Replacement 3,4-dihydroisoquinolin-1(2H)-one derivatives and related uses

Abstract

The present disclosure relates to compounds of formula (I) and their pharmaceutically acceptable salts, pharmaceutical compositions, methods of use, and methods for their preparation. The compounds disclosed herein are useful for inhibiting the maturation of cytokines of the IL-1 family by inhibiting the inflammasome and can be used in the treatment of disorders associated with inflammasome activity, such as inflammatory, autoinflammatory, and autoimmune diseases, as well as cancer. TIFF2025522354000387.tif30128

Description

Technical Field

[0001] Related Applications This application claims the benefit and priority of U.S. Provisional Patent Application No. 63 / 349,762, filed on June 7, 2022, which is incorporated herein by reference in its entirety.

Background Art

[0002] Background Autoimmune diseases are associated with the overproduction of inflammatory mediators. One of these is interleukin-1 (IL-1), which is produced by activated macrophages, monocytes, fibroblasts, dendritic cells, and other components of the innate immune system. IL-1 is involved in a variety of cellular activities, including cell proliferation, differentiation, and apoptosis (Masters, S. L., et. al., Annu. Rev. Immunol. 2009. 27:621-68 (Non-Patent Document 1)).

[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. Multiple NLR family members are associated with inflammasome formation.

[0004] Although the activation of inflammasomes appears to have evolved as an important component of host immunity against pathogens, the NLRP3 inflammasome is characterized by its ability to be activated in response to endogenous sterile danger signals. A number of such sterile signals have been elucidated, and their formation is associated with specific pathological conditions. For example, uric acid crystals found in patients with gout are effective triggers for the activation of NLRP3. Similarly, cholesterol crystals found in patients with atherosclerosis can also promote the activation of NLRP3. The recognition of the role of sterile danger signals as NLRP3 activators has led to the association of IL-1 and IL-18 with a wide range of pathophysiological symptoms including metabolic, physiological, inflammatory, hematological, and immunological disorders.

[0005] The disclosure arises from the need to provide further compounds for the specific modulation of NLRP3-dependent cellular processes. In particular, compounds with improved physicochemical, pharmacological, and pharmaceutical properties compared to existing compounds are desired.

Prior Art Documents

Non-Patent Documents

[0006]

Non-Patent Document 1

Summary of the Invention

[0007] Summary In some aspects, the disclosure relates to a compound of formula (I), or a prodrug, solvate, or pharmaceutically acceptable salt thereof, TIFF2025522354000002.tif30128wherein each TIFF2025522354000003.tif7128is independently, to the extent permitted by valence, a single bond or a double bond; A2 is, to the extent permitted by valence, CR 2 , N, NR2a is O, or S; A3 is CR as long as the valence permits, 2 N, NR, 2a O, or S; A4 is CR as long as the valence permits, 2 N, NR, 2a O, or S; A5 is C or N as long as the valence permits, wherein at least one of A2, A3, A4, or A5 is N, NR, 2a O, or S; R 1 is H, -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C3-C 12 cycloalkyl, where -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C3-C 12 cycloalkyl may be substituted with one or more R 1S ; each R 1S is independently halogen, cyano, -OH, or C1-C6 alkyl; R 1a is H or C1-C6 alkyl, or R 1 and R 1a together with the atom to which they are attached form C2-C6 alkenyl, C3-C7 cycloalkyl, or 3-7 membered heterocycloalkyl, or R 1a and R 3 together with the atom to which they are attached form C3-C 12 cycloalkyl or 3-12 membered heterocycloalkyl; each R 2 is independently H, halogen, cyano, -OH, -NH2, -NO2, -C(=O)NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C3-C 12Cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C 10 Aryl, or 5- to 10-membered heteroaryl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C3-C 12 Cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C 10 Aryl, or 5- to 10-membered heteroaryl may be substituted with one or more R 2S and optionally, or two Rs 2 together with the atoms to which they are attached form a C3-C 12 Cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C 10 Aryl, or 5- to 10-membered heteroaryl, wherein C3-C 12 Cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C 10 Aryl, or 5- to 10-membered heteroaryl may be substituted with one or more R 2S and optionally; Each R 2S is independently halogen, -OH, C1-C6 alkyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, or C3-C 12 cycloalkyl; R 3 is H, -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C3-C 12 cycloalkyl, wherein -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C3-C 12 cycloalkyl may be substituted with one or more R 3S and optionally, R 1 and R 3 together with the atoms to which they are attached form a C3-C 12 cycloalkyl or 3- to 12-membered heterocycloalkyl; Each R 3Sis independently halogen, cyano, -OH, or C1-C6 alkyl; Each R 2a is independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, -(CH2) 0~3 -(C3-C 12 cycloalkyl), or -(CH2) 0~3 -(3- to 12-membered heterocycloalkyl); Each R a is independently H or C1-C6 alkyl; or two Rs a together with the atom to which they are attached form C2-C6 alkenyl or C3-C 12 cycloalkyl; R N1 is H or C1-C6 alkyl; R N2 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O-(C1-C6 alkyl), -O-(C2-C6 alkenyl), -O-(C2-C6 alkynyl), -NH-(C1-C6 alkyl), -NH-(C2-C6 alkenyl), -NH-(C2-C6 alkynyl), C3-C 12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl, -(C1-C6 alkyl)-(C3-C 12 cycloalkyl), -(C1-C6 alkyl)-(3- to 12-membered heterocycloalkyl), -(C1-C6 alkyl)-(C6-C 10 aryl), or -(C1-C6 alkyl)-(5- to 10-membered heteroaryl); where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O-(C1-C6 alkyl), -O-(C2-C6 alkenyl), -O-(C2-C6 alkynyl), -NH-(C1-C6 alkyl), -NH-(C2-C6 alkenyl), -NH-(C2-C6 alkynyl), C3-C 12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl, -(C1-C6 alkyl)-(C3-C 12cycloalkyl), -(C1-C6 alkyl)-(3-12 membered heterocycloalkyl), -(C1-C6 alkyl)-(C6-C 10 aryl), or -(C1-C6 alkyl)-(5-10 membered heteroaryl) may be substituted with one or more R N2a ; Each R N2a is independently oxo, halogen, cyano, -OH, -NH2, -NO2, -C(=O)H, -C(=O)OH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -C(=O)(C1-C6 alkyl), -C(=O)O(C1-C6 alkyl), -NHC(=O)O(C1-C6 alkyl), -S(=O)2(C1-C6 alkyl), -S(=O)2N(C1-C6 alkyl)2, C3-C 12 cycloalkyl, 3-12 membered heterocycloalkyl, C6-C 10 aryl, 5-10 membered heteroaryl, -(C1-C6 alkyl)-(C3-C 12 cycloalkyl), -(C1-C6 alkyl)-(3-12 membered heterocycloalkyl), -(C1-C6 alkyl)-(C6-C 10 aryl), or -(C1-C6 alkyl)-(5-10 membered heteroaryl); wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -C(=O)(C1-C6 alkyl), -C(=O)O(C1-C6 alkyl), -NHC(=O)O(C1-C6 alkyl), -S(=O)2(C1-C6 alkyl), -S(=O)2N(C1-C6 alkyl)2, C3-C 12 cycloalkyl, 3-12 membered heterocycloalkyl, C6-C 10 aryl, 5-10 membered heteroaryl, -(C1-C6 alkyl)-(C3-C 12 cycloalkyl), -(C1-C6 alkyl)-(3-12 membered heterocycloalkyl), -(C1-C6 alkyl)-(C6-C 10-aryl), or -(C1-C6 alkyl)-(5-10 membered heteroaryl), may be substituted by one or more Rs N2ab and; each R N2ab is independently oxo, halogen, cyano, -OH, -NH2, -C(=O)H, -C(=O)OH, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -C(=O)(C1-C6 alkyl), -C(=O)O(C1-C6 alkyl), -NHC(=O)O(C1-C6 alkyl), -S(=O)2(C1-C6 alkyl), or -S(=O)2N(C1-C6 alkyl)2; or R N1 and R N2 together with the atom to which they are attached form a 3-12 membered heterocycloalkyl which may be substituted by one or more Rs b ; each R b is independently oxo, halogen, cyano, -OH, -NH2, -C(=O)H, -C(=O)OH, C1-C6 alkyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -C(=O)(C1-C6 alkyl), -C(=O)O(C1-C6 alkyl), -NHC(=O)O(C1-C6 alkyl), -S(=O)2(C1-C6 alkyl), or -S(=O)2N(C1-C6 alkyl)2, where C1-C6 alkyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -C(=O)(C1-C6 alkyl), -C(=O)O(C1-C6 alkyl), -NHC(=O)O(C1-C6 alkyl), -S(=O)2(C1-C6 alkyl), or -S(=O)2N(C1-C6 alkyl)2 may be substituted by one or more Rs b1 and; each R b1 is independently oxo, halogen, cyano, -OH, or -NH2.

[0008] In some aspects, the present disclosure provides compounds that can be obtained or have been obtained by a method for preparing the compounds described herein.

[0009] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound described herein and one or more pharmaceutically acceptable carriers or excipients.

[0010] In some aspects, the present disclosure provides intermediates described herein that are suitable for use in a method for preparing the compounds described herein.

[0011] In some aspects, the present disclosure provides a method of inhibiting (e.g., in vitro or in vivo) inflammasome (e.g., NLRP3 inflammasome) activity, the method comprising contacting a cell with an effective amount of a compound of the present disclosure.

[0012] In some aspects, the present disclosure provides a method of treating or preventing a disease or disorder disclosed herein in a subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound of the present disclosure or a pharmaceutical composition of the present disclosure.

[0013] In some aspects, the present disclosure provides a compound of the present disclosure for use in inhibiting (e.g., in vitro or in vivo) inflammasome (e.g., NLRP3 inflammasome) activity.

[0014] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of a disease or disorder disclosed herein.

[0015] In some aspects, the present disclosure provides the use of a compound of the present disclosure in the manufacture of a medicament for inhibiting (e.g., in vitro or in vivo) inflammasome (e.g., NLRP3 inflammasome) activity.

[0016] In some aspects, the disclosure provides for the use of the compounds of the disclosure in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0017] In some aspects, the disclosure provides methods for preparing the compounds of the disclosure.

[0018] In some aspects, the disclosure provides methods for preparing a compound, comprising one or more steps described herein.

[0019] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In this specification, unless the context clearly dictates otherwise, the singular form also includes the plural form. Methods and materials similar or equivalent to those described herein can be used in the practice or testing of the disclosure, but the preferred methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated herein by reference. The references cited herein are not admitted to be prior art with respect to the claimed invention. In case of conflict, this specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting. In case of conflict between the chemical structure and the name of the compounds disclosed herein, the chemical structure will control.

[0020] Other features and advantages of the disclosure will become apparent from the following detailed description and the claims.

DETAILED DESCRIPTION

[0021] Detailed Description Autoimmune diseases are associated with the overproduction of inflammatory mediators. One of these is interleukin-1 (IL-1), which is produced by activated macrophages, monocytes, fibroblasts, dendritic cells, and other components of the innate immune system, and is involved in various cellular activities including cell proliferation, differentiation, and apoptosis (Masters, S. L. et. al., Annu. Rev. Immunol. 2009. 27:621-68).

[0022] Autoimmune diseases are associated with the overproduction of inflammatory mediators. One of these is interleukin-1 (IL-1), which is produced by activated macrophages, monocytes, fibroblasts, dendritic cells, and other components of the innate immune system, and is involved in various cellular activities including cell proliferation, differentiation, and apoptosis (Masters, S. L., et. al. Annu. Rev. Immunol. 2009. 27:621-68).

[0023] Cytokines from the IL-1 family are highly active and are mainly associated with acute and chronic inflammation as important mediators of inflammation (Sims, J. et al., Nature Reviews Immunology 10, 89-102 (February 2010)). The overproduction of IL-1 is thought to be a mediator of some autoimmune and autoinflammatory diseases. Autoinflammatory diseases are characterized by recurrent and unprovoked inflammation in the absence of autoantibodies, infection, and antigen-specific T lymphocytes.

[0024] Inflammatory cytokines of the IL-1 superfamily include IL-1α, IL-1β, IL-18, and IL-36α, β, λ, and are produced in response to pathogens and other cellular stressors as part of the host innate immune response. Unlike many other secreted cytokines that are processed and released via the standard cellular secretory organs consisting of the endoplasmic reticulum and Golgi apparatus, IL-1 family members lack the leader sequence required for entry into the endoplasmic reticulum and thus remain intracellular after translation. Furthermore, IL-1β, IL-18, and IL-36α, β, λ are synthesized as pro-cytokines that require proteolytic activation to become optimal ligands for binding to cognate receptors on target cells.

[0025] In the case of IL-1α, IL-1β, and IL-18, it is now recognized that a multimeric protein complex known as the inflammasome is responsible for the activation of the pro-forms of IL-1β and IL-18 and the extracellular release of these cytokines. The inflammasome complex typically consists of a sensor molecule such as an NLR (nucleotide oligomerization domain (NOD)-like receptor), an adapter molecule ASC (CARD (caspase recruitment domain)-containing apoptosis-related speck-like protein), and pro-caspase-1. In response to various "danger signals" including pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs), the subunits of the inflammasome oligomerize to form a supramolecular structure within the cell. 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 or exogenous sterile triggers including monosodium urate crystals, silica, alum, asbestos, fatty acids, ceramides, cholesterol crystals, and aggregates of beta-amyloid peptides. The construction of the inflammasome platform promotes the autocatalytic action of pro-caspase-1, resulting in a highly active cysteine protease responsible for the activation and release of pro-IL-1β and pro-IL-18. Thus, the release of these highly inflammatory cytokines is achieved only in response to inflammasome sensors that detect and respond to specific molecular danger signals.

[0026] In humans, 22 types of 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. Multiple NLR family members, including NLRP1, NLRP3, NLRP6, NLRP7, NLRP12, and NLRC4 (IPAF), are associated with inflammasome formation.

[0027] Two other structurally distinct inflammasome structures containing a PYHIN domain (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) is another type of representative inflammasome platform associated with proIL-1β activation (Chae et al., Immunity 34, 755-768, 2011).

[0028] The construction of the inflammasome platform is required to achieve the activation and release of IL-1β and IL-18 from monocytes and macrophages, ensuring that their production is carefully carried out through a two-step process. First, the cell must encounter a priming ligand (e.g., the TLR4 receptor ligand LPS or an inflammatory cytokine such as TNFα), which leads to the transcription of NFkB-dependent NLRP3, pro-IL-1β, and pro-IL-18. The newly translated pro-cytokines remain intracellular and inactive unless the producing cell encounters a second signal that leads to the activation of the inflammasome scaffold and the maturation of procaspase-1.

[0029] In addition to proteolytic activation of pro-IL-1β and pro-IL-18, active caspase-1 also causes a form of inflammatory cell death known as pyroptosis through cleavage of gasdermin-D. Pyroptosis releases the mature forms of IL-1β and IL-18 extracellularly, along with the release of alarmin molecules such as high-mobility group box 1 protein (HMGB1), IL-33, and IL-1α (compounds that promote inflammation and activate innate and adaptive immunity).

[0030] Although inflammasome activation appears to have evolved as an important component of host immunity against pathogens, the NLRP3 inflammasome is characterized by its ability to activate in response to both endogenous and exogenous sterile danger signals. A number of such sterile signals have been elucidated, and their formation is associated with specific pathologies. For example, uric acid crystals found in patients with gout are effective triggers for NLRP3 activation. Similarly, cholesterol crystals found in patients with atherosclerosis can also promote NLRP3 activation. Recognition of the role of sterile danger signals as NLRP3 activators has implicated IL-1β and IL-18 in a wide range of pathophysiological manifestations, including metabolic, physiological, inflammatory, hematological, and immunological disorders.

[0031] The association with human diseases is best exemplified by the finding that mutations in the NLRP3 gene that result in gain of function cause a spectrum 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, the sterile mediator-induced activation of NLRP3 has been associated with a wide range of disorders, including joint degeneration (gout, rheumatoid arthritis, osteoarthritis), cardiometabolism (type 2 diabetes, atherosclerosis, hypertension), central nervous system (Alzheimer's disease, Parkinson's disease, multiple sclerosis), gastrointestinal (Crohn's disease, ulcerative colitis), lung (chronic obstructive pulmonary disease (COPD), asthma, idiopathic pulmonary fibrosis), and liver (fibrosis, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis (NASH)). Furthermore, NLRP3 activation is thought to contribute to chronic kidney disease (CKD) as it promotes nephritis.

[0032] Current treatment options for diseases in which IL-1 has been implicated as a contributing factor to pathogenesis include anakinra, an IL-1 receptor antagonist, rilonacept, an Fc-containing fusion construct of the extracellular domains of the IL-1 receptor and IL-1 receptor accessory protein, and canakinumab, an anti-IL-1β monoclonal antibody. 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.

[0033] Some small molecules have been reported to inhibit the function of the NLRP3 inflammasome. For example, glyburide is a specific inhibitor of NLRP3 activation, although at micromolar concentrations that are likely to be unattainable in vivo. Non-specific agents such as parthenolide, Bay 11-7082, and 3,4-methylenedioxy-β-nitrostyrene have been reported to attenuate NLRP3 activation, but their therapeutic utility is considered limited because they share a common structural feature consisting of an olefin activated by substitution with an electron-withdrawing group; this can lead to the undesirable formation of covalent adducts with protein-containing thiol groups. Many natural products, such as β-hydroxybutyric acid, sulforaphane, quercetin, and salvianolic acid, have also been reported to suppress the activation of NLRP3. Similarly, many effector / modulators of other molecular targets, including agonists of the G protein-coupled receptor TGR5, inhibitors of the sodium-glucose cotransporter empagliflozin, the dopamine receptor antagonist A-68930, the serotonin reuptake inhibitor fluoxetine, fenamate non-steroidal anti-inflammatory drugs, and the β-adrenergic receptor blocker nebivolol, have been reported to attenuate NLRP3 activation. The utility of these molecules as therapeutic agents for the long-term treatment of NLRP3-dependent inflammatory disorders has not yet been established.

[0034] The disclosure relates to compounds useful for the specific modulation of NLRP3-dependent cellular processes. In particular, compounds with improved physicochemical, pharmacological, and pharmaceutical properties compared to existing NLRP3 modulating compounds are desired.

[0035] The compounds of the disclosure In some aspects, the disclosure relates to compounds of formula (I), or prodrugs, solvates, or pharmaceutically acceptable salts thereof, TIFF2025522354000004.tif30128wherein each TIFF2025522354000005.tif7128is independently, to the extent permitted by valence, a single bond or a double bond; A2 is CR, as long as the valence permits, 2 , N, NR, 2a , O, or S; A3 is CR, as long as the valence permits, 2 , N, NR, 2a , O, or S; A4 is CR, as long as the valence permits, 2 , N, NR, 2a , O, or S; A5 is C or N, as long as the valence permits, wherein at least one of A2, A3, A4, or A5 is N, NR, 2a , O, or S; R 1 is H, -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C3-C 12 cycloalkyl, where -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C3-C 12 cycloalkyl may be substituted with one or more R 1S ; each R 1S is independently halogen, cyano, -OH, or C1-C6 alkyl; R 1a is H or C1-C6 alkyl, or R 1 and R 1a together with the atom to which they are attached form C2-C6 alkenyl, C3-C7 cycloalkyl, or 3-7 membered heterocycloalkyl, or R 1a and R 3 together with the atom to which they are attached form C3-C 12 cycloalkyl or 3-12 membered heterocycloalkyl; each R 2 is independently H, halogen, cyano, -OH, -NH2, -NO2, -C(=O)NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C3-C12 Cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C 10 Aryl, or 5- to 10-membered heteroaryl, where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C3-C 12 Cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C 10 Aryl, or 5- to 10-membered heteroaryl may be substituted with one or more R 2S and optionally, or two R 2 together with the atoms to which they are attached form a C3-C 12 Cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C 10 Aryl, or 5- to 10-membered heteroaryl, where C3-C 12 Cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C 10 Aryl, or 5- to 10-membered heteroaryl may be substituted with one or more R 2S and optionally; Each R 2S is independently halogen, -OH, C1-C6 alkyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, or C3-C 12 cycloalkyl; R 3 is H, -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C3-C 12 cycloalkyl, where -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C3-C 12 cycloalkyl may be substituted with one or more R 3S and optionally, or R 1 and R 3 together with the atoms to which they are attached form a C3-C 12 cycloalkyl or 3- to 12-membered heterocycloalkyl; Each R 3Sis independently halogen, cyano, -OH, or C1-C6 alkyl; Each R 2a is independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, -(CH2) 0~3 -(C3-C 12 cycloalkyl), or -(CH2) 0~3 -(3-12 membered heterocycloalkyl); Each R a is independently H or C1-C6 alkyl; or two Rs a together with the atom to which they are attached form C2-C6 alkenyl or C3-C 12 cycloalkyl; R N1 is H or C1-C6 alkyl; R N2 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O-(C1-C6 alkyl), -O-(C2-C6 alkenyl), -O-(C2-C6 alkynyl), -NH-(C1-C6 alkyl), -NH-(C2-C6 alkenyl), -NH-(C2-C6 alkynyl), C3-C 12 cycloalkyl, 3-12 membered heterocycloalkyl, C6-C 10 aryl, 5-10 membered heteroaryl, -(C1-C6 alkyl)-(C3-C 12 cycloalkyl), -(C1-C6 alkyl)-(3-12 membered heterocycloalkyl), -(C1-C6 alkyl)-(C6-C 10 aryl), or -(C1-C6 alkyl)-(5-10 membered heteroaryl); wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O-(C1-C6 alkyl), -O-(C2-C6 alkenyl), -O-(C2-C6 alkynyl), -NH-(C1-C6 alkyl), -NH-(C2-C6 alkenyl), -NH-(C2-C6 alkynyl), C3-C 12 cycloalkyl, 3-12 membered heterocycloalkyl, C6-C 10 aryl, 5-10 membered heteroaryl, -(C1-C6 alkyl)-(C3-C 12cycloalkyl), -(C1-C6 alkyl)-(3-12 membered heterocycloalkyl), -(C1-C6 alkyl)-(C6-C 10 aryl), or -(C1-C6 alkyl)-(5-10 membered heteroaryl) may be substituted with one or more R N2a ; Each R N2a is independently oxo, halogen, cyano, -OH, -NH2, -NO2, -C(=O)H, -C(=O)OH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -C(=O)(C1-C6 alkyl), -C(=O)O(C1-C6 alkyl), -NHC(=O)O(C1-C6 alkyl), -S(=O)2(C1-C6 alkyl), -S(=O)2N(C1-C6 alkyl)2, C3-C 12 cycloalkyl, 3-12 membered heterocycloalkyl, C6-C 10 aryl, 5-10 membered heteroaryl, -(C1-C6 alkyl)-(C3-C 12 cycloalkyl), -(C1-C6 alkyl)-(3-12 membered heterocycloalkyl), -(C1-C6 alkyl)-(C6-C 10 aryl), or -(C1-C6 alkyl)-(5-10 membered heteroaryl); wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -C(=O)(C1-C6 alkyl), -C(=O)O(C1-C6 alkyl), -NHC(=O)O(C1-C6 alkyl), -S(=O)2(C1-C6 alkyl), -S(=O)2N(C1-C6 alkyl)2, C3-C 12 cycloalkyl, 3-12 membered heterocycloalkyl, C6-C 10 aryl, 5-10 membered heteroaryl, -(C1-C6 alkyl)-(C3-C 12 cycloalkyl), -(C1-C6 alkyl)-(3-12 membered heterocycloalkyl), -(C1-C6 alkyl)-(C6-C 10(Aryl), or -(C1-C6 alkyl)-(5-10 membered heteroaryl) may be substituted by one or more Rs N2ab and; each R N2ab is independently oxo, halogen, cyano, -OH, -NH2, -C(=O)H, -C(=O)OH, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -C(=O)(C1-C6 alkyl), -C(=O)O(C1-C6 alkyl), -NHC(=O)O(C1-C6 alkyl), -S(=O)2(C1-C6 alkyl), or -S(=O)2N(C1-C6 alkyl)2; or R N1 and R N2 together with the atom to which they are attached form a 3-12 membered heterocycloalkyl which may be substituted by one or more Rs b ; each R b is independently oxo, halogen, cyano, -OH, -NH2, -C(=O)H, -C(=O)OH, C1-C6 alkyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -C(=O)(C1-C6 alkyl), -C(=O)O(C1-C6 alkyl), -NHC(=O)O(C1-C6 alkyl), -S(=O)2(C1-C6 alkyl), or -S(=O)2N(C1-C6 alkyl)2, where C1-C6 alkyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -C(=O)(C1-C6 alkyl), -C(=O)O(C1-C6 alkyl), -NHC(=O)O(C1-C6 alkyl), -S(=O)2(C1-C6 alkyl), or -S(=O)2N(C1-C6 alkyl)2 may be substituted by one or more Rs b1 and; each R b1 is independently oxo, halogen, cyano, -OH, or -NH2.

[0036] For the compound of formula (I), A2, A3, A4, A5, R 1 , R 1S , R2 , R 2S , R 3 , R 3S , n, R a , R 2a , R N1 , R N2 , R N2a , R N2ab , R b , and R b1 can each, when applicable, be selected from the groups described herein, A2, A3, A4, A5, R 1 , R 1S , R 2 , R 2S , R 3 , R 3S , n, R a , R 2a , R N1 , R N2 , R N2a , R N2ab , R b , and R b1 Any group described herein for any one of or can, when applicable, be combined with any group described herein for any one or more of the remaining A2, A3, A4, A5, R 1 , R 1S , R 2 , R 2S , R 3 , R 3S , n, R a , R 2a , R N1 , R N2 , R N2a , R N2ab , R b , and R b1 It is understood that it can be combined with any group described herein for one or more of

[0037] Variable elements A2, A3, A4, and A5 In some embodiments, each TIFF2025522354000006.tif7128 is, independently, a single bond or a double bond to the extent permitted by its valence.

[0038] In some embodiments, TIFF2025522354000007.tif7128 is a single bond. In some embodiments, TIFF2025522354000008.tif7128 is a double bond.

[0039] In some embodiments, A2 is, as valence permits, CR 2 , N, NR 2a , O, or S.

[0040] In some embodiments, A2 is, as valence permits, CR 2 , NR 2a , or S.

[0041] In some embodiments, A2 is CR 2 . In some embodiments, A2 is N. In some embodiments, A2 is NR 2a . In some embodiments, A2 is O. In some embodiments, A2 is S.

[0042] In some embodiments, A3 is, as valence permits, CR 2 , N, NR 2a , O, or S. In some embodiments, A3 is, as valence permits, CR 2 or NR 2a .

[0043] In some embodiments, A3 is CR 2 . In some embodiments, A3 is N. In some embodiments, A3 is NR 2a . In some embodiments, A3 is O. In some embodiments, A3 is S.

[0044] In some embodiments, A4 is, as valence permits, CR 2 , N, NR 2a , O, or S.

[0045] In some embodiments, A4 is, as valence permits, CR 2 , N, or O.

[0046] In some embodiments, A4 is CR 2 In some embodiments, A4 is N. In some embodiments, A4 is NR 2a In some embodiments, A4 is O. In some embodiments, A4 is S.

[0047] In some embodiments, A5 is C or N, as valence permits.

[0048] In some embodiments, A5 is C. In some embodiments, A5 is N.

[0049] In some embodiments, at least one of A2, A3, A4, or A5 is N, NR 2a , O, or S.

[0050] In some embodiments, at least one of A2, A3, A4, or A5 is N. In some embodiments, at least one of A2, A3, A4, or A5 is NR 2a In some embodiments, at least one of A2, A3, A4, or A5 is O. In some embodiments, at least one of A2, A3, A4, or A5 is S.

[0051] In some embodiments, A2 is CR 2 and A3 is CR 2 and A4 is CR 2 and A5 is N.

[0052] In some embodiments, A2 is CR 2 and A3 is CR 2 and A4 is CR 2 and A5 is N, where the CRs of A3 and A4 2 are linked to form a thienyl or thiazolyl ring.

[0053] In some embodiments, A2 is CR 2 and A3 is NR 2awhere A4 is N and A5 is C.

[0054] In some embodiments, A2 is CR 2 where A3 is CR 2 where A4 is N and A5 is N.

[0055] In some embodiments, A2 is S and A3 is CR 2 where A4 is N and A5 is C.

[0056] In some embodiments, A2 is S and A3 is CR 2 where A4 is CR 2 where A5 is C.

[0057] In some embodiments, A2 is CR 2 where A3 is CR 2 where A4 is O and A5 is C.

[0058] In some embodiments, A2 is NR 2a where A3 is CR 2 where A4 is CR 2 where A5 is C.

[0059] In some embodiments, A2 is NR 2a where A3 is CR 2 where A4 is N and A5 is C.

[0060] In some embodiments, A2 is CR 2 where A3 is CR 2 where A4 is S and A5 is C.

[0061] In some embodiments, A2 is CR 2 where A3 is CR 2 where A4 is CR 2 where A5 is N, and optionally here, the CR of A3 and A4 2 are connected to form a thienyl ring or a thiazolyl ring; or A2 is CR2 where A3 is NR 2a where A4 is N and A5 is C; or A2 is CR 2 where A3 is CR 2 where A4 is N and A5 is N; or A2 is S and A3 is CR 2 where A4 is N and A5 is C; or A2 is S and A3 is CR 2 where A4 is CR 2 where A5 is C; or A2 is CR 2 where A3 is CR 2 where A4 is O and A5 is C; or A2 is NR 2a where A3 is CR 2 where A4 is CR 2 where A5 is C, where R 2 and R 2a are as defined herein.

[0062] In some embodiments, A2 is CR 2 where A3 is CR 2 where A4 is CR 2 where A5 is N, and optionally, the CR of A3 and A4 2 are linked to form a thienyl or thiazolyl ring; or A2 is CR 2 where A3 is NR 2a where A4 is N and A5 is C; or A2 is CR 2 where A3 is CR 2 where A4 is N and A5 is N; or A2 is S and A3 is CR 2 where A4 is N and A5 is C; or A2 is S and A3 is CR 2 where A4 is CR 2 where A5 is C; or A2 is CR 2 and A3 is CR 2 and A4 is O and A5 is C; or A2 is NR 2a and A3 is CR 2 and A4 is CR 2 and A5 is C; or A2 is NR 2a and A3 is CR 2 and A4 is N and A5 is C; or A2 is CR 2 and A3 is CR 2 and A4 is S and A5 is C, wherein R 2 and R 2a are as defined herein.

[0063] The variable elements R 1 , R 1S , and R 1a In some embodiments, R 1 is H.

[0064] In some embodiments, R 1 is -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C3-C 12 cycloalkyl, wherein -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C3-C 12 cycloalkyl may be substituted with one or more R 1S .

[0065] In some embodiments, R 1 is optionally substituted with one or more R 1S -N(C1-C6 alkyl)2.

[0066] In some embodiments, R 1 is -N(C1-C6 alkyl)2.

[0067] In some embodiments, R1 is -N(CH3)2.

[0068] In some embodiments, R 1 is C1 - C6 alkyl optionally substituted with one or more R 1S .

[0069] In some embodiments, R 1 is C1 - C6 alkyl substituted with one or more R 1S .

[0070] In some embodiments, R 1 is propyl (e.g., isopropyl).

[0071] In some embodiments, R 1 is propyl (e.g., isopropyl) substituted with one or more R 1S .

[0072] In some embodiments, R 1 is C2 - C6 alkenyl optionally substituted with one or more R 1S .

[0073] In some embodiments, R 1 is C2 - C6 alkenyl substituted with one or more R 1S .

[0074] In some embodiments, R 1 is propenyl (e.g., isopropenyl).

[0075] In some embodiments, R 1 is propenyl (e.g., isopropenyl) substituted with one or more R 1S .

[0076] In some embodiments, R 1 is C3 - C 1S cycloalkyl optionally substituted with one or more R 12 .

[0077] In some embodiments, R 1 is C3-C 1S cycloalkyl substituted with one or more R 12 .

[0078] In some embodiments, R 1 is cyclopropyl

[0079] In some embodiments, R 1 is cyclopropyl substituted with one or more R 1S .

[0080] In some embodiments, at least one R 1S is halogen

[0081] In some embodiments, at least one R 1S is F, Cl, or Br

[0082] In some embodiments, at least one R 1S is F

[0083] In some embodiments, at least one R 1S is Cl

[0084] In some embodiments, at least one R 1S is Br

[0085] In some embodiments, at least one R 1S is cyano

[0086] In some embodiments, at least one R 1S is -OH

[0087] In some embodiments, at least one R 1S is C1-C6 alkyl

[0088] In some embodiments, R 1ais H or C1-C6 alkyl. In some embodiments, R 1a is H or methyl.

[0089] In some embodiments, R 1a is H.

[0090] In some embodiments, R 1a is C1-C6 alkyl. In some embodiments, R 1a is methyl.

[0091] In some embodiments, R 1 is H and R 1a is H.

[0092] In some embodiments, R 1 is C1-C6 alkyl and R 1a is H.

[0093] In some embodiments, R 1 is H and R 1a is C1-C6 alkyl.

[0094] In some embodiments, R 1 is methyl and R 1a is H.

[0095] In some embodiments, R 1 is H and R 1a is methyl.

[0096] In some embodiments, R 1 and R 1a together with the atom to which they are attached form a C3-C7 cycloalkyl.

[0097] In some embodiments, R 1 and R 1a together with the atom to which they are attached form cyclopropyl.

[0098] In some embodiments, R1 is H, and R 1a is H; or R 1 is C1-C6 alkyl, and R 1a is H; or R 1 is H, and R 1a is C1-C6 alkyl; or R 1 is methyl, and R 1a is H; or R 1 is H, and R 1a is methyl; or R 1 and R 1a together with the atom to which they are attached form C3-C7 cycloalkyl; or R 1 and R 1a together with the atom to which they are attached form cyclopropyl.

[0099] In some embodiments, R 1 is H, and R 1a is H; or R 1 is C1-C6 alkyl, and R 1a is H; or R 1 is H, and R 1a is C1-C6 alkyl; or R 1 and R 1a together with the atom to which they are attached form C3-C7 cycloalkyl.

[0100] In some embodiments, R 1 is H, and R 1a is H; or R 1 is methyl, and R 1a is H; or R 1 is H, and R 1a is methyl; or R 1 and R 1a together with the atoms to which they are attached form a cyclopropyl group.

[0101] In some embodiments, R 1 and R 1a together with the atoms to which they are attached form a C2-C6 alkenyl group.

[0102] In some embodiments, R 1 and R 1a together with the atoms to which they are attached form a C2 alkenyl group.

[0103] In some embodiments, R 1 and R 1a together with the atoms to which they are attached form a C3-C7 cycloalkyl or 3-7 membered heterocycloalkyl group.

[0104] In some embodiments, R 1 and R 1a together with the atoms to which they are attached form a C3-C7 cycloalkyl group.

[0105] In some embodiments, R 1 and R 1a together with the atoms to which they are attached form a C3 cycloalkyl group.

[0106] In some embodiments, R 1 and R 1a together with the atoms to which they are attached form a C4 cycloalkyl group.

[0107] In some embodiments, R 1 and R 1a together with the atoms to which they are attached form a 3-7 membered heterocycloalkyl group.

[0108] In some embodiments, R 1a and R 3together with the atoms to which they are attached form a C3-C 12 cycloalkyl or 3- to 12-membered heterocycloalkyl.

[0109] In some embodiments, R 1a and R 3 together with the atoms to which they are attached form a C3-C7 cycloalkyl or 3- to 7-membered heterocycloalkyl.

[0110] In some embodiments, R 1a and R 3 together with the atoms to which they are attached form a C3-C 12 cycloalkyl.

[0111] In some embodiments, R 1a and R 3 together with the atoms to which they are attached form a C3-C7 cycloalkyl.

[0112] In some embodiments, R 1a and R 3 together with the atoms to which they are attached form a C3 cycloalkyl (e.g., cyclopropyl).

[0113] In some embodiments, R 1a and R 3 together with the atoms to which they are attached form a C4 cycloalkyl (e.g., cyclobutyl).

[0114] In some embodiments, R 1a and R 3 together with the atoms to which they are attached form a 3- to 12-membered heterocycloalkyl.

[0115] In some embodiments, R 1a and R 3 together with the atoms to which they are attached form a 3- to 7-membered heterocycloalkyl.

[0116] Variable element R2 and R 2S In some embodiments, R 2 is H, C1-C6 alkyl optionally substituted with one or more R 2S , -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), or C3-C 2S cycloalkyl optionally substituted with one or more R 12 , or two Rs 2 together with the atom to which they are attached form a 5- to 10-membered heteroaryl optionally substituted with one or more R 2S .

[0117] In some embodiments, R 2 is H, C1-C6 alkyl optionally substituted with halogen, -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), or C3-C 12 cycloalkyl optionally substituted with C1-C6 alkyl, or two Rs 2 together with the atom to which they are attached form a 5- to 10-membered heteroaryl optionally substituted with one or more halogen or C1-C6 alkyl.

[0118] In some embodiments, R 2 is H, C1-C6 alkyl, -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), or C3-C 12 cycloalkyl, or two Rs 2 together with the atom to which they are attached form a 5- to 10-membered heteroaryl optionally substituted with one or more R 2S .

[0119] In some embodiments, R 2 is H, methyl, ethyl, isopropyl, cyclopropyl, -CH2-CHF2, -NH-methyl, NH-ethyl, or -O-ethyl, or two Rs 2Together with the atoms to which they are attached, they form a thienyl ring or a thiazolyl ring which may be substituted with one or more Cl or methyls.

[0120] In some embodiments, R 2 is H, methyl, ethyl, isopropyl, cyclopropyl, -NH-ethyl, or -O-ethyl, or two Rs 2 together with the atoms to which they are attached, form a thienyl ring or a thiazolyl ring which may be substituted with one or more Rs 2S s.

[0121] In some embodiments, each R 2 is independently H.

[0122] In some embodiments, each R 2 is independently a halogen.

[0123] In some embodiments, each R 2 is independently cyano.

[0124] In some embodiments, each R 2 is independently -OH or -NH2.

[0125] In some embodiments, each R 2 is independently -NO2.

[0126] In some embodiments, each R 2 is independently -C(=O)NH2.

[0127] In some embodiments, each R 2 is independently C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, where C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl may be substituted with one or more Rs 2S s.

[0128] In some embodiments, each R 2is independently one or more Rs 2S and is C1-C6 alkyl which may be substituted with

[0129] In some embodiments, each R 2 is independently C1-C6 alkyl.

[0130] In some embodiments, each R 2 is independently ethyl or isopropyl.

[0131] In some embodiments, each R 2 is independently C1-C6 alkyl substituted with one or more Rs 2S .

[0132] In some embodiments, each R 2 is independently C2-C6 alkenyl which may be substituted with one or more Rs 2S .

[0133] In some embodiments, each R 2 is independently C2-C6 alkenyl.

[0134] In some embodiments, each R 2 is independently C2-C6 alkenyl substituted with one or more Rs 2S .

[0135] In some embodiments, each R 2 is independently C2-C6 alkynyl which may be substituted with one or more Rs 2S .

[0136] In some embodiments, each R 2 is independently C2-C6 alkynyl.

[0137] In some embodiments, each R 2 is independently C2-C6 alkynyl substituted with one or more Rs 2S .

[0138] In some embodiments, each R2 is independently -O(C1 - C6 alkyl), -NH(C1 - C6 alkyl), or -N(C1 - C6 alkyl)2, where -O(C1 - C6 alkyl), -NH(C1 - C6 alkyl), or -N(C1 - C6 alkyl)2 may be substituted with one or more R 2S and may be substituted.

[0139] In some embodiments, each R 2 is independently -O(C1 - C6 alkyl) which may be substituted with one or more R 2S and may be substituted.

[0140] In some embodiments, each R 2 is independently -O(C1 - C6 alkyl).

[0141] In some embodiments, each R 2 is independently -O(ethyl).

[0142] In some embodiments, each R 2 is independently -NH(C1 - C6 alkyl) or -N(C1 - C6 alkyl)2 which may be substituted with one or more R 2S and may be substituted.

[0143] In some embodiments, each R 2 is independently -NH(C1 - C6 alkyl) or -N(C1 - C6 alkyl)2.

[0144] In some embodiments, each R 2 is independently -NH(ethyl).

[0145] In some embodiments, each R 2 is independently C3 - C 12 cycloalkyl, 3 - 12 membered heterocycloalkyl, C6 - C 10 aryl, or 5 - 10 membered heteroaryl, where C3 - C 12 cycloalkyl, 3 - 12 membered heterocycloalkyl, C6 - C 10Aryl, or a 5- to 10-membered heteroaryl, may be substituted with one or more R 2S and may be substituted.

[0146] In some embodiments, each R 2 is independently a C3-C 2S cycloalkyl which may be substituted with one or more R 12 and is cycloalkyl.

[0147] In some embodiments, each R 2 is independently C3-C 12 and is cycloalkyl.

[0148] In some embodiments, each R 2 is independently cyclopropyl or cyclobutyl.

[0149] In some embodiments, each R 2 is independently a C3-C 2S cycloalkyl substituted with one or more R 12 and is cycloalkyl.

[0150] In some embodiments, each R 2 is independently a 3- to 12-membered heterocycloalkyl which may be substituted with one or more R 2S and may be substituted.

[0151] In some embodiments, each R 2 is independently 3- to 12-membered heterocycloalkyl.

[0152] In some embodiments, each R 2 is independently a 3- to 12-membered heterocycloalkyl substituted with one or more R 2S and may be substituted.

[0153] In some embodiments, each R 2 is independently a C6-C 2S aryl which may be substituted with one or more R 10 and is aryl.

[0154] In some embodiments, each R2 is independently C6 - C 10 is aryl.

[0155] In some embodiments, each R 2 is independently C6 - C 2S aryl substituted with one or more R 10 is aryl.

[0156] In some embodiments, each R 2 is independently 5 - to 10 - membered heteroaryl which may be substituted with one or more R 2S is heteroaryl.

[0157] In some embodiments, each R 2 is independently 5 - to 10 - membered heteroaryl.

[0158] In some embodiments, each R 2 is independently 5 - to 10 - membered heteroaryl substituted with one or more R 2S is heteroaryl.

[0159] In some embodiments, two R2s together with the atom to which they are attached form C3 - C 12 cycloalkyl or 3 - to 12 - membered heterocycloalkyl, where the C3 - C 12 cycloalkyl or 3 - to 12 - membered heterocycloalkyl may be substituted with one or more R 2S is substituted.

[0160] In some embodiments, two R2s together with the atom to which they are attached form C3 - C 12 cycloalkyl or 3 - to 12 - membered heterocycloalkyl.

[0161] In some embodiments, two R2s together with the atom to which they are attached form C3 - C 2S cycloalkyl which may be substituted with one or more R 12 is cycloalkyl.

[0162] In some embodiments, the two R2s, together with the atom to which they are attached, form a C3-C 12 cycloalkyl.

[0163] In some embodiments, the two R2s, together with the atom to which they are attached, form a 3- to 12-membered heterocycloalkyl optionally substituted with one or more R 2S s.

[0164] In some embodiments, the two R2s, together with the atom to which they are attached, form a 3- to 12-membered heterocycloalkyl.

[0165] In some embodiments, the two R2s, together with the atom to which they are attached, form a thiazolyl or thienyl.

[0166] In some embodiments, at least one R 2S is halogen or C1-C6 alkyl. In some embodiments, R 2S is chlorine or methyl.

[0167] In some embodiments, R 2S is halogen. In some embodiments, at least one R 2S is F, Cl, or Br.

[0168] In some embodiments, at least one R 2S is F.

[0169] In some embodiments, at least one R 2S is Cl.

[0170] In some embodiments, at least one R 2S is Br.

[0171] In some embodiments, at least one R 2S is -OH.

[0172] In some embodiments, at least one R 2S is C1-C6 alkyl.

[0173] In some embodiments, at least one R 2S is methyl.

[0174] In some embodiments, at least one R 2S is -O(C1-C6 alkyl).

[0175] In some embodiments, at least one R 2S is -NH(C1-C6 alkyl) or -N(C1-C6 alkyl)2.

[0176] In some embodiments, at least one R 2S is C3-C 12 cycloalkyl.

[0177] In some embodiments, at least one R 2S is C3 cycloalkyl. In some embodiments, at least one R 2S is C4 cycloalkyl. In some embodiments, at least one R 2S is C5 cycloalkyl. In some embodiments, at least one R 2S is C6 cycloalkyl. In some embodiments, at least one R 2S is C7 cycloalkyl. In some embodiments, at least one R 2S is C8 cycloalkyl. In some embodiments, at least one R 2S is C9 cycloalkyl. In some embodiments, at least one R 2S is C 10 cycloalkyl. In some embodiments, at least one R 2S is C 11 cycloalkyl. In some embodiments, at least one R 2S is C 12 cycloalkyl.

[0178] Variable element R3 and R 3S In some embodiments, R 3 is H, -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C3-C 12 cycloalkyl, where -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C3-C 12 cycloalkyl may be substituted with one or more R 3S s.

[0179] In some embodiments, R 3 is -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C3-C 12 cycloalkyl, where -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C3-C 12 cycloalkyl may be substituted with one or more R 3S s.

[0180] In some embodiments, R 3 is H or C1-C6 alkyl. In some embodiments, R 3 is H or methyl. In some embodiments, R 3 is H.

[0181] In some embodiments, R 3 is C1-C6 alkyl. In some embodiments, R 3 is methyl.

[0182] In some embodiments, R 3 is -N(C1-C6 alkyl)2 substituted with one or more R 3S s.

[0183] In some embodiments, R 3 is -N(C1-C6 alkyl)2.

[0184] In some embodiments, R 3 is one or more R3S It may be C1-C6 alkyl which may be substituted.

[0185] In some embodiments, R 3 is C1-C6 alkyl.

[0186] In some embodiments, R 3 is C2-C6 alkenyl which may be substituted with one or more R 3S s.

[0187] In some embodiments, R 3 is C2-C6 alkenyl.

[0188] In some embodiments, R 3 is C3-C 3S cycloalkyl which may be substituted with one or more R 12 s.

[0189] In some embodiments, R 3 is C3-C 12 cycloalkyl.

[0190] In some embodiments, R 3 is H; or R 3 is C1-C6 alkyl; or R 3 is methyl; or R 3 and R 1a together with the atom to which they are attached form C3-C7 cycloalkyl; or R 3 and R 1a together with the atom to which they are attached form cyclopropyl; or R 3 and R 1 together with the atom to which they are attached form C3-C7 cycloalkyl; or R 3 and R 1Together with the atoms to which they are attached, they form a cyclopropyl group.

[0191] In some embodiments, R 3 is H; or R 3 is C1-C6 alkyl; or R 3 and R 1a together with the atoms to which they are attached, form C3-C7 cycloalkyl; or R 3 and R 1 together with the atoms to which they are attached, form C3-C7 cycloalkyl; or R 3 and R 1 together with the atoms to which they are attached, form a cyclopropyl group.

[0192] In some embodiments, R 3 is H; or R 3 is methyl; or R 3 and R 1a together with the atoms to which they are attached, form a cyclopropyl group; or R 3 and R 1 together with the atoms to which they are attached, form a cyclopropyl group.

[0193] In some embodiments, at least one R 3S is halogen.

[0194] In some embodiments, at least one R 3S is cyano.

[0195] In some embodiments, at least one R 3S is -OH.

[0196] In some embodiments, at least one R3S is C1-C6 alkyl.

[0197] In some embodiments, R 1 and R 3 together with the atom to which they are attached form a C3-C 12 cycloalkyl or 3- to 12-membered heterocycloalkyl.

[0198] In some embodiments, R 1 and R 3 together with the atom to which they are attached form a C3-C7 cycloalkyl or 3- to 7-membered heterocycloalkyl.

[0199] In some embodiments, R 1 and R 3 together with the atom to which they are attached form a C3-C 12 cycloalkyl.

[0200] In some embodiments, R 1 and R 3 together with the atom to which they are attached form a C3-C7 cycloalkyl.

[0201] In some embodiments, R 1 and R 3 together with the atom to which they are attached form a C3 cycloalkyl (e.g., cyclopropyl).

[0202] In some embodiments, R 1 and R 3 together with the atom to which they are attached form a C4 cycloalkyl (e.g., cyclobutyl).

[0203] In some embodiments, R 1 and R 3 together with the atom to which they are attached form a 3- to 12-membered heterocycloalkyl.

[0204] In some embodiments, R 1and R 3 together with the atoms to which they are attached form a 3- to 7-membered heterocycloalkyl.

[0205] Variable element R 2a and R a In some embodiments, each R 2a is independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, -(CH2) 0~3 -(C3-C 12 cycloalkyl), or -(CH2) 0~3 -(3- to 12-membered heterocycloalkyl).

[0206] In some embodiments, each R 2a is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, -(CH2) 0~3 -(C3-C 12 cycloalkyl), or -(CH2) 0~3 -(3- to 12-membered heterocycloalkyl).

[0207] In some embodiments, R 2a is H or C1-C6 alkyl.

[0208] In some embodiments, R 2a is H, methyl, ethyl, or isopropyl.

[0209] In some embodiments, R 2a is H.

[0210] In some embodiments, R 2a is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C1-C6 haloalkyl.

[0211] In some embodiments, R 2a is C1-C6 alkyl (e.g., methyl, ethyl, or propyl).

[0212] In some embodiments, R 2a is C2-C6 alkenyl. In some embodiments, R 2a is C2-C6 alkynyl. In some embodiments, R 2a is C1-C6 haloalkyl.

[0213] In some embodiments, each R 2a is independently -(CH2) 0~3 -(C3-C 12 cycloalkyl) or -(CH2) 0~3 -(3- to 12-membered heterocycloalkyl).

[0214] In some embodiments, at least one R a is H. In some embodiments, all of the Rs a are H.

[0215] In some embodiments, at least one R a is C1-C6 alkyl (e.g., methyl, ethyl, or propyl).

[0216] In some embodiments, at least one R a is C1-C4 alkyl (e.g., methyl, ethyl, or propyl).

[0217] In some embodiments, one R a is H and the other R a is C1-C6 alkyl (e.g., methyl, ethyl, or propyl).

[0218] In some embodiments, one R a is H and the other R a is C1-C4 alkyl (e.g., methyl, ethyl, or propyl).

[0219] In some embodiments, two Rs a together with the atom to which they are attached form a C2-C6 alkenyl or C3-C 12 cycloalkyl.

[0220] In some embodiments, two Rs a together with the atoms to which they are attached form a C2-C6 alkenyl.

[0221] In some embodiments, two Rs a together with the atoms to which they are attached form a C3-C 12 cycloalkyl.

[0222] In some embodiments, two Rs a together with the atoms to which they are attached form a C3-C6 cycloalkyl.

[0223] In some embodiments, two Rs a together with the atoms to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0224] In some embodiments, two Rs a together with the atoms to which they are attached form a cyclopropyl.

[0225] The variable elements R N1 , R N2 , R N2a , R N2ab , R b , and R b1 In some embodiments, R N1 is H or C1-C6 alkyl.

[0226] In some embodiments, R N1 is H.

[0227] In some embodiments, R N1 is C1-C6 alkyl.

[0228] In some embodiments, R N1 is methyl.

[0229] In some embodiments, R N2is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O-(C1-C6 alkyl), -O-(C2-C6 alkenyl), -O-(C2-C6 alkynyl), -NH-(C1-C6 alkyl), -NH-(C2-C6 alkenyl), -NH-(C2-C6 alkynyl), C3-C 12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl, -(C1-C6 alkyl)-(C3-C 12 cycloalkyl), -(C1-C6 alkyl)-(3- to 12-membered heterocycloalkyl), -(C1-C6 alkyl)-(C6-C 10 aryl), or -(C1-C6 alkyl)-(5- to 10-membered heteroaryl); wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O-(C1-C6 alkyl), -O-(C2-C6 alkenyl), -O-(C2-C6 alkynyl), -NH-(C1-C6 alkyl), -NH-(C2-C6 alkenyl), -NH-(C2-C6 alkynyl), C3-C 12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl, -(C1-C6 alkyl)-(C3-C 12 cycloalkyl), -(C1-C6 alkyl)-(3- to 12-membered heterocycloalkyl), -(C1-C6 alkyl)-(C6-C 10 aryl), or -(C1-C6 alkyl)-(5- to 10-membered heteroaryl) may be substituted with one or more R N2a .

[0230] In some embodiments, R N2is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O-(C1-C6 alkyl), -O-(C2-C6 alkenyl), -O-(C2-C6 alkynyl), -NH-(C1-C6 alkyl), -NH-(C2-C6 alkenyl), or -NH-(C2-C6 alkynyl), where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O-(C1-C6 alkyl), -O-(C2-C6 alkenyl), -O-(C2-C6 alkynyl)-NH-(C1-C6 alkyl), -NH-(C2-C6 alkenyl), or -NH-(C2-C6 alkynyl) may be substituted with one or more R N2a and may be substituted with one or more R

[0231] In some embodiments, R N2 is "C3-C 12 cycloalkyl, 3- to 12-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, where C3-C 12 cycloalkyl, 3- to 12-membered heterocycloalkyl, or 5- to 10-membered heteroaryl may be substituted with one or more R N2a and may be substituted with one or more R

[0232] In some embodiments, R N2 is C3-C 12 cycloalkyl, 3- to 12-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, where C3-C 12 cycloalkyl, 3- to 12-membered heterocycloalkyl, or 5- to 10-membered heteroaryl is substituted with one or more R N2a and may be substituted with one or more R

[0233] In some embodiments, R N2 is C3-C 12 cycloalkyl, 3- to 12-membered heterocycloalkyl, or 5- to 10-membered heteroaryl.

[0234] In some embodiments, R N2is cyclobutyl, piperidinyl, oxaspiro[3.3]heptanyl, thiadiazolyl, or pyrimidinyl, where cyclobutyl, piperidinyl, oxaspiro[3.3]heptanyl, thiadiazolyl, or pyrimidinyl is optionally substituted with one or more R N2a groups.

[0235] In some embodiments, R N2 is cyclobutyl, piperidinyl, oxaspiro[3.3]heptanyl, thiadiazolyl, or pyrimidinyl, where cyclobutyl, piperidinyl, oxaspiro[3.3]heptanyl, thiadiazolyl, or pyrimidinyl is substituted with one or more R N2a groups.

[0236] In some embodiments, R N2 is cyclobutyl, piperidinyl, oxaspiro[3.3]heptanyl, thiadiazolyl, or pyrimidinyl.

[0237] In some embodiments, R N2 is C1-C6 alkyl optionally substituted with one or more R N2a groups.

[0238] In some embodiments, R N2 is C1-C6 alkyl.

[0239] In some embodiments, R N2 is C1-C6 alkyl substituted with one or more R N2a groups.

[0240] In some embodiments, R N2 is C2-C6 alkenyl optionally substituted with one or more R N2a groups.

[0241] In some embodiments, R N2 is C2-C6 alkenyl.

[0242] In some embodiments, RN2 is C2-C6 alkenyl substituted with one or more R N2a .

[0243] In some embodiments, R N2 is C2-C6 alkynyl optionally substituted with one or more R N2a .

[0244] In some embodiments, R N2 is C2-C6 alkynyl.

[0245] In some embodiments, R N2 is C2-C6 alkynyl substituted with one or more R N2a .

[0246] In some embodiments, R N2 is -O-(C1-C6 alkyl) optionally substituted with one or more R N2a .

[0247] In some embodiments, R N2 is -O-(C1-C6 alkyl).

[0248] In some embodiments, R N2 is -O-(C1-C6 alkyl) substituted with one or more R N2a .

[0249] In some embodiments, R N2 is -O-(C2-C6 alkenyl) optionally substituted with one or more R N2a .

[0250] In some embodiments, R N2 is -O-(C2-C6 alkenyl).

[0251] In some embodiments, R N2 is -O-(C2-C6 alkenyl) substituted with one or more R N2a .

[0252] In some embodiments, R N2 may be -O-(C2-C6 alkynyl) optionally substituted with one or more R N2a .

[0253] In some embodiments, R N2 is -O-(C2-C6 alkynyl).

[0254] In some embodiments, R N2 is -O-(C2-C6 alkynyl) substituted with one or more R N2a .

[0255] In some embodiments, R N2 may be -NH-(C1-C6 alkyl) optionally substituted with one or more R N2a .

[0256] In some embodiments, R N2 is -NH-(C1-C6 alkyl).

[0257] In some embodiments, R N2 is -NH-(C1-C6 alkyl) substituted with one or more R N2a .

[0258] In some embodiments, R N2 may be -NH-(C2-C6 alkenyl) optionally substituted with one or more R N2a .

[0259] In some embodiments, R N2 is -NH-(C2-C6 alkenyl).

[0260] In some embodiments, R N2 is -NH-(C2-C6 alkenyl) substituted with one or more R N2a .

[0261] In some embodiments, R N2 may be -NH-(C1-C6 alkyl) optionally substituted with one or more R N2aIt may be replaced by -NH-(C2-C6 alkynyl).

[0262] In some embodiments, R N2 is -NH-(C2-C6 alkynyl).

[0263] In some embodiments, R N2 is -NH-(C2-C6 alkynyl) substituted with one or more R N2a .

[0264] In some embodiments, R N2 is C3-C 12 cycloalkyl, 3-12 membered heterocycloalkyl, C6-C 10 aryl, or 5-10 membered heteroaryl, where C3-C 12 cycloalkyl, 3-12 membered heterocycloalkyl, C6-C 10 aryl, or 5-10 membered heteroaryl may be substituted with one or more R N2a .

[0265] In some embodiments, R N2 is C3-C N2a cycloalkyl which may be substituted with one or more R 12 . In some embodiments, R N2 is cyclobutyl which may be substituted with one or more R N2a .

[0266] In some embodiments, R N2 is C3-C 12 cycloalkyl. In some embodiments, R N2 is cyclobutyl.

[0267] In some embodiments, R N2 is C3-C N2a cycloalkyl substituted with one or more R 12 . In some embodiments, R N2 is cyclobutyl substituted with one or more R N2a .

[0268] In some embodiments, R N2 is a 3- to 12-membered heterocycloalkyl which may be substituted with one or more R N2a . In some embodiments, R N2 is piperidinyl or oxaspiro[3.3]heptanyl, where the piperidinyl or oxaspiro[3.3]heptanyl may be substituted with one or more R N2a .

[0269] In some embodiments, R N2 is piperidinyl which may be substituted with one or more R N2a . In some embodiments, R N2 is oxaspiro[3.3]heptanyl which may be substituted with one or more R N2a .

[0270] In some embodiments, R N2 is a 3- to 12-membered heterocycloalkyl. In some embodiments, R N2 is piperidinyl or oxaspiro[3.3]heptanyl. In some embodiments, R N2 is piperidinyl. In some embodiments, R N2 is oxaspiro[3.3]heptanyl.

[0271] In some embodiments, R N2 is a 3- to 12-membered heterocycloalkyl substituted with one or more R N2a . In some embodiments, R N2 is piperidinyl or oxaspiro[3.3]heptanyl, where the piperidinyl or oxaspiro[3.3]heptanyl is substituted with one or more R N2a . In some embodiments, R N2 is piperidinyl substituted with one or more R N2a . In some embodiments, R N2 is oxaspiro[3.3]heptanyl substituted with one or more R N2a .

[0272] In some embodiments, R N2 is C6-C N2a aryl which may be substituted with one or more R 10 s.

[0273] In some embodiments, R N2 is C6-C 10 aryl.

[0274] In some embodiments, R N2 is C6-C N2a aryl substituted with one or more R 10 s.

[0275] In some embodiments, R N2 is 5- to 10-membered heteroaryl which may be substituted with one or more R N2a s. In some embodiments, R N2 is thiadiazolyl or pyrimidinyl, where the thiadiazolyl, oxazolyl, or pyrimidinyl may be substituted with one or more R N2a s. In some embodiments, R N2 is thiadiazolyl or pyrimidinyl, where the thiadiazolyl or pyrimidinyl may be substituted with one or more R N2a s.

[0276] In some embodiments, R N2 is thiadiazolyl which may be substituted with one or more R N2a s. In some embodiments, R N2 is pyrimidinyl which may be substituted with one or more R N2a s. In some embodiments, R N2 is oxazolyl which may be substituted with one or more R N2a s.

[0277] In some embodiments, R N2 is 5- to 10-membered heteroaryl. In some embodiments, R N2is thiazolyl, oxazolyl, or pyrimidinyl. In some embodiments, R N2 is thiazolyl or pyrimidinyl. In some embodiments, R N2 is thiazolyl. In some embodiments, R N2 is pyrimidinyl. In some embodiments, R N2 is oxazolyl.

[0278] In some embodiments, R N2 is a 5- to 10-membered heteroaryl substituted with one or more R N2a . In some embodiments, R N2 is thiazolyl, oxazolyl, or pyrimidinyl, wherein the thiazolyl, oxazolyl, or pyrimidinyl is substituted with one or more R N2a . In some embodiments, R N2 is thiazolyl or pyrimidinyl, wherein the thiazolyl or pyrimidinyl is substituted with one or more R N2a .

[0279] In some embodiments, R N2 is thiazolyl substituted with one or more R N2a . In some embodiments, R N2 is pyrimidinyl substituted with one or more R N2a . In some embodiments, R N2 is oxazolyl substituted with one or more R N2a .

[0280] In some embodiments, R N2 is a 5-membered heteroaryl optionally substituted with one or more R N2a .

[0281] In some embodiments, R N2 is a 5-membered heteroaryl.

[0282] In some embodiments, R N2 is substituted with one or more R N2ais a 5-membered heteroaryl replaced by

[0283] In some embodiments, R N2 is a 6-membered heteroaryl which may be substituted with one or more R N2a s.

[0284] In some embodiments, R N2 is a 6-membered heteroaryl.

[0285] In some embodiments, R N2 is a 6-membered heteroaryl substituted with one or more R N2a s.

[0286] In some embodiments, R N2 is pyridine or pyrimidine, where pyridine or pyrimidine may be substituted with one or more R N2a s.

[0287] In some embodiments, R N2 is pyridine or pyrimidine.

[0288] In some embodiments, R N2 is pyridine or pyrimidine, where pyridine or pyrimidine is substituted with one or more R N2a s.

[0289] In some embodiments, R N2 is 2-pyrimidine which may be substituted with one or more R N2a s.

[0290] In some embodiments, R N2 is 2-pyrimidine.

[0291] In some embodiments, R N2 is 2-pyrimidine substituted with one or more R N2a s.

[0292] In some embodiments, R N2is pyrimidin-4(3H)-onyl, imidazo[2,1-f]pyridinyl, [1,2,4]triazolo[3,4-f]pyridinyl, [1,2,4]triazolo[3,4-f]pyridazinyl, 7,9-dihydro-8H-purin-8-onyl, or 1,3-dihydro-2H-benzo[d]imidazol-2-onyl.

[0293] In some embodiments, R N2 is pyrimidin-4(3H)-onyl. In some embodiments, R N2 is imidazo[2,1-f]pyridinyl. In some embodiments, R N2 is [1,2,4]triazolo[3,4-f]pyridinyl. In some embodiments, R N2 is [1,2,4]triazolo[3,4-f]pyridazinyl. In some embodiments, R N2 is 7,9-dihydro-8H-purin-8-onyl. In some embodiments, R N2 is 1,3-dihydro-2H-benzo[d]imidazol-2-onyl.

[0294] In some embodiments, R N2 is pyrimidin-4(3H)-onyl, imidazo[2,1-f]pyridinyl, [1,2,4]triazolo[3,4-f]pyridinyl, [1,2,4]triazolo[3,4-f]pyridazinyl, 7,9-dihydro-8H-purin-8-onyl, or 1,3-dihydro-2H-benzo[d]imidazol-2-onyl, wherein pyrimidin-4(3H)-onyl, imidazo[2,1-f]pyridinyl, [1,2,4]triazolo[3,4-f]pyridinyl, [1,2,4]triazolo[3,4-f]pyridazinyl, 7,9-dihydro-8H-purin-8-onyl, or 1,3-dihydro-2H-benzo[d]imidazol-2-onyl may be substituted with one or more R N2a groups.

[0295] In some embodiments, R N2 is one or more R N2aIt may be pyrimidin-4(3H)-onyl which may be replaced. In some embodiments, R N2 is imidazo[2,1-f]pyridinyl which may be substituted with one or more R N2a In some embodiments, R N2 is [1,2,4]triazolo[3,4-f]pyridinyl which may be substituted with one or more R N2a In some embodiments, R N2 is [1,2,4]triazolo[3,4-f]pyridazinyl which may be substituted with one or more R N2a In some embodiments, R N2 is 7,9-dihydro-8H-purin-8-onyl which may be substituted with one or more R N2a In some embodiments, R N2 is 1,3-dihydro-2H-benzo[d]imidazol-2-onyl which may be substituted with one or more R N2a In some embodiments, R

[0296] In some embodiments, R N2 is pyrimidin-4(3H)-onyl, imidazo[2,1-f]pyridinyl, [1,2,4]triazolo[3,4-f]pyridinyl, [1,2,4]triazolo[3,4-f]pyridazinyl, 7,9-dihydro-8H-purin-8-onyl, or 1,3-dihydro-2H-benzo[d]imidazol-2-onyl, where pyrimidin-4(3H)-onyl, imidazo[2,1-f]pyridinyl, [1,2,4]triazolo[3,4-f]pyridinyl, [1,2,4]triazolo[3,4-f]pyridazinyl, 7,9-dihydro-8H-purin-8-onyl, or 1,3-dihydro-2H-benzo[d]imidazol-2-onyl is substituted with one or more R N2a In some embodiments, R

[0297] In some embodiments, R N2 is pyrimidin-4(3H)-onyl substituted with one or more R N2a In some embodiments, R N2 is [1,2,4]triazolo[3,4-f]pyridinyl substituted with one or more R N2ais imidazo[2,1-f]pyridinyl substituted with. In some embodiments, R N2 is [1,2,4]triazolo[3,4-f]pyridinyl substituted with one or more R N2a . In some embodiments, R N2 is [1,2,4]triazolo[3,4-f]pyridazinyl substituted with one or more R N2a . In some embodiments, R N2 is 7,9-dihydro-8H-purin-8-onyl substituted with one or more R N2a . In some embodiments, R N2 is 1,3-dihydro-2H-benzo[d]imidazol-2-onyl substituted with one or more R N2a .

[0298] In some embodiments, R N2 is -(C1-C6 alkyl)-(C3-C 12 cycloalkyl), -(C1-C6 alkyl)-(3-12 membered heterocycloalkyl), -(C1-C6 alkyl)-(C6-C 10 aryl), or -(C1-C6 alkyl)-(5-10 membered heteroaryl); wherein, -(C1-C6 alkyl)-(C3-C 12 cycloalkyl), -(C1-C6 alkyl)-(3-12 membered heterocycloalkyl), -(C1-C6 alkyl)-(C6-C 10 aryl), or -(C1-C6 alkyl)-(5-10 membered heteroaryl) may be substituted with one or more R N2a .

[0299] In some embodiments, R N2 is -(C1-C6 alkyl)-(C3-C N2a cycloalkyl) which may be substituted with one or more R 12 .

[0300] In some embodiments, R N2 is -(C1-C6 alkyl)-(C3-C 12 cycloalkyl).

[0301] In some embodiments, R N2 is -(C1-C6 alkyl)-(C3-C N2a cycloalkyl) substituted with one or more R 12 .

[0302] In some embodiments, R N2 is optionally substituted with one or more R N2a -(C1-C6 alkyl)-(3-12 membered heterocycloalkyl).

[0303] In some embodiments, R N2 is -(C1-C6 alkyl)-(3-12 membered heterocycloalkyl).

[0304] In some embodiments, R N2 is -(C1-C6 alkyl)-(3-12 membered heterocycloalkyl) substituted with one or more R N2a .

[0305] In some embodiments, R N2 is optionally substituted with one or more R N2a -(C1-C6 alkyl)-(C6-C 10 aryl).

[0306] In some embodiments, R N2 is -(C1-C6 alkyl)-(C6-C 10 aryl).

[0307] In some embodiments, R N2 is -(C1-C6 alkyl)-(C6-C N2a aryl) substituted with one or more R 10 .

[0308] In some embodiments, R N2 is optionally substituted with one or more R N2a -(C1-C6 alkyl)-(5-10 membered heteroaryl).

[0309] In some embodiments, R N2 is -(C1-C6 alkyl)-(5-10 membered heteroaryl).

[0310] In some embodiments, R N2 is -(C1-C6 alkyl)-(5-10 membered heteroaryl) substituted with one or more R N2a .

[0311] In some embodiments, R N2 is pyrimidinyl, pyridinyl, pyrimidin-4(3H)-onyl, oxazolyl, thiadiazolyl, piperidinyl, cyclobutyl, 2-oxaspiro[3.3]heptanyl, imidazo[2,1-f]pyridinyl, [1,2,4]triazolo[3,4-f]pyridinyl, [1,2,4]triazolo[3,4-f]pyridazinyl, 7,9-dihydro-8H-purin-8-onyl, or 1,3-dihydro-2H-benzo[d]imidazol-2-onyl, where pyrimidine, pyridine, pyrimidin-4(3H)-one, oxazole, thiadiazole, piperidine, cyclobutyl, 2-oxaspiro[3.3]heptane, imidazo[2,1-f]pyridine, [1,2,4]triazolo[3,4-f]pyridine, [1,2,4]triazolo[3,4-f]pyridazine, 7,9-dihydro-8H-purin-8-one, or 1,3-dihydro-2H-benzo[d]imidazol-2-one may be substituted with one or more R N2a .

[0312] In some embodiments, R N2 is TIFF2025522354000009.tif228159.

[0313] In some embodiments, at least one R N2ais independently oxo, halogen, cyano, -OH, -NH2, -NO2, -C(=O)H, -C(=O)OH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -C(=O)(C1-C6 alkyl), -C(=O)O(C1-C6 alkyl), -NHC(=O)O(C1-C6 alkyl), -S(=O)2(C1-C6 alkyl), -S(=O)2N(C1-C6 alkyl)2, C3-C 12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl, -(C1-C6 alkyl)-(C3-C 12 cycloalkyl), -(C1-C6 alkyl)-(3- to 12-membered heterocycloalkyl), -(C1-C6 alkyl)-(C6-C 10 aryl), or -(C1-C6 alkyl)-(5- to 10-membered heteroaryl); wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -C(=O)(C1-C6 alkyl), -C(=O)O(C1-C6 alkyl), -NHC(=O)O(C1-C6 alkyl), -S(=O)2(C1-C6 alkyl), -S(=O)2N(C1-C6 alkyl)2, C3-C 12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl, -(C1-C6 alkyl)-(C3-C 12 cycloalkyl), -(C1-C6 alkyl)-(3- to 12-membered heterocycloalkyl), -(C1-C6 alkyl)-(C6-C 10 aryl), or -(C1-C6 alkyl)-(5- to 10-membered heteroaryl) may be substituted with one or more R N2ab s.

[0314] In some embodiments, at least one R N2a is halogen, -OH, C1-C6 alkyl, -C(=O)O(C1-C6 alkyl), or C3-C 12It is cycloalkyl.

[0315] In some embodiments, at least one R N2a is fluorine, -OH, methyl, -C(=O)O(ethyl), or cyclobutyl.

[0316] In some embodiments, at least one R N2a is oxo.

[0317] In some embodiments, at least two Rs N2a are oxo.

[0318] In some embodiments, at least one R N2a is halogen.

[0319] In some embodiments, at least one R N2a is F, Cl, or Br.

[0320] In some embodiments, at least one R N2a is F.

[0321] In some embodiments, at least one R N2a is Cl.

[0322] In some embodiments, at least one R N2a is Br.

[0323] In some embodiments, at least one R N2a is cyano.

[0324] In some embodiments, at least one R N2a is -OH, -NH2, -NO2, -C(=O)H, or -C(=O)OH.

[0325] In some embodiments, at least one R N2a is -OH.

[0326] In some embodiments, at least one R N2a is -NH2.

[0327] In some embodiments, at least one R N2a is -NO2.

[0328] In some embodiments, at least one R N2a is -C(=O)H.

[0329] In some embodiments, at least one R N2a is -C(=O)OH.

[0330] In some embodiments, at least one R N2a is C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, where C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl may be substituted with one or more R N2ab s.

[0331] In some embodiments, at least one R N2a is C1-C6 alkyl optionally substituted with one or more R N2ab s.

[0332] In some embodiments, at least one R N2a is C1-C6 alkyl. In some embodiments, at least one R N2a is methyl.

[0333] In some embodiments, at least one R N2a is C1-C6 alkyl substituted with one or more R N2ab s.

[0334] In some embodiments, at least one R N2a is C2-C6 alkenyl optionally substituted with one or more R N2ab s.

[0335] In some embodiments, at least one R N2a is C2-C6 alkenyl.

[0336] In some embodiments, at least one R N2a is C2-C6 alkenyl substituted with one or more R N2ab .

[0337] In some embodiments, at least one R N2a is C2-C6 alkynyl which may be substituted with one or more R N2ab .

[0338] In some embodiments, at least one R N2a is C2-C6 alkynyl.

[0339] In some embodiments, at least one R N2a is C2-C6 alkynyl substituted with one or more R N2ab .

[0340] In some embodiments, at least one R N2a is -O(C1-C6 alkyl), -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2, where -O(C1-C6 alkyl), -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2 may be substituted with one or more R N2ab .

[0341] In some embodiments, at least one R N2a is -O(C1-C6 alkyl) which may be substituted with one or more R N2ab .

[0342] In some embodiments, at least one R N2a is -O(C1-C6 alkyl).

[0343] In some embodiments, at least one R N2ais -NH(C1-C6 alkyl) or -N(C1-C6 alkyl)2, where -NH(C1-C6 alkyl) or -N(C1-C6 alkyl)2 may be substituted with one or more R N2ab and may be substituted with one or more R

[0344] In some embodiments, at least one R N2a is -NH(C1-C6 alkyl) or -N(C1-C6 alkyl)2.

[0345] In some embodiments, at least one R N2a is -C(=O)(C1-C6 alkyl), -C(=O)O(C1-C6 alkyl), or -NHC(=O)O(C1-C6 alkyl), where -C(=O)(C1-C6 alkyl), -C(=O)O(C1-C6 alkyl), or -NHC(=O)O(C1-C6 alkyl) may be substituted with one or more R N2ab and may be substituted with one or more R

[0346] In some embodiments, at least one R N2a is -C(=O)(C1-C6 alkyl) which may be substituted with one or more R N2ab and may be substituted with one or more R

[0347] In some embodiments, at least one R N2a is -C(=O)(C1-C6 alkyl).

[0348] In some embodiments, at least one R N2a is -C(=O)(C1-C6 alkyl) substituted with one or more R N2ab and may be substituted with one or more R

[0349] In some embodiments, at least one R N2a is -C(=O)O(C1-C6 alkyl) which may be substituted with one or more R N2ab and may be substituted with one or more R

[0350] In some embodiments, at least one R N2ais -C(=O)O(C1-C6 alkyl). In some embodiments, at least one R N2a is -C(=O)O(ethyl).

[0351] In some embodiments, at least one R N2a is -C(=O)O(C1-C6 alkyl) substituted with one or more R N2ab .

[0352] In some embodiments, at least one R N2a is -NHC(=O)O(C1-C6 alkyl) optionally substituted with one or more R N2ab .

[0353] In some embodiments, at least one R N2a is -NHC(=O)O(C1-C6 alkyl).

[0354] In some embodiments, at least one R N2a is -NHC(=O)O(C1-C6 alkyl) substituted with one or more R N2ab .

[0355] In some embodiments, at least one R N2a is -S(=O)2(C1-C6 alkyl) or -S(=O)2N(C1-C6 alkyl)2, where -S(=O)2(C1-C6 alkyl) or -S(=O)2N(C1-C6 alkyl)2 is optionally substituted with one or more R N2ab .

[0356] In some embodiments, at least one R N2a is -S(=O)2(C1-C6 alkyl) optionally substituted with one or more R N2ab .

[0357] In some embodiments, at least one R N2a is -S(=O)2(C1-C6 alkyl).

[0358] In some embodiments, at least one R N2a is -S(=O)2(C1-C6 alkyl) substituted with one or more R N2ab .

[0359] In some embodiments, at least one R N2a is optionally -S(=O)2N(C1-C6 alkyl)2 substituted with one or more R N2ab .

[0360] In some embodiments, at least one R N2a is -S(=O)2N(C1-C6 alkyl)2

[0361] In some embodiments, at least one R N2a is optionally -S(=O)2N(C1-C6 alkyl)2 substituted with one or more R N2ab .

[0362] In some embodiments, at least one R N2a is C3-C 12 cycloalkyl, 3-12 membered heterocycloalkyl, C6-C 10 aryl, or 5-10 membered heteroaryl, where C3-C 12 cycloalkyl, 3-12 membered heterocycloalkyl, C6-C 10 aryl, or 5-10 membered heteroaryl may be substituted with one or more R N2ab .

[0363] In some embodiments, at least one R N2a is optionally C3-C N2ab cycloalkyl substituted with one or more R 12 . In some embodiments, at least one R N2a is optionally cyclobutyl substituted with one or more R N2ab .

[0364] In some embodiments, at least one R N2a is C3-C 12It is cycloalkyl. In some embodiments, at least one R N2a is cyclobutyl.

[0365] In some embodiments, at least one R N2a is C3-C N2ab cycloalkyl substituted with one or more R 12 In some embodiments, at least one R N2a is cyclobutyl substituted with one or more R N2ab In some embodiments, at least one R

[0366] is optionally substituted 3- to 12-membered heterocycloalkyl with one or more R N2a In some embodiments, at least one R N2ab is 3- to 12-membered heterocycloalkyl.

[0367] In some embodiments, at least one R N2a is 3- to 12-membered heterocycloalkyl substituted with one or more R

[0368] In some embodiments, at least one R N2a is optionally substituted C6-C N2ab aryl with one or more R

[0369] In some embodiments, at least one R N2a is C6-C N2ab aryl. 10 In some embodiments, at least one R

[0370] is optionally substituted C6-C N2a aryl with one or more R 10 In some embodiments, at least one R

[0371] In some embodiments, at least one R N2a is C6-C N2ab aryl substituted with one or more R 10 In some embodiments, at least one R

[0372] In some embodiments, at least one RN2a is a 5- to 10-membered heteroaryl which may be substituted with one or more R N2ab s.

[0373] In some embodiments, at least one R N2a is a 5- to 10-membered heteroaryl.

[0374] In some embodiments, at least one R N2a is a 5- to 10-membered heteroaryl substituted with one or more R N2ab s.

[0375] In some embodiments, at least one R N2a is -(C1-C6 alkyl)-(C3-C 12 cycloalkyl), -(C1-C6 alkyl)-(3- to 12-membered heterocycloalkyl), -(C1-C6 alkyl)-(C6-C 10 aryl), or -(C1-C6 alkyl)-(5- to 10-membered heteroaryl), where -(C1-C6 alkyl)-(C3-C 12 cycloalkyl), -(C1-C6 alkyl)-(3- to 12-membered heterocycloalkyl), -(C1-C6 alkyl)-(C6-C 10 aryl), or -(C1-C6 alkyl)-(5- to 10-membered heteroaryl) may be substituted with one or more R N2ab s.

[0376] In some embodiments, at least one R N2a is an optionally substituted -(C1-C6 alkyl)-(C3-C N2ab cycloalkyl) substituted with one or more R 12 s.

[0377] In some embodiments, at least one R N2a is -(C1-C6 alkyl)-(C3-C 12 cycloalkyl).

[0378] In some embodiments, at least one R N2ais one or more Rs N2ab substituted -(C1-C6 alkyl)-(C3-C 12 cycloalkyl).

[0379] In some embodiments, at least one R N2a is optionally substituted by one or more Rs N2ab -(C1-C6 alkyl)-(3-12 membered heterocycloalkyl).

[0380] In some embodiments, at least one R N2a is -(C1-C6 alkyl)-(3-12 membered heterocycloalkyl).

[0381] In some embodiments, at least one R N2a is optionally substituted by one or more Rs N2ab -(C1-C6 alkyl)-(3-12 membered heterocycloalkyl).

[0382] In some embodiments, at least one R N2a is optionally substituted by one or more Rs N2ab -(C1-C6 alkyl)-(C6-C 10 aryl).

[0383] In some embodiments, at least one R N2a is -(C1-C6 alkyl)-(C6-C 10 aryl).

[0384] In some embodiments, at least one R N2a is optionally substituted by one or more Rs N2ab -(C1-C6 alkyl)-(C6-C 10 aryl).

[0385] In some embodiments, at least one R N2a is optionally substituted by one or more Rs N2ab -(C1-C6 alkyl)-(5-10 membered heteroaryl).

[0386] In some embodiments, at least one R N2a is -(C1-C6 alkyl)-(5-10 membered heteroaryl).

[0387] In some embodiments, at least one R N2a is -(C1-C6 alkyl)-(5-10 membered heteroaryl) substituted with one or more R N2ab s.

[0388] In some embodiments, at least one R N2a is oxo, halogen, cyano, -OH, -NH2, -NO2, -C1-C6 alkyl optionally substituted with one or more R N2ab s, -O(C1-C6 alkyl), -C(=O)O(C1-C6 alkyl), or 5-10 membered heteroaryl.

[0389] In some embodiments, at least one R N2a is oxo, halogen, cyano, -OH, -NH2, -NO2, -C1-C6 alkyl optionally substituted with one or more halogens, -O(C1-C6 alkyl), -C(=O)O(C1-C6 alkyl), or 5-6 membered heteroaryl.

[0390] In some embodiments, at least one R N2a is oxo, F, Cl, cyano, -OH, -NH2, -NO2, methyl, CF3, -O(methyl), -C(=O)O(ethyl), or pyrazolyl.

[0391] In some embodiments, at least one R N2ab is oxo, halogen, cyano, -OH, -NH2, -C(=O)H, -C(=O)OH, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -C(=O)(C1-C6 alkyl), -C(=O)O(C1-C6 alkyl), -NHC(=O)O(C1-C6 alkyl), -S(=O)2(C1-C6 alkyl), or -S(=O)2N(C1-C6 alkyl)2.

[0392] In some embodiments, at least one R N2ab is oxo.

[0393] In some embodiments, at least two Rs N2ab are oxo.

[0394] In some embodiments, at least one R N2ab is halogen.

[0395] In some embodiments, at least one R N2ab is F, Cl, or Br.

[0396] In some embodiments, at least one R N2ab is F.

[0397] In some embodiments, at least one R N2ab is Cl.

[0398] In some embodiments, at least one R N2ab is Br.

[0399] In some embodiments, at least one R N2ab is cyano.

[0400] In some embodiments, at least one R N2ab is -OH, -NH2, -C(=O)H, or -C(=O)OH.

[0401] In some embodiments, at least one R N2ab is -OH.

[0402] In some embodiments, at least one R N2ab is -NH2.

[0403] In some embodiments, at least one R N2ab is -C(=O)H.

[0404] In some embodiments, at least one R N2ab is -C(=O)OH.

[0405] In some embodiments, at least one R N2ab is -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -C(=O)(C1-C6 alkyl), -C(=O)O(C1-C6 alkyl), or -NHC(=O)O(C1-C6 alkyl).

[0406] In some embodiments, at least one R N2ab is -O(C1-C6 alkyl).

[0407] In some embodiments, at least one R N2ab is -NH(C1-C6 alkyl) or -N(C1-C6 alkyl)2.

[0408] In some embodiments, at least one R N2ab is -C(=O)(C1-C6 alkyl).

[0409] In some embodiments, at least one R N2ab is -C(=O)O(C1-C6 alkyl).

[0410] In some embodiments, at least one R N2ab is -NHC(=O)O(C1-C6 alkyl).

[0411] In some embodiments, at least one R N2ab is -S(=O)2(C1-C6 alkyl) or -S(=O)2N(C1-C6 alkyl)2.

[0412] In some embodiments, at least one R N2ab is -S(=O)2(C1-C6 alkyl).

[0413] In some embodiments, at least one RN2ab is -S(=O)2N(C1 - C6 alkyl)2.

[0414] In some embodiments, R N1 and R N2 together with the atoms to which they are attached form a 3 - to 12 - membered heterocycloalkyl optionally substituted with one or more R b .

[0415] In some embodiments, R N1 and R N2 together with the atoms to which they are attached form a 3 - to 12 - membered heterocycloalkyl.

[0416] In some embodiments, R N1 and R N2 together with the atoms to which they are attached form a 3 - to 12 - membered heterocycloalkyl substituted with one or more R b .

[0417] In some embodiments, at least one R b is oxo.

[0418] In some embodiments, at least two R b are oxo.

[0419] In some embodiments, at least one R b is halogen.

[0420] In some embodiments, at least one R b is F, Cl, or Br.

[0421] In some embodiments, at least one R b is F.

[0422] In some embodiments, at least one R b is Cl.

[0423] In some embodiments, at least one Rb is Br.

[0424] In some embodiments, at least one R b is cyano.

[0425] In some embodiments, at least one R b is -OH, -NH2, -C(=O)H, or -C(=O)OH.

[0426] In some embodiments, at least one R b is -OH.

[0427] In some embodiments, at least one R b is -NH2.

[0428] In some embodiments, at least one R b is -C(=O)H.

[0429] In some embodiments, at least one R b is -C(=O)OH.

[0430] In some embodiments, at least one R b is C1-C6 alkyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -C(=O)(C1-C6 alkyl), -C(=O)O(C1-C6 alkyl), or -NHC(=O)O(C1-C6 alkyl), where C1-C6 alkyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -C(=O)(C1-C6 alkyl), -C(=O)O(C1-C6 alkyl), -NHC(=O)O(C1-C6 alkyl), -S(=O)2(C1-C6 alkyl), or -S(=O)2N(C1-C6 alkyl)2 may be substituted with one or more Rs b1 optionally.

[0431] In some embodiments, at least one R b is one or more Rsb1 It may be C1-C6 alkyl which may be substituted.

[0432] In some embodiments, at least one R b is C1-C6 alkyl.

[0433] In some embodiments, at least one R b is -O(C1-C6 alkyl) which may be substituted with one or more Rs b1 b1

[0434] In some embodiments, at least one R b is -O(C1-C6 alkyl).

[0435] In some embodiments, at least one R b is -NH(C1-C6 alkyl) which may be substituted with one or more Rs b1 b1

[0436] In some embodiments, at least one R b is -NH(C1-C6 alkyl).

[0437] In some embodiments, at least one R b is -N(C1-C6 alkyl)2 which may be substituted with one or more Rs b1 b1

[0438] In some embodiments, at least one R b is -N(C1-C6 alkyl)2.

[0439] In some embodiments, at least one R b is -C(=O)(C1-C6 alkyl) which may be substituted with one or more Rs b1 b1

[0440] In some embodiments, at least one R b is -C(=O)(C1-C6 alkyl).

[0441] In some embodiments, at least one R b is -C(=O)O(C1-C6 alkyl) which may be substituted with one or more R b1 s.

[0442] In some embodiments, at least one R b is -C(=O)O(C1-C6 alkyl).

[0443] In some embodiments, at least one R b is -NHC(=O)O(C1-C6 alkyl) which may be substituted with one or more R b1 s.

[0444] In some embodiments, at least one R b is -NHC(=O)O(C1-C6 alkyl).

[0445] In some embodiments, at least one R b is -S(=O)2(C1-C6 alkyl) which may be substituted with one or more R b1 s.

[0446] In some embodiments, at least one R b is -S(=O)2(C1-C6 alkyl).

[0447] In some embodiments, at least one R b is -S(=O)2N(C1-C6 alkyl)2 which may be substituted with one or more R b1 s.

[0448] In some embodiments, at least one R b is -S(=O)2N(C1-C6 alkyl)2.

[0449] In some embodiments, at least one R b1 is oxo.

[0450] In some embodiments, at least one R b1 is a halogen (e.g., F, Cl, or Br).

[0451] In some embodiments, at least one R b1 is cyano.

[0452] In some embodiments, at least one R b1 is -OH.

[0453] In some embodiments, at least one R b1 is -NH2.

[0454] Exemplary embodiments of the compound In some embodiments, the compound is of formula (I), wherein A2 is CR 2 , NR 2a , or S; A3 is CR 2 , NR 2a , or O; A4 is CR 2 , N, S, or O; A5 is C or N; wherein at least one of A2, A3, A4, or A5 is N, NR 2a , O, or S; R 1 is H; R 1a is H or C1-C6 alkyl, or R 1 and R 1a together with the atom to which they are attached form a C3-C7 cycloalkyl, or R 1a and R 3 together with the atom to which they are attached form a C3-C 12 cycloalkyl; each R 2 is independently H, C1-C6 alkyl, -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), or C3-C 12Is cycloalkyl, or two Rs 2 together with the atoms to which they are attached form a 5- to 10-membered heteroaryl optionally substituted with one or more Rs 2S ; each R 2S is independently halogen or C1-C6 alkyl; each R 2a is independently H or C1-C6 alkyl; R 3 is H or C1-C6 alkyl; each R a is independently H; R N1 is H; R N2 is C3-C 12 cycloalkyl, 3- to 12-membered heterocycloalkyl, or 5- to 10-membered heteroaryl; wherein the C3-C 12 cycloalkyl, 3- to 12-membered heterocycloalkyl, or 5- to 10-membered heteroaryl may be substituted with one or more Rs N2a ; and each R N2a is independently halogen, -OH, C1-C6 alkyl, -C(=O)O(C1-C6 alkyl), or C3-C 12 cycloalkyl.

[0455] In some embodiments, the compound is of formula (I), wherein A2 is CR 2 , NR 2a , or S; A3 is CR 2 , NR 2a , or O; A4 is CR 2 , N, S, or O; A5 is C or N; wherein at least one of A2, A3, A4, or A5 is N, NR 2a , O, or S; R 1 is H; R 1ais H or methyl, or R 1 and R 1a together with the atom to which they are attached form cyclopropyl, or R 1a and R 3 together with the atom to which they are attached form cyclobutyl; each R 2 is independently H, methyl, ethyl, isopropyl, cyclopropyl, -NH-ethyl, or -O-ethyl, or alternatively, two Rs 2 together with the atom to which they are attached form a thienyl or thiazolyl ring optionally substituted with one or more Rs 2S ; each R 2S is independently chlorine or methyl; each R 2a is independently H, methyl, ethyl or isopropyl; R 3 is H or methyl; each R a is independently H; R N1 is H; R N2 is cyclobutyl, piperidinyl, oxaspiro[3.3]heptanyl, thiadiazolyl, or pyrimidinyl, each of which may be optionally substituted with one or more Rs N2a ; and each R N2a is independently fluorine, -OH, methyl, -C(=O)O(ethyl), or cyclobutyl.

[0456] In some embodiments, the compound is of formula (I) wherein A2 is, as valency permits, CR 2 or S; A3 is, as valency permits, CR 2 ; A4 is, as valency permits, CR 2 , N, or O; A5 is C or N, as allowed by the valence, wherein at least one of A2, A3, A4, or A5 is N, NR 2a , O, or S; R 1 is H or C1-C6 alkyl; R 1a is H or C1-C6 alkyl, or R 1 and R 1a together with the atom to which they are attached form C3-C7 cycloalkyl; each R 2 is independently H, C1-C6 alkyl, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, or C3-C 12 cycloalkyl, where C1-C6 alkyl, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, or C3-C 12 cycloalkyl may be substituted with one or more R 2S ; or two Rs 2 together with the atom to which they are attached form 5-10 membered heteroaryl; each R 2S is independently halogen; R 3 is H; each R a is independently H; R N1 is H; R N2 is 3-12 membered heterocycloalkyl or 5-10 membered heteroaryl; where 3-12 membered heterocycloalkyl or 5-10 membered heteroaryl may be substituted with one or more R N2a ; each R N2a is independently oxo, halogen, cyano, -OH, -NH2, -NO2, C1-C6 alkyl, -O(C1-C6 alkyl), or 5-10 membered heteroaryl; where C1-C6 alkyl, -O(C1-C6 alkyl), or 5-10 membered heteroaryl may be substituted with one or more R N2abmay be replaced by; and each R N2ab is independently halogen.

[0457] In some embodiments, the compound is of formula (II), or a prodrug, solvate, or pharmaceutically acceptable salt thereof. TIFF2025522354000010.tif27128

[0458] In some embodiments, the compound is of formula (I-a), or a prodrug, solvate, or pharmaceutically acceptable salt thereof. TIFF2025522354000011.tif23128

[0459] In some embodiments, the compound is of formula (I-b), or a prodrug, solvate, or pharmaceutically acceptable salt thereof. TIFF2025522354000012.tif23128

[0460] In some embodiments, the compound is of formula (I-c), or a prodrug, solvate, or pharmaceutically acceptable salt thereof. TIFF2025522354000013.tif23128

[0461] In some embodiments, the compound is of formula (I-d), or a prodrug, solvate, or pharmaceutically acceptable salt thereof. TIFF2025522354000014.tif23128

[0462] In some embodiments, the compound is of formula (I-e), or a prodrug, solvate, or pharmaceutically acceptable salt thereof. TIFF2025522354000015.tif24128

[0463] In some embodiments, the compound is of formula (I-f), or a prodrug, solvate, or pharmaceutically acceptable salt thereof. TIFF2025522354000016.tif23128

[0464] In some embodiments, the compound is of formula (I-g), or a prodrug, solvate, or pharmaceutically acceptable salt thereof. TIFF2025522354000017.tif23128

[0465] In some embodiments, the compound is of formula (I-h), or a prodrug, solvate, or pharmaceutically acceptable salt thereof. TIFF2025522354000018.tif23128

[0466] In some embodiments, the compound is of formula (I-i), or a prodrug, solvate, or pharmaceutically acceptable salt thereof. TIFF2025522354000019.tif23128

[0467] In some embodiments, the compound is of formula (I-j), or a prodrug, solvate, or pharmaceutically acceptable salt thereof. TIFF2025522354000020.tif23128

[0468] In some embodiments, the compound is of formula (I-k), or a prodrug, solvate, or pharmaceutically acceptable salt thereof. TIFF2025522354000021.tif23128

[0469] In some embodiments, the compound is of formula (I-l), or a prodrug, solvate, or pharmaceutically acceptable salt thereof. TIFF2025522354000022.tif23128

[0470] In some embodiments, the compound is of formula (I-m), or a prodrug, solvate, or pharmaceutically acceptable salt thereof. TIFF2025522354000023.tif23128

[0471] In some embodiments, the compound is of formula (I-n), or a prodrug, solvate, or pharmaceutically acceptable salt thereof. TIFF2025522354000024.tif23128

[0472] In some embodiments, the compound is of formula (I-o), or a prodrug, solvate, or pharmaceutically acceptable salt thereof. TIFF2025522354000025.tif23128

[0473] In some embodiments, the compound is of formula (I-p), or a prodrug, solvate, or pharmaceutically acceptable salt thereof. TIFF2025522354000026.tif25128

[0474] In some embodiments, the compound is of formula (I-q), or a prodrug, solvate, or pharmaceutically acceptable salt thereof. TIFF2025522354000027.tif25128

[0475] In some embodiments, the compound is of formula (I-r), or a prodrug, solvate, or pharmaceutically acceptable salt thereof. TIFF2025522354000028.tif25128

[0476] In some embodiments, the compound is of formula (I-s), or a prodrug, solvate, or pharmaceutically acceptable salt thereof. TIFF2025522354000029.tif25128

[0477] In some embodiments, the compound is of formula (I-t), or a prodrug, solvate, or pharmaceutically acceptable salt thereof. TIFF2025522354000030.tif25128

[0478] In some embodiments, the compound is of formula (I-u), or a prodrug, solvate, or pharmaceutically acceptable salt thereof. TIFF2025522354000031.tif25128

[0479] In some embodiments, the compound is of formula (I-v), or a prodrug, solvate, or pharmaceutically acceptable salt thereof. TIFF2025522354000032.tif23128

[0480] In some embodiments, the compound is of formula (I-w), or a prodrug, solvate, or pharmaceutically acceptable salt thereof. TIFF2025522354000033.tif23128

[0481] In some embodiments, the compound is of formula (I-x), or a prodrug, solvate, or pharmaceutically acceptable salt thereof. TIFF2025522354000034.tif23128

[0482] In some embodiments, the compound is of formula (I-y), or a prodrug, solvate, or pharmaceutically acceptable salt thereof. TIFF2025522354000035.tif27128

[0483] In some embodiments, the compound is of formula (I-z), or a prodrug, solvate, or pharmaceutically acceptable salt thereof. TIFF2025522354000036.tif30128

[0484] In some embodiments, the compound is of formula (I-aa), or a prodrug, solvate, or pharmaceutically acceptable salt thereof. TIFF2025522354000037.tif29128

[0485] In some embodiments, the compound is of formula (I-ab), or a prodrug, solvate, or pharmaceutically acceptable salt thereof. TIFF2025522354000038.tif27128

[0486] In some embodiments, the compound is of formula (I-ac), or a prodrug, solvate, or pharmaceutically acceptable salt thereof. TIFF2025522354000039.tif27128

[0487] In some embodiments, the compound is of formula (I-ad), or a prodrug, solvate, or pharmaceutically acceptable salt thereof. TIFF2025522354000040.tif27128

[0488] In some embodiments, the compound is of formula (I-ae), or a prodrug, solvate, or pharmaceutically acceptable salt thereof. TIFF2025522354000041.tif27128

[0489] In some embodiments, the compound is of formula (I-af), or a prodrug, solvate, or pharmaceutically acceptable salt thereof. TIFF2025522354000042.tif27128

[0490] In some embodiments, the compound is of formula (I-ag), or a prodrug, solvate, or pharmaceutically acceptable salt thereof. TIFF2025522354000043.tif27128

[0491] In some embodiments, the compound is selected from the compounds set forth in Table 1 and their prodrugs and pharmaceutically acceptable salts.

[0492] In some embodiments, the compound is a compound described in Table 1 or a prodrug or pharmaceutically acceptable salt thereof.

[0493] In some embodiments, the compound is selected from the compounds described in Table 1 and their pharmaceutically acceptable salts.

[0494] In some embodiments, the compound is a compound described in Table 1 or a pharmaceutically acceptable salt thereof.

[0495] In some embodiments, the compound is selected from the compounds described in Table 1.

[0496] In some embodiments, the compound is a compound described in Table 1.

[0497] [Table 1] TIFF2025522354000045.tif20883TIFF2025522354000046.tif20483TIFF2025522354000047.tif21883TIFF2025522354000048.tif20883TIFF2025522354000049.tif20883TIFF2025522354000050.tif21283TIFF2025522354000051.tif21383

[0498] In some embodiments, the compound of formula (I) is selected from Compounds 1-43 or a pharmaceutically acceptable salt thereof.

[0499] In some embodiments, the compound of formula (I) is selected from Compounds 44-77 or a pharmaceutically acceptable salt thereof.

[0500] In some aspects, the disclosure provides a compound that is an isotope derivative (e.g., an isotope-labeled compound) of any one of the compounds of the formulas disclosed herein.

[0501] In some embodiments, the compound is an isotope derivative of any one of the compounds described in Table 1, as well as its prodrugs and pharmaceutically acceptable salts.

[0502] In some embodiments, the compound is an isotope derivative of any one of the compounds described in Table 1, or its prodrug or pharmaceutically acceptable salt.

[0503] In some embodiments, the compound is an isotope derivative of any one of the compounds described in Table 1 and its pharmaceutically acceptable salt.

[0504] In some embodiments, the compound is an isotope derivative of any one of the compounds described in Table 1 or its pharmaceutically acceptable salt.

[0505] In some embodiments, the compound is an isotope derivative of any one of the compounds described in Table 1.

[0506] It is understood that isotope derivatives can be prepared using any of a variety of techniques recognized in the art. For example, isotope derivatives can generally be prepared by substituting non-isotope labeled reagents with isotope labeled reagents and performing the procedures disclosed in the schemes and / or examples described herein.

[0507] In some embodiments, the isotope derivative is a deuterium-labeled compound.

[0508] In some embodiments, the isotope derivative is a deuterium-labeled compound of any one of the compounds of the formula disclosed herein.

[0509] In some embodiments, the compound is a deuterium-labeled compound of any one of the compounds described in Table 1, as well as its prodrugs and pharmaceutically acceptable salts.

[0510] In some embodiments, the compound is a deuterium-labeled compound of any one of the compounds described in Table 1, or a prodrug or pharmaceutically acceptable salt thereof.

[0511] In some embodiments, the compound is a deuterium-labeled compound of any one of the compounds described in Table 1 or a pharmaceutically acceptable salt thereof.

[0512] In some embodiments, the compound is a deuterium-labeled compound of any one of the compounds described in Table 1.

[0513] The deuterium-labeled compound is understood to contain deuterium atoms at a deuterium abundance ratio significantly higher than the natural abundance of deuterium, which is 0.015%.

[0514] In some embodiments, the deuterium-labeled compound has a deuterium enrichment factor of at least 3500 (52.5% deuterium incorporation at each deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation) for each deuterium atom. As used herein, the term "deuterium enrichment factor" means the ratio of the abundance of deuterium to the natural abundance of deuterium.

[0515] The deuterium-labeled compound is understood to be preparable using any of a variety of techniques recognized in the art. For example, the deuterium-labeled compound can generally be prepared by substituting a non-deuterium-labeled reagent with a deuterium-labeled reagent and performing the procedures disclosed in the schemes and / or examples described herein.

[0516] The compound of the invention containing the deuterium atom, or a pharmaceutically acceptable salt or solvate thereof, is within the scope of the invention. Further, substitution with deuterium (i.e., 2 H) may provide certain therapeutic advantages resulting from greater metabolic stability, e.g., an extended in vivo half-life or a reduced required dosage.

[0517] For the sake of avoiding misunderstanding, it should be understood that when a group meets the requirement of being "described herein" in this specification, the group encompasses all of the broadest definition described first and the specific definitions for that group.

[0518] Suitable pharmaceutically acceptable salts of the disclosed compounds are, for example, acid addition salts of the disclosed compounds that are sufficiently basic, e.g., acid addition salts with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, formic acid, citric acid, methanesulfonic acid or maleic acid. Further, suitable pharmaceutically acceptable salts of the disclosed compounds that are sufficiently acidic are alkali metal salts such as sodium or potassium salts, alkaline earth metal salts such as calcium or magnesium salts, ammonium salts, or salts with organic bases that yield pharmaceutically acceptable cations such as methylamine, dimethylamine, diethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.

[0519] It will be understood that the compounds of any one of the formulas disclosed herein and any of their pharmaceutically acceptable salts include the stereoisomers of the compounds, mixtures of stereoisomers, and polymorphs of all isomeric forms.

[0520] As used herein, the term "isomer" means compounds that have the same molecular formula but differ in the order of attachment of their atoms or in the arrangement of those atoms in space. Isomers that differ in the arrangement of atoms in space are called "stereoisomers". Stereoisomers that are not mirror images of each other are called "diastereoisomers", and stereoisomers that are mirror images that cannot be superimposed on each other are called "enantiomers" or sometimes optical isomers. A mixture that contains equal amounts of the individual enantiomeric forms with opposite chirality is called a "racemic mixture".

[0521] As used herein, the term "chiral center" refers to an atom bonded to four non-identical substituents.

[0522] As used herein, the term "chiral isomer" means a compound having at least one chiral center. Compounds having more than one chiral center can exist either as individual diastereomers or as a mixture of diastereomers called a "mixture of diastereomers". When there is one chiral center, the stereoisomers can be characterized by the absolute configuration (R or S) of that chiral center. The absolute configuration refers to the spatial arrangement of the substituents bonded to the chiral center. The substituents bonded to the chiral center under consideration are ranked according to the Cahn, Ingold and Prelog sequence rules. (Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahn et al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951 (London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116).

[0523] As used herein, the term "geometric isomer" means a diastereomer that exists due to restricted rotation around a double bond or a cycloalkyl linker (e.g., 1,3-cyclobutyl). These configurations are distinguished by the prefixes cis and trans or Z and E, which indicate whether the groups are on the same side or opposite sides of the double bond in the molecule according to the Cahn-Ingold-Prelog rules.

[0524] It should be understood that the compounds of the present disclosure may be depicted as different chiral or geometric isomers. If a compound has chiral or geometric isomeric forms, it is intended that all such isomeric forms are included within the scope of the present disclosure, and it should also be understood that the names of the compounds do not exclude any isomeric forms, and that not all isomers will have the same level of activity.

[0525] It should be understood that the structures and other compounds considered in the present disclosure include all their atropisomers. It should also be understood that not all atropisomers will have the same level of activity.

[0526] As used herein, the term "atropisomer" refers to a type of stereoisomer in which the atoms of two isomers are differently arranged in space. Atropisomers owe their existence to restricted rotation caused by the hindrance of the rotation of large groups around a central bond. Such atropisomers typically exist as mixtures, but as a result of recent advances in chromatography techniques, it has become possible to separate mixtures of two atropisomers in certain cases.

[0527] As used herein, the term "tautomer" is one of two or more structural isomers that exist in equilibrium and are readily convertible from one isomeric form to another. This conversion results in a formal shift of a hydrogen atom accompanied by the switching of adjacent conjugated double bonds. Tautomers exist as a mixture of a set of tautomers in solution. In a solution where tautomerization is possible, a chemical equilibrium of tautomers will be reached. The exact ratio of tautomers will vary depending on several factors including temperature, solvent, and pH. The concept of tautomers that are interconvertible by tautomerization is called tautomerism. Of the various types of tautomerism that are possible, two are commonly observed. In keto-enol tautomerism, a simultaneous shift of an electron and a hydrogen atom occurs. Ring-chain tautomerism results from the reaction of an aldehyde group (-CHO) in a sugar molecule with one of the hydroxyl groups (-OH) in the same molecule, giving rise to a cyclic (ring-shaped) structure as shown by glucose.

[0528] It should be understood that the compounds of the present disclosure may be depicted as different tautomers. When a compound has tautomeric forms, it is intended that all isomeric forms are included within the scope of the present disclosure, and it should also be understood that the name of the compound does not exclude any tautomeric form. It will be understood that a particular tautomer may have a higher level of activity than others.

[0529] Compounds that have the same molecular formula but differ in the nature or order of atom bonding or in the arrangement of atoms in space are called "isomers". Isomers that differ in the arrangement of atoms in space are called "stereoisomers". Stereoisomers that are not mirror images of each other are called "diastereoisomers", and those that are mirror images that cannot be superimposed on each other are called "enantiomers". When a compound has an asymmetric center, for example, when it is bonded to four different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric center, either by the Cahn and Prelog R and S ranking rules or in the manner in which the molecule rotates the plane of polarization and is designated as dextrorotatory or levorotatory (i.e., the (+) or (-) isomers, respectively). Chiral compounds can exist either as individual enantiomers or as mixtures thereof. A mixture containing enantiomers in equal proportions is called a "racemic mixture".

[0530] The compounds of the present disclosure may have one or more asymmetric centers, and such compounds can thus be produced as individual (R) or (S) stereoisomers or as mixtures thereof. Unless otherwise specified, the description or name of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures such as racemates. Methods for the determination of stereochemistry and the separation of stereoisomers are well known in the art (see the discussion in Chapter 4 of "Advanced Organic Chemistry", 4th edition J. March, John Wiley and Sons, New York, 2001), for example, by synthesis from optically active starting materials or by resolution of the racemic form. Some of the disclosed compounds may have geometric isomeric centers (E and Z isomers). It is to be understood that the present disclosure encompasses all optical, diastereoisomeric, and geometric isomers and mixtures thereof having inflammasome inhibitory activity.

[0531] The present disclosure also encompasses the disclosed compounds as defined herein that contain one or more isotope substitutions.

[0532] Any compound of any formula described herein is to be understood to include the compound itself and, where applicable, its salts and its solvates. For example, salts can be formed between a positively charged group (e.g., amino) on a substituted compound disclosed herein and an anion. Suitable anions include chloride, bromide, iodide, sulfate, bisulfate, sulfamate, nitrate, phosphate, citrate, methanesulfonate, glutamate, glucuronate, glutarate, malate, maleate, succinate, fumarate, tartrate, tosylate, salicylate, lactate, naphthalenesulfonate, and acetate.

[0533] As used herein, the term "pharmaceutically acceptable anion" refers to an anion suitable for forming a pharmaceutically acceptable salt. Similarly, salts can also be formed between a negatively charged group (e.g., carboxylate) on a substituted compound disclosed herein and a cation. Suitable cations include sodium ion, potassium ion, magnesium ion, calcium ion, and ammonium cations such as tetramethylammonium ion or diethylamine ion. Substituted compounds disclosed herein also include those containing a quaternary nitrogen atom.

[0534] It is to be understood that the compounds of the present disclosure, e.g., salts of the compounds, can exist in either hydrated or non-hydrated (anhydrous) form, or as solvates with other solvent molecules. Non-limiting examples of hydrates include monohydrate, dihydrate, etc. Non-limiting examples of solvates include ethanol solvate, acetone solvate, etc.

[0535] As used herein, the term "solvate" means a solvate form containing a stoichiometric or non-stoichiometric amount of a solvent. Some compounds have a tendency to form solvates by entrapping a certain molar ratio of solvent molecules in the crystalline solid state. When the solvent is water, the resulting solvate is a hydrate, and when the solvent is an alcohol, the resulting solvate is an alcoholate. Hydrates are formed by the combination of one or more water molecules with one molecule of a substance, where water retains its molecular state as H2O.

[0536] As used herein, the term "analog" refers to a chemical compound that is structurally similar to another but has a slightly different composition (when one atom is replaced by an atom of another element or when a particular functional group is present, or when one functional group is replaced by another functional group). Thus, an analog is a compound that has similar or equivalent function and appearance but is not similar or equivalent in structure and origin to the reference compound.

[0537] As used herein, the term "derivative" refers to a compound having a common core structure and substituted with various groups described herein.

[0538] As used herein, the term "biological equivalent" refers to a compound resulting from the exchange of an atom or group of atoms with another broadly similar atom or group of atoms. The purpose of replacing with a biological equivalent is to create a new compound having biological properties similar to those of the parent compound. The replacement with a biological equivalent may be based on physicochemical or morphological grounds. Examples of carboxylic acid biological equivalents include, but are not limited to, acylsulfonamides, tetrazoles, sulfonates, and phosphonates. See, for example, Patani and LaVoie, Chem. Rev. 96, 3147-3176, 1996.

[0539] It should also be understood that any one specific compound of the formulas disclosed herein can exist in solvated and unsolvated forms, such as, for example, a hydrated form. Suitable pharmaceutically acceptable solvates are hydrates such as, for example, hemihydrate, monohydrate, dihydrate or trihydrate. The disclosure is to be understood to encompass all such solvated forms having inflammasome inhibitory activity.

[0540] It should also be understood that any one specific compound of the formulas disclosed herein can exhibit polymorphism, and that the disclosure encompasses all such forms or mixtures thereof having inflammasome inhibitory activity. It is generally known that crystalline materials can be analyzed using conventional techniques such as X-ray powder diffraction analysis, differential scanning calorimetry, thermogravimetric analysis, diffuse reflectance infrared Fourier transform (DRIFT) spectroscopy, near infrared (NIR) spectroscopy, solution and / or solid state nuclear magnetic resonance spectroscopy. The water content of such crystalline substances can be determined by Karl Fischer analysis.

[0541] Any one compound of the formulas disclosed herein can exist in a number of different tautomeric forms, and reference to a compound of formula (I) includes all such forms. To avoid misunderstanding, if a compound exists in one of several tautomeric forms and only one is specifically described or shown, all others are still encompassed by formula (I). Examples of tautomeric forms include, for example, the following tautomer pairs: keto / enol (illustrated below), imine / enamine, amide / imino alcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol, and forms of keto, enol, and enolate such as nitro / acyinitro. TIFF2025522354000052.tif23128

[0542] Any one of the compounds of any one of the formulas disclosed herein that contain an amine functional group can also form an N-oxide. References herein to compounds of formula (I) that contain an amine functional group include N-oxides. When a compound contains several amine functional groups, one or more nitrogen atoms may be oxidized to form an N-oxide. Specific examples of N-oxides are N-oxides of tertiary amines or nitrogen atoms of nitrogen-containing heterocycles. N-oxides can be formed by treating the corresponding amine with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid), see, for example, Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages. More specifically, N-oxides can be prepared by the procedure of L. W. Deady (Syn. Comm. 1977, 7, 509-514), where the amine compound is reacted with meta-chloroperoxybenzoic acid (mCPBA) in an inert solvent such as dichloromethane.

[0543] Any one of the compounds of any one of the formulas disclosed herein can be administered in the form of a prodrug that is decomposed in the human or animal body to release the disclosed compound. Prodrugs can be used to alter the physical properties and / or pharmacokinetic properties of the disclosed compound. A prodrug can be formed when the disclosed compound contains a suitable group or substituent to which a group that modifies the property can be attached. Examples of prodrugs include derivatives containing an alkyl or acyl substituent that is cleavable in vivo on the sulfonylurea group in any one of the compounds of any one of the formulas disclosed herein.

[0544] Accordingly, the present disclosure includes a compound of any one of the formulas disclosed herein as defined above when made available by organic synthesis and when made available in the body of a human or animal by cleavage of its prodrug. Accordingly, the present disclosure includes a compound of any one of the formulas disclosed herein produced by organic synthetic means, as well as a compound produced in the body of a human or animal by metabolism of a precursor compound, i.e., a compound of any one of the formulas disclosed herein may be a synthetically produced compound or a metabolically produced compound.

[0545] Suitable pharmaceutically acceptable prodrugs of the compounds of any one of the formulas disclosed herein are based on reasonable medical judgment that they are suitable for administration to the human or animal body without undesirable pharmacological activity and without undue toxicity. Various forms of prodrugs are described, for example, in the following documents: a) Methods in Enzymology, Vol. 42, p.309-396, edited by K. Widder, et al. (Academic Press, 1985); b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985); c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 "Design and Application of Pro-drugs", by H. Bundgaard p. 113-191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); f) N. Kakeya, et al., Chem. Pharm. Bull., 32, 692 (1984); g) T. Higuchi and V. Stella, "Pro-Drugs as Novel Delivery Systems", A.C.S. Symposium Series, Volume 14; and h) E. Roche (editor), "Bioreversible Carriers in Drug Design", Pergamon Press, 1987.

[0546] Suitable pharmaceutically acceptable prodrugs of any one of the compounds of the formulas disclosed herein having a hydroxyl group are, for example, its esters or ethers cleavable in vivo. In vivo cleavable esters or ethers of any one of the compounds of the formulas disclosed herein containing a hydroxyl group are, for example, pharmaceutically acceptable esters or ethers that are cleaved in the human or animal body to produce the parent hydroxy compound. Suitable pharmaceutically acceptable ester-forming groups for a hydroxyl group include inorganic esters such as phosphate esters (including phosphoramidocyclic esters). Further, suitable pharmaceutically acceptable ester-forming groups for a hydroxyl group include C1-C 10 alkanoyl groups, ethoxycarbonyl, N,N-(C1-C6 alkyl)2 carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl groups such as C1-C 10 alkoxycarbonyl groups. Examples of ring substituents on phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4-(C1-C4 alkyl)piperazin-1-ylmethyl. Suitable pharmaceutically acceptable ether-forming groups for a hydroxyl group include α-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.

[0547] Suitable pharmaceutically acceptable prodrugs of any one of the compounds of the formulas disclosed herein having a carboxy group are, for example, its amides cleavable in vivo, for example, amides formed by amines such as ammonia, C1-4 alkylamines such as methylamine, (C1-C4 alkyl)2 amines such as dimethylamine, N-ethyl-N-methylamine or diethylamine, C1-C4 alkoxy-C2-C4 alkylamines such as 2-methoxyethylamine, phenyl-C1-C4 alkylamines such as benzylamine, and amino acids such as glycine or their esters.

[0548] Suitable pharmaceutically acceptable prodrugs of any one of the compounds of any one of the formulas disclosed herein having an amino group are, for example, cleavable amide derivatives thereof in vivo. Suitable pharmaceutically acceptable amides from amino groups include, for example, C1-C 10 Amides formed by alkanoyl groups. Examples of ring substituents on phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl, and 4-(C1-C4 alkyl)piperazin-1-ylmethyl.

[0549] The in vivo effects of any one of the compounds of any one of the formulas disclosed herein may be exerted in part by one or more metabolites formed in the body of a human or animal after administration of any one of the compounds of any one of the formulas disclosed herein. As described above, the in vivo effects of any one of the compounds of any one of the formulas disclosed herein may also be exerted through the metabolism of a precursor compound (prodrug).

[0550] Preferably, the present disclosure excludes any individual compound that does not have the biological activity defined herein.

[0551] Synthesis method In some aspects, the present disclosure provides methods for preparing the compounds of the present disclosure.

[0552] In some aspects, the present disclosure provides methods for compounds that include one or more steps described herein.

[0553] In some aspects, the present disclosure provides compounds that can be obtained, have been obtained, or are directly obtained by a method for preparing the compounds described herein.

[0554] In some aspects, the present disclosure provides intermediates described herein that are suitable for use in methods for preparing the compounds described herein.

[0555] The compounds of the present disclosure can be prepared by any suitable technique known in the art. Specific processes for the preparation of these compounds are further described in the accompanying examples.

[0556] It should be understood that, in the description of the synthetic methods described herein, and in any of the referenced synthetic methods used to prepare starting materials, all proposed reaction conditions, including the choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment, and work-up procedures, can be selected by one of ordinary skill in the art.

[0557] Those skilled in the art of organic synthesis will understand that the functional groups present in the various parts of the molecule must be compatible with the reagents and reaction conditions utilized.

[0558] It will be recognized that in the synthesis of the disclosed compounds in the processes defined herein, or in the synthesis of certain starting materials, it may be desirable to protect certain substituents to prevent their unwanted reactions. A skilled chemist will recognize when such protection is necessary and how such protecting groups can be placed and later removed. For examples of protecting groups, see one of the many general documents on this theme, for example, "Protective Groups in Organic Synthesis" by Theodora Green (Publisher: John Wiley & Sons). The protecting groups can be removed by any convenient method known to the skilled chemist as being described in the literature or appropriate for the removal of the protecting group in question, and such methods are selected to effect the removal of the protecting group while minimizing disruption of groups at other positions within the molecule. Thus, if the reactants contain groups such as, for example, amino, carboxy or hydroxy, it may be desirable to protect the groups in some of the reactions described herein.

[0559] Examples of suitable protecting groups for amino or alkylamino groups include, for example, acyl groups such as alkanoyl groups like acetyl, alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, or t-butoxycarbonyl groups, arylmethoxycarbonyl groups such as benzyloxycarbonyl, or aroyl groups such as benzoyl. The deprotection conditions of the above protecting groups will necessarily vary depending on the choice of the protecting group. Thus, for example, an acyl group such as alkanoyl or an alkoxycarbonyl group or an aroyl group may be removed by hydrolysis with a suitable base such as an alkali metal hydroxide such as lithium hydroxide or sodium hydroxide. Alternatively, an acyl group such as a tert-butoxycarbonyl group may be removed by treatment with a suitable acid such as hydrochloric acid, sulfuric acid, phosphoric acid, or trifluoroacetic acid, and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed by hydrogenation on a catalyst such as palladium carbon or by treatment with a Lewis acid such as boron tris(trifluoroacetate). An alternative protecting group suitable for a primary amino group is, for example, a phthaloyl group that can be removed by treatment with, for example, an alkylamine such as dimethylaminopropylamine or hydrazine.

[0560] Examples of suitable protecting groups for hydroxy groups include, for example, acyl groups such as alkanoyl groups like acetyl, aroyl groups such as benzoyl, or arylmethyl groups such as benzyl. The deprotection conditions of the above protecting groups will necessarily vary depending on the choice of the protecting group. Thus, for example, an acyl group such as alkanoyl or an aroyl group may be removed by hydrolysis with a suitable base such as an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide, or ammonia. Alternatively, an arylmethyl group such as a benzyl group may be removed by hydrogenation on a catalyst such as palladium carbon.

[0561] Suitable protecting groups for carboxy groups are, for example, esterifying groups such as methyl or ethyl groups, which may be removed by hydrolysis with a base such as sodium hydroxide, or, for example, tert-butyl groups, which may be removed by treatment with an acid such as an organic acid like trifluoroacetic acid, or, for example, benzyl groups, which may be removed by hydrogenation on a catalyst such as palladium on carbon.

[0562] After the compound of formula (I) is synthesized by any one of the processes defined herein, the process may further include the following additional steps: (i) a step of removing all protecting groups present; (ii) a step of converting the compound of formula (I) into another compound of formula (I); (iii) a step of forming its pharmaceutically acceptable salt, hydrate or solvate; and / or (iv) a step of forming its prodrug.

[0563] The obtained compound of formula (I) can be isolated and purified using techniques well known in the art.

[0564] In some embodiments, the reaction of the compounds is carried out in the presence of a suitable solvent that is 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, carbon tetrachloride, 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; glycol ethers such as ethylene glycol monomethyl or 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 these solvents or mixtures with water, but are not limited thereto.

[0565] The reaction temperature is preferably in the range of about -100°C to 300°C depending on the reaction steps and conditions used.

[0566] The reaction time generally ranges from a fraction of a minute to several days depending on the reactivity of each compound and each reaction condition. Suitable reaction times can be easily determined by methods known in the art, for example, by monitoring the reaction. Based on the above reaction temperature, the suitable reaction time generally ranges from 10 minutes to 48 hours.

[0567] Furthermore, by utilizing the procedures described herein, additional compounds of the present disclosure can be readily prepared in conjunction with ordinary techniques in the art. Those skilled in the art will readily appreciate that these compounds can be prepared using the conditions of the following preparation procedures and known variations of the processes.

[0568] As will be appreciated by those skilled in organic synthesis, the compounds of the present disclosure are readily accessible by various synthetic routes, some of which are exemplified in the appended examples. Those skilled in the art will readily recognize what types of reagents and reaction conditions should be used to obtain the compounds of the present disclosure, and how they should be applied and adapted, if necessary or useful, in any particular case. Furthermore, some of the compounds of the present disclosure can be readily synthesized by reacting other compounds of the present disclosure under suitable conditions, for example, by applying standard synthetic methods such as reduction, oxidation, addition, or substitution reactions to convert one specific functional group present in a compound of the present disclosure or its appropriate precursor molecule into another; those methods are well known to those skilled in the art. Similarly, those skilled in the art will apply synthetic protecting (or safeguarding) groups if necessary or useful; suitable protecting groups and methods for introducing and removing them are well known to those skilled in chemical synthesis and are described in more detail, for example, in P.G.M. Wuts, T.W. Greene, "Greene's Protective Groups in Organic Synthesis", 4th edition (2006) (John Wiley & Sons).

[0569] The compounds of formula (I) can be prepared as described in the examples.

[0570] In some embodiments, the compounds of formula (I) can be prepared as described in Scheme 1. TIFF2025522354000053.tif77155

[0571] The selected compound of formula (I) can be synthesized according to Scheme 1, where X 1 and X 2 are defined as follows. X 1 is C1-C6 alkyl (e.g., methyl or ethyl), and X 2 is a leaving group (e.g., bromo, chloro, iodo, mesylate or triflate). Step (a) is, for example, a cyanide substitution reaction using sodium cyanide or trimethylsilyl cyanide and a base. Step (b) is, for example, a cyclopropyl ring formation reaction using 1-bromo-2-chloroethane or 1,2-dichloroethane and a suitable base, such as lithium diisopropylamide or sodium hydride. Step (c) is a catalytic introduction of an ester group while heating, for example, using PdCl2(dppf), methanol, carbon monoxide and a base. Step (d) is, for example, a nitrile reduction-cyclization reaction in which the nitrile is reduced using hydrogen and Raney nickel, followed by cyclization under basic conditions, such as an ammonium hydroxide solution. Step (e) is, for example, an alkylation of acetate using ethyl bromoacetate and a base. Step (f) is, for example, a hydrolysis using sodium hydroxide or lithium hydroxide. Step (g) is, for example, an amide coupling reaction using an amine, a base, and an amide coupling reagent such as COMU or HATU. Step (h) is, for example, a conversion from an ester to an amide using an amine and trimethylaluminum, or an amine and a suitable base such as LiHMDS. Step (i) is, for example, an alkylation using the corresponding 2-haloacetamide and a base.

[0572] Biological assay Compounds designed, selected, and / or optimized by the methods described above are, after being manufactured, characterized using various assays known to those skilled in the art to determine whether the compounds have biological activity. For example, the molecules can be characterized by conventional assays including but not limited to the assays described below to determine whether they have the predicted activity, binding activity, and / or binding specificity.

[0573] Furthermore, high-throughput screening can be used to speed up the analysis using such assays. As a result, it becomes possible to rapidly screen the activity of the molecules described herein using techniques known in the art. General methodologies for performing high-throughput screening are described, for example, in Devlin (1998) High Throughput Screening, Marcel Dekker and U.S. Patent No. 5,763,263. High-throughput assays can use one or more different assay techniques including but not limited to those described below.

[0574] Various in vitro or in vivo biological assays can be suitable for detecting the effects of the compounds of the present disclosure. These in vitro or in vivo biological assays include but are not limited to enzyme activity assays, gel shift assays, reporter gene assays, in vitro cell viability assays, and the assays described herein.

[0575] In some embodiments, the biological assay is a biological assay for testing the inhibitory activity against IL-1β release upon NLRP3 activation in peripheral blood mononuclear cells (PBMC).

[0576] In some embodiments, the biological assay is a PBMC IC 50 determination assay. In some embodiments, the biological assay is the PBMC IC described in Example 13 50It is a determination assay.

[0577] In some embodiments, the compounds of the present disclosure can be tested for inhibitory activity against IL-1β release upon NLRP3 activation in blood cells (e.g., peripheral blood mononuclear cells (PBMCs)).

[0578] In some embodiments, PBMCs can be isolated, seeded into wells of a plate, and cultured for a certain period (e.g., with lipopolysaccharides for 3 hours). After culturing, the medium can be exchanged, a compound (e.g., a compound of the present disclosure) can be added to the wells, and the cells can be cultured. Next, the cells can be stimulated (e.g., with ATP or nigericin), and the cell culture medium can be collected for further analysis.

[0579] In some embodiments, the release of IL-1β into the medium can be determined by quantitative detection of IL-1β in the medium (e.g., using ELISA).

[0580] In some embodiments, PBMCs can be isolated (e.g., from a buffy coat). The separated cells can be seeded into wells and cultured (e.g., with lipopolysaccharides for 3 hours). Then a compound of the present disclosure can be added, and the cells can be cultured. Next, the cells can be stimulated, and the medium can be collected from the wells for further analysis.

[0581] In some embodiments, the release of IL-1β into the medium can be determined by quantitative detection (e.g., of IL-1β in the medium using HTRF®).

[0582] Pharmaceutical composition In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure as an active ingredient.

[0583] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound described herein and one or more pharmaceutically acceptable carriers or excipients. In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound selected from Table 1.

[0584] As used herein, the term "composition" is intended to encompass a product that contains specific ingredients in specific amounts, as well as any product that results directly or indirectly from a combination of specific amounts of specific ingredients.

[0585] The compounds of the present disclosure can be formulated for oral administration in forms such as tablets, capsules (each of which includes sustained release or extended release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. The compounds of the present disclosure can also be formulated for intravenous (bolus or infusion), intraperitoneal, topical, subcutaneous, intramuscular, or transdermal (e.g., patch) administration using forms well known to those skilled in the pharmaceutical arts.

[0586] The formulations of the present disclosure may be in the form of an aqueous solution containing an aqueous vehicle. The aqueous vehicle component may include water and at least one pharmaceutically acceptable excipient. Suitable acceptable excipients include those selected from the group consisting of solubilizing agents, chelating agents, preservatives, isotonic agents, viscosity / suspending agents, buffers, and pH adjusters, and mixtures thereof.

[0587] Any suitable solubilizing agent can be used. Examples of solubilizing agents include cyclodextrins such as hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, randomly methylated-β-cyclodextrin, ethylated-β-cyclodextrin, triacetyl-β-cyclodextrin, peracetylated-β-cyclodextrin, carboxymethyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, 2-hydroxy-3-(trimethylammonio)propyl-β-cyclodextrin, glucosyl-β-cyclodextrin, sulfated β-cyclodextrin (S-β-CD), maltosyl-β-cyclodextrin, β-cyclodextrin sulfobutyl ether, branched-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, randomly methylated-γ-cyclodextrin, and trimethyl-γ-cyclodextrin, and those selected from the group consisting of mixtures thereof.

[0588] Any suitable chelating agent can be used. Examples of suitable chelating agents include those selected from the group consisting of ethylenediaminetetraacetic acid and its metal salts, disodium edetate, trisodium edetate, and tetrasodium edetate, and mixtures thereof.

[0589] Any suitable preservative can be used. Examples of preservatives include quaternary ammonium salts such as benzalkonium halide (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetylpyridinium chloride, benzyl bromide, phenylmercuric nitrate, phenylmercuric acetate, phenylmercuric neodecanoate, thimerosal, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethyl p-hydroxybenzoate, propylaminopropylbiguanide, and butyl p-hydroxybenzoate, and sorbic acid, and mixtures thereof.

[0590] The aqueous vehicle may also contain an isotonic agent for adjusting isotonicity (osmotic pressure). The isotonic agent can be selected from the group consisting of glycols (such as propylene glycol, diethylene glycol, triethylene glycol, etc.), glycerol, dextrose, glycerin, mannitol, potassium chloride, and sodium chloride, and mixtures thereof.

[0591] The aqueous vehicle may also contain a viscosity / suspending agent. Suitable viscosity / suspending agents include cellulose derivatives such as methylcellulose, ethylcellulose, hydroxyethylcellulose, polyethylene glycols (such as polyethylene glycol 300, polyethylene glycol 400, etc.), carboxymethylcellulose, hydroxypropylmethylcellulose, and cross-linked acrylic acid polymers (carbomers) cross-linked with polyalkenyl ethers or divinyl glycol, such as Carbopol (such as Carbopol 934, Carbopol 934P, Carbopol 971, Carbopol 974, and Carbopol 974P), and mixtures thereof.

[0592] To adjust the formulation to an acceptable pH (typically in the pH range of about 5.0 to about 9.0, more preferably about 5.5 to about 8.5, particularly about 6.0 to about 8.5, about 7.0 to about 8.5, about 7.2 to about 7.7, about 7.1 to about 7.9, or about 7.5 to about 8.0), the formulation may contain a pH adjuster. The pH adjuster is typically selected from the group of mineral acids or metal hydroxide bases, preferably sodium hydroxide and / or hydrochloric acid, such as potassium hydroxide, sodium hydroxide, and hydrochloric acid, and mixtures thereof. These acidic and / or basic pH adjusters are added to adjust the formulation to the target acceptable pH range. Thus, it may not be necessary to use both an acid and a base depending on the formulation, and the addition of one of the acid or base may be sufficient to bring the mixture to the desired pH range.

[0593] The aqueous vehicle may also contain a buffering agent to stabilize the pH. When used, the buffering agent is selected from the group consisting of phosphate buffers (such as sodium dihydrogen phosphate and disodium hydrogen phosphate), borate buffers (such as boric acid or its salts containing disodium tetraborate), citrate buffers (such as citric acid or its salts containing sodium citrate), and ε-aminocaproic acid, and mixtures thereof.

[0594] The formulation may further contain a wetting agent. Suitable classes of wetting agents include those selected from the group consisting of polyoxypropylene-polyoxyethylene block copolymers (poloxamers), polyethoxylated ethers of castor oil, polyoxyethylated sorbitan esters (polysorbates), polymers of oxyethylated octylphenol (tyloxapol), polyoxyl 40 stearate, fatty acid glycol esters, fatty acid glyceryl esters, sucrose fatty esters, and polyoxyethylene fatty acid esters, and mixtures thereof.

[0595] Oral compositions generally contain an inert diluent or an edible pharmaceutically acceptable carrier. They can be encapsulated in gelatin capsules or tableted. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, and the compound in the fluid carrier is applied orally, swished, and either spat out or swallowed. Pharmaceutically compatible binders and / or auxiliary substances can be included as part of the composition. Tablets, pills, capsules, troches, etc. can contain any of the following ingredients: binders such as microcrystalline cellulose, tragacanth gum, or gelatin; excipients such as starch or lactose; disintegrants such as alginic acid, Primogel, or corn starch; lubricants such as magnesium stearate or Sterotes; glidants such as colloidal silicon dioxide; sweetening agents such as sucrose or saccharin; or flavoring agents such as peppermint, methyl salicylate, or orange flavor, or compounds of a similar nature.

[0596] According to a further aspect of the disclosure, there is provided a pharmaceutical composition comprising the disclosed compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in combination with a pharmaceutically acceptable diluent or carrier.

[0597] The disclosed compositions may be in a form suitable for oral use (for example, as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), topical use (for example, as creams, ointments, gels, or aqueous or oily solutions or suspensions), administration by inhalation (for example, as micronized powders or liquid aerosols), administration by insufflation (for example, as micronized powders) or parenteral administration (for example, as sterile aqueous or oily solutions for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular injection, or as suppositories for rectal administration).

[0598] The disclosed compositions may be obtained by conventional procedures using conventional pharmaceutical excipients well known in the art. Thus, compositions intended for oral use may contain, for example, one or more colorants, sweeteners, flavoring agents and / or preservatives.

[0599] An effective amount of the compounds of the present disclosure for use in therapy is an amount sufficient to treat or prevent the inflammasome-related conditions mentioned herein, slow their progression, and / or reduce the symptoms associated with the condition.

[0600] The dosage of the compounds of formula (I) for therapeutic or prophylactic purposes will of course vary according to the nature and severity of the condition, the age and sex of the animal or patient, and the route of administration, in accordance with well-known medical principles.

[0601] Method of Use In some aspects, the present disclosure provides a method of inhibiting inflammasome (for example, NLRP3 inflammasome) activity (for example, in vitro or in vivo), comprising contacting a cell with an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0602] 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 a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0603] In some aspects, the present disclosure provides a method of treating or preventing a disease or disorder disclosed herein in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present disclosure.

[0604] In some aspects, the present disclosure provides a method of treating or preventing a disease or disorder disclosed herein in a subject, comprising administering to the subject in need thereof a compound of the present disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present disclosure.

[0605] In some embodiments, the disease or disorder is associated with an associated inflammasome activity. In some embodiments, the disease or disorder is a disease or disorder with which inflammasome activity is associated.

[0606] In some embodiments, the disease or disorder is an inflammatory disorder, an autoinflammatory disorder, an autoimmune disorder, a neurodegenerative disease, or cancer.

[0607] In some embodiments, the disease or disorder is an inflammatory disorder, an autoinflammatory disorder, and / or an autoimmune disorder.

[0608] In some embodiments, the disease or disorder is cytokine release syndrome (CRS).

[0609] In some embodiments, the disease or disorder is selected from neuroinflammation occurring in cryopyrin-associated autoinflammatory syndromes (CAPS; e.g., familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurologic cutaneous articular (CINCA) syndrome / neonatal-onset multisystem inflammatory disease (NOMID)), familial Mediterranean fever (FMF), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), gout, rheumatoid arthritis, osteoarthritis, Crohn's disease, chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD), fibrosis, obesity, type 2 diabetes, multiple sclerosis, skin diseases (e.g., acne), and protein misfolding diseases (e.g., prion diseases).

[0610] In some embodiments, the disease or disorder is a neurodegenerative disease.

[0611] In some embodiments, the disease or disorder is Parkinson's disease or Alzheimer's disease.

[0612] In some embodiments, the disease or disorder is a skin disease.

[0613] In some embodiments, the skin disease is acne.

[0614] In some embodiments, the disease or disorder is cancer.

[0615] In some embodiments, the cancer is metastatic cancer, gastrointestinal cancer, skin cancer, non-small cell lung cancer, brain cancer (e.g., glioblastoma), or colorectal adenocarcinoma.

[0616] In some aspects, the present disclosure provides a method of treating or preventing an autoinflammatory disorder, an autoimmune disorder, a neurodegenerative disorder, or cancer in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present disclosure.

[0617] In some aspects, the present disclosure provides a method of treating or preventing an autoinflammatory disorder, an autoimmune disorder, a neurodegenerative disorder, or cancer in a subject, comprising administering to the subject in need thereof a compound of the present disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present disclosure.

[0618] In some aspects, the present disclosure provides a method of treating an autoinflammatory disorder, an autoimmune disorder, a neurodegenerative disorder, or cancer in a subject, comprising administering to the subject in need thereof a compound of the present disclosure or a pharmaceutically acceptable salt thereof or a therapeutically effective amount of a pharmaceutical composition of the present disclosure.

[0619] In some aspects, the present disclosure provides a method of treating an autoinflammatory disorder, an autoimmune disorder, a neurodegenerative disorder, or cancer in a subject, comprising administering to the subject in need thereof a compound of the present disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present disclosure.

[0620] In some aspects, the present disclosure provides a method of treating or preventing an inflammatory disorder, an autoinflammatory disorder, and / or an autoimmune disorder selected from neuroinflammation occurring in cryopyrin-associated periodic syndromes (CAPS; e.g., familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurologic cutaneous articular (CINCA) syndrome / neonatal-onset multisystem inflammatory disease (NOMID)), familial Mediterranean fever (FMF), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), gout, rheumatoid arthritis, osteoarthritis, Crohn's disease, chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD), fibrosis, obesity, type 2 diabetes, multiple sclerosis, skin diseases (e.g., acne), and protein misfolding diseases (e.g., prion diseases) in a subject in need thereof, the method comprising administering to the subject a compound of the present disclosure or a pharmaceutically acceptable salt thereof or a therapeutically effective amount of a pharmaceutical composition of the present disclosure.

[0621] In some aspects, the present disclosure provides a method of treating or preventing an inflammatory disorder, an autoinflammatory disorder, and / or an autoimmune disorder selected from neuroinflammation occurring in cryopyrin-associated periodic syndromes (CAPS; e.g., familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurologic cutaneous articular (CINCA) syndrome / neonatal-onset multisystem inflammatory disease (NOMID)), familial Mediterranean fever (FMF), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), gout, rheumatoid arthritis, osteoarthritis, Crohn's disease, chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD), fibrosis, obesity, type 2 diabetes, multiple sclerosis, skin diseases (e.g., acne), and protein misfolding diseases (e.g., prion diseases) in a subject in need thereof, the method comprising administering to the subject a compound of the present disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutically composition of the present disclosure in a therapeutically effective amount.

[0622] In some aspects, the present disclosure provides a method of treating an inflammatory disorder, an autoinflammatory disorder, and / or an autoimmune disorder selected from neuroinflammation occurring in cryopyrin-associated periodic syndromes (CAPS; e.g., familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurologic cutaneous articular (CINCA) syndrome / neonatal-onset multisystem inflammatory disease (NOMID)), familial Mediterranean fever (FMF), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), gout, rheumatoid arthritis, osteoarthritis, Crohn's disease, chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD), fibrosis, obesity, type 2 diabetes, multiple sclerosis, skin diseases (e.g., acne), and protein misfolding diseases (e.g., prion diseases) in a subject in need thereof, the method comprising administering to the subject a compound of the present disclosure or a pharmaceutically acceptable salt thereof or a therapeutically effective amount of a pharmaceutically composition of the present disclosure.

[0623] In some aspects, the present disclosure provides a method of treating an inflammatory disorder, an autoinflammatory disorder, and / or an autoimmune disorder selected from neuroinflammation occurring in cryopyrin-associated autoinflammatory syndromes (CAPS; e.g., familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurologic cutaneous articular (CINCA) syndrome / neonatal-onset multisystem inflammatory disease (NOMID)), familial Mediterranean fever (FMF), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), gout, rheumatoid arthritis, osteoarthritis, Crohn's disease, chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD), fibrosis, obesity, type 2 diabetes, multiple sclerosis, skin diseases (e.g., acne), and protein misfolding diseases (e.g., prion diseases) in a subject in need thereof, the method comprising administering to the subject a compound of the present disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present disclosure.

[0624] In some aspects, the present disclosure provides a method of treating or preventing cytokine release syndrome (CRS) in a subject in need thereof, the method comprising administering to the subject a compound of the present disclosure or a pharmaceutically acceptable salt thereof or a therapeutically effective amount of a pharmaceutical composition of the present disclosure. In some embodiments, CRS is associated with COVID-19. In some embodiments, CRS is associated with adoptive cell therapy.

[0625] In some aspects, the present disclosure provides a method of treating or preventing cytokine release syndrome (CRS) in a subject in need thereof, the method comprising administering to the subject a compound of the present disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present disclosure. In some embodiments, CRS is associated with COVID-19. In some embodiments, CRS is associated with adoptive cell therapy.

[0626] In some aspects, the present disclosure provides a method of treating cytokine release syndrome (CRS) in a subject in need thereof, the method comprising administering to the subject a compound of the present disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutically effective amount of a pharmaceutical composition of the present disclosure. In some embodiments, the CRS is associated with COVID-19. In some embodiments, the CRS is associated with adoptive cell therapy.

[0627] In some aspects, the present disclosure provides a method of treating cytokine release syndrome (CRS) in a subject in need thereof, the method comprising administering to the subject a compound of the present disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present disclosure. In some embodiments, the CRS is associated with COVID-19. In some embodiments, the CRS is associated with adoptive cell therapy.

[0628] In some aspects, the present disclosure provides a method of treating or preventing a neurodegenerative disease (e.g., Parkinson's disease or Alzheimer's disease) in a subject in need thereof, the method comprising administering to the subject a compound of the present disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutically effective amount of a pharmaceutical composition of the present disclosure.

[0629] In some aspects, the present disclosure provides a method of treating or preventing a neurodegenerative disease (e.g., Parkinson's disease or Alzheimer's disease) in a subject in need thereof, the method comprising administering to the subject a compound of the present disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present disclosure.

[0630] In some aspects, the present disclosure provides a method of treating a neurodegenerative disease (e.g., Parkinson's disease or Alzheimer's disease) in a subject in need thereof, the method comprising administering to the subject a pharmaceutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present disclosure.

[0631] In some aspects, the present disclosure provides a method of treating a neurodegenerative disease (e.g., Parkinson's disease or Alzheimer's disease) in a subject in need thereof, the method comprising administering to the subject a compound of the present disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present disclosure.

[0632] In some aspects, the present disclosure provides a method of treating or preventing cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present disclosure.

[0633] In some aspects, the present disclosure provides a method of treating or preventing cancer in a subject in need thereof, the method comprising administering to the subject a compound of the present disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present disclosure.

[0634] In some aspects, the present disclosure provides a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present disclosure.

[0635] In some aspects, the present disclosure provides a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a compound of the present disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present disclosure.

[0636] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in modulating inflammasome (e.g., NLRP3 inflammasome) activity (e.g., in vitro or in vivo).

[0637] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of a disease or disorder disclosed herein.

[0638] In some aspects, the present disclosure provides the compounds of the present disclosure or pharmaceutically acceptable salts thereof for use in the treatment of the diseases or disorders disclosed herein.

[0639] In some aspects, the present disclosure provides the compounds of the present disclosure or pharmaceutically acceptable salts thereof for use in the treatment or prevention of inflammatory disorders, autoinflammatory disorders, autoimmune disorders, neurodegenerative diseases, or cancer in a subject in need thereof.

[0640] In some aspects, the present disclosure provides the compounds of the present disclosure or pharmaceutically acceptable salts thereof for use in the treatment of inflammatory disorders, autoinflammatory disorders, autoimmune disorders, neurodegenerative diseases, or cancer in a subject in need thereof.

[0641] In some aspects, the present disclosure provides the compounds of the present disclosure or pharmaceutically acceptable salts thereof for use in the treatment or prevention of inflammatory disorders, autoinflammatory disorders, and / or autoimmune disorders selected from cryopyrin-associated periodic syndromes (CAPS; e.g., familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurologic cutaneous 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, and neuroinflammation occurring in protein misfolding diseases (e.g., prion diseases) in a subject in need thereof.

[0642] In some aspects, the present disclosure provides the compounds of the present disclosure or pharmaceutically acceptable salts thereof for use in the treatment of inflammatory disorders, autoinflammatory disorders and / or autoimmune disorders selected from cryopyrin-associated periodic syndromes (CAPS; e.g., familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurologic cutaneous 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, and neuroinflammation occurring in protein misfolding diseases (e.g., prion diseases) in a subject in need thereof.

[0643] In some aspects, the present disclosure provides the compounds of the present disclosure or pharmaceutically acceptable salts thereof for use in the treatment or prevention of CRS in a subject in need thereof.

[0644] In some aspects, the present disclosure provides the compounds of the present disclosure or pharmaceutically acceptable salts thereof for use in the treatment of CRS in a subject in need thereof.

[0645] In some aspects, the present disclosure provides the compounds of the present disclosure or pharmaceutically acceptable salts thereof for use in the treatment or prevention of neurodegenerative diseases (e.g., Parkinson's disease or Alzheimer's disease) in a subject in need thereof.

[0646] In some aspects, the present disclosure provides the compounds of the present disclosure or pharmaceutically acceptable salts thereof for use in the treatment of neurodegenerative diseases (e.g., Parkinson's disease or Alzheimer's disease) in a subject in need thereof.

[0647] In some aspects, the present disclosure provides the compounds of the present disclosure or pharmaceutically acceptable salts thereof for use in the treatment or prevention of cancer in a subject in need thereof.

[0648] In some aspects, the disclosure provides the compounds of the disclosure or pharmaceutically acceptable salts thereof for use in the treatment of cancer in a subject in need thereof.

[0649] In some aspects, the disclosure provides the use of the compounds of the disclosure or pharmaceutically acceptable salts thereof in the manufacture of a medicament for inhibiting inflammasome (e.g., NLRP3 inflammasome) activity (e.g., in vitro or in vivo).

[0650] In some aspects, the disclosure provides the use of the compounds of the disclosure or pharmaceutically acceptable salts thereof in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0651] In some aspects, the disclosure provides the use of the compounds of the disclosure or pharmaceutically acceptable salts thereof in the manufacture of a medicament for treating a disease or disorder disclosed herein.

[0652] In some aspects, the disclosure provides the use of the compounds of the disclosure or pharmaceutically acceptable salts thereof in the manufacture of a medicament for treating or preventing an inflammatory disorder, an autoinflammatory disorder, an autoimmune disorder, a neurodegenerative disease, or cancer in a subject in need thereof.

[0653] In some aspects, the disclosure provides the use of the compounds of the disclosure or pharmaceutically acceptable salts thereof in the manufacture of a medicament for treating an inflammatory disorder, an autoinflammatory disorder, an autoimmune disorder, a neurodegenerative disease, or cancer in a subject in need thereof.

[0654] In some aspects, the present disclosure provides for the use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing an inflammatory disorder, an autoinflammatory disorder, and / or an autoimmune disorder selected from neuroinflammation occurring in cryopyrin-associated periodic syndromes (CAPS; e.g., familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurologic cutaneous articular (CINCA) syndrome / neonatal-onset multisystem inflammatory disease (NOMID)), familial Mediterranean fever (FMF), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), gout, rheumatoid arthritis, osteoarthritis, Crohn's disease, chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD), fibrosis, obesity, type 2 diabetes, multiple sclerosis, skin disorders (e.g., acne), and protein misfolding diseases (e.g., prion diseases) in a subject in need thereof.

[0655] In some aspects, the present disclosure provides for the use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing an inflammatory disorder, an autoinflammatory disorder, and / or an autoimmune disorder selected from neuroinflammation occurring in cryopyrin-associated periodic syndromes (CAPS; e.g., familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurologic cutaneous articular (CINCA) syndrome / neonatal-onset multisystem inflammatory disease (NOMID)), familial Mediterranean fever (FMF), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), gout, rheumatoid arthritis, osteoarthritis, Crohn's disease, chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD), fibrosis, obesity, type 2 diabetes, multiple sclerosis, skin disorders (e.g., acne), and protein misfolding diseases (e.g., prion diseases) in a subject in need thereof.

[0656] In some aspects, the present disclosure provides for the use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing CRS in a subject in need thereof.

[0657] In some aspects, the present disclosure provides the use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating CRS in a subject in need thereof.

[0658] In some aspects, the present disclosure provides the use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a neurodegenerative disease (such as Parkinson's disease or Alzheimer's disease) in a subject in need thereof.

[0659] In some aspects, the present disclosure provides the use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a neurodegenerative disease (such as Parkinson's disease or Alzheimer's disease) in a subject in need thereof.

[0660] In some aspects, the present disclosure provides the use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing cancer in a subject in need thereof.

[0661] In some aspects, the present disclosure provides the use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating cancer in a subject in need thereof.

[0662] The present disclosure provides compounds that function as inhibitors of inflammasome activity. Accordingly, the present disclosure provides a method of inhibiting inflammasome activity in vitro or in vivo, comprising the step of contacting a cell with an effective amount of a compound as defined herein or a pharmaceutically acceptable salt thereof.

[0663] The efficacy of the disclosed compounds can be determined according to standard methods for elucidating this, by industry-accepted assays / disease models described in the art and found in current general knowledge.

[0664] The present disclosure also provides a method of treating a disease or disorder associated with inflammasome activity in a patient in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

[0665] At a general level, the compounds of the present disclosure that inhibit the maturation of IL-1 family cytokines are effective in all therapeutic indications mediated by or associated with an increase in the level of active cytokines belonging to the IL-1 family of cytokines (Sims J. et al. Nature Reviews Immunology 10, 89-102 (February 2010)).

[0666] Exemplary diseases and corresponding references are shown below: inflammatory, autoinflammatory and autoimmune diseases, such as CAPS (Dinarello, C. A. Immunity. 2004 Mar; 20(3):243-4; Hoffman, H. M. et al. Reumatologia 2005; 21(3)), gout, rheumatoid arthritis (Gabay, C. et al. Arthritis Research & Therapy 2009, 11:230; Schett, G. et al. Nat Rev Rheumatol. 2016 Jan; 12(1):14-24.), Crohn's disease (Jung Mogg Kim Korean J. Gastroenterol. Vol. 58 No. 6, 300-310), COPD (Mortaz, E. et al. Tanaffos. 2011; 10(2): 9-14.), fibrosis (Gasse, P. et al. Am. J. Respir. Crit. Care Med. 2009 May 15; 179(10):903-13), obesity, type 2 diabetes ((Dinarello, C. A. et al. Curr. Opin. Endocrinol. Diabetes Obes. 2010 Aug; 17(4):314-21)) multiple sclerosis (see the EAE model in Coll, R. C. et al. Nat. Med. 2015 Mar; 21(3):248-55) and many others (Martinon, F. et al. Immunol. 2009. 27:229-65), such as Parkinson's disease or Alzheimer's disease (Michael, T. et al. Nature 493, 674-678 (31 January 2013); Halle, A. et al., Nat. Immunol. 2008 Aug;9(8):857-65; Saresella, M. et al. Mol. Neurodegener. 2016 Mar 3;11:23) and some neoplastic diseases.

[0667] Preferably, the compounds according to the present disclosure can be used for the treatment of diseases selected from the group consisting of cytokine release syndrome (CRS), inflammatory diseases, autoinflammatory diseases, autoimmune diseases, neurodegenerative diseases, and cancer. The inflammatory, autoinflammatory and autoimmune diseases are preferably selected from the group consisting of cryopyrin-associated periodic syndromes (CAPS, such as familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurologic cutaneous articular (CINCA) syndrome / neonatal-onset multisystem inflammatory disease (NOMID)), familial Mediterranean fever (FMF), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), chronic kidney disease (CKD), gout, rheumatoid arthritis, osteoarthritis, Crohn's disease, COPD, fibrosis, obesity, type 2 diabetes, multiple sclerosis, skin diseases (such as acne), and protein misfolding diseases, such as neuroinflammation occurring in prion diseases. The neurodegenerative diseases include, but are not limited to, Parkinson's disease and Alzheimer's disease.

[0668] Thus, the compounds of the present disclosure can be used for the treatment of diseases selected from the group consisting of cryopyrin-associated periodic syndromes (CAPS, such as familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurologic cutaneous articular (CINCA) syndrome / neonatal-onset multisystem inflammatory disease (NOMID)), familial Mediterranean fever (FMF), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), chronic kidney disease (CKD), gout, rheumatoid arthritis, osteoarthritis, Crohn's disease, COPD, fibrosis, obesity, type 2 diabetes, multiple sclerosis, skin diseases (such as acne), and protein misfolding diseases, such as neuroinflammation occurring in prion diseases, neurodegenerative diseases (such as Parkinson's disease, Alzheimer's disease) and neoplastic diseases.

[0669] Inflammatory diseases associated with infectious diseases In some embodiments, the disease or disorder is an inflammatory disease.

[0670] In some embodiments, the inflammatory disease is associated with an infectious disease.

[0671] In some embodiments, the inflammatory disease is associated with a viral infectious disease.

[0672] In some embodiments, the inflammatory disease is associated with an infection by an RNA virus. In some embodiments, the RNA virus is a single-stranded RNA virus. Single-stranded RNA viruses include Group 4 (plus-strand) and Group 5 (minus-strand) single-stranded RNA viruses. Group 4 viruses include coronaviruses.

[0673] In some embodiments, the inflammatory disease is associated with an infection by a coronavirus. In some embodiments, the coronavirus is severe acute respiratory syndrome coronavirus 2 (SARS-CoV 2), SARS coronavirus (SARS CoV) or Middle East respiratory syndrome-related coronavirus (MERS).

[0674] In some embodiments, the inflammatory disease is associated with an infection by SARS-CoV 2. In some embodiments, the SARS-CoV 2 infection results in coronavirus disease 2019 (COVID-19).

[0675] In some embodiments, the inflammatory disease is a pulmonary inflammatory disease.

[0676] In some embodiments, the pulmonary inflammatory disease is associated with an infection by SARS-CoV 2.

[0677] In some embodiments, the inflammatory disease includes cytokine release syndrome (CRS).

[0678] In some embodiments, cytokine release syndrome (CRS) is associated with an infection by SARS-CoV 2.

[0679] Cytokine Release Syndrome and Immunotherapy In some embodiments, the disease or disorder is an inflammatory disease.

[0680] In some embodiments, the inflammatory disease is associated with immunotherapy.

[0681] In some embodiments, the immunotherapy causes cytokine release syndrome (CRS).

[0682] The effectiveness of immunotherapies such as CAR-T is hampered by the frequency with which such therapies induce cytokine release syndrome. Without wishing to be bound by theory, the severity of CRS induced by immunotherapy is thought to be mediated by the production of IL-6, IL-1 and NO (Giavridis et al. Nature Medicine; doi.org / 10.1038 / s41591-018-0041-7). Alternatively, or in addition, CRS may occur when the cells targeted by adoptive cell therapy undergo pyroptosis, which is a highly inflammatory form of programmed cell death. Pyroptosis results in the release of factors that stimulate macrophages to produce inflammatory cytokines, leading to CRS (Liu et al. Science Immunology (2020) V: eeax7969).

[0683] In some embodiments, the immunotherapy includes an antibody or adoptive cell therapy.

[0684] In some embodiments, the adoptive cell therapy includes CAR-T or TCR-T cell therapy.

[0685] In some embodiments, the adoptive cell therapy includes cancer treatment. For example, the cancer treatment may be for treating B cell lymphoma or B cell acute lymphoblastic leukemia. For example, the adoptive cells may express a CAR that targets CD19+ B cell acute lymphoblastic leukemia cells.

[0686] In some embodiments, the adoptive cell therapy includes administration of T cells, B cells or NK cells.

[0687] In some embodiments, the adoptive cell therapy is autologous.

[0688] In some embodiments, the adoptive therapy is allogeneic.

[0689] Cancer treatment; Association with inflammasome Chronic inflammatory responses have long been observed to be associated with various types of cancer. During malignant transformation or cancer therapy, the inflammasome may be activated in response to danger signals, and this activation can be either beneficial or harmful to cancer.

[0690] The expression of IL-1β is elevated in various cancers (including breast, prostate, colon, lung, head and neck cancers, and melanoma), and patients with IL-1β-producing tumors generally have a worse prognosis (Lewis, Anne M., et al. "Interleukin-1 and cancer progression: the emerging role of interleukin-1 receptor antagonist as a novel therapeutic agent in cancer treatment." Journal of translational medicine 4.1 (2006): 48).

[0691] Cancers derived from epithelial cells (carcinomas) or cancers derived from glandular epithelium (adenocarcinomas) are heterogeneous and composed of many different cell types. This can include, among other things, fibroblasts, immune cells, adipocytes, endothelial cells, and pericytes, all of which can secrete cytokines / chemokines (Grivennikov, Sergei I., Florian R. Greten, and Michael Karin. "Immunity, inflammation, and cancer." Cell 140.6 (2010): 883-899). This can cause inflammation associated with cancer through infiltration of immune cells. The presence of leukocytes within tumors is known, but it is only very recently that it has become clear that an inflammatory microenvironment is an essential element of all tumors. Most tumors (>90%) are the result of somatic mutations or environmental factors rather than germline mutations, and many of the environmental causes of cancer are associated with chronic inflammation (20% of cancers are associated with chronic infections, 30% are associated with smoking / inhaled pollutants, and 35% are associated with dietary factors (20% of all cancers are associated with obesity) (Aggarwal, Bharat B., R. V. Vijayalekshmi, and Bokyung Sung. "Targeting inflammatory pathways for prevention and therapy of cancer: short-term friend, long-term foe." Clinical Cancer Research 15.2 (2009): 425-430).

[0692] GI cancer Gastrointestinal (GI) tract cancers are often associated with chronic inflammation. For example, Helicobacter pylori infection is associated with gastric cancer (Amieva, Manuel, and Richard M. Peek. "Pathobiology of Helicobacter pylori-Induced Gastric Cancer." Gastroenterology 150.1 (2016): 64-78). Colorectal cancer is associated with inflammatory bowel disease (Bernstein, Charles N., et al. "Cancer risk in patients with inflammatory bowel disease." Cancer 91.4 (2001): 854-862). Chronic gastric inflammation leads to upregulation of IL-1 and other cytokines (Basso, D. et al., (1996) Helicobacter pylori infection enhances mucosal interleukin-1 beta, interleukin-6, and the soluble receptor of interleukin-2. Int J Clin Lab Res 26:207-210), and polymorphisms in the IL-1β gene may increase the risk of gastric cancer (Wang, P. et al., (2007) Association of interleukin-1 gene polymorphisms with gastric cancer: a meta-analysis. Int J Cancer 120:552-562).

[0693] Caspase-1 expression is decreased in 19% of gastric cancer cases, which correlates with stage, lymph node metastasis, and survival rate (Jee et al., 2005). Mycoplasma hyorhinis is associated with the development of gastric cancer, and its NLRP3 inflammasome activation may be associated with promoting gastric cancer metastasis (Xu et al., 2013).

[0694] Skin cancer Ultraviolet light is the greatest environmental risk factor for skin cancer, which is promoted by causing DNA damage, immunosuppression, and inflammation. Melanoma, the most malignant form of skin cancer, is characterized by the upregulation of inflammatory cytokines, all of which can be regulated by IL-1β (Lazar-Molnar, Eszter, et al. "Autocrine and paracrine regulation by cytokines and growth factors in melanoma." Cytokine 12.6 (2000): 547-554). Systemic inflammation induces increased metastasis and growth of melanoma cells by IL-1-dependent mechanisms in vivo. Using thymoquinone, it has been shown that the inhibition of metastasis in the B16F10 mouse melanoma model is dependent on the inhibition of the NLRP3 inflammasome (Ahmad, Israr, et al. "Thymoquinone suppresses metastasis of melanoma cells by inhibition of NLRP3 inflammasome." Toxicology and applied pharmacology 270.1 (2013): 70-76).

[0695] Glioblastoma NLRP3 contributes to radiotherapy resistance in glioblastoma. Ionizing radiation can induce NLRP3 expression, but NLRP3 inhibition reduces tumor growth and prolongs the survival of mice after radiotherapy. Therefore, NLRP3 inflammasome inhibition may provide a therapeutic strategy for radiation-resistant glioblastoma (Li, Lianling, and Yuguang Liu. "Aging-related gene signature regulated by Nlrp3 predicts glioma progression." American journal of cancer research 5.1 (2015): 442).

[0696] Metastasis More generally, Applicants believe that NLRP3 is involved in promoting metastasis and that as a result, modulation of NLRP3 should credibly prevent this. IL-1 is involved in tumorigenesis, tumor invasiveness, metastasis, tumor-host interactions (Apte, Ron N., et al. "The involvement of IL-1 in tumorigenesis, tumour invasiveness, metastasis and tumour-host interactions." Cancer and Metastasis Reviews 25.3 (2006): 387-408) and angiogenesis (Voronov, Elena, et al. "IL-1 is required for tumor invasiveness and angiogenesis." Proceedings of the National Academy of Sciences 100.5 (2003): 2645-2650).

[0697] The IL-1 gene is often expressed in metastases from patients with several types of human cancer. For example, IL-1 mRNA is highly expressed in more than half of all examined metastatic human tumor samples, specifically including tumor samples from non-small cell lung cancer, colorectal adenocarcinoma, and melanoma (Elaraj, Dina M., et al. "The role of interleukin 1 in growth and metastasis of human cancer xenografts." Clinical Cancer Research 12.4 (2006): 1088-1096), and IL-1RA inhibits the growth of xenografts in IL-1-producing tumors but has no anti-proliferative effect in vitro.

[0698] Furthermore, IL-1 signaling is a biomarker for predicting breast cancer patients at increased risk of developing bone metastasis. In a mouse model, in breast cancer cells that metastasize to bone, IL-1β and its receptor are upregulated compared to non-metastatic cells. In a mouse model, anakinra, an IL-1 receptor antagonist, not only has a significant effect on the tumor microenvironment that reduces bone metabolism markers IL-1β and TNF alpha, but also reduces proliferation and angiogenesis (Holen, Ingunn, et al. "IL-1 drives breast cancer growth and bone metastasis in vivo." Oncotarget (2016).

[0699] IL-18 induced the production of MMP-9 in the human leukemia cell line HL-60, and thus promoted the degradation of the extracellular matrix and the migration and invasion of cancer cells (Zhang, Bin, et al. "IL-18 increases invasiveness of HL-60 myeloid leukemia cells: up-regulation of matrix metalloproteinases-9 (MMP-9) expression." Leukemia research 28.1 (2004): 91-95). Furthermore, IL-18 can support the progression of tumor metastasis in the liver by inducing the expression of VCAM-1 on liver sinusoidal endothelial cells (Carrascal, Maria Teresa, et al. "Interleukin-18 binding protein reduces b16 melanoma hepatic metastasis by neutralizing adhesiveness and growth factors of sinusoidal endothelium." Cancer Research 63.2 (2003): 491-497).

[0700] CD36 The fatty acid scavenger receptor CD36 plays a dual role in priming the gene transcription of pro-IL-1β and inducing the construction of the NLRP3 inflammasome complex. CD36 and the TLR4-TLR6 heterodimer recognize oxLDL, which initiates a signaling pathway that leads to the transcriptional upregulation of NLRP3 and pro-IL-1β (signal 1). CD36 also mediates the internalization of oxLDL into the lysosomal compartment, where crystals are formed that induce lysosomal rupture and the activation of the NLRP3 inflammasome (signal 2) (Kagan, J. and Horng T., "NLRP3 inflammasome activation: CD36 serves double duty." Nature immunology 14.8 (2013): 772-774).

[0701] Subpopulations of human oral cancer cells express high levels of the fatty acid scavenger receptor CD36 and are characterized by the ability to initiate metastasis. Palmitic acid or a high-fat diet enhanced the metastatic ability of CD36+ cells. Neutralizing anti-CD36 antibodies blocked metastasis in an orthotopic mouse model of human oral cancer. The presence of CD36+ metastasis-initiating cells correlates with poor prognosis in many types of cancer. It is suggested that dietary lipids may promote metastasis (Pasqual, G, Avgustinova, A., Mejetta, S, Martin, M, Castellanos, A, Attolini, CS-O, Berenguer, A., Prats, N, Toll, A, Hueto, JA, Bescos, C, Di Croce, L, and Benitah, SA. 2017 "Targeting metastasis-initiating cells through the fatty acid receptor CD36" Nature 541:41-45).

[0702] In hepatocellular carcinoma, exogenous palmitic acid activates an epithelial-mesenchymal transition (EMT)-like program and induces migration that is decreased by oleic acid sulfo-N-succinimidyl, a CD36 inhibitor (Nath, Aritro, et al. "Elevated free fatty acid uptake via CD36 promotes epithelial-mesenchymal transition in hepatocellular carcinoma." Scientific reports 5 (2015). It was emphasized that body mass index was not associated with the degree of EMT and that actually CD36 and free fatty acids were important.

[0703] Cancer stem cells (CSCs) use CD36 to promote their maintenance. Oxidized phospholipids, which are ligands of CD36, are present in glioblastoma, and exposure to oxidized LDL increased the proliferation of CSCs but not that of non-CSCs. CD36 was also correlated with the prognosis of patients.

[0704] Chemotherapy resistance In addition to their direct cytotoxic effects, chemotherapeutic agents utilize the host immune system, which contributes to antitumor activity. However, gemcitabine and 5-FU have been shown to activate NLRP3 in myeloid-derived suppressor cells, resulting in the production of IL-1β, which suppresses antitumor effects. Mechanistically, these agents destabilize lysosomes and release cathepsin B, which activates NLRP3. IL-1β promotes the production of IL-17 from CD4+ T cells, which in turn blunts the efficacy of chemotherapy. When tumors were formed in NLRP3- / - or Caps1- / - mice or WT mice treated with IL-1RA, higher antitumor effects were observed with both gemcitabine and 5-FU. Activation of myeloid-derived suppressor cell NLRP3 thus limits the antitumor effects of gemcitabine and 5-FU (Bruchard, Melanie, et al. "Chemotherapy-triggered cathepsin B release in myeloid-derived suppressor cells activates the Nlrp3 inflammasome and promotes tumour growth." Nature medicine 19.1 (2013): 57-64.). The compounds of the present disclosure can thus be useful for chemotherapy for treating a wide range of cancers.

[0705] The compounds of the present disclosure or pharmaceutically acceptable salts thereof may be administered alone as the sole monotherapy or may be administered in combination with one or more other substances and / or treatments. Such co-treatments may be achieved by simultaneous, sequential, or separate administration of the individual components of the treatment.

[0706] For example, the therapeutic effect may be enhanced by the administration of an adjuvant (i.e., the adjuvant alone may have minimal therapeutic effect, but when combined with other therapeutic agents, the overall therapeutic effect on the individual is enhanced). Alternatively, by way of mere illustration, the benefit experienced by an individual may be increased by administering a compound of formula (I) in combination with another therapeutic agent (which also includes a treatment regimen) that also has a therapeutic advantage.

[0707] When the compounds of the present disclosure are administered in combination with other therapeutic agents, the disclosed compounds need not be administered via the same route as the other therapeutic agents and may be administered via different routes due to their different physical and chemical properties. For example, the compounds of the present disclosure may be administered orally to produce and maintain their good blood concentrations, while the other therapeutic agents may be administered intravenously. The initial administration may be carried out according to established protocols known in the art, and then, based on the observed effects, the dosage, mode of administration, and administration time can be changed by a skilled clinician.

[0708] The specific choice of other therapeutic agents will vary depending on the diagnosis of the attending physician and their judgment of the individual's condition and appropriate treatment protocol. According to this aspect of the present disclosure, there is provided a combination for use in the treatment of diseases associated with inflammasome activity, comprising a compound of the disclosure as defined above or a pharmaceutically acceptable salt thereof and other suitable agents.

[0709] According to a further aspect of the disclosure, there is provided a pharmaceutical composition comprising a compound of the disclosure or a pharmaceutically acceptable salt thereof in combination with a suitable pharmaceutically acceptable diluent or carrier.

[0710] In addition to their use in therapeutic medicine, the compounds of formula (I) and their pharmaceutically acceptable salts are also useful as pharmacological tools in the development and standardization of in vitro and in vivo test systems for evaluating the inhibitory effect of inflammasomes in experimental animals such as dogs, rabbits, monkeys, rats, and mice as part of the search for new therapeutic agents.

[0711] In any of the above pharmaceutical compositions, processes, methods, uses, drugs, and manufacturing features of the present disclosure, any of the alternative embodiments of the polymers of the present disclosure described herein apply.

[0712] Route of administration The disclosed compounds, or pharmaceutical compositions containing these compounds, can be administered to a subject by any convenient route of administration, whether systemic / peripheral or local (i.e., at the site of the desired action).

[0713] Routes of administration include oral (e.g., by ingestion); buccal; sublingual; transdermal (including those by patch, plaster, etc.); transmucosal (including those by patch, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., through the mouth or nose, e.g., via an aerosol, e.g., by inhalation or insufflation therapy); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, e.g., by injection including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subepidermal, intraarticular, subarachnoid, and intrasternal; including, but not limited to, depot or reservoir implantation (e.g., subcutaneous or intramuscular).

[0714] Definitions Unless otherwise specified, the following terms used in the specification and claims have the following meanings as set forth below.

[0715] Although not intended to be limited by this description, various options are described herein for each variable element, and it is understood that the disclosure is intended to encompass practicable aspects having combinations of the options. The disclosure may be interpreted to exclude impracticable aspects caused by particular combinations of the options.

[0716] The compounds of the present disclosure may be depicted in neutral form, cationic form (e.g., having one or more positive charges), or anionic form (e.g., having one or more negative charges), and it is understood that all of these are intended to be included within the scope of the present disclosure. For example, if a compound of the present disclosure is depicted in anionic form, such depiction also refers to various neutral forms, cationic forms, and anionic forms of the compound. As another example, if a compound of the present disclosure is depicted in anionic form, such depiction also refers to various salts (e.g., sodium salt) of the anionic form of the compound.

[0717] "Therapeutically effective amount" means an amount of a compound that, when administered to a mammal for treating a disease, is sufficient to effect such treatment of the disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity, as well as the age, weight, etc. of the mammal being treated.

[0718] As used herein, "alkyl", "C1, C2, C3, C4, C5 or C6 alkyl" or "C1-C6 alkyl" is intended to include C1, C2, C3, C4, C5 or C6 straight-chain (linear) saturated aliphatic hydrocarbon groups and C3, C4, C5 or C6 branched saturated aliphatic hydrocarbon groups. For example, C1-C6 alkyl is intended to include C1, C2, C3, C4, C5 and C6 alkyl groups. Examples of alkyl include moieties having from 1 to 6 carbon atoms, such as, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, or n-hexyl, but are not limited thereto. In some embodiments, the straight-chain or branched alkyl has 6 or fewer carbon atoms (e.g., C1-C6 for straight-chain and C3-C6 for branched-chain), and in another embodiment, the straight-chain or branched alkyl has 4 or fewer carbon atoms.

[0719] As used herein, the term "optionally substituted alkyl" refers to unsubstituted alkyl or alkyl having one or more designated substituents that replace one or more hydrogen atoms on one or more carbons of the hydrocarbon backbone. Such substituents include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, heterocyclyl, alkylaryl, or may contain an aromatic or heteroaromatic moiety.

[0720] As used herein, the term "alkenyl" includes an unsaturated aliphatic group having a length similar to and that may be substituted on the alkyl described above and containing at least one double bond. For example, the term "alkenyl" includes straight-chain alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl), and branched alkenyl groups. In certain embodiments, the straight-chain or branched alkenyl group has 6 or fewer carbon atoms in its backbone (e.g., C2-C6 for straight-chain and C3-C6 for branched-chain). The term "C2-C6" includes alkenyl groups containing 2 to 6 carbon atoms. The term "C3-C6" includes alkenyl groups containing 3 to 6 carbon atoms.

[0721] As used herein, the term "optionally substituted alkenyl" refers to unsubstituted alkenyl or alkenyl having one or more designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, heterocyclyl, alkylaryl, or may include an aromatic or heteroaromatic moiety.

[0722] As used herein, the term "alkynyl" includes an unsaturated aliphatic group having a length similar to and possibly substituted for the alkyl described above, and containing at least one triple bond. For example, "alkynyl" includes straight-chain alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl), and branched alkynyl groups. In certain embodiments, the straight-chain or branched alkynyl group has 6 or fewer carbon atoms in its backbone (e.g., C2-C6 for straight-chain and C3-C6 for branched-chain). The term "C2-C6" includes alkynyl groups containing 2 to 6 carbon atoms. The term "C3-C6" includes alkynyl groups containing 3 to 6 carbon atoms. As used herein, a "C2-C6 alkenylene linker" or a "C2-C6 alkynylene linker" is intended to include a C2, C3, C4, C5 or C6 chain (straight-chain or branched) divalent unsaturated aliphatic hydrocarbon group. For example, a C2-C6 alkenylene linker is intended to include C2, C3, C4, C5 and C6 alkenylene linker groups.

[0723] As used herein, the term "optionally substituted alkynyl" refers to unsubstituted alkynyl or alkynyl having one or more specified substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, heterocyclyl, alkylaryl, or may include aromatic or heteroaromatic moieties.

[0724] Other optionally substituted moieties (such as optionally substituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, etc.) include both unsubstituted moieties and moieties having one or more specified substituents. For example, substituted heterocycloalkyl includes those substituted with one or more alkyl groups such as 2,2,6,6-tetramethyl-piperidinyl and 2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridinyl.

[0725] As used herein, the term "cycloalkyl" refers to a group having 3 to 30 carbon atoms (e.g., C3~C 12 、C3~C 10refers to a saturated or partially unsaturated hydrocarbon monocyclic or polycyclic (e.g., fused, bridged, or spiro ring) system having 3 to 8 carbon atoms (e.g., C3 to C8). Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,2,3,4-tetrahydronaphthalenyl, and adamantyl. In the case of polycyclic cycloalkyl, only one of the rings in the cycloalkyl needs to be non-aromatic.

[0726] As used herein, the term "heterocycloalkyl" refers to a saturated or partially unsaturated monocyclic 3- to 8-membered ring, 6- to 12-membered bicyclic (fused, bridged, or spiro ring), or 11- to 14-membered tricyclic system (fused, bridged, or spiro ring) having one or more heteroatoms (such as O, N, S, P, or Se) independently selected from the group consisting of nitrogen, oxygen, and sulfur, for example, 1 or 1 to 2 or 1 to 3 or 1 to 4 or 1 to 5 or 1 to 6 heteroatoms, or, for example, 1, 2, 3, 4, 5, or 6 heteroatoms, unless otherwise specified.Examples of heterocycloalkyl groups include, but are not limited to, piperidinyl, piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, isoindolinyl, indolinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, oxiranyl, azetidinyl, oxetanyl, thietanyl, 1,2,3,6 - tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, pyranyl, morpholinyl, tetrahydrothiopyranyl, 1,4 - diazepanyl, 1,4 - oxazepanyl, 2 - oxa - 5 - azabicyclo[2.2.1]heptanyl, 2,5 - diazabicyclo[2.2.1]heptanyl, 2 - oxa - 6 - azaspiro[3.3]heptanyl, 2,6 - diazaspiro[3.3]heptanyl, 1,4 - dioxo - 8 - azaspiro[4.5]decanyl, 1,4 - dioxaspiro[4.5]decanyl, 1 - oxaspiro[4.5]decanyl, 1 - azaspiro[4.5]decanyl, 3'H - spiro[cyclohexane - 1,1'-isobenzofuran]-yl, 7'H - spiro[cyclohexane - 1,5'-furo[3,4 - b]pyridine]-yl, 3'H - spiro[cyclohexane - 1,1'-furo[3,4 - c]pyridine]-yl, 3 - azabicyclo[3.1.0]hexanyl, 3 - azabicyclo[3.1.0]hexan - 3 - yl, 1,4,5,6 - tetrahydropyrrolo[3,4 - c]pyrazolyl, 3,4,5,6,7,8 - hexahydropyrido[4,3 - d]pyrimidinyl, 4,5,6,7 - tetrahydro - 1H - pyrazolo[3,4 - c]pyridinyl, 5,6,7,8 - tetrahydropyrido[4,3 - d]pyrimidinyl, 2 - azaspiro[3.3]heptanyl, 2 - methyl - 2 - azaspiro[3.3]heptanyl, 2 - azaspiro[3.5]nonanyl, 2 - methyl - 2 - azaspiro[3.5]nonanyl, 2 - azaspiro[4.5]decanyl, 2 - methyl - 2 - azaspiro[4.5]decanyl, 2 - oxa - azaspiro[3.4]octanyl, 2 - oxa - azaspiro[3.4]octan - 6 - yl, etc. In the case of polycyclic heterocycloalkyl, only one of the rings in the heterocycloalkyl needs to be non - aromatic.

[0727] As used herein, the term "aryl" includes groups having aromaticity including "conjugation" or polycyclic systems having one or more aromatic rings, and contains no heteroatoms in the ring structure. The term aryl includes both monovalent and divalent species. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, etc.

[0728] As used herein, the term "heteroaryl" refers to a stable 5-, 6-, or 7-membered monocyclic or 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic aromatic heterocyclic ring consisting of a carbon atom and one or more heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur, for example, 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or, for example, 1, 2, 3, 4, 5, or 6 heteroatoms. It should be noted that the nitrogen atom may be substituted or unsubstituted (i.e., N or NR, where R is H or another substituent as defined). The nitrogen and sulfur heteroatoms may be oxidized (i.e., N→O and S(O) p , where p = 1 or 2). Note that the total number of S and O atoms in the aromatic heterocycle is not more than 1. Examples of heteroaryl groups include pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, pyridine, pyrazine, pyridazine, pyrimidine, etc. The heteroaryl group may also be condensed or bridged with an alicyclic or heterocyclic ring that is not aromatic to form a polycyclic system (e.g., 4,5,6,7-tetrahydrobenzo[c]isoxazolyl).

[0729] Furthermore, the terms "aryl" and "heteroaryl" include polycyclic, e.g., tricyclic, bicyclic aryl and heteroaryl groups such as naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzimidazole, benzothiophene, quinoline, isoquinoline, naphthyridine, indole, benzofuran, purine, deazapurine, indolizine.

[0730] The cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring may be substituted at one or more ring positions (e.g., ring-forming carbon or heteroatom, e.g., N) with substituents such as those described above, e.g., alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, heterocyclyl, alkylaryl, or may be substituted with an aromatic or heteroaromatic moiety. Aryl and heteroaryl groups may also be condensed or bridged with an alicyclic or heterocyclic ring that is not aromatic so as to form a polycyclic system (e.g., methylenedioxyphenyl such as tetralin, benzo[d][1,3]dioxol-5-yl).

[0731] As used herein, the term "substituted" means that any one or more hydrogen atoms on a designated atom are replaced with those selected from the indicated groups, provided that the normal valence of the designated atom is not exceeded and the substitution results in a stable compound. When the substituent is oxo or keto (i.e., =O), two hydrogen atoms on the atom are replaced. The keto substituent is not present in the aromatic moiety. A ring double bond as used herein is a double bond formed between two adjacent ring atoms (e.g., C=C, C=N or N=N). "Stable compound" and "stable structure" mean compounds that are robust enough to withstand isolation from the reaction mixture to useful purity and formulation into effective therapeutic agents.

[0732] When the bond to a substituent is shown to cross a bond connecting two atoms within the ring, such a substituent may be bonded to any atom within the ring. When a substituent is described without indicating the atom to which such a substituent is bonded to the remainder of the compound of a given formula, such a substituent may be bonded through any atom in such a formula. Combinations of substituents and / or variable elements are acceptable only if such combinations result in a stable compound.

[0733] If any component of a compound or any variable element (e.g., R) in a formula appears more than once, its definition at each occurrence is independent of its definition at other occurrences. Thus, for example, if a group is shown to be substituted with 0 to 2 R moieties, the group may be substituted with up to 2 R moieties, and each occurrence of R is independently selected from the definition of R. Also, combinations of substituents and / or variable elements are acceptable only if such combinations result in a stable compound.

[0734] As used herein, the term "hydroxy" or "hydroxyl" includes a group having -OH or -O - thereof.

[0735] As used herein, the terms "halo" or "halogen" refer to fluoro, chloro, bromo and iodo.

[0736] The terms "haloalkyl" or "haloalkoxyl" refer to alkyl or alkoxyl substituted with one or more halogen atoms.

[0737] As used herein, the term "optionally substituted haloalkyl" refers to unsubstituted haloalkyl having one or more designated substituents that replace one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents are, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, heterocyclyl, alkylaryl, or may contain an aromatic or heteroaromatic moiety.

[0738] As used herein, the term "alkoxy" or "alkoxyl" includes substituted and unsubstituted alkyl, alkenyl, and alkynyl groups covalently bonded to an oxygen atom. Examples of alkoxy groups or alkoxyl radicals include, but are not limited to, methoxy, ethoxy, isopropyloxy, propoxy, butoxy, and pentyloxy groups. Examples of substituted alkoxy groups include halogenated alkoxy groups. An alkoxy group may be substituted, for example, with groups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, heterocyclyl, alkylaryl, or aromatic or heteroaromatic moieties. Examples of halogen-substituted alkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, and trichloromethoxy.

[0739] As used herein, expressions such as "one or more of A, B, or C", "one or more of A, B, or C", "one or more of A, B, and C", "one or more of A, B, and C", "selected from the group consisting of A, B, and C", "selected from A, B, and C", etc. are used interchangeably, unless otherwise indicated, and all refer to those selected from the group consisting of A, B, and / or C, that is, one or more of A, one or more of B, one or more of C, or any combination thereof.

[0740] As used herein, "severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)" refers to the coronavirus that causes coronavirus disease 2019 (COVID-19). COVID-19 was first identified in Wuhan, China in 2019 and is currently causing a global pandemic. As of August 2020, more than 25 million cases have been reported worldwide, resulting in an estimated 848,000 deaths. Common symptoms of COVID-19 include fever, cough, fatigue, shortness of breath, and loss of smell and taste. While many people have mild symptoms, some people develop acute respiratory distress syndrome due to cytokine release syndrome (CRS), multiple organ failure, septic shock, and thrombosis, among other causes. The time from exposure to the virus to the appearance of symptoms is typically about 5 days, but can range from 2 to 14 days.

[0741] As used herein, "cytokine release syndrome (CRS)" refers to a systemic inflammatory response caused by various factors including, but not limited to, drugs, infections such as SARS-CoV-2, and immunotherapies such as chimeric antigen receptor T cell (CAR-T) therapy. In CRS, a large number of immune cells (e.g., T cells) are activated and release inflammatory cytokines, which in turn activate additional immune cells. Symptoms include fever, fatigue, loss of appetite, muscle and joint pain, nausea, vomiting, diarrhea, rash, respiratory failure, low blood pressure, seizures, headache, and confusion. CRS can respond to inhibition of the IL-6 receptor and large amounts of steroids.

[0742] As used herein, "adoptive cell therapy" refers to a form of treatment that uses immune cells to treat diseases such as cancer. Immune cells, such as T cells, are collected from a subject or another source, expanded in large numbers, and transplanted into the subject to help the immune system fight the disease. Types of adoptive cell therapy include chimeric antigen receptor T cell (CAR-T) therapy, tumor-infiltrating lymphocyte (TIL) therapy, and T cell receptor T cell (TCR-T) therapy.

[0743] As used herein, the term "chimeric antigen receptor (CAR)" refers to, for example, an artificial T cell receptor, chimeric T cell receptor, or chimeric immune receptor, and may include an artificially engineered receptor that confers artificial specificity to a particular immune effector cell. CARs can be used to confer the specificity of monoclonal antibodies to T cells, thereby making it possible to generate large numbers of specific T cells for use, for example, in adoptive cell therapy. For example, CARs can direct the specificity of cells expressing the CAR towards tumor-associated antigens. In some embodiments, a CAR includes an intracellular activation domain, a transmembrane domain, an extracellular domain including an antigen-binding domain, and optionally an extracellular hinge. The antigen-binding domain can be any antigen-binding domain known in the art, including antigen-binding domains derived from antibodies, Fab, F(ab')2, nanobodies, single-domain antigen-binding domains, scFv, VHH, etc. In certain aspects, a CAR includes a fusion of a single-chain variable region fragment (scFv) derived from a monoclonal antibody, fused to a CD3 transmembrane domain and an endodomain. Optionally, a CAR includes domains for additional co-stimulation signaling, such as CD3, FcR, CD27, CD28, CD137, DAP10, and / or OX40.

[0744] The "T cell receptor (TCR)" is a protein complex found on the surface of T cells or T lymphocytes, and plays a role in recognizing fragments of antigens as peptides bound to major histocompatibility complex (MHC) molecules. The T cell receptor can be artificially engineered to express an antigen-binding domain specific to a particular antigen and can be used in the adoptive cell therapy described herein.

[0745] It should be understood that the present disclosure provides methods for the synthesis of compounds of any of the formulas described herein. The present disclosure also provides detailed methods for the synthesis of various disclosed compounds and those shown in the examples according to the following schemes.

[0746] Throughout the specification, when a composition is described as having, including, or comprising certain components, it should be understood that the composition is also contemplated to consist essentially of or consist of the recited components. Similarly, when a method or process is described as having, including, or comprising certain process steps, the process also consists essentially of or consists of the recited process steps. Also, as long as the invention is practicable, the order of steps or the order for performing certain acts is not important. Further, two or more steps or acts can be performed simultaneously.

[0747] It should be understood that since the disclosed synthetic process can tolerate various functional groups, various substituted starting materials can be used. The process generally provides the desired final compound at or near the end of the overall process, but in certain cases, it may be desirable to further convert the compound to its pharmaceutically acceptable salt.

[0748] The compounds of the present disclosure can be prepared in a variety of ways using commercially available starting materials, intermediates known from the literature or readily prepared, by employing standard synthetic methods and procedures known to those skilled in the art or that will become 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 for the conversion and manipulation of functional groups can be obtained from the relevant scientific literature or standard textbooks in the field. Without limitation to any one or more sources, the classic textbooks such as Smith, M. B., March, J., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5 th edition, John Wiley & Sons: New York, 2001; Greene, T.W., Wuts, P.G. M., 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 references for organic synthesis known to those skilled in the art.

[0749] One skilled in the art will recognize that, in the reaction sequences and synthetic schemes described herein, the order of certain steps, such as the introduction and removal of protecting groups, may be varied. One skilled in the art will recognize that certain groups may need to be protected from the reaction conditions via the use of protecting groups. Protecting groups may also be used to distinguish similar functional groups within a molecule. A list of protecting groups and methods for introducing and removing these groups can be found in Greene, T.W., Wuts, P.G. M., Protective Groups in Organic Synthesis, 3 rd edition, John Wiley & Sons: New York, 1999.

[0750] Unless otherwise specified, any description of a method of treatment includes the use of a compound for providing treatment or prophylaxis as described herein, and the use of a compound for the preparation of a medicament for treating or preventing such a condition. Treatment includes treatment of humans or non-human animals, including murine and other disease models.

[0751] As used herein, the term "subject" includes humans and non-human animals, as well as cell lines, cell cultures, tissues, and organs. In some embodiments, the subject is a mammal. The mammal can be, for example, a human, or a suitable non-human mammal such as a primate, mouse, rat, dog, cat, cow, horse, goat, camel, sheep, or pig. The subject can also be a bird or fowl. In some embodiments, the subject is a human.

[0752] As used herein, the term "subject in need thereof" refers to a subject having a disease or at high risk of developing a disease. The subject in need thereof can be a subject previously diagnosed or identified as having a disease or disorder disclosed herein. The subject in need thereof can also be a subject affected by a disease or disorder disclosed herein. Alternatively, the subject in need thereof can be a subject at high risk of developing such a disease or disorder as compared to the population as a whole (i.e., a subject having a predisposition to develop such a disorder as compared to the population as a whole). The 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). The subject may be resistant at the start of treatment or may become resistant during treatment. In some embodiments, the subject in need thereof has received all known effective treatments for a disease or disorder disclosed herein and they have not worked. In some embodiments, the subject in need thereof has received at least one prior treatment.

[0753] As used herein, the terms "treating" or "treatment" describe 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 disclosure, or a pharmaceutically acceptable salt, polymorph, or solvate thereof, to alleviate the symptoms or complications of a disease, condition, or disorder, or to eliminate a disease, condition, or disorder. The term "treating" can also include in vitro treatment of cells, or animal models. Reference to "being under treatment" or "treatment" is to be understood to include the alleviation of established symptoms of a condition. "Being under treatment" or "treatment" of a condition, disorder, or state thus means, (1) preventing or delaying the appearance of clinical symptoms of a condition, disorder, or state that may afflict or have a predisposition to afflict a human who has not yet experienced and exhibited the clinical and preclinical symptoms of the condition, disorder, and state, (2) inhibiting a condition, disorder, or state, i.e., arresting, reducing, or delaying the development or recurrence of a disease (in the case of maintenance therapy) or at least one of its clinical or preclinical symptoms, or (3) alleviating or abating a disease, i.e., causing regression of at least one of a condition, disorder, or state or its clinical or preclinical symptoms.

[0754] It is to be understood that the compounds of the disclosure, or pharmaceutically acceptable salts, polymorphs, or solvates thereof, can also be used or may be used to prevent a related disease, condition, or disorder or to identify suitable candidates for such purposes.

[0755] As used herein, the terms "preventing", "prevention", or "protecting from" describe reducing or eliminating the onset of symptoms or complications of such a disease, condition, or disorder.

[0756] Those skilled in the art should understand that they can refer to general references for detailed descriptions of the known or equivalent techniques considered in this specification. These references include Ausubel et al., Current Protocols in Molecular Biology, John Wiley and Sons, Inc. (2005); Sambrook et al., Molecular Cloning, A Laboratory Manual (3 rd edition), Cold Spring Harbor Press, Cold Spring Harbor, New York (2000); Coligan et al., Current Protocols in Immunology, John Wiley & Sons, N.Y.; Enna et al., Current Protocols in Pharmacology, John Wiley & Sons, N.Y.; Fingl et al., The Pharmacological Basis of Therapeutics (1975), Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 18 th edition (1990). Of course, these references can be referred to when preparing or using aspects of the disclosure.

[0757] It should be understood that the present disclosure also provides pharmaceutical compositions comprising any of the compounds described herein in combination with at least one pharmaceutically acceptable excipient or carrier.

[0758] As used herein, the term "pharmaceutical composition" refers to a formulation containing a compound of the present disclosure in a form suitable for administration to a subject. In one aspect, the pharmaceutical composition is in bulk or unit dosage form. The unit dosage form can be, for example, any of a variety of forms including capsules, IV bags, tablets, a single pump on an aerosol inhaler, or vials. The amount of the active ingredient (e.g., a formulation of the disclosed compound, or a salt, hydrate, solvate or isomer thereof) in the unit dosage composition is an effective amount and varies depending on the specific treatment involved. One of ordinary skill in the art will recognize that in some cases it may be necessary to make routine modifications to the dosage depending on the age and condition of the patient. The dosage will also vary depending on the route of administration. A variety of routes are contemplated including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalation, buccal mucosa, sublingual, intrapleural, intrathecal, intranasal, etc. 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 aspect, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives, buffers, or propellants.

[0759] As used herein, the term "pharmaceutically acceptable salt" refers to a compound, anion, cation, substance, composition, carrier, and / or dosage form that is suitable for use in contact with human and animal tissues within the scope of sound medical judgment, without undue toxicity, irritation, allergic response, and other problems and complications, and is balanced with a reasonable benefit / risk ratio.

[0760] 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 for preparing a pharmaceutical composition, including excipients acceptable for veterinary use and pharmaceutical use in humans. As used in this specification and the claims, "pharmaceutically acceptable excipient" includes both one and a plurality of such excipients.

[0761] 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, for example, intravenous, intradermal, subcutaneous, oral (e.g., ingestion), inhalation, transdermal (topical), and transmucosal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application may contain the following components: sterile diluents such as water for injection, saline, fixed oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methylparaben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetate, citrate or phosphate, and agents for adjusting isotonicity such as sodium chloride or dextrose. The pH can be adjusted with an acid or base such as hydrochloric acid or sodium hydroxide. Parenteral formulations can be placed in ampoules, disposable syringes, or multiple-dose vials made of glass or plastic.

[0762] It should be understood that the disclosed compounds or pharmaceutical compositions can be administered to a subject in many of the well-known methods currently used for chemotherapeutic treatment. For example, the disclosed compounds may be injected into the bloodstream or body cavity, or orally ingested, or applied through the skin using a patch. The dosage selected should be sufficient to constitute an effective treatment but not so high as to cause unacceptable side effects. The condition of the medical condition (e.g., the diseases or disorders disclosed herein) and the health of the patient are preferably closely monitored during and for a reasonable period after treatment.

[0763] As used herein, the term "therapeutically effective amount" refers to the amount of a pharmaceutical agent for treating, ameliorating, or preventing an identified disease, disorder, or condition, or for achieving a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. The exact effective amount for each subject will vary depending upon the subject's weight, size, health; the nature and degree of the condition; and the therapeutic agent or combination of therapeutic agents selected for administration. A therapeutically effective amount for a given situation can be determined by routine experimentation within the skill and judgment of the clinician.

[0764] It should be understood that for any given compound, a therapeutically effective amount can first be estimated in cell culture assays, e.g., in neonatal cells, or in animal models, usually rats, mice, rabbits, dogs, or pigs. Appropriate concentration ranges and routes of administration may also be determined using animal models. Such information can then be used to determine useful dosages and routes of administration in humans. The effectiveness and toxicity of treatment / prevention can be determined by standard pharmacological techniques in cell culture or experimental animals, e.g., ED 50 (therapeutically effective dose in 50% of the population) and LD 50 (lethal dose for 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and can be expressed as the ratio LD 50 / ED 50 . Pharmaceutical compositions with a large therapeutic index are preferred. The dosage may vary within this range depending on the dosage form employed, the sensitivity of the patient, and the route of administration.

[0765] The dosage and method of administration are adjusted to provide a sufficient level of the active agent or to maintain the desired effect. Factors that may be considered include the severity of the condition, the overall health of the subject, the age, weight, and sex of the subject, diet, time and frequency of administration, drug combination, responsiveness, and tolerance / response to treatment. Long-acting pharmaceutical compositions may be administered every 3 - 4 days, weekly, or once every two weeks, depending on the half-life and clearance rate of the particular formulation.

[0766] Pharmaceutical compositions containing the active compounds of the present disclosure may be manufactured in a generally known manner, for example, by conventional mixing, dissolving, granulating, sugar coating, pulverizing, emulsifying, encapsulating, entrapping, or lyophilization processes. The pharmaceutical compositions may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers including excipients and / or auxiliaries that facilitate the processing of the active compounds into pharmaceutically usable formulations. Of course, the appropriate formulation will vary depending on the selected route of administration.

[0767] Pharmaceutical compositions suitable for injection use include sterile aqueous solutions (in the case of water-soluble), dispersions, and sterile powders for the immediate preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL (trademark) (BASF, Parsippany, N.J.), or phosphate-buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that it is easily fillable / dischargeable from a syringe (syringeability). It must be stable under the conditions of manufacture and storage and must be protected from the contaminating action of microorganisms such as bacteria and fungi. The carrier can be, for example, a solvent or dispersion medium containing water, ethanol, polyols (such as glycerol, propylene glycol, and liquid polyethylene glycol, etc.), and suitable mixtures thereof. Appropriate fluidity can be maintained, for example, by the use of coatings such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, etc. In many cases, it is preferred to include in the composition isotonic agents, such as sugars, polyhydric alcohols such as mannitol and sorbitol, and sodium chloride. Sustained absorption of the injectable composition can be brought about by including in the composition agents that delay absorption, such as aluminum monostearate and gelatin.

[0768] The sterile injectable solutions can be prepared by filtration sterilization after incorporating the required amount of the active compound into a suitable solvent containing, as required, one or a combination of the ingredients enumerated above. Generally, the dispersion is prepared by incorporating the active compound into a sterile vehicle containing the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the methods of preparation are vacuum drying and freeze-drying from which the powder of the active ingredient plus any additional desired ingredients are obtained from previously sterile-filtered solutions.

[0769] Oral compositions generally include an inert diluent or an edible pharmaceutically acceptable carrier. They can be enclosed in gelatin capsules or tableted. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a liquid carrier for use as a mouthwash, wherein the compound in the liquid carrier is applied orally, gargled, and spat out or swallowed. Pharmaceutically compatible binders and / or auxiliary substances can be included as part of the composition. Tablets, pills, capsules, troches, etc. can contain any of the following ingredients: binders such as microcrystalline cellulose, tragacanth gum, or gelatin; excipients such as starch or lactose; disintegrants such as alginic acid, Primogel, or corn starch; lubricants such as magnesium stearate or Sterotes; flow promoters such as colloidal silicon dioxide; sweetening agents such as sucrose or saccharin; or flavoring agents such as peppermint, methyl salicylate, or orange flavor, or compounds of similar nature.

[0770] For administration by inhalation, the compounds are delivered in the form of an aerosol spray from a pressurized container or dispenser containing a suitable propellant, e.g., a gas such as carbon dioxide, or in the form of a nebulizer.

[0771] Systemic administration may also be by transmucosal or transdermal means. For transmucosal or transdermal administration, a penetration enhancer appropriate to the barrier to be permeated is used in the formulation. Such penetration enhancers are generally known in the art and include, for example, surfactants, bile salts, and fusidic acid derivatives for transmucosal administration. Transmucosal administration can be achieved through the use of nasal drops or suppositories. For transdermal administration, the active compound is formulated into an ointment, salve, gel, or cream as generally known in the art.

[0772] The active compound can be prepared with a pharmaceutically acceptable carrier that protects the compound from rapid elimination in the body, such as a controlled release formulation including implants and microencapsulation delivery systems. Biodegradable biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid can be used. Methods for the preparation of such formulations will be apparent to those skilled in the art. Such materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc. Liposome suspensions (including liposomes targeting infected cells having monoclonal antibodies against viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811.

[0773] It is particularly advantageous to formulate oral or parenteral compositions in unit dosage form for ease of administration and uniformity of dosage. As used herein, a unit dosage form refers to a physically discrete unit suitable as a single dosage for the subject to be treated, each unit containing a predetermined quantity of the active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specifications for each disclosed unit dosage form depend on the particular properties of the active compound and the particular therapeutic effect to be achieved and vary directly accordingly.

[0774] In therapeutic use, the dosage of the pharmaceutical composition used in accordance with the disclosure will vary depending among other factors affecting the selected dosage, on the medicament, the age, weight, and clinical condition of the patient who is the recipient, as well as the experience and judgment of the clinician or practitioner conducting the treatment. Generally, the dosage should be sufficient to slow, preferably reverse, and more preferably cause complete regression of the symptoms of the disease or disorder disclosed herein. The dosage can range from about 0.01 mg / kg per day to about 5000 mg / kg per day. In a preferred embodiment, the dosage can range from about 1 mg / kg per day to about 1000 mg / kg per day. In some aspects, the dosage will range from about 0.1 mg / day to about 50 g / day; about 0.1 mg / day to about 25 g / day; about 0.1 mg / day to about 10 g / day; about 0.1 mg / day to about 3 g / day; or about 0.1 mg to about 1 g / day in single, divided, or continuous administration (this dosage may be adjusted according to the patient's weight in kg, body surface area in m 2 2, and age). The effective amount of a pharmaceutical is the amount that produces an objectively identifiable improvement as pointed out by a clinician or other qualified observer. Improvement in survival and growth represents regression. As used herein, the term "dosage in an effective manner" refers to the amount of the active compound to produce the desired biological effect in a subject or cell.

[0775] It should be understood that the pharmaceutical composition can be contained in a container, pack, or dispenser together with instructions for administration.

[0776] If the compounds of the present disclosure are further capable of forming salts, it should be understood that any of those forms are contemplated within the scope of the claimed disclosure.

[0777] As used herein, the term "pharmaceutically acceptable salt" refers to derivatives of the compounds of the present disclosure in which the parent compound is modified by making its acid or base salts. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines, and alkali or organic salts of acidic residues such as carboxylic acids. Pharmaceutically acceptable salts include conventional non-toxic salts or quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts are 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, dicarboxylic acid, carboxylic acid, citric acid, edetic acid, ethanedisulfonic acid, 1,2-ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, glycollyarsanilic acid, hexylresorcinol, hydrabamic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxymaleic acid, hydroxynaphthoic acid, isethionic acid, lactic acid, lactobionic acid, laurylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, naphthylic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, basic acetic acid, succinic acid, sulfamic acid, sulfanilic acid, sulfuric acid, tannic acid, tartaric acid, toluenesulfone, and those derived from inorganic and organic acids selected from naturally occurring amino acids such as glycine, alanine, phenylalanine, arginine, etc., but are not limited thereto.

[0778] In some embodiments, the pharmaceutically acceptable salt is a sodium salt, potassium salt, calcium salt, magnesium salt, diethylamine salt, choline salt, meglumine salt, benzathine salt, tromethamine salt, ammonia salt, arginine salt, or lysine salt.

[0779] Other examples of pharmaceutically acceptable salts include hexanoic acid, cyclopentanepropionic acid, pyruvic acid, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo-[2.2.2]-oct-2-ene-1-carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, muconic acid, and the like. The present disclosure also encompasses salts formed when an acidic proton present in the parent compound is replaced with a metal ion, such as an alkali metal ion, an alkaline earth ion, or an aluminum ion, or coordinated with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. In salt form, the ratio of the compound to the cation or anion of the salt can be understood to be 1:1, or any ratio other than 1:1, such as 3:1, 2:1, 1:2, or 1:3.

[0780] Any reference to a pharmaceutically acceptable salt is to be understood as including the solvate (solvent addition form) or crystal form (polymorph) of the salt as defined herein.

[0781] The compound or its pharmaceutically acceptable salt is administered orally, nasally, transdermally, via the lung, by inhalation, via the buccal mucosa, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally, and parenterally. In one aspect, the compound is administered orally. One skilled in the art will recognize the advantages of a particular route of administration.

[0782] The dosing regimen utilizing the compound is selected according to various factors including the type, species, age, weight, sex, and medical condition of the patient; the severity of the condition being treated; the route of administration; the renal and hepatic function of the patient; and the specific compound or its salt employed. A routine skilled physician or veterinarian can readily determine and prescribe an effective amount of the drug necessary to prevent, counteract, or arrest the progression of the condition.

[0783] Techniques for the formulation and administration of the disclosed compounds of the disclosure can be found in Remington: the Science and Practice of Pharmacy, 19 th edition, Mack Publishing Co., Easton, PA (1995). In one aspect, the compounds described herein, and their pharmaceutically acceptable salts, are used in pharmaceutical formulations in combination with a pharmaceutically acceptable carrier or diluent. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions. The compounds will be present in such pharmaceutical compositions in an amount sufficient to provide the desired dosage within the ranges described herein.

[0784] All percentages and ratios used herein are by weight unless otherwise indicated. Other features and advantages of the present disclosure will be apparent from the different examples. The examples provided illustrate different components and methodologies useful for practicing the present disclosure. The examples do not limit the claimed disclosure. Based on the present disclosure, one of ordinary skill in the art can identify and employ other components and methodologies useful for practicing the present disclosure.

[0785] In the synthetic schemes described herein, for the sake of simplicity, compounds may be illustrated in one particular configuration. Such a particular configuration should not be construed as limiting the disclosure to one or another isomer, tautomer, positional isomer, and stereoisomer, and does not exclude mixtures of isomers, tautomers, positional isomers, and stereoisomers, but 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.

[0786] All publications and patent documents cited in this specification are hereby incorporated by reference as if each such individual publication or document was specifically and individually indicated to be incorporated herein by reference. The citation of publications and patent documents is not intended to admit that any of them are prior art relevant to the present invention, nor is any admission made as to their content or date. Although the invention has been described above in terms of a written description, those skilled in the art will recognize that the invention can be practiced in various ways, and that the above description and the following examples are for purposes of illustration and not limitation of the scope of the claims that follow.

[0787] As used herein, the expression "disclosed compound" refers to the compounds disclosed herein, both generally and specifically.

[0788] Exemplary embodiments Exemplary embodiment 1. A compound of formula (I), or a prodrug, solvate, or pharmaceutically acceptable salt thereof: TIFF2025522354000054.tif30128 wherein each TIFF2025522354000055.tif7128 is independently, to the extent permitted by valence, a single bond or a double bond; A2 is, to the extent permitted by valence, CR 2 , N, NR 2a , O, or S; A3 is, to the extent permitted by valence, CR 2 , N, NR 2a , O, or S; A4 is, to the extent permitted by valence, CR 2 , N, NR 2a , O, or S; A5 is, to the extent permitted by valence, C or N, wherein at least one of A2, A3, A4, or A5 is N, NR 2a , O, or S; R 1is H, -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C3-C 12 cycloalkyl, where -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C3-C 12 cycloalkyl may be substituted with one or more R 1S ; each R 1S is independently halogen, cyano, -OH, or C1-C6 alkyl; R 1a is H or C1-C6 alkyl, or R 1 and R 1a together with the atom to which they are attached form C2-C6 alkenyl, C3-C7 cycloalkyl, or 3-7 membered heterocycloalkyl, or R 1a and R 3 together with the atom to which they are attached form C3-C 12 cycloalkyl or 3-12 membered heterocycloalkyl; each R 2 is independently H, halogen, cyano, -OH, -NH2, -NO2, -C(=O)NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C3-C 12 cycloalkyl, 3-12 membered heterocycloalkyl, C6-C 10 aryl, or 5-10 membered heteroaryl, where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C3-C 12 cycloalkyl, 3-12 membered heterocycloalkyl, C6-C 10 aryl, or 5-10 membered heteroaryl may be substituted with one or more R 2S ; or two R 2 together with the atom to which they are attached form C3-C 12Cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C 10 Aryl, or 5- to 10-membered heteroaryl, where C3-C 12 Cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C 10 Aryl, or 5- to 10-membered heteroaryl may be substituted with one or more R 2S ; Each R 2S Is independently halogen, C1-C6 alkyl, -OH, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, or C3-C 12 Cycloalkyl; R 3 Is H, -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C3-C 12 Cycloalkyl, where -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C3-C 12 Cycloalkyl may be substituted with one or more R 3S ; or R 1 And R 3 Together with the atoms to which they are attached form a C3-C 12 Cycloalkyl or 3- to 12-membered heterocycloalkyl; Each R 3S Is independently halogen, cyano, -OH, or C1-C6 alkyl; Each R 2a Is independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, -(CH2) 0~3 -(C3-C 12 Cycloalkyl), or -(CH2) 0~3 -(3- to 12-membered heterocycloalkyl); Each R a Is independently H or C1-C6 alkyl; or two R a Together with the atoms to which they are attached form a C2-C6 alkenyl or C3-C 12 Cycloalkyl; R N1 is H or C1-C6 alkyl; R N2 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O-(C1-C6 alkyl), -O-(C2-C6 alkenyl), -O-(C2-C6 alkynyl), -NH-(C1-C6 alkyl), -NH-(C2-C6 alkenyl), -NH-(C2-C6 alkynyl), C3-C 12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl, -(C1-C6 alkyl)-(C3-C 12 cycloalkyl), -(C1-C6 alkyl)-(3- to 12-membered heterocycloalkyl), -(C1-C6 alkyl)-(C6-C 10 aryl), or -(C1-C6 alkyl)-(5- to 10-membered heteroaryl); wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O-(C1-C6 alkyl), -O-(C2-C6 alkenyl), -O-(C2-C6 alkynyl), -NH-(C1-C6 alkyl), -NH-(C2-C6 alkenyl), -NH-(C2-C6 alkynyl), C3-C 12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl, -(C1-C6 alkyl)-(C3-C 12 cycloalkyl), -(C1-C6 alkyl)-(3- to 12-membered heterocycloalkyl), -(C1-C6 alkyl)-(C6-C 10 aryl), or -(C1-C6 alkyl)-(5- to 10-membered heteroaryl) may be substituted with one or more R N2a ; Each R N2ais independently oxo, halogen, cyano, -OH, -NH2, -NO2, -C(=O)H, -C(=O)OH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -C(=O)(C1-C6 alkyl), -C(=O)O(C1-C6 alkyl), -NHC(=O)O(C1-C6 alkyl), -S(=O)2(C1-C6 alkyl), -S(=O)2N(C1-C6 alkyl)2, C3-C 12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl, -(C1-C6 alkyl)-(C3-C 12 cycloalkyl), -(C1-C6 alkyl)-(3- to 12-membered heterocycloalkyl), -(C1-C6 alkyl)-(C6-C 10 aryl), or -(C1-C6 alkyl)-(5- to 10-membered heteroaryl); where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -C(=O)(C1-C6 alkyl), -C(=O)O(C1-C6 alkyl), -NHC(=O)O(C1-C6 alkyl), -S(=O)2(C1-C6 alkyl), -S(=O)2N(C1-C6 alkyl)2, C3-C 12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl, -(C1-C6 alkyl)-(C3-C 12 cycloalkyl), -(C1-C6 alkyl)-(3- to 12-membered heterocycloalkyl), -(C1-C6 alkyl)-(C6-C 10 aryl), or -(C1-C6 alkyl)-(5- to 10-membered heteroaryl) may be substituted with one or more R N2ab ; and each R N2abis independently oxo, halogen, cyano, -OH, -NH2, -C(=O)H, -C(=O)OH, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -C(=O)(C1-C6 alkyl), -C(=O)O(C1-C6 alkyl), -NHC(=O)O(C1-C6 alkyl), -S(=O)2(C1-C6 alkyl), or -S(=O)2N(C1-C6 alkyl)2; or R N1 and R N2 together with the atom to which they are attached form a 3- to 12-membered heterocycloalkyl optionally substituted with one or more R b ; each R b is independently oxo, halogen, cyano, -OH, -NH2, -C(=O)H, -C(=O)OH, C1-C6 alkyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -C(=O)(C1-C6 alkyl), -C(=O)O(C1-C6 alkyl), -NHC(=O)O(C1-C6 alkyl), -S(=O)2(C1-C6 alkyl), or -S(=O)2N(C1-C6 alkyl)2, wherein C1-C6 alkyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -C(=O)(C1-C6 alkyl), -C(=O)O(C1-C6 alkyl), -NHC(=O)O(C1-C6 alkyl), -S(=O)2(C1-C6 alkyl), or -S(=O)2N(C1-C6 alkyl)2 may be substituted with one or more R b1 ; and each R b1 is independently oxo, halogen, cyano, -OH, or -NH2.

[0789] Exemplary embodiment 2. A2 is CR 2 and A3 is CR 2 and A4 is CR 2 and A5 is N, optionally, wherein the CR 2 of A3 and A4 are linked to form a thienyl ring or a thiazolyl ring; or A2 is CR 2 and A3 is NR 2a and A4 is N and A5 is C; or A2 is CR 2 and A3 is CR 2 and A4 is N and A5 is N; or A2 is S and A3 is CR 2 and A4 is N and A5 is C; or A2 is S and A3 is CR 2 and A4 is CR 2 and A5 is C; or A2 is CR 2 and A3 is CR 2 and A4 is O and A5 is C; or A2 is NR 2a and A3 is CR 2 and A4 is CR 2 and A5 is C; or A2 is NR 2a and A3 is CR 2 and A4 is N and A5 is C; or A2 is CR 2 and A3 is CR 2 and A4 is S and A5 is C; wherein R 2 and R 2a are as defined in Exemplary Embodiment 1, a compound according to Exemplary Embodiment 1.

[0790] Exemplary Embodiment 3. A compound according to any one of the preceding exemplary embodiments, wherein R 1 is H.

[0791] Exemplary Embodiment 4. A compound according to any one of the preceding exemplary embodiments, wherein R 1a is H.

[0792] Exemplary Embodiment 5. A compound according to any one of the preceding exemplary embodiments, wherein R 1a is methyl.

[0793] Exemplary Embodiment 5A. R1 is H, and R 1a is H; or R 1 is C1-C6 alkyl, and R 1a is H; or R 1 is H, and R 1a is C1-C6 alkyl; or R 1 is methyl, and R 1a is H; or R 1 is H, and R 1a is methyl; or R 1 and R 1a together with the atom to which they are attached form C3-C7 cycloalkyl; or R 1 and R 1a together with the atom to which they are attached form cyclopropyl, a compound of any one of the preceding exemplary embodiments.

[0794] Exemplary embodiment 6. R 1a is methyl, a compound of any one of the preceding exemplary embodiments.

[0795] Exemplary embodiment 7. R 1 and R 1a together with the atom to which they are attached form C3-C7 cycloalkyl, a compound of any one of the preceding exemplary embodiments.

[0796] Exemplary embodiment 8. R 1 and R 1a together with the atom to which they are attached form cyclopropyl, a compound of any one of the preceding exemplary embodiments.

[0797] Exemplary embodiment 9. R 2 is H, C1-C6 alkyl, -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), or C3-C 12 cycloalkyl, or two Rs2 which, together with the atoms to which they are attached, form one or more R 2S a compound of any one of the preceding exemplary embodiments, which may be substituted with a 5- to 10-membered heteroaryl forming

[0798] Exemplary embodiment 10. R 2 is H, methyl, ethyl, isopropyl, cyclopropyl, -NH-ethyl, or -O-ethyl, or two Rs 2 which, together with the atoms to which they are attached, form a thienyl ring or a thiazolyl ring which may be substituted with one or more Rs 2S a compound of any one of the preceding exemplary embodiments

[0799] Exemplary embodiment 11. At least one R 2S is halogen or C1-C6 alkyl, a compound of any one of the preceding exemplary embodiments

[0800] Exemplary embodiment 12. At least one R 2S is chlorine or methyl, a compound of any one of the preceding exemplary embodiments

[0801] Exemplary embodiment 13. R 2a is H or C1-C6 alkyl, a compound of any one of the preceding exemplary embodiments

[0802] Exemplary embodiment 14. R 2a is H, methyl, ethyl or isopropyl, a compound of any one of the preceding exemplary embodiments

[0803] Exemplary embodiment 15. R 3 is H or C1-C6 alkyl, a compound of any one of the preceding exemplary embodiments

[0804] Exemplary embodiment 15A. R 3 is H; or R 3 is C1-C6 alkyl; or R 3is methyl; or R 3 and R 1a together with the atom to which they are attached form a C3-C7 cycloalkyl; or R 3 and R 1a together with the atom to which they are attached form a cyclopropyl; or R 3 and R 1 together with the atom to which they are attached form a C3-C7 cycloalkyl; or R 3 and R 1 together with the atom to which they are attached form a cyclopropyl, a compound of any one of the preceding exemplary embodiments.

[0805] Exemplary embodiment 16. R 3 is H or methyl, a compound of any one of the preceding exemplary embodiments.

[0806] Exemplary embodiment 17. R 1 and R 3 together with the atom to which they are attached form a C3-C 12 cycloalkyl, a compound of any one of the preceding exemplary embodiments.

[0807] Exemplary embodiment 18. R 1 and R 3 together with the atom to which they are attached form a cyclobutyl, a compound of any one of the preceding exemplary embodiments.

[0808] Exemplary embodiment 19. At least one R a is H, a compound of any one of the preceding exemplary embodiments.

[0809] Exemplary embodiment 20. R a are both H, a compound of any one of the preceding exemplary embodiments.

[0810] Exemplary embodiment 21. RN1 A compound of any one of the preceding exemplary embodiments, wherein R is H.

[0811] Exemplary embodiment 22. R N2 is C3-C 12 is cycloalkyl, 3-12 membered heterocycloalkyl, or 5-10 membered heteroaryl; wherein C3-C 12 cycloalkyl, 3-12 membered heterocycloalkyl, or 5-10 membered heteroaryl may be substituted with one or more R N2a A compound of any one of the preceding exemplary embodiments, which may be substituted.

[0812] Exemplary embodiment 23. R N2 is cyclobutyl, piperidinyl, oxaspiro[3.3]heptanyl, thiadiazolyl, or pyrimidinyl, each of which may be substituted with one or more R N2a A compound of any one of the preceding exemplary embodiments, which may be substituted.

[0813] Exemplary embodiment 23A. R N2 is TIFF2025522354000056.tif221168, a compound of any one of the preceding exemplary embodiments.

[0814] Exemplary embodiment 24. At least one R N2a is halogen, -OH, C1-C6 alkyl, -C(=O)O(C1-C6 alkyl), or C3-C 12 cycloalkyl, a compound of any one of the preceding exemplary embodiments.

[0815] Exemplary embodiment 25. At least one R N2a is fluorine, -OH, methyl, -C(=O)O(ethyl), or cyclobutyl, a compound of any one of the preceding exemplary embodiments.

[0816] Exemplary embodiment 25A. At least one R N2aA compound of any one of the preceding exemplary embodiments, where A is oxo, F, Cl, cyano, -OH, -NH2, -NO2, methyl, CF3, -O(methyl), -C(=O)O(ethyl), or pyrazolyl.

[0817] Exemplary embodiment 26. A2 is CR 2 , NR 2a , or S; A3 is CR 2 , NR 2a , or O; A4 is CR 2 , S, or O; A5 is C or N; where at least one of A2, A3, A4, or A5 is N, NR 2a , O, or S; R 1 is H; R 1a is H or C1-C6 alkyl, or R 1 and R 1a together with the atoms to which they are attached form C3-C7 cycloalkyl, or R 1a and R 3 together with the atoms to which they are attached form C3-C 12 cycloalkyl; each R 2 is independently H, C1-C6 alkyl, -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), or C3-C 12 cycloalkyl, or alternatively, two Rs 2 together with the atoms to which they are attached form a 5- to 10-membered heteroaryl optionally substituted with one or more Rs 2S ; each R 2S is independently halogen or C1-C6 alkyl; each R 2a is independently H or C1-C6 alkyl; R 3 is H or C1-C6 alkyl; each Ra is independently H; R N1 is H; R N2 is C3-C 12 cycloalkyl, 3- to 12-membered heterocycloalkyl, or 5- to 10-membered heteroaryl; wherein C3-C 12 cycloalkyl, 3- to 12-membered heterocycloalkyl, or 5- to 10-membered heteroaryl may be substituted with one or more R N2a and; each R is independently halogen, -OH, C1-C6 alkyl, -C(=O)O(C1-C6 alkyl), or C3-C N2a cycloalkyl, 12 a compound according to Exemplary Embodiment 1. Exemplary Embodiment 1.

[0818] Exemplary Embodiment 27. A2 is CR 2 NR 2a or S; A3 is CR 2 NR 2a or O; A4 is CR 2 N, S, or O; A5 is C or N; wherein at least one of A2, A3, A4, or A5 is N, NR 2a O, or S; R 1 is H; R 1a is H or methyl, or R 1 and R 1a together with the atom to which they are attached form cyclopropyl, or R 1a and R 3 together with the atom to which they are attached form cyclobutyl; each R 2 is independently H, methyl, ethyl, isopropyl, cyclopropyl, -NH-ethyl, or -O-ethyl, or or, two R 2which, together with the atoms to which they are attached, form one or more optionally R- 2S substituted thienyl or thiazolyl rings; each R 2S is independently chlorine or methyl; each R 2a is independently H, methyl, ethyl or isopropyl; R 3 is H or methyl; each R a is independently H; R N1 is H; R N2 is cyclobutyl, piperidinyl, oxaspiro[3.3]heptanyl, thiadiazolyl, or pyrimidinyl, each of which may be substituted with one or more R N2a and; each R N2a is independently fluorine, -OH, methyl, -C(=O)O(ethyl), or cyclobutyl, A compound according to Exemplary Embodiment 1 or Exemplary Embodiment 26.

[0819] Exemplary Embodiment 28. A compound according to any one of the preceding exemplary embodiments, which is a compound of formula (II), or a prodrug, solvate, or pharmaceutically acceptable salt thereof: TIFF2025522354000057.tif27128.

[0820] Exemplary Embodiment 28A. A compound according to any one of the preceding exemplary embodiments, which is a compound of formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-l), (I-m), (I-n), (I-o), (I-p), (I-q), (I-r), (I-s), (I-t), (I-u), (I-v), (I-w), (I-x), (I-y), (I-z), (I-aa), (I-ab), (I-ac), (I-ad), (I-ae), (I-af), or (I-ag), or a prodrug, solvate, or pharmaceutically acceptable salt thereof: TIFF2025522354000058.tif205109TIFF2025522354000059.tif202134TIFF2025522354000060.tif58141。

[0821] Exemplary embodiment 29. A compound according to any one of the preceding exemplary embodiments, selected from the compounds described in Table 1 and their prodrugs and pharmaceutically acceptable salts.

[0822] Exemplary embodiment 30. A compound that is an isotope derivative of a compound according to any one of the preceding exemplary embodiments.

[0823] Exemplary embodiment 31. A compound obtainable or obtained by the methods described herein.

[0824] Exemplary embodiment 32. An intermediate obtained by a method for preparing a compound according to any one of the preceding exemplary embodiments.

[0825] Exemplary embodiment 33. A pharmaceutical composition comprising a compound according to any one of the preceding exemplary embodiments and a pharmaceutically acceptable diluent or carrier.

[0826] Exemplary embodiment 34. A method for inhibiting inflammasome activity, comprising the step of contacting a cell with an effective amount of a compound according to any one of the preceding exemplary embodiments, optionally, the inflammasome is the NLRP3 inflammasome and the activity is in vitro or in vivo, said method.

[0827] Exemplary embodiment 35. A method of treating or preventing a disease or disorder in a subject in need thereof, comprising the step of administering to the subject a compound according to any one of the preceding exemplary embodiments or a pharmaceutical composition according to any one of the preceding exemplary embodiments thereof.

[0828] Exemplary embodiment 36. Use in the inhibition of inflammasome activity, Use, optionally wherein the inflammasome is the NLRP3 inflammasome and the activity is in vitro or in vivo, of any one of the preceding exemplary embodiments of a compound or pharmaceutical composition of any one of the preceding exemplary embodiments for such use

[0829] Exemplary embodiment 37. Use of a compound or pharmaceutical composition of any one of the preceding exemplary embodiments for the treatment or prevention of a disease or disorder

[0830] Exemplary embodiment 38. Inhibition of inflammasome activity, optionally wherein the inflammasome is the NLRP3 inflammasome and the activity is in vitro or in vivo, of any one of the preceding exemplary embodiments for the manufacture of a medicament Use of a compound of any one of the preceding exemplary embodiments in the manufacture of a medicament for such inhibition

[0831] Exemplary embodiment 39. Use of a compound of any one of the preceding exemplary embodiments in the manufacture of a medicament for treating or preventing a disease or disorder

[0832] Exemplary embodiment 40. A method, compound, pharmaceutical composition, or use of any one of the preceding exemplary embodiments, wherein the disease or disorder is associated with an associated inflammasome activity, and optionally, the disease or disorder is a disease or disorder in which the inflammasome activity is associated Use of any one of the preceding exemplary embodiments

[0833] Exemplary embodiment 41. A method, compound, pharmaceutical composition, or use of any one of the preceding exemplary embodiments, wherein the disease or disorder is an inflammatory disorder, an autoinflammatory disorder, an autoimmune disorder, a neurodegenerative disease, or cancer

[0834] Exemplary embodiment 42. A method, compound, pharmaceutical composition, or use of any one of the preceding exemplary embodiments, wherein the disease or disorder is an inflammatory disorder, an autoinflammatory disorder, or an autoimmune disorder, and Optionally, the disease or disorder is selected from cryopyrin-associated periodic syndrome (CAPS), Muckle-Wells syndrome (MWS), chronic infantile neurologic cutaneous articular (CINCA) syndrome / neonatal-onset multisystem inflammatory disease (NOMID), familial Mediterranean fever (FMF), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), gout, rheumatoid arthritis, osteoarthritis, Crohn's disease, chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD), fibrosis, obesity, type 2 diabetes, multiple sclerosis, skin diseases, and neuroinflammation occurring in protein misfolding diseases. The method, compound, pharmaceutical composition, or use of any one of the preceding exemplary embodiments.

[0835] Exemplary embodiment 43. The disease or disorder is a neurodegenerative disease, and optionally, the disease or disorder is Parkinson's disease or Alzheimer's disease. The method, compound, pharmaceutical composition, or use of any one of the preceding exemplary embodiments.

[0836] Exemplary embodiment 44. The disease or disorder is cancer, and optionally, the cancer is metastatic cancer, brain cancer, gastrointestinal cancer, skin cancer, non-small cell lung cancer, head and neck squamous cell carcinoma, or colorectal adenocarcinoma. The method, compound, pharmaceutical composition, or use of any one of the preceding exemplary embodiments.

[0837] Exemplary embodiment 45. The disease or disorder is an inflammatory disease, and the method, compound, pharmaceutical composition, or use of any one of the preceding exemplary embodiments.

[0838] Exemplary embodiment 46. The inflammatory disease is associated with an infectious disease, and the method, compound, pharmaceutical composition, or use of any one of the preceding exemplary embodiments.

[0839] Exemplary embodiment 47. The infectious disease is a viral infectious disease, and the method, compound, pharmaceutical composition, or use of any one of the preceding exemplary embodiments.

[0840] Exemplary Aspect 48. A method, compound, pharmaceutical composition, or use according to any one of the preceding exemplary aspects, wherein the viral infection is caused by a single-stranded RNA virus.

[0841] Exemplary Aspect 49. A method, compound, pharmaceutical composition, or use according to any one of the preceding exemplary aspects, wherein the single-stranded RNA virus is a coronavirus.

[0842] Exemplary Aspect 50. A method, compound, pharmaceutical composition, or use according to any one of the preceding exemplary aspects, wherein the coronavirus is severe acute respiratory syndrome coronavirus 2 (SARS-CoV 2).

[0843] Exemplary Aspect 51. A method, compound, pharmaceutical composition, or use according to any one of the preceding exemplary aspects, wherein the inflammatory disease is associated with an infection by SARS-CoV 2 that causes coronavirus disease 2019 (COVID-19).

[0844] Exemplary Aspect 52. A method, compound, pharmaceutical composition, or use according to any one of the preceding exemplary aspects, wherein the inflammatory disease includes cytokine release syndrome (CRS).

[0845] Exemplary Aspect 53. A method, compound, pharmaceutical composition, or use according to any one of the preceding exemplary aspects, wherein CRS is associated with COVID-19.

[0846] Exemplary Aspect 54. A method, compound, pharmaceutical composition, or use according to any one of the preceding exemplary aspects, wherein CRS is associated with adoptive cell therapy.

[0847] Exemplary Aspect 55. A method, compound, pharmaceutical composition, or use according to any one of the preceding exemplary aspects, wherein the adoptive cell therapy includes chimeric antigen receptor T cell (CAR-T) therapy.

Examples

[0848] Examples For illustrative purposes, salts of the compounds of formula (I) were synthesized and tested in the examples. It is understood that the neutral compounds of formula (I) can be similarly synthesized and tested using the exemplary procedures described in the examples. Further, salts of the compounds of formula (I) (e.g., sodium salts) can be converted to the corresponding neutral compounds using conventional techniques in the art (e.g., pH adjustment and, optionally, extraction (e.g., into the aqueous phase)).

[0849] Example A. Synthesis of Compounds The compounds of formula (I) can be prepared using the methods detailed herein. One of ordinary skill in the art can envision alternative synthetic routes using various starting materials and reagents to prepare and further modify the disclosed compounds of formula (I). For illustrative purposes, some salts of the compounds of formula (I) were synthesized and tested in the examples. It is understood that the neutral compounds of formula (I) can be similarly synthesized and tested using the exemplary procedures described in the examples. Further, salts of the compounds of formula (I) (e.g., hydrochloride salts) can be converted to the corresponding neutral compounds using conventional techniques in the art (e.g., pH adjustment and, optionally, extraction (e.g., into the aqueous phase)).

[0850] 1 H, 13 C and 19 F nuclear magnetic resonance (NMR) spectra were recorded at 400 MHz or 300 MHz as described and, unless otherwise specified, at 300.3 K; chemical shifts (δ) were reported in parts per million (ppm) relative to the residual solvent peak, and multiplicities were reported together with the relevant coupling constants (J) where applicable. Spectra were recorded with 8, 16, 32, or 64 scans using a Bruker or Varian instrument.

[0851] The LC-MS chromatograms and spectra were recorded using an Agilent 1200 or Shimadzu LC-20 AD & MS 2020 instrument with a C-18 column such as Luna-C18 2.0×30 mm or Xbridge Shield RPC18 2.1×50 mm. The injection volume was 0.7 - 8.0 μL and the flow rate was typically 0.8 or 1.2 mL / min. The detection methods were diode array (DAD), evaporative light scattering (ELSD), or positive electrospray ionization. The MS range was 100 - 1000 Da. The solvent was a gradient of water and acetonitrile, each containing a modifier such as trifluoroacetic acid or ammonium carbonate (typically 0.01 - 0.04%).

[0852] UPLC-MS analysis was performed using a Waters Acquity UPLC system consisting of an Acquity I-Class Sample Manager-FL, an Acquity I-Class Binary Solvent Manager, and an Acquity UPLC Column Manager. UV detection was carried out using an Acquity UPLC PDA detector (scanning from 210 - 400 nm), while mass detection was achieved using an Acquity QDa detector (mass scan from 100 - 1250 Da; positive and negative modes simultaneously), and ELS detection was achieved using an Acquity UPLC ELS detector. The analytes were separated using a Waters Acquity UPLC BEH C18 column (2.1×50 mm, 1.7 mm).

[0853] Samples were typically prepared by dissolving (with or without sonication) in 1 mL of 50% (v / v) aqueous MeCN. The resulting solution was then filtered through a 0.2 mm syringe filter and subjected to analysis. All solvents containing formic acid and 36% ammonia solution were purchased as HPLC grade. The solvent was a gradient of water and acetonitrile, each containing a modifier such as formic acid or ammonia (typically 0.01 - 0.04%).

[0854] Abbreviations TIFF2025522354000061.tif188159

[0855] Intermediate A1. (3R)-3-[(2-Chloroacetyl)amino]piperidine-1-carboxylic acid tert-butyl TIFF2025522354000062.tif1412825 °C in THF (150 mL) of (3R)-3-aminopiperidine-1-carboxylic acid tert-butyl (10 g, 49.9 mmol) mixture was added TEA (10.4 mL, 74.9 mmol). The solution was stirred for 30 minutes, then 2-chloroacetyl chloride (3.97 mL, 49.93 mmol) was added. The RM was stirred for 1 hour, diluted with water (100 mL), and extracted with ethyl acetate (3 × 150 mL). The combined organic phases were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the title compound as a solid (Y = 98%). TIFF2025522354000063.tif19153

[0856] Intermediate A2. 2-Chloro-N-[(3R)-1-cyclopropyl-3-piperidyl]acetamide TIFF2025522354000064.tif15140Step 1. 2-Chloro-N-[(3R)-3-piperidyl]acetamide hydrochloride. (3R)-3-[(2-Chloroacetyl)amino]piperidine-1-carboxylic acid tert-butyl (1.5 g, 5.42 mmol) was stirred in 4N HCl (50 mL) in EtOAc at 25 °C for 1 hour. The RM was concentrated in vacuo to give the title compound as a yellow solid (quantitative), which was used without purification.

[0857] Step 2. tert-Butyl (3R)-3-[(2-chloroacetyl)amino]piperidine-1-carboxylate. To a mixture of 2-chloro-N-[(3R)-3-piperidyl]acetamide hydrochloride (1.16 g, 5.44 mmol) and (1-ethoxycyclopropoxy)-trimethyl-silane (6.02 mL, 29.9 mmol) in MeOH (10 mL) were added AcOH (0.25 mL, 4.35 mmol) and NaBH3CN (1.37 g, 21.8 mmol). The reaction was stirred at 45 °C for 8 h. The reaction was carried out a total of 3 times, the batches were combined and concentrated in vacuo. The residue was diluted with water (10 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic phases were washed with brine (3 × 10 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound as a yellow solid, which was used in the next reaction without purification. (5.4 g, crude).

[0858] Intermediate A3. 2-Chloro-N-[(3R)-1-methyl-3-piperidyl]acetamide TIFF2025522354000065.tifTo a solution of (3R)-1-methylpiperidin-3-amine (1.0 g, 8.76 mmol) in DCM (10 mL) at 25 °C were added dropwise TEA (1.83 mL, 13.1 mmol) and 2-chloroacetyl chloride (836 μL, 10.5 mmol). The mixture was stirred at 25 °C for 1 h, diluted with water (10 mL) and extracted with DCM (3 × 10 mL). The organic layers were combined and concentrated under reduced pressure. The residue obtained was purified by preparative HPLC (column: Phenomenex Luna C18, 80 × 40 mm, 3 μm; mobile phase: [water (0.04% HCl)~MeCN]; B: 1~5%, 4 min). MeCN was removed from the fractions under reduced pressure. The aqueous phase was basified to pH 8 with saturated aqueous Na2CO3 solution and the solution was extracted with DCM (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4 and concentrated to give the title compound as a yellow oil. Y = 60%.

[0859] Intermediate A4. 2-Chloro-N-pyrimidin-2-yl-acetamide A solution of 2-aminopyrimidine (15.0 g, 158 mmol) in DCM (150 mL) at 0 °C under 14128 ppm nitrogen was added with triethylamine (33 mL, 237 mmol). The resulting solution was added dropwise at 0 °C under nitrogen to a solution of chloroacetyl chloride (19 mL, 237 mmol) in DCM (15 mL). The reaction was brought to room temperature and stirred for 2 hours. The reaction mixture (RM) was diluted with water (150 mL) and filtered. The filter cake was resuspended in water three times and then dried under vacuum to obtain the title compound as a solid. Yield = 36%. TIFF2025522354000067.tif5159

[0860] Intermediate B1. 3-Methyl-3,4-dihydro-2H-pyrrolo[1,2-a]pyrazin-1-one Step 1. Ethyl 1-[2-(tert-butoxycarbonylamino)propyl]pyrrole-2-carboxylate. To a solution of ethyl 1H-pyrrole-2-carboxylate (500 mg, 3.59 mmol) in dioxane (20 mL) were added tert-butyl 4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (1.11 g, 4.67 mmol), 1,4,7,10,13,16-hexaoxacyclooctadecane (237 mg, 0.90 mmol) and K2CO3 (4.47 g, 32.3 mmol) at 25 °C. The reaction mixture was stirred at 50 °C for 12 hours under N2. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. Purification by FCC (SiO2, 4 - 10% EtOAc in petroleum ether) gave the title compound as a yellow solid. Yield = 39%. TIFF2025522354000069.tif19161

[0861] Step 2. Ethyl 1-(2-aminopropyl)pyrrole-2-carboxylate trifluoroacetate. TFA (1 mL) was added to a solution of ethyl 1-[2-(tert-butoxycarbonylamino)propyl]pyrrole-2-carboxylate (420 mg, 1.42 mmol) in DCM (4 mL) at 25 °C, and the mixture was stirred at 25 °C for 2 h. The solution was concentrated in vacuo to give the title compound as a yellow gum, which was used without further purification. Y = quantitative.

[0862] Step 3. 3-Methyl-3,4-dihydro-2H-pyrrolo[1,2-a]pyrazin-1-one. K2CO3 (784 mg, 5.67 mmol) was added to a solution of ethyl 1-(2-aminopropyl)pyrrole-2-carboxylate trifluoroacetate (440 mg, 1.42 mmol) in EtOH (10 mL). The mixture was stirred at reflux for 12 h. The solution was concentrated in vacuo. The residue was purified by preparative TLC (EtOAc) to give the title compound as a colorless gum. Y = 200 mg.

[0863] Intermediate B2. 4-Chlorospiro[5-thia-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),3,7-triene-12,1'-cyclopropane]-9-one TIFF2025522354000070.tif52153Step 1. Ethyl 2-chloro-4H-thieno[3,2-b]pyrrole-5-carboxylate. NCS (20.5 g, 153 mmol) was added to a solution of ethyl 4H-thieno[3,2-b]pyrrole-5-carboxylate (23 g, 118 mmol) in THF (460 mL) at 25 °C. The mixture was stirred at 55 °C for 4 h. The resulting mixture was diluted with H2O (70 mL) and extracted with EtOAc (3 × 70 mL). The combined organic layers were washed with brine (70 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. Purification by preparative HPLC (column: Phenomenex Luna C18 250 mm × 100 mm, 10 μm, mobile phase: [H2O (TFA)-MeCN], B: 40 - 70%, 20 min) gave the title compound as a white solid. Y = 74%. TIFF2025522354000071.tif12128

[0864] Step 2. Ethyl 4-(1-tert-butoxycarbonylvinyl)-2-chloro-thieno[3,2-b]pyrrole-5-carboxylate. To a solution of ethyl 2-chloro-4H-thieno[3,2-b]pyrrole-5-carboxylate (5.0 g, 21.8 mmol) and PPh3 (5.71 g, 21.8 mmol) in DCM (100 mL) was added tert-butyl prop-2-ynoate (3.29 mL, 24.0 mmol) at 0 °C. The mixture was stirred at 25 °C for 12 h. The resulting mixture was diluted with H2O (100 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by FCC (SiO2, 0 - 100% EtOAc in petroleum ether) to give the title compound as a white solid. Y = 90%. TIFF2025522354000072.tif19157

[0865] Step 3. Ethyl 4-(1-tert-butoxycarbonylcyclopropyl)-2-chloro-thieno[3,2-b]pyrrole-5-carboxylate. To a solution of trimethylsulfoxonium iodide (3.71 g, 16.9 mmol) in DMSO (15 mL) was added NaH (60% in mineral oil, 674 mg, 16.9 mmol) at 25 °C. The mixture was stirred at 25 °C for 40 min under N2. Ethyl 4-(1-tert-butoxycarbonylvinyl)-2-chloro-thieno[3,2-b]pyrrole-5-carboxylate (3 g, 8.43 mmol) in DMSO (30 mL) was added at 25 °C. The RM was stirred at 25 °C for 1 h under N2. The RM was quenched with a saturated aqueous NH4Cl solution (60 mL) at 0 °C. The mixture was extracted with EtOAc (3 × 60 mL). The combined organic layers were washed with brine (60 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. Purification by FCC (SiO2, 0 - 100% EtOAc in petroleum ether) gave the title compound as a white solid. Y = 96%.

[0866] Step 4. 1-(2-Chloro-5-ethoxycarbonyl-thieno[3,2-b]pyrrol-4-yl)cyclopropanecarboxylic acid. A mixture of ethyl 4-(1-tert-butoxycarbonylcyclopropyl)-2-chloro-thieno[3,2-b]pyrrole-5-carboxylate (3.0 g, 8.11 mmol) and HCl (4 M in EtOAc, 30 mL) was stirred at 25 °C for 5 h. The resulting mixture was filtered, and the filter cake was dried in vacuo to give the title compound as a white solid. Y = 98%. TIFF2025522354000073.tif12157

[0867] Step 5. Ethyl 4-(1-carbamoylcyclopropyl)-2-chloro-thieno[3,2-b]pyrrole-5-carboxylate. To a solution of 1-(2-chloro-5-ethoxycarbonyl-thieno[3,2-b]pyrrol-4-yl)cyclopropanecarboxylic acid (700 mg, 2.23 mmol) in DMF (7 mL) were added HOBt (904 mg, 6.69 mmol) and EDCI (1.28 g, 6.69 mmol) at 0 °C. The mixture was stirred for 0.5 h. DIPEA (2.33 mL, 13.4 mmol) and NH4Cl (1.19 g, 22.3 mmol) were added. The reaction mixture was stirred at 25 °C for 3 h. The resulting mixture was diluted with H2O (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. Purification by column chromatography (0 - 100% EtOAc in petroleum ether) gave the title compound as a white solid. Y = 93%. TIFF2025522354000074.tif26155

[0868] Step 6. Ethyl 2-chloro-4-(1-cyanocyclopropyl)thieno[3,2-b]pyrrole-5-carboxylate. A mixture of ethyl 4-(1-carbamoylcyclopropyl)-2-chloro-thieno[3,2-b]pyrrole-5-carboxylate (1.3 g, 4.16 mmol) and POCl3 (13 mL) was stirred at 50 °C for 3 h. The reaction mixture was quenched with H2O (20 mL) at 25 °C, and the resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound as a white solid. Y = 98%.

[0869] Step 7. 4-Chlorospiro[5-thia-1,10-diazatricyclo[6.4.0.0 2,6 dodeca-2(6),3,7-triene-12,1'-cyclopropane]-9-one. To a solution of ethyl 2-chloro-4-(1-cyanocyclopropyl)thieno[3,2-b]pyrrole-5-carboxylate (600 mg, 2.04 mmol) in EtOH (6 mL) were added NH3·H2O (3.14 mL, 20.4 mmol) and Raney Ni (400 mg) under N2. The mixture was stirred at 25 °C for 3 h under H2 (15 Psi). The reaction mixture was filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure. Purification by preparative TLC (SiO2, 100% EtOAc) gave the title compound as a white solid. Y = 97%.

[0870] Intermediate B3. 2-(4-Chloro-9-oxo-spiro[5-thia-1,10-diazatricyclo[6.4.0.0 2,6 dodeca-2(6),3,7-triene-12,1'-cyclopropane]-10-yl)acetic acid TIFF2025522354000075.tif22128To a solution of 2-bromoacetic acid (34.2 μL, 475 μmol) in THF (1 mL) were added t-BuOLi (0.11 M in THF, 178 μL, 1.98 mmol) and 4-chlorospiro[5-thia-1,10-diazatricyclo[6.4.0.0 2,6Dodeca-2(6),3,7-triene-12,1'-cyclopropane]-9-one (intermediate B2, 100 mg, 396 μmol) was added at 25 °C. The mixture was stirred at 80 °C for 3 hours. The resulting mixture was adjusted to pH = 4 - 5 with 2M HCl and then extracted with EtOAc (3 × 3 mL). The combined organic layers were washed with brine (3 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound as a white solid. Y = 81%. TIFF2025522354000076.tif19153

[0871] Intermediate B4. 2-(2-Ethyl-4-oxo-spiro[6H-pyrazolo[4,3-c]pyridine-7,1'-cyclopropane]-5-yl)acetic acid TIFF2025522354000077.tif39158 Step 1. Ethyl 4-chloro-2-(ethoxymethylene)-3-oxo-butanoate. Diethoxymethoxyethane (20.2 mL, 122 mmol) was added to a solution of ethyl 4-chloro-3-oxo-butanoate (10 g, 60.8 mmol) in Ac2O (22.8 mL, 243 mmol) at 25 °C. The RM was stirred at 110 °C for 3 hours. The solution was concentrated in vacuo to obtain the title compound as a yellow solid. Y = 97%.

[0872] Step 2. Ethyl 3-(chloromethyl)-1H-pyrazole-4-carboxylate. Hydrazine hydrate (674 μL, 13.6 mmol) at 25 °C was added to a solution of ethyl 4-chloro-2-(ethoxymethylene)-3-oxo-butanoate (3 g, 13.60 mmol) in MTBE (20 mL), and the mixture was stirred for 2 hours. The solution was diluted with H2O (30 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The title compound was obtained as a yellow solid by column chromatography (SiO2, purification with 50% EtOAc in petroleum ether). Y = 66%. TIFF2025522354000078.tif12150

[0873] Step 3. Ethyl 3-(cyanomethyl)-1H-pyrazole-4-carboxylate. Ethyl 3-(chloromethyl)-1H-pyrazole-4-carboxylate (1.0 g, 5.30 mmol) was added to a solution of NaCN (780 mg, 15.9 mmol) in MeCN (50 mL) and H2O (7.7 mL) at 25 °C, and the mixture was stirred at 25 °C for 2 h. The resulting mixture was diluted with H2O (40 mL) and extracted with EtOAc (3 × 40 mL). The combined organic layers were washed with brine (40 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound as a white solid, which was used without further purification. Y = 950 mg.

[0874] Step 4. Ethyl 3-(cyanomethyl)-1-ethyl-pyrazole-4-carboxylate. K2CO3 (463 mg, 3.35 mmol) and iodoethane (147 μL, 1.84 mmol) were added to a solution of ethyl 3-(cyanomethyl)-1H-pyrazole-4-carboxylate (300 mg, 1.67 mmol) in DMF (4 mL) at 25 °C. The RM was stirred at 80 °C for 1 h. The solution was concentrated in vacuo. The residue was purified by preparative HPLC (column: Waters Xbridge BEH C18, 100 × 30 mm, 10 μm; mobile phase: [H2O (NH4HCO3)-MeCN], B: 20~50%, 10 min) to give the title compound as a white solid. Y = 40%.

[0875] Step 5. Ethyl 3-(1-cyanocyclopropyl)-1-ethyl-pyrazole-4-carboxylate. LDA (2 M in THF, 2.12 mL, 4.24 mmol) at -78 °C was added to a solution of ethyl 3-(cyanomethyl)-1-ethyl-pyrazole-4-carboxylate (220 mg, 1.06 mmol) in THF (2 mL), and the mixture was stirred for 0.5 h. Then, 1,2-dibromoethane (481 μL, 6.37 mmol) was added to the above mixture at 25 °C for 2 h. The reaction mixture was quenched by the addition of saturated aqueous NH4Cl solution (2 mL) at 0 °C, and the resulting mixture was extracted with EtOAc (3 × 3 mL). The combined organic layers were washed with brine (3 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound as a yellow oil. Y = 89%.

[0876] Step 6. 2-Ethylspiro[5,6-dihydropyrazolo[4,3-c]pyridine-7,1'-cyclopropane]-4-one. Raney Ni (162 mg) was added to a solution of ethyl 3-(1-cyanocyclopropyl)-1-ethyl-pyrazole-4-carboxylate (220 mg, 943 μmol) in EtOH (3 mL) and NH3·H2O (1.45 mL, 9.43 mmol) under N2. The mixture was stirred at 25 °C for 2 h under H2 (15 psi). The solution was filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure to give the title compound as a yellow solid. Y = 94%. TIFF2025522354000079.tif19153

[0877] Step 7. 2-(2-Ethyl-4-oxo-spiro[6H-pyrazolo[4,3-c]pyridine-7,1'-cyclopropane]-5-yl)acetic acid. t-BuOLi (THF solution, 71 μL, 784 μmol) and 2-bromoacetic acid (21 μL, 288 μmol) were added to a solution of 2-ethylspiro[5,6-dihydropyrazolo[4,3-c]pyridine-7,1'-cyclopropane]-4-one (50 mg, 261 μmol) in THF (1.5 mL) at 25 °C. The reaction mixture was stirred at 80 °C for 2 h. The resulting mixture was adjusted to pH = 4 - 5 with 2 M HCl, and the mixture was extracted with EtOAc (3 × 3 mL). The combined organic layers were washed with brine (3 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound as a yellow gum, which was used without further purification. Y = 50 mg.

[0878] Intermediate B5. 2-Isopropylspiro[5,6-dihydropyrazolo[1,5-a]pyrazine-7,1'-cyclopropane]-4-one TIFF2025522354000080.tif Project 1. Methyl 3-isopropyl-1H-pyrazole-5-carboxylate. To a solution of 3-isopropyl-1H-pyrazole-5-carboxylic acid (5.0 g, 32.43 mmol) in MeOH (50 mL) was added SOCl2 (7.06 mL, 97.3 mmol) at 25 °C. The reaction mixture was stirred at 35 °C for 16 h. The reaction mixture was concentrated under reduced pressure to remove MeOH. The residue was diluted with H2O (50 mL), and the aqueous mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound as a yellow solid. Y = 92%. TIFF2025522354000081.tif12128

[0879] Project 2. Methyl 2-(cyanomethyl)-5-isopropylpyrazole-3-carboxylate. To a solution of methyl 3-isopropyl-1H-pyrazole-5-carboxylate (5.0 g, 29.7 mmol) in DMF (50 mL) were added 3-bromoprop-1-yne (2.82 mL, 32.7 mmol) and K2CO3 (6.16 g, 44.6 mmol) at 25 °C. The reaction mixture was stirred at 80 °C for 4 h. The reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. Purification by FCC (SiO2, 10 - 20% EtOAc in petroleum ether) gave the title compound as a colorless oil. Y = 49%. TIFF2025522354000082.tif12155

[0880] Step 3. Methyl 2-(1-cyanocyclopropyl)-5-isopropylpyrazole-3-carboxylate. 1-Bromo-2-chloroethane (3.60 mL, 43.4 mmol) was added to a solution of methyl 2-(cyanomethyl)-5-isopropylpyrazole-3-carboxylate (3.0 g, 14.5 mmol) in DMF (10 mL) at 0 °C. NaH (60%, 1.45 g, 36.19 mmol) was added at 0 °C, and the resulting mixture was stirred at 25 °C for 3 h. The RM was quenched with ice water (20 mL) and extracted with EtOAc (3 × 30 mL). The combined organic phases were washed with brine (2 × 30 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The title compound was obtained as a white solid by purification by preparative HPLC (column: Phenomenex Luna C18 (250 × 70 mm, 15 μm); mobile phase: [water (NH4HCO3)-MeCN]; B: 40 - 60%, 20 min). Y = 25%. TIFF2025522354000083.tif19153

[0881] Step 4. 2-Isopropylspiro[5,6-dihydropyrazolo[1,5-a]pyrazine-7,1'-cyclopropane]-4-one. CoCl2·6H2O (1.02 g, 4.29 mmol) and NaBH4 (649 mg, 17.2 mmol) were added to a solution of methyl 2-(1-cyanocyclopropyl)-5-isopropylpyrazole-3-carboxylate (500 mg, 2.14 mmol) in MeOH (10 mL) at 0 °C. The mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched by the addition of H2O (5 mL) at 0 °C. The resulting mixture was concentrated under reduced pressure to remove MeOH, the aqueous phase was adjusted to pH = 2 with 1 M HCl, and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The title compound was obtained as a white solid by purification by FCC (SiO2, 10 - 100% EtOAc in petroleum ether). Y = 20%. TIFF2025522354000084.tif12132

[0882] Intermediate B6. 2-[(12R)-4-chloro-12-methyl-9-oxo-5-thia-1,10-diazatricyclo[6.4.0.0 2,6 dodeca-2(6),3,7-trien-10-yl]acetic acid TIFF2025522354000085.tif22143 Step 1. (12R)-4-chloro-12-methyl-5-thia-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),3,7-trien-9-one. NaH (60% in mineral oil, 56 mg, 1.39 mmol) was added to a cooled (0 °C) solution of ethyl 2-chloro-4H-thieno[3,2-b]pyrrole-5-carboxylate (120 mg, 0.52 mmol) and (S)-tert-butyl 5-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (124 mg, 0.52 mmol) in THF (9 mL), and the RM was stirred at room temperature for 24 h. The reaction was further treated with (S)-tert-butyl 5-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (62 mg, 0.26 mmol) and NaH (60% in mineral oil, 28 mg, 0.70 mmol), and the mixture was stirred at room temperature for 24 h. The reaction was treated with 10% aqueous citric acid and stirred at ambient temperature for 1 h. The reaction mixture was extracted twice with EtOAc, the combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was dissolved in DCM (5 mL) and treated with TFA (1.3 mL, 17.4 mmol). The RM was stirred at room temperature for 1 h. The RM was concentrated in vacuo, the residue was dissolved in THF (9 mL), treated with potassium carbonate (561 mg, 4.06 mmol), and stirred at room temperature for 18 h. The RM was diluted with water and extracted three times with EtOAc. The combined organics were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to afford the title compound as an off-white solid. Y = 71%. TIFF2025522354000086.tif26160

[0883] Step 2. 2-[(12R)-4-Chloro-12-methyl-9-oxo-5-thia-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),3,7-triene-10-yl]acetic acid. (12R)-4-Chloro-12-methyl-5-thia-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),3,7-triene-9-one (237 mg, 0.985 mmol) was dissolved in THF (2.5 mL), and NaH (60% in mineral oil, 79 mg, 1.97 mmol) was added. The reaction was stirred for 10 minutes. 2-Bromomethyl acetate (0.14 mL, 1.48 mmol) was added, and the reaction was stirred at room temperature for 1 hour. Then MeOH (2.5 mL) and water (5 mL) were added, followed by sodium hydroxide (197 mg, 4.92 mmol). The resulting reaction mixture was stirred at ambient temperature for 2 hours, concentrated in vacuo, and the crude residue was taken up in 1 M NaOH. The solution was acidified to pH 2 with 1 M aqueous hydrochloric acid and extracted with EtOAc (3×). The combined organic extracts were washed with brine, dried over sodium sulfate, and concentrated in vacuo to afford the title compound as an off-white solid. Y = 95%. TIFF2025522354000087.tif26159

[0884] Intermediate B7. 2-Ethylspiro[5,6-dihydrothiazolo[5,4-c]pyridine-7,1'-cyclopropane]-4-one TIFF2025522354000088.tif63157 Step 1. Methyl 2-vinylthiazole-4-carboxylate. To a solution of methyl 2-bromothiazole-4-carboxylate (25 g, 113 mmol) in H2O (40 mL) and THF (200 mL) were added Pd(PPh3)4 (1.30 g, 1.13 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (95.5 mL, 563 mmol) and Na2CO3 (35.8 g, 338 mmol) at 25 °C. The mixture was heated to reflux under N2 for 12 h. The RM was concentrated under reduced pressure to remove THF. The residue was diluted with H2O (100 mL) and extracted with EtOAc (3 × 150 mL). The combined organic layers were washed with brine (2 × 150 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. Purification by FCC (SiO2, 10 - 20% EtOAc in petroleum ether) afforded the title compound as a white solid. Y = 89%. TIFF2025522354000089.tif12128

[0885] Step 2. Methyl 2-ethylthiazole-4-carboxylate. To a solution of methyl 2-vinylthiazole-4-carboxylate (17 g, 100 mmol) in MeOH (170 mL) was added Pd / C (10%, 50% in water, 2 g) under N2. The mixture was stirred at 25 °C under H2 (15 psi) for 2 h. The RM was filtered through a pad of celite and the filtrate was concentrated in vacuo to afford the title compound as a white solid. Y = 87%. TIFF2025522354000090.tif12128

[0886] Step 3. (2-Ethylthiazol-4-yl)methanol. To a solution of methyl 2-ethylthiazole-4-carboxylate (8.7 g, 50.8 mmol) in THF (90 mL) was added LiAlH4 (2.89 g, 76.2 mmol) at -78 °C. The mixture was stirred at -78 °C for 3 h. The reaction mixture was quenched by the addition of H2O (3 mL) at 0 °C and 10% aqueous NaOH solution (3 mL). The resulting mixture was filtered and the filtrate was concentrated under reduced pressure to afford the title compound as a white solid. Y = 82%. TIFF2025522354000091.tif12129

[0887] Step 4. (5-Bromo-2-ethyl-thiazol-4-yl)methanol. NBS (6.84 g, 38.4 mmol) was added to a solution of (2-ethylthiazol-4-yl)methanol (5.5 g, 38.41 mmol) in MeCN (72 mL) at 25 °C. The mixture was stirred at 25 °C for 2 h. The RM was quenched by the addition of a saturated aqueous Na2S2O3 solution (50 mL) at 25 °C and extracted with DCM (3 × 50 mL). The combined organic layers were washed with brine (2 × 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. Purification by FCC (SiO2, 20 - 100% EtOAc in petroleum ether) gave the title compound as a pink solid. Y = 64%. TIFF2025522354000092.tif5160

[0888] Step 5. (5-Bromo-2-ethyl-thiazol-4-yl)methyl methanesulfonate. TEA (2.82 mL, 20.3 mmol) was added to a solution of (5-bromo-2-ethyl-thiazol-4-yl)methanol (4.5 g, 20.2 mmol) in DCM (45 mL) at 0 °C. MsCl (1.57 mL, 20.3 mmol) was added dropwise at 0 °C under N2. The resulting mixture was stirred at 0 °C for 1 h. The mixture was quenched with H2O (20 mL) and extracted with DCM (3 × 20 mL). The combined organic layers were washed with brine (2 × 15 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the title compound as an oil. Y = 99%.

[0889] Step 6. 2-(5-Bromo-2-ethyl-thiazol-4-yl)acetonitrile. Cesium fluoride (2.21 mL, 60.0 mmol) was added to a solution of (5-bromo-2-ethyl-thiazol-4-yl)methyl methanesulfonate (6.0 g, 20.0 mmol) in MeCN (50 mL) at 0 °C. Trimethylsilyl cyanide (7.50 mL, 60.0 mmol) was added dropwise at 0 °C. The resulting mixture was stirred at 25 °C for 12 h. The RM was concentrated under reduced pressure to remove MeCN (50 mL). The residue was diluted with H2O (30 mL) and extracted with DCM (3 × 30 mL). The combined organic layers were washed with brine (2 × 20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. Purification by FCC (SiO2, 10 - 50% EtOAc in petroleum ether) gave the title compound as a yellow oil. Y = 74%. TIFF2025522354000093.tif12132

[0890] Step 7. 1-(5-Bromo-2-ethyl-thiazol-4-yl)cyclopropanecarbonitrile. 1,2-Dibromoethane (1.66 mL, 22.1 mmol) was added dropwise to a solution of 2-(5-bromo-2-ethyl-thiazol-4-yl)acetonitrile (3.4 g, 14.7 mmol) in DMF (30 mL) at 25 °C. NaH (60% in mineral oil, 1.77 g, 44.1 mmol) was added at 0 °C and the mixture was stirred at 0 °C for 1 h. The RM was quenched by the addition of H2O (20 mL) at 0 °C and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (5 × 30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. Purification by FCC (SiO2, 20 - 50% EtOAc in petroleum ether) gave the title compound as a yellow oil. Y = 53%. TIFF2025522354000094.tif12128

[0891] Step 8. Methyl 4-(1-cyanocyclopropyl)-2-ethyl-thiazole-5-carboxylate. To a solution of 1-(5-bromo-2-ethyl-thiazol-4-yl)cyclopropanecarbonitrile (1.3 g, 5.06 mmol) in MeOH (15 mL) were added DIPEA (2.64 mL, 15.2 mmol) and Pd(dppf)Cl2 (370 mg, 506 μmol) at 25 °C. The mixture was stirred at 80 °C for 12 h under CO (50 psi). The reaction mixture was quenched with H2O (20 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. Purification by FCC (SiO2, 30 - 100% EtOAc in petroleum ether) afforded the title compound as a yellow oil. Yield = 59%. TIFF2025522354000095.tif12136

[0892] Step 9. 2-Ethylspiro[5,6-dihydrothiazolo[5,4-c]pyridine-7,1'-cyclopropane]-4-one. To a solution of methyl 4-(1-cyanocyclopropyl)-2-ethyl-thiazole-5-carboxylate (0.54 g, 2.29 mmol) in MeOH (6 mL) was added CoCl2·6H2O (1.09 g, 4.57 mmol) at 25 °C. NaBH4 (692 mg, 18.3 mmol) was added at 0 °C and the mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched with H2O (10 mL) at 0 °C. The resulting mixture was adjusted to pH = 2 with 1 M HCl, stirred for 1 h, and extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. Purification by FCC (SiO2, 30 - 100% EtOAc in petroleum ether) afforded the title compound as a white solid. Yield = 63%. TIFF2025522354000096.tif12130

[0893] Intermediate B8. 2-Ethylspiro[5,6-dihydrothieno[2,3-c]pyridine-4,1'-cyclopropane]-7-one TIFF2025522354000097.tif63155 Step 1. Methyl 5-vinylthiophene-3-carboxylate. To a solution of methyl 5-bromothiophene-3-carboxylate (7.8 g, 35.3 mmol) in THF (100 mL) and H2O (20 mL) were added 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (18.0 mL, 106 mmol), Pd(PPh3)4 (4.08 g, 3.53 mmol) and Na2CO3 (11.2 g, 106 mmol) at 25 °C under N2. The mixture was stirred at 80 °C for 12 h under N2. The reaction mixture was diluted with H2O (50 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Purification by FCC (SiO2, 10 - 30% EtOAc in petroleum ether) afforded the title compound as a yellow liquid. Yield = 78%. TIFF2025522354000098.tif19158

[0894] Step 2. Methyl 5-ethylthiophene-3-carboxylate. To a solution of methyl 5-vinylthiophene-3-carboxylate (4.6 g, 27.4 mmol) in MeOH (100 mL) was added Pd (10% on carbon, 50 wt% in H2O, 4.6 g) at 25 °C under N2. The mixture was stirred at 25 °C for 2 h under H2 (15 psi). The residue was filtered through a pad of celite. The filtrate was concentrated under reduced pressure to afford the title compound as a colorless liquid. Yield = 97%. TIFF2025522354000099.tif12129

[0895] Step 3. Methyl 2-bromo-5-ethyl-thiophene-3-carboxylate. NBS (4.71 g, 26.4 mmol) was added to a solution of methyl 5-ethylthiophene-3-carboxylate (4.5 g, 26.4 mmol) in DMF (50 mL) at 0 °C, and the mixture was stirred at 25 °C for 1 h. The reaction mixture was diluted with H2O (50 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. Purification by FCC (SiO2, 20% EtOAc in petroleum ether) gave the title compound as a colorless oil. Y = 53%. TIFF2025522354000100.tif12160

[0896] Step 4. (2-Bromo-5-ethyl-3-thienyl)methanol. LiBH4 (612 mg, 28.1 mmol) was added to a solution of methyl 2-bromo-5-ethyl-thiophene-3-carboxylate (3.5 g, 14.1 mmol) in THF (40 mL) at 0 °C, and the mixture was stirred at 75 °C for 2 h. The reaction mixture was quenched with H2O (15 mL), and the resulting mixture was extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. Purification by FCC (SiO2, 10 - 20% EtOAc in petroleum ether) gave the title compound as a colorless liquid. Y = 90%. TIFF2025522354000101.tif12153

[0897] Step 5. (2-Bromo-5-ethyl-3-thienyl)methyl methanesulfonate. MsCl (840 μL, 10.9 mmol) and TEA (2.27 mL, 16.3 mmol) were added to a solution of (2-bromo-5-ethyl-3-thienyl)methanol (1.2 g, 5.43 mmol) in DCM (10 mL) at 0 °C. The reaction mixture was stirred at 25 °C for 3 h. The reaction mixture was quenched with H2O (10 mL) and extracted with DCM (3 × 10 mL). The combined organic layers were washed with brine (3 × 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound as a yellow oil. Y = 1.5 g.

[0898] Step 6. 2-(2-Bromo-5-ethyl-3-thienyl)acetonitrile. Trimethylsilyl cyanide (1.88 mL, 15.0 mmol) and CsF (555 μL, 15.0 mmol) were added to a solution of (2-bromo-5-ethyl-3-thienyl)methyl methanesulfonate (1.5 g, 5.01 mmol) in MeCN (30 mL) at 25 °C. The mixture was stirred at 25 °C for 12 h. The reaction mixture was diluted with H2O (10 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. Purification by FCC (SiO2, 10 - 20...

Claims

1. Compounds of formula (I), their solvates, or pharmaceutically acceptable salts: During the ceremony each They are independently single or double bonds, insofar as their valence allows; A 2 As long as the valence allows, CR 2 , N, NR 2a It is O, or S; A 3 As long as the valence allows, CR 2 , N, NR 2a It is O, or S; A 4 is, to the extent permitted by valence, CR 2 , N, NR 2a , O, or S; A 5 It is C or N, as long as its valence allows. Here, A 2 , A 3 , A 4 , or A 5 At least one of them is N, NR 2a It is O, or S; R1 is methyl and R1a is H; or R1 is H and R1a is methyl; or R 1 and R 1a These, together with the atoms to which they are bonded, form C3-C 7 Forms a cycloalkyl group, or R 1a and R 3 These, together with the atoms to which they are bonded, form cyclobutyl; Each R 2 H and C 1-C are independent. 6 Alkyl, -O(C 1 ~C 6 Alkyl), -NH(C 1 ~C 6 Alkyl), or C 3 ~C 12 It is a cycloalkyl, or two R's 2 These, together with the atoms to which they are bonded, form a 5- to 10-membered heteroaryl, where the 5- to 10-membered heteroaryl is one or more R 2S It is also fine if it is replaced with; Each R 2S These are halogen and C 1 ~C 6 alkyl, -OH, -O(C 1 ~C 6 Alkyl), -NH(C 1 ~C 6 Alkyl), -N(C 1 ~C 6 Alkyl) 2 , or C 3 ~C 12 It is a cycloalkyl; R 3 H, -N(C 1 ~C 6 Alkyl) 2 , C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, or C 3 ~C 12 It is a cycloalkyl, where -N(C 1 ~C 6 Alkyl) 2 , C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, or C 3 ~C 12 Cycloalkyl is one or more R 3S It may be replaced with, or R 1 and R 3 They, together with the atoms to which they are bonded, form a cyclopropyl; Each R 3S These are independently halogens, cyano, -OH, or C 1 ~C 6 It is alkyl; Each R 2a H and C are independent of each other. 1 ~C 6 Alkyl, C 2 ~C 6 Alkenil, C 2 ~C 6 Alkinyl, C 1 ~C 6 Haloalkyl, -(CH 2 ) 0～3 -(C 3 ~C 12 Cycloalkyl), or -(CH 2 ) 0～3 -(3-12 member heterocycloalkyl); Each R a is independently H or C 1 to C 6 alkyl; or two Rs a together with the atom to which they are attached form C 2 to C 6 alkenyl or C 3 to C 12 cycloalkyl; R N1 is H or C 1 ~C 6 It is alkyl; R N2 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, -O-(C 1 -C 6 alkyl), -O-(C 2 -C 6 alkenyl), -O-(C 2 -C 6 alkynyl), -NH-(C 1 -C 6 alkyl), -NH-(C 2 -C 6 alkenyl), -NH-(C 2 -C 6 alkynyl), C 3 -C 12 cycloalkyl, 3- to 12-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, -(C 1 -C 6 alkyl)-(C 3 -C 12 cycloalkyl), -(C 1 -C 6 alkyl)-(3- to 12-membered heterocycloalkyl), -(C 1 -C<00001​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​ 2 ~C 6 Alkenyl), -NH-(C 2 ~C 6 Alkinyl), C 3 ~C 12 Cycloalkyl, 3-12 member heterocycloalkyl, C 6 ~C 10 Aryl, 5-10 member heteroaryl, -(C 1 ~C 6 Alkyl)-(C 3 ~C 12 Cycloalkyl), -(C 1 ~C 6 Alkyl)-(3-12 member heterocycloalkyl),-(C 1 ~C 6 Alkyl)-(C 6 ~C 10 (aryl), or -(C 1 ~C 6 Alkyl)-(5-10 member heteroaryl) is one or more R N2a It is also fine if it is replaced with; Each R N2a These are independently oxo, halogen, cyano, -OH, and -NH 2 , -NO 2 -C(=O)H, -C(=O)OH, C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenil, C 2 ~C 6 Alkinyl, -O(C 1 ~C 6 Alkyl), -NH(C 1 ~C 6 Alkyl), -N(C 1 ~C 6 Alkyl) 2 -C(=O)(C 1 ~C 6 Alkyl), -C(=O)O(C 1 ~C 6 Alkyl), -NHC(=O)O(C 1 ~C 6 Alkyl), -S (=O) 2 (C 1 ~C 6 Alkyl), -S (=O) 2 N(C 1 ~C 6 Alkyl) 2 , C 3 ~C 12 Cycloalkyl, 3-12 member heterocycloalkyl, C 6 ~C 10 Aryl, 5-10 member heteroaryl, -(C 1 ~C 6 Alkyl)-(C 3 ~C 12 Cycloalkyl), -(C 1 ~C 6 Alkyl)-(3-12 member heterocycloalkyl),-(C 1 ~C 6 Alkyl)-(C 6 ~C 10 (aryl), or -(C 1 ~C 6 It is an alkyl)-(5-10 member heteroaryl); where C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenil, C 2 ~C 6 Alkinyl, -O(C 1 ~C 6 Alkyl), -NH(C 1 ~C 6 Alkyl), -N(C 1 ~C 6 Alkyl) 2 -C(=O)(C 1 ~C 6 Alkyl), -C(=O)O(C 1 ~C 6 Alkyl), -NHC(=O)O(C 1 ~C 6 Alkyl), -S (=O) 2 (C 1 ~C 6 Alkyl), -S (=O) 2 N(C 1 ~C 6 Alkyl) 2 , C 3 ~C 12 Cycloalkyl, 3-12 member heterocycloalkyl, C 6 ~C 10 Aryl, 5-10 member heteroaryl, -(C 1 ~C 6 Alkyl)-(C 3 ~C 12 Cycloalkyl), -(C 1 ~C 6 Alkyl)-(3-12 member heterocycloalkyl),-(C 1 ~C 6 Alkyl)-(C 6 ~C 10 (aryl), or -(C 1 ~C 6 Alkyl)-(5-10 member heteroaryl) is one or more R N2ab It may be replaced by and Each R N2ab These are independently oxo, halogen, cyano, -OH, and -NH 2 -C(=O)H, -C(=O)OH, -O(C 1 ~C 6 Alkyl), -NH(C 1 ~C 6 Alkyl), -N(C 1 ~C 6 Alkyl) 2 -C(=O)(C 1 ~C 6 Alkyl), -C(=O)O(C 1 ~C 6 Alkyl), -NHC(=O)O(C 1 ~C 6 Alkyl), -S (=O) 2 (C 1 ~C 6 Alkyl), or -S (=O) 2 N(C 1 ~C 6 Alkyl) 2 is; or R N1 and R N2 Together with the atoms they bond to, one or more R b Forms a 3- to 12-membered heterocycloalkyl group which may be substituted with; Each R b These are independently oxo, halogen, cyano, -OH, and -NH 2 -C(=O)H, -C(=O)OH, C 1 ~C 6 Alkyl, -O(C 1 ~C 6 Alkyl), -NH(C 1 ~C 6 Alkyl), -N(C 1 ~C 6 Alkyl) 2 -C(=O)(C 1 ~C 6 Alkyl), -C(=O)O(C 1 ~C 6 Alkyl), -NHC(=O)O(C 1 ~C 6 Alkyl), -S (=O) 2 (C 1 ~C 6 Alkyl), or -S (=O) 2 N(C 1 ~C 6 Alkyl) 2 And here, C 1 ~C 6 Alkyl, -O(C 1 ~C 6 Alkyl), -NH(C 1 ~C 6 Alkyl), -N(C 1 ~C 6 Alkyl) 2 -C(=O)(C 1 ~C 6 Alkyl), -C(=O)O(C 1 ~C 6 Alkyl), -NHC(=O)O(C 1 ~C 6 Alkyl), -S (=O) 2 (C 1 ~C 6 Alkyl), or -S (=O) 2 N(C 1 ~C 6 Alkyl) 2 is one or more R b1 It may be replaced by and Each R b1 These are independently oxo, halogen, cyano, -OH, or -NH 2 That is the case.

2. A 2 CR 2 A 3 CR 2 A 4 CR 2 A 5 Let N be arbitrary, A 3 and A 4 CR 2 They are linked to form a thienyl ring or a thiazolyl ring; or A 2 CR 2 A 3 NR 2a A 4 N is A 5 Is C; or A 2 CR 2 A 3 CR 2 A 4 N is A 5 Is N; or A 2 S is A 3 CR 2 A 4 N is A 5 Is C; or A 2 S is A 3 CR 2 A 4 CR 2 A 5 Is C; or A 2 CR 2 A 3 CR 2 A 4 O is A 5 Is C; or A 2 NR 2a A 3 CR 2 A 4 CR 2 A 5 Is C; or A 2 NR 2a A 3 CR 2 A 4 N is A 5 Is C; or A 2 CR 2 A 3 CR 2 A 4 S is A 5 C is; Here, R 2 and R 2a This is as defined in claim 1, The compound according to claim 1.

3. R 1 and R 1a The compound according to claim 1, wherein they combine with the atoms to which they are bonded to form a cyclopropyl group.

4. (a) at least one R 2S is halogen or C 1 ~C 6 It is alkyl; or (b)R 2a is H or C 1 ~C 6 The compound according to claim 1, wherein it is alkyl.

5. R 3 Is H; or R 3 C 1 ~C 6 It is alkyl; or R 3 is methyl The compound according to claim 1.

6. (a) at least one R a Is H; or (b)R a The compound according to claim 1, wherein all of them are H.

7. R N1 The compound according to claim 1, wherein is H.

8. (a)R N2 However, C 3 ~C 12 They are cycloalkyl, 3- to 12-membered heterocycloalkyl, or 5- to 10-membered heteroaryl; where C 3 ~C 12 Cycloalkyl, 3-12 member heterocycloalkyl, or 5-10 member heteroaryl may be one or more R N2a It may be replaced with; or (b)R N2 but The compound according to claim 1.

9. at least one R N2a However, oxo, F, Cl, cyano, -OH, -NH 2 , -NO 2 methyl, CF 3 The compound according to claim 1, wherein the compound is -O(methyl), -C(=O)O(ethyl), or pyrazolyl.

10. A 2 CR 2 , NR 2a , or S; A 3 CR 2 , NR 2a , or O; A 4 CR 2 It is S or O; A 5 is C or N; Here, A 2 , A 3 , A 4 , or A 5 At least one of them is N, NR 2a It is O, or S; R1 is methyl and R1a is H; or R1 is H and R1a is methyl; or R 1 and R 1a However, together with the atoms to which they are bonded, C 3 ~C 7 Forms a cycloalkyl group, or R 1a and R 3 However, together with the atoms to which they are bonded, they form cyclobutyl; Each R 2 H and C are independent. 1 ~C 6 Alkyl, -O-(C 1 ~C 6 Alkyl), -NH-(C 1 ~C 6 Alkyl), or C 3 ~C 12 Is it cycloalkyl? or two R's 2 However, together with the atoms to which they are bonded, one or more R 2S Forms a 5- to 10-membered heteroaryl that may be substituted with; each R 2S Independently halogen or C 1 ~C 6 It is alkyl; Each R 2a H or C 1 ~C 6 It is alkyl; R 3 is H or C 1 ~C 6 It is alkyl; Each R a H is independent of each other; R N1 H is; R N2 However, C 3 ~C 12 They are cycloalkyl, 3- to 12-membered heterocycloalkyl, or 5- to 10-membered heteroaryl; where C 3 ~C 12 Cycloalkyl, 3-12 member heterocycloalkyl, or 5-10 member heteroaryl may be one or more R N2a It may be replaced by and Each R N2a These are independently halogen, -OH, and C 1 ~C 6 Alkyl, -C(=O)O(C 1 ~C 6 Alkyl), or C 3 ~C 12 It is a cycloalkyl, The compound according to claim 1.

11. A 2 CR 2 , NR 2a , or S; A 3 CR 2 , NR 2a , or O; A 4 CR 2 , N, S, or O; A 5 is C or N; Here, A 2 , A 3 , A 4 , or A 5 At least one of them is N, NR 2a It is O, or S; R1 is methyl and R1a is H; or R1 is H and R1a is methyl; or R 1 and R 1a However, together with the atoms to which they are bonded, they form a cyclopropyl, or R 1a and R 3 However, together with the atoms to which they are bonded, they form cyclobutyl; Each R 2 Whether they are independently H, methyl, ethyl, isopropyl, cyclopropyl, -NH-ethyl, or -O-ethyl, or two R's 2 However, together with the atoms to which they are bonded, one or more R 2S It forms a thienyl ring or thiazolyl ring which may be substituted with; Each R 2S These are independently chlorine or methyl; Each R 2a These are independently H, methyl, ethyl, or isopropyl; R 3 is H or methyl; Each R a H is independent of each other; R N1 H is; R N2 However, these are cyclobutyl, piperidinyl, oxaspiro[3.3]heptanyl, thiadiazolyl, or pyrimidinyl, each of which contains one or more R N2a It may be replaced by and Each R N2a These are independently fluorine, -OH, methyl, -C(=O)O(ethyl), or cyclobutyl. The compound according to claim 1.

12. The compound according to claim 1, which is a compound of formula (II), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (Ix), (Iy), (Iz), (I-aa), (I-ab), (I-ac), (I-ad), (I-ae), (I-af), or (I-ag), or a solvate thereof, or a pharmaceutically acceptable salt thereof: 。

13. The following: A compound selected from the above, or its solvate, or a pharmaceutically acceptable salt thereof.

14. A compound that is an isotopic derivative of the compound described in Claim 1.

15. A pharmaceutical composition comprising a compound according to any one of claims 1 to 14 and a pharmaceutically acceptable diluent or carrier.

16. The pharmaceutical composition according to claim 15 for use in the following: (a) treatment or prevention of disease or disorder; or (b) Treatment or prevention of a disease or disorder in which the disease or disorder is associated with associated inflammasome activity, and optionally the disease or disorder is a disease or disorder in which inflammasome activity is associated; or (c) Treatment of a disease or disorder in which the disease or disorder is selected from inflammatory disorders, autoinflammatory disorders, autoimmune disorders, neurodegenerative diseases, or cancer; or (d) Treatment of a disease or disorder in which the disease or disorder is an inflammatory disorder, autoinflammatory disorder, or autoimmune disorder, and optionally the disease or disorder is selected from cryopyrin-associated autoinflammatory syndrome (CAPS), Muckle-Wells syndrome (MWS), chronic infantile neurocutaneous arthritis (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 mellitus, multiple sclerosis, skin diseases, and neuroinflammation occurring in protein misfolding disorders; or (e) Treatment of a disease or disorder in which the disease or disorder is a neurodegenerative disease, and optionally, the treatment of a disease or disorder in which the disease or disorder is Parkinson's disease or Alzheimer's disease; or (f) Treatment of a disease or disorder in which the disease or disorder is cancer, and optionally the cancer is metastatic cancer, brain cancer, gastrointestinal cancer, skin cancer, non-small cell lung cancer, head and neck squamous cell carcinoma, or colorectal adenocarcinoma; or (g) Treatment of a disease or disorder in which the disease or disorder is an inflammatory disease; or (h) Treatment of a disease or disorder in which the disease or disorder is associated with an inflammatory disease or an infection, and optionally the infection is a viral infection; or (i) Treatment of a disease or disorder in which the disease or disorder is a viral infection caused by a single-stranded RNA virus, and optionally the single-stranded RNA virus is a coronavirus; or (j) Treatment of a disease or disorder in which the disease or disorder is an inflammatory disease and includes cytokine release syndrome (CRS), for example, in which CRS is associated with COVID-19 or adoptive cell therapy, in particular adoptive cell therapy including chimeric antigen receptor T cell (CAR-T) therapy.

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