% increase from 40 to 90% RH and no hysteresis, remaining as Form 1. The sample was 99.4% pure by HPLC, and ion chromatography showed no residual cations or anions in the sample. The particles in the supplied batch had a needle-like morphology of various sizes, averaging approximately 150 μm. A Raman spectrum showing multiple signals was collected as a reference. Scanning IC showed no traces of cations or anions.

[0250] Example 2. Exemplary Preparation of Form 2 Form 1 (500 mg) was dissolved in 30 ml of 2-methyl-1-propanol at 5° C. Heptane (30 ml) was added and stirred for 10 minutes, and additional heptane (30 ml) was added and stirred overnight to give a white precipitate. The suspension was filtered under vacuum and dried for 30 minutes. XRPD analysis showed this to be Form 1. The mother liquor was concentrated by evaporation, seeded with Form 2, and then evaporated to dryness. Yield: 63.9%.

[0251] Form 2 was characterized using a wide range of techniques to investigate its solid-state morphology and chemical properties (Figures 7-11B). A summary of the results is provided below. Tables B and C show the characterization results for two batches of Form 2.

[0252] [Table B]

[0253] Analysis showed crystalline Form 2 by XRPD and high purity (99.2%) by HPLC. 1 H-NMR analysis was consistent with the expected structure, and thermal analysis showed no weight loss and a sharp endothermic onset at approximately 129.3°C (89 J / g) prior to decomposition by TGA. Form 2 was found to be stable upon elevated storage at 25°C / 97% RH and 40°C / 75% RH for up to one week.

[0254] [Table C]

[0255] Analysis by XRPD showed Form 2, 1 H-NMR was consistent with the expected structure. Thermal analysis showed no weight loss before decomposition beginning at approximately 190 °C, and DSC showed no thermal events before a large, sharp endotherm with an onset temperature of approximately 128.4 °C (89.4 °J / g). Microscopy showed the particles to be 50-75 μm needles. Form 2 was found by GVS to be non-hygroscopic and hysteresis-free, and remained as Form 2 by XRPD after the GVS experiment. The solid form was also found to be stable under elevated conditions.

[0256] Example 3. Solubility studies of solvents and morphic forms Using Form 2 as the starting material, the solubility of Form 1 was measured in several single solvents. The results showed that Form 2 was converted to Form 1 after slurrying at 20-25 °C in all selected solvents except water. Form 1 exhibited good solubility in MeOH, acetone, MEK, EtOAc, and IPAc, moderate solubility in EtOH and IPA, and poor solubility in n-heptane and water. Therefore, MeOH, acetone, MEK, EtOAc, and IPAc were selected for further chemical stability evaluation before starting solubility studies using antisolvents.

[0257] [Table D]

[0258] The solubility of Form 1 was further measured in the IPAc / heptane system using various ratios from 0 to 50° C. The solubility data indicated that this solvent system is a viable design for cryo- and anti-solvent crystallization.

[0259] [Table E]

[0260] Example 4. Chemical stability evaluation of morphic forms The chemical stability of this compound was evaluated at different temperatures in MeOH, acetone, MEK, EtOAc, and IPAc. The table below shows that the compound was chemically stable in IPAc at 50°C for 24 hours. However, after stirring for 23 hours, significant decomposition was observed in MeOH and MEK, and slight decomposition was observed in acetone and EtOAc.

[0261] [Table F]

[0262] Example 5. Crystallization studies of morphic forms Based on the solubility data, a crystallization process in IPAc / n-heptane was carried out. One batch experiment was performed using 8 volumes of IPAc for dissolution at 50°C. Then, 2 volumes of heptane were added at 50°C to a 4 / 1 ratio to create supersaturation. After adding 1% seeds and aging for 3 hours, 22 volumes of heptane were added to the system at 50°C over 8 hours. The suspension was then cooled to 0-5°C over 6 hours. This process yielded the correct morphology with good purity, acceptable mother liquor loss, and little residual solvent. However, some solids were observed to stick to the wall, which could result in a lower solid yield. This may be due to solvent evaporation, which leads to precipitation of solids on the wall when adding the antisolvent at high temperatures.

[0263] To avoid solid sticking, another batch crystallization experiment was performed at a lower temperature. After dissolving in 8 volumes of IPAc at 50°C, the solution was cooled to 40°C for seeding. The contents were then further cooled to 30°C for the addition of antisolvent. The reactor was clean and there was no solid sticking phenomenon. This optimized process consistently produced good results.

[0264] A 20 g scale-up experiment was carried out following the same process. Ultimately, the scale-up experiment resulted in a 96.5% solid yield, correct morphology, and several hundred ppm of residual solvent. The results indicated that the process was successfully scaled up.

[0265] [Table G]

[0266] Example 6. Drying stability test of morphic forms Drying stability was evaluated under vacuum at 50°C for a total of 70 hours, and the results showed no decomposition or morphological changes during drying. Compound A (Form 1) has been demonstrated to be chemically and physically stable at elevated temperatures.

[0267] [Table I]

[0268] equivalent The details of one or more aspects of the present disclosure are set forth in the accompanying description above. Although any methods and materials similar or equivalent to those described herein can be used in practicing or testing the present disclosure, preferred methods and materials are currently described. Other features, goals, and advantages of the present disclosure will be apparent from the description and claims. In this specification and the appended claims, the singular form "a," "an," or "the" can include plural referents unless the context clearly dictates otherwise. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs. All patents and publications cited herein are incorporated by reference.

[0269] The foregoing description has been presented for purposes of illustration only, and it is not intended to limit the disclosure to the precise form disclosed, but rather to be limited by the claims appended hereto.

Claims

1. Compound A: Morphic form of.

2. 2. The morphic form of claim 1, which is a crystalline form of Compound A.

3. 2. The morphic form of any one of the preceding claims, which is Form 1 of Compound A.

4. The morphic form according to any one of the preceding claims, characterized by at least one of the following features: (a) XRPD pattern containing signals at 8.7 ± 0.5, 15.3 ± 0.5, and 15.9 ± 0.5°2θ using Cu Kα radiation; (b) XRPD pattern containing signals at 7.9 ± 0.5, 8.7 ± 0.5, 15.3 ± 0.5, and 15.9 ± 0.5°2θ using Cu Kα radiation; (c) XRPD pattern containing signals at 7.9 ± 0.5, 8.7 ± 0.5, 15.3 ± 0.5, 15.9 ± 0.5, and 24.4 ± 0.5°2θ using Cu Kα radiation; (d) XRPD pattern containing signals at 7.9 ± 0.5, 8.7 ± 0.5, 15.3 ± 0.5, 15.9 ± 0.5, 22.3 ± 0.5, and 24.4 ± 0.5° 2θ using Cu Kα radiation; (e) an XRPD pattern containing signals at 7.9±0.5, 8.7±0.5, 15.3±0.5, 15.9±0.5, 22.3±0.5, 23.9±0.5, and 24.4±0.5 degrees 2θ using Cu Kα radiation; or (f) XRPD pattern containing signals at 5.9 ± 0.5, 7.9 ± 0.5, 8.7 ± 0.5, 15.3 ± 0.5, 15.9 ± 0.5, 22.3 ± 0.5, 23.9 ± 0.5, and 24.4 ± 0.5 °2θ using Cu Kα radiation.

5. 10. The morphic form of any one of the preceding claims, characterized by an XRPD pattern comprising one or more signals set forth in Table 1.

6. 3. The morphic form of any one of the preceding claims, characterized by an XRPD pattern substantially similar to that depicted in Figure 2.

7. 3. The morphic form of claim 1 or claim 2, which is Form 2 of Compound A.

8. The morphic form according to any one of claims 1 to 2 and 7, characterized by at least one of the following features: (a) XRPD pattern containing signals at 7.6 ± 0.5, 9.4 ± 0.5, and 15.9 ± 0.5°2θ using Cu Kα radiation; (b) XRPD pattern containing signals at 7.6 ± 0.5, 9.4 ± 0.5, 15.2 ± 0.5, and 15.9 ± 0.5°2θ using Cu Kα radiation; (c) XRPD pattern containing signals at 6.0 ± 0.5, 7.6 ± 0.5, 9.4 ± 0.5, 15.2 ± 0.5, and 15.9 ± 0.5°2θ using Cu Kα radiation; (d) XRPD pattern containing signals at 6.0 ± 0.5, 7.6 ± 0.5, 9.4 ± 0.5, 15.2 ± 0.5, 15.9 ± 0.5, and 21.5 ± 0.5 °2θ using Cu Kα radiation; (e) an XRPD pattern containing signals at 6.0±0.5, 7.6±0.5, 9.4±0.5, 15.2±0.5, 15.9±0.5, 21.5±0.5, and 23.9±0.5 degrees 2θ using Cu Kα radiation; and (f) XRPD pattern containing signals at 6.0 ± 0.5, 7.6 ± 0.5, 9.4 ± 0.5, 15.2 ± 0.5, 15.9 ± 0.5, 21.2 ± 0.5, 21.5 ± 0.5, and 23.9 ± 0.5 °2θ using Cu Kα radiation.

9. 9. The morphic form of any one of claims 1-2 and 7-8, characterized by an XRPD pattern comprising one or more signals set out in Table 2.

10. 10. The morphic form of any one of claims 1-2 and 7-9, characterized by an XRPD pattern substantially similar to that depicted in Figure 8.

11. 2. The morphic form of any preceding claim, having a purity of about 80% or more, about 85% or more, about 90% or more, about 91% or more, about 92% or more, about 93% or more, about 94% or more, about 95% or more, about 96% or more, about 97% or more, about 98% or more, about 99% or more, about 99.1% or more, about 99.2% or more, about 99.3% or more, about 99.4% or more, about 99.5% or more, about 99.6% or more, about 99.7% or more, about 99.8% or more, or about 99.9% or more.

12. 9. The morphic form of any one of the preceding claims, having a morphic purity of about 80% or more, about 85% or more, about 90% or more, about 91% or more, about 92% or more, about 93% or more, about 94% or more, about 95% or more, about 96% or more, about 97% or more, about 98% or more, about 99% or more, about 99.1% or more, about 99.2% or more, about 99.3% or more, about 99.4% or more, about 99.5% or more, about 99.6% or more, about 99.7% or more, about 99.8% or more, or about 99.9% or more.

13. 10. The morphic form of any one of the preceding claims, exhibiting less than about 10%, less than about 9%, less than about 8%, less than about 7%, less than about 6%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, less than about 1%, less than about 0.9%, less than about 0.8%, less than about 0.7%, less than about 0.6%, less than about 0.5%, less than about 0.4%, less than about 0.3%, less than about 0.2%, or less than about 0.1% impurities over 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, or 4 months at 25°C and 97% relative humidity (RH).

14. 10. The morphic form of any one of the preceding claims, exhibiting less than about 10%, less than about 9%, less than about 8%, less than about 7%, less than about 6%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, less than about 1%, less than about 0.9%, less than about 0.8%, less than about 0.7%, less than about 0.6%, less than about 0.5%, less than about 0.4%, less than about 0.3%, less than about 0.2%, or less than about 0.1% impurities over 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, or 4 months at 40°C and 75% relative humidity (RH).

15. A method for preparing the morphic form of compound A according to any one of the preceding claims.

16. 10. A pharmaceutical composition comprising a morphic form of compound A according to any one of the preceding claims and one or more pharmaceutically acceptable carriers or excipients.

17. 19. A method for preventing or treating a disease or disorder in a subject, the method comprising administering to said subject a morphic form of compound A according to any one of claims 1 to 14 or a pharmaceutical composition according to claim 16.

18. A morphic form of compound A according to any one of claims 1 to 14 or a pharmaceutical composition according to claim 16 for use in preventing or treating a disease or disorder in a subject.

19. A method for inhibiting inflammasome activity in a subject, comprising contacting a cell with a morphic form of compound A described in any one of claims 1 to 14 or a pharmaceutical composition described in claim 16.

20. 20. The method, morphic form, pharmaceutical composition or use of any one of claims 17 to 19, wherein the subject is a human.

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