Bicyclic phthalazin-1(2H)-one derivatives and related uses

Abstract

The present disclosure relates to compounds of formula (III), as well as their pharma- ceutically acceptable salts, pharmaceutical compositions, methods of use, and methods for their preparation. The compounds disclosed herein are useful for inhibiting the maturation of IL-1 family cytokines by inhibiting inflammasomes, and can be used to treat diseases involving inflammasome activity, such as inflammatory, autoinflammatory, and autoimmune diseases, and cancer. TIFF2025504374000481.tif21128

Description

[Technical field]

[0001] Related Applications This application claims priority to U.S. Provisional Patent Application No. 63 / 297,444, filed January 7, 2022, which is incorporated by reference in its entirety. [Background technology]

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

[0003] In humans, 22 NLR proteins have been 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. Several NLR family members have been associated with inflammasome formation.

[0004] Although inflammasome activation appears to have evolved as a critical component of host immunity against pathogens, the NLRP3 inflammasome is characterized by its ability to activate in response to endogenous 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. The recognition of the role of sterile danger signals as NLRP3 activators has linked IL-1 and IL-18 to a wide range of pathophysiological indications, including metabolic, physiological, inflammatory, hematological, and immunological disorders.

[0005] The present disclosure arises from the need to provide further compounds for the specific regulation 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 literature]

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

[0007] overview In some aspects, the present disclosure provides a compound of formula (III): TIFF2025504374000002.tif26128 or a prodrug, solvate, or pharma- ceutically acceptable salt thereof, During the ceremony, each TIFF2025504374000003.tif7128 are independently single or double bonds, as valence permits; A 2is as CR as the valence allows. 2 , N, N.R. 2a , O, or S; A 3 is as CR as the valence allows. 2 , N, N.R. 2a , O, or S; A 4 is as long as the valence allows. 2 , N, N.R. 2a , O, or S; Here, A 2 , A 3 , or A 4 At least one of them is N, NR 2a , O, or S, except A 2 If S, then A 4 is CR 2 , N.R. 2a , O, or S; R 1 is H, -N(C 1 ~C 6 Alkyl) 2 , C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, or C 3 ~C 12 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 1S may be substituted with; Each R 1S are independently halogen, cyano, -OH, or C 1 ~C 6 is alkyl; Each R 2 are independently H, halogen, cyano, -OH, -NH 2 , -NO 2 , -C(=O)NH 2 , C 1~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, -O(C 1 ~C 6 alkyl), -NH(C 1 ~C 6 alkyl), -N(C 1 ~C 6 Alkyl) 2 , C 3 ~C 12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6 ~C 10 aryl, or 5-10 membered heteroaryl, where C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, -O(C 1 ~C 6 alkyl), -NH(C 1 ~C 6 alkyl), -N(C 1 ~C 6 Alkyl) 2 , C 3 ~C 12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6 ~C 10 Aryl or 5-10 membered heteroaryl is one or more R 2S or or two R's 2 together with the atoms to which they are attached, C 3 ~C 12 cycloalkyl or 3- to 12-membered heterocycloalkyl, where C 3 ~C 12 Cycloalkyl or 3- to 12-membered heterocycloalkyl may be one or more R 2S may be substituted with; Each R 2S are independently halogen, -OH, -O(C 1 ~C 6 alkyl), -NH2 , -NH(C 1 ~C 6 alkyl), -N(C 1 ~C 6 Alkyl) 2 , or C 3 ~C 12 is cycloalkyl; Each R 2a are independently H, C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, C 1 ~C 6 Haloalkyl, -(CH 2 ) 0~3 -(C 3 ~C 12 ) cycloalkyl, or -(CH 2 ) 0~3 -(3 to 12 membered heterocycloalkyl); Each R a are independently H or C 1 ~C 6 alkyl; or two R a together with the atoms to which they are attached, C 3 ~C 12 Forming a cycloalkyl; 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 ~C12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6 ~C 10 Aryl, 5-10 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 6 Alkyl)-(C 6 ~C 10 aryl), or -(C 1 ~C 6 alkyl)-(5-10 membered heteroaryl); 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, 3-12 membered heterocycloalkyl, C 6 ~C 10 Aryl, 5-10 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 6 Alkyl)-(C 6 ~C 10aryl), or -(C 1 ~C 6 alkyl)-(5-10 membered heteroaryl) is one or more R N2a may be substituted with; Each R N2a are independently oxo, halogen, cyano, -OH, -NH 2 , -C(=O)H, -C(=O)OH, C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, -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 membered heterocycloalkyl, C 6 ~C 10 Aryl, 5-10 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 6 Alkyl)-(C 6 ~C 10 aryl), or -(C 1 ~C 6alkyl)-(5-10 membered heteroaryl); 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, -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 membered heterocycloalkyl, C 6 ~C 10 Aryl, 5-10 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 6 Alkyl)-(C 6 ~C 10 aryl), or -(C 1 ~C 6 alkyl)-(5-10 membered heteroaryl) is one or more R N2ab and Each R N2ab are independently oxo, halogen, cyano, -OH, -NH 2 , -C(=O)H, -C(=O)OH, -O(C1 ~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 It is.

[0008] In some aspects, the disclosure provides compounds obtainable or obtained by the methods for preparing the compounds described herein.

[0009] In some aspects, the disclosure provides pharmaceutical compositions comprising a compound described herein and one or more pharma- ceutically acceptable carriers or excipients.

[0010] In some aspects, the disclosure provides intermediates described herein suitable for use in the methods for preparing the compounds described herein.

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

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

[0013] In some aspects, the present disclosure provides a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutical composition of the present disclosure.

[0014] In some aspects, the disclosure provides compounds of the disclosure for use in inhibiting inflammasome (e.g., NLRP3 inflammasome) activity (e.g., in vitro or in vivo).

[0015] In some aspects, the disclosure provides a compound of the disclosure, or a pharma- ceutically acceptable salt thereof, for use in treating or preventing a disease or disorder disclosed herein.

[0016] In some aspects, the disclosure provides use of a compound of the disclosure in the manufacture of a medicament for inhibiting inflammasome (e.g., NLRP3 inflammasome) activity (e.g., in vitro or in vivo).

[0017] In some aspects, the disclosure provides the use of a compound of the disclosure in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0018] In some aspects, the disclosure provides methods of preparing the disclosed compounds.

[0019] In some aspects, the disclosure provides methods of preparing compounds comprising one or more of the steps described herein.

[0020] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as that normally understood by those skilled in the art to which this disclosure belongs. In the specification, the singular form includes the plural form unless the context clearly indicates otherwise. Methods and materials similar or equivalent to those described herein can be used in the practice or testing of this disclosure, and suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference. References cited herein are not admitted to be prior art to the claimed invention. In case of conflict, the present specification, including definitions, will take precedence. In addition, materials, methods, and examples are merely illustrative and are not intended to be limiting. In case of conflict between the chemical structure and the name of a compound disclosed herein, the chemical structure will take precedence.

[0021] Other features and advantages of the disclosure will become apparent from the following detailed description and claims. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

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

[0023] Autoimmune diseases are associated with the overproduction of proinflammatory factors, one of which is interleukin-1 (IL-1), which is produced by activated macrophages, monocytes, fibroblasts, and other components of the innate immune system, such as dendritic cells, and is involved in various cellular activities, including cell proliferation, differentiation, and apoptosis (Masters, SL, et. al. Annu. Rev. Immunol. 2009. 27:621-68).

[0024] Cytokines from the IL-1 family are highly active and are primarily associated with acute and chronic inflammation as key mediators of inflammation (Sims, J. et al., Nature Reviews Immunology 10, 89-102 (February 2010)). Overproduction of IL-1 is thought to be a mediator of some autoimmune and autoinflammatory diseases. Autoinflammatory diseases are characterized by relapsing and unprovoked inflammation in the absence of autoantibodies, infection, or antigen-specific T lymphocytes.

[0025] Inflammatory cytokines of the IL-1 superfamily include IL-1α, IL-1β, IL-18, and IL-36α, β, and 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 apparatus consisting of the endoplasmic reticulum and Golgi apparatus, IL-1 family members are retained intracellularly after translation because they lack leader sequences required for entry into the endoplasmic reticulum. Furthermore, IL-1β, IL-18, and IL-36α, β, and λ are synthesized as procytokines that require proteolytic activation to become optimal ligands for binding to their cognate receptors on target cells.

[0026] 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 proforms of IL-1β and IL-18, and the extracellular release of these cytokines. The inflammasome complex typically consists of a sensor molecule such as NLR (nucleotide oligomerization domain (NOD)-like receptor), an adaptor molecule ASC (CARD (caspase recruitment domain)-containing apoptosis-associated speck-like protein), and procaspase-1. In response to a variety of "danger signals," including pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs), the subunits of the inflammasome oligomerize to form supramolecular structures within the cell. PAMPs 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 assembly of the inflammasome platform promotes the autocatalysis of procaspase-1 to generate a highly active cysteine ​​protease responsible for the activation and release of pro-IL-1β and pro-IL-18. Thus, the release of these hyperinflammatory cytokines is achieved only in response to inflammasome sensors that detect and respond to specific molecular danger signals.

[0027] In humans, 22 NLR proteins have been 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.

[0028] Two other structurally distinct inflammasome structures containing PYHIN domains (pylin and HIN domain-containing proteins), namely Absent in Melanoma 2 (AIM2) and IFN-lambda-inducible protein 16 (IFI16) (Latz et al., Nat Rev Immunol 2013 13(6) 397-311), act as intracellular DNA sensors. Pylin (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).

[0029] The assembly of the inflammasome platform required to achieve activation of IL-1β and IL-18 and their release from monocytes and macrophages ensures their careful production via a two-step process. First, cells must encounter a priming ligand (e.g., the TLR4 receptor ligand LPS, or a proinflammatory cytokine such as TNFα), which leads to NFkB-dependent transcription of NLRP3, pro-IL-1β, and pro-IL-18. The newly translated procytokines remain intracellular and inactive unless the producing cell encounters a second signal that leads to activation of the inflammasome scaffold and maturation of pro-caspase-1.

[0030] In addition to the proteolytic activation of pro-IL-1β and pro-IL-18, active caspase 1 also triggers a form of inflammatory cell death known as pyroptosis through cleavage of gasdermin-D. Pyroptosis liberates the mature forms of IL-1β and IL-18 outside the cell along with the release of alarmin molecules (compounds that promote inflammation and activate innate and adaptive immunity), such as high-mobility group box 1 protein (HMGB1), IL-33, and IL-1α.

[0031] Inflammasome activation appears to have evolved as a critical component of host immunity against pathogens, whereas the NLRP3 inflammasome is characterized by its ability to activate in response to 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 gout patients are effective triggers for NLRP3 activation. Similarly, cholesterol crystals found in atherosclerosis patients can also promote NLRP3 activation. The recognition of the role of sterile danger signals as NLRP3 activators has linked IL-1β and IL-18 to a wide range of pathophysiological indications, including metabolic, physiological, inflammatory, hematological and immunological disorders.

[0032] The relevance to human disease is best exemplified by the discovery that mutations in the NLRP3 gene that result in gain of function cause a series of autoinflammatory conditions collectively known as cryopyrin-associated periodic syndromes (CAPS), including familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS) and neonatal-onset multisystem inflammatory disease (NOMID) (Hoffman et al., Nat. Genet. 29(3) (2001) 301-305). Similarly, sterile mediator-induced activation of NLRP3 has been associated with a wide range of disorders including joint degeneration (gout, rheumatoid arthritis, osteoarthritis), cardiometabolic (type 2 diabetes, atherosclerosis, hypertension), central nervous system (Alzheimer's disease, Parkinson's disease, multiple sclerosis), gastrointestinal (Crohn's disease, ulcerative colitis), pulmonary (chronic obstructive pulmonary disease (COPD), asthma, idiopathic pulmonary fibrosis), and hepatic (fibrosis, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis (NASH)). Furthermore, NLRP3 activation is believed to contribute to chronic kidney disease (CKD) as it promotes nephropathy.

[0033] Current treatment options for diseases in which IL-1 has been implicated as a contributing factor in the pathogenesis include the IL-1 receptor antagonist anakinra, an Fc-containing fusion construct of the extracellular domain of the IL-1 receptor and IL-1 receptor accessory protein (rilonacept), and the anti-IL-1β monoclonal antibody canakinumab, which 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.

[0034] Some small molecules have been reported to inhibit the function of the NLRP3 inflammasome. For example, glyburide is a specific inhibitor of NLRP3 activation, albeit at micromolar concentrations that are unlikely to be achievable in vivo. Nonspecific 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 likely limited because they share a common structural feature consisting of an olefin activated by substitution with an electron-withdrawing group; this may result in the undesired 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 NLRP3 activation. Similarly, many effectors / modulators of other molecular targets have been reported to attenuate NLRP3 activation, including agonists of the G protein-coupled receptor TGR5, inhibitors of sodium-glucose cotransport epigliflozin, dopamine receptor antagonist A-68930, serotonin rebinding inhibitor fluoxetine, fenamate nonsteroidal anti-inflammatory drugs, and β-adrenergic receptor blocker nebivolol. The utility of these molecules as therapeutic agents for the long-term treatment of NLRP3-dependent inflammatory disorders remains to be established.

[0035] The present disclosure relates to compounds useful for specifically modulating NLRP3-dependent cellular processes. In particular, compounds with improved physicochemical, pharmacological and pharmaceutical properties compared to existing NLRP3-modulating compounds are desirable.

[0036] Compounds of the Disclosure In some aspects, the present disclosure provides a compound of formula (III): TIFF2025504374000004.tif26128 or a prodrug, solvate, or pharma- ceutically acceptable salt thereof, During the ceremony, each TIFF2025504374000005.tif7128 are independently single or double bonds, as valence permits; A 2 is as long as the valence allows. 2 , N, N.R. 2a , O, or S; A 3 is as long as the valence allows. 2 , N, N.R. 2a , O, or S; A 4 is as long as the valence allows. 2 , N, N.R. 2a , O, or S; Here, A 2 , A 3 , or A 4 At least one of them is N, NR 2a , O, or S, except A 2 If S, then A 4 is CR 2 , N.R. 2a , O, or S; R 1 is H, -N(C 1 ~C 6 Alkyl) 2 , C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, or C 3 ~C 12 cycloalkyl, where -N(C1 ~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 1S may be substituted with; Each R 1S are independently halogen, cyano, -OH, or C 1 ~C 6 is alkyl; Each R 2 are independently H, halogen, cyano, -OH, -NH 2 , -NO 2 , -C(=O)NH 2 , C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, -O(C 1 ~C 6 alkyl), -NH(C 1 ~C 6 alkyl), -N(C 1 ~C 6 Alkyl) 2 , C 3 ~C 12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6 ~C 10 aryl, or 5-10 membered heteroaryl, where C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, -O(C 1 ~C 6 alkyl), -NH(C 1 ~C 6 alkyl), -N(C 1 ~C 6 Alkyl) 2 , C 3 ~C 12Cycloalkyl, 3-12 membered heterocycloalkyl, C 6 ~C 10 Aryl or 5-10 membered heteroaryl is one or more R 2S or or two R's 2 together with the atoms to which they are attached, C 3 ~C 12 cycloalkyl or 3- to 12-membered heterocycloalkyl, where C 3 ~C 12 Cycloalkyl or 3- to 12-membered heterocycloalkyl may be one or more R 2S may be substituted with; Each R 2S are independently halogen, -OH, -O(C 1 ~C 6 alkyl), -NH 2 , -NH(C 1 ~C 6 alkyl), -N(C 1 ~C 6 Alkyl) 2 , or C 3 ~C 12 is cycloalkyl; Each R 2a are independently H, C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, C 1 ~C 6 Haloalkyl, -(CH 2 ) 0~3 -(C 3 ~C 12 ) cycloalkyl, or -(CH 2 ) 0~3 -(3 to 12 membered heterocycloalkyl); Each R a are independently H or C 1 ~C 6 alkyl; or two R a together with the atoms to which they are attached, C 3 ~C 12Forming a cycloalkyl; 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, 3-12 membered heterocycloalkyl, C 6 ~C 10 Aryl, 5-10 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 6 Alkyl)-(C 6 ~C 10 aryl), or -(C 1 ~C 6 alkyl)-(5-10 membered heteroaryl); 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 ~C6 alkyl), -NH-(C 2 ~C 6 alkenyl), -NH-(C 2 ~C 6 alkynyl), C 3 ~C 12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6 ~C 10 Aryl, 5-10 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 6 Alkyl)-(C 6 ~C 10 aryl), or -(C 1 ~C 6 alkyl)-(5-10 membered heteroaryl) is one or more R N2a may be substituted with; Each R N2a are independently oxo, halogen, cyano, -OH, -NH 2 , -C(=O)H, -C(=O)OH, C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, -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 membered heterocycloalkyl, C 6 ~C 10 Aryl, 5-10 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 6 Alkyl)-(C 6 ~C 10 aryl), or -(C 1 ~C 6 alkyl)-(5-10 membered heteroaryl); 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, -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 membered heterocycloalkyl, C 6 ~C 10Aryl, 5-10 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 6 Alkyl)-(C 6 ~C 10 aryl), or -(C 1 ~C 6 alkyl)-(5-10 membered heteroaryl) is one or more R N2ab and Each R N2ab are independently oxo, halogen, cyano, -OH, -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 It is.

[0037] In some aspects, the present disclosure provides a compound of formula (I): TIFF2025504374000006.tif26128 or a prodrug, solvate, or pharma- ceutically acceptable salt thereof, During the ceremony, each TIFF2025504374000007.tif7128 are independently single or double bonds, as valence permits; A 1 does not exist or, as far as valence allows, CR 2 , N, N.R. 2a , O, or S; A 2 is as long as the valence allows. 2 , N, N.R. 2a , O, or S; A 3 is as long as the valence allows. 2 , N, N.R. 2a , O, or S; A 4 is as long as the valence allows. 2 , N, N.R. 2a , O, or S; Here, A 1 , A 2 , A 3 , or A 4 At least one of them is N, NR 2a , O, or S; R 1 is H, -N(C 1 ~C 6 Alkyl) 2 , C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, or C 3 ~C 12 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 1S may be substituted with; Each R 1S are independently halogen, cyano, -OH, or C 1 ~C 6 is alkyl; Each R 2 are independently H, halogen, cyano, -OH, -NH 2 , -NO 2 , -C(=O)NH 2 , C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, -O(C 1 ~C 6 alkyl), -NH(C 1 ~C 6 alkyl), -N(C 1 ~C 6 Alkyl) 2 , C 3 ~C 12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6 ~C 10 aryl, or 5-10 membered heteroaryl, where C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, -O(C 1 ~C 6 alkyl), -NH(C 1 ~C 6 alkyl), -N(C 1 ~C 6 Alkyl) 2 , C 3 ~C 12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6 ~C 10 Aryl or 5-10 membered heteroaryl is one or more R 2S or or two R's 2 together with the atoms to which they are attached, C 3 ~C 12 cycloalkyl or 3- to 12-membered heterocycloalkyl, where C 3 ~C 12 Cycloalkyl or 3- to 12-membered heterocycloalkyl may be one or more R 2Smay be substituted with; Each R 2S are independently halogen, -OH, -O(C 1 ~C 6 alkyl), -NH 2 , -NH(C 1 ~C 6 alkyl), -N(C 1 ~C 6 Alkyl) 2 , or C 3 ~C 12 is cycloalkyl; Each R 2a are independently H, C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, C 1 ~C 6 Haloalkyl, -(CH 2 ) 0~3 -(C 3 ~C 12 ) cycloalkyl, or -(CH 2 ) 0~3 -(3 to 12 membered heterocycloalkyl); Each R a are independently H or C 1 ~C 6 or two R a together with the atoms to which they are attached, C 3 ~C 12 Forming a cycloalkyl; R N1 is H or C 1 ~C 6 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 ~C6 alkynyl), -NH-(C 1 ~C 6 alkyl), -NH-(C 2 ~C 6 alkenyl), -NH-(C 2 ~C 6 alkynyl), C 3 ~C 12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6 ~C 10 Aryl, 5-10 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 6 Alkyl)-(C 6 ~C 10 aryl), or -(C 1 ~C 6 alkyl)-(5-10 membered heteroaryl); 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, 3-12 membered heterocycloalkyl, C 6 ~C 10 Aryl, 5-10 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 6 Alkyl)-(C 6 ~C 10 aryl), or -(C 1 ~C 6 alkyl)-(5-10 membered heteroaryl) is one or more R N2a may be substituted with; Each R N2a are independently oxo, halogen, cyano, -OH, -NH 2 , -C(=O)H, -C(=O)OH, C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, -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 membered heterocycloalkyl, C 6 ~C 10 Aryl, 5-10 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 6 Alkyl)-(C 6 ~C 10 aryl), or -(C 1 ~C 6 alkyl)-(5-10 membered heteroaryl); 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, -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 membered heterocycloalkyl, C 6 ~C 10 Aryl, 5-10 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 6 Alkyl)-(C 6 ~C 10 aryl), or -(C 1 ~C 6alkyl)-(5-10 membered heteroaryl) is one or more R N2ab and Each R N2ab are independently oxo, halogen, cyano, -OH, -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 or R N1 and R N2 together with the atoms to which they are attached, form one or more R b forming an optionally substituted 3- to 12-membered heterocycloalkyl; Each R b1 are independently oxo, halogen, cyano, -OH, -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(C1 ~C 6 Alkyl), -S(=O) 2 (C 1 ~C 6 alkyl), or -S(=O) 2 N(C 1 ~C 6 Alkyl) 2 where 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 and Each R b1 are independently oxo, halogen, cyano, -OH, or -NH 2 It is.

[0038] In some aspects, the present disclosure relates to a compound of formula (III), wherein: R 1 is C 1 ~C 6 Alkyl or C 2 ~C 6 alkenyl, where C 1 ~C 6 Alkyl or C 2 ~C 6 Alkenyl can be one or more R 1S may be substituted with; Each R1S are independently halogen or C 1 ~C 6 is alkyl; Each R 2 are independently H, halogen, cyano, or C 1 ~C 6 Alkyl, or C 3 ~C 12 cycloalkyl, where C 1 ~C 6 Alkyl or C 3 ~C 12 Cycloalkyl is one or more R 2S may be substituted with; Each R 2S are independently halogen, -O(C 1 ~C 6 alkyl), or C 3 ~C 12 is cycloalkyl; Each R 2a are independently H, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, or -(CH 2 ) 0~3 -C 3 ~C 12 is cycloalkyl; Each R a are independently H; or two R a together with the atoms to which they are attached, C 3 ~C 12 Forming a cycloalkyl; R N2 is a 3- to 12-membered heterocycloalkyl or a 5- to 10-membered heteroaryl, wherein the 3- to 12-membered heterocycloalkyl or the 5- to 10-membered heteroaryl is selected from one or more R N2a and Each R N2a are independently halogens, C 1 ~C 6 Alkyl, or C 3 ~C 12 It is cycloalkyl.

[0039] In some aspects, the present disclosure relates to a compound of formula (III), wherein: R 1 is C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, or C 3 ~C 7 cycloalkyl, where C 1 ~C 6 Alkyl is one or more R 1S may be substituted with; Each R 1S are independently halogen; Each R 2 are independently H, halogen, cyano, -NH 2 , 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 3 ~C 12 cycloalkyl, where C 1 ~C 6 Alkyl and -NH(C 1 ~C 6 alkyl) is one or more R 2S may be substituted with; Each R 2S are independently halogen, -O(C 1 ~C 6 Alkyl, or -NH 2 and; Each R 2a is independently C 1 ~C 6 Alkyl or -(CH 2 ) 0~3 -C 3 ~C 12 is cycloalkyl; R N2 is C 3 ~C 12cycloalkyl, 3- to 12-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, where C 3 ~C 12 Cycloalkyl, 3- to 12-membered heterocycloalkyl, or 5- to 10-membered heteroaryl can be one or more R N2a may be substituted with; Each R N2a are independently halogen, cyano, -OH, C 1 ~C 6 Alkyl, C 3 ~C 12 Cycloalkyl, -C(=O)O(C 1 ~C 6 alkyl), where C 1 ~C 6 Alkyl is one or more R N2ab and Each R N2ab are independently -C(=O)O(C 1 ~C 6 alkyl).

[0040] For the compound of formula (III), A 2 , A 3 , A 4 , R 1 , R 1S , R 2 , R 2S , R 2a , n, R a , R N2 , R N2a , and R N2ab may each be selected from the groups described herein, where applicable; A 2 , A 3 , A 4 , R 1 , R 1S , R 2 , R 2S , R 2a , n, R a , R N2 , R N2a , and R N2ab Any group described herein for any of the remaining A 2 , A 3 , A4 , R 1 , R 1S , R 2 , R 2S , R 2a , n, R a , R N2 , R N2a , and R N2ab It is understood that one or more of may be combined with any group described herein.

[0041] Variable symbol A 2 , A 3 , and A 4 In some embodiments, each TIFF2025504374000008.tif7128 is a single or double bond where valences permit.

[0042] In some embodiments, each TIFF2025504374000009.tif7128 is a single bond as far as valence allows.

[0043] In some embodiments, each TIFF2025504374000010.tif7128 is double bonded as far as valences permit.

[0044] In some embodiments, A 2 is as long as the valence allows. 2 , N, N.R. 2a , O, or S.

[0045] In some embodiments, A 2 is CR 2 , N, O, or S.

[0046] In some embodiments, A 2 is CR 2 It is.

[0047] In some embodiments, A 2 is CH.

[0048] In some embodiments, A 2 is NR 2a It is.

[0049] In some embodiments, A 2 is N(CH 3 ).

[0050] In some embodiments, A 2 is N, O, or S.

[0051] In some embodiments, A 2 is N. In some embodiments, A 2 is O. In some embodiments, A 2 is S.

[0052] In some embodiments, A 2 is CH, N(CH 3 ), N, O, or S.

[0053] In some embodiments, A 3 is as long as the valence allows. 2 , N, N.R. 2a , O, or S.

[0054] In some embodiments, A 3 is CR 2 , N, O, or S.

[0055] In some embodiments, A 3 is CR 2 It is.

[0056] In some embodiments, A 2 is CH, C(Cl), C(Br), C(CN), C(CH 3 ), C(CH 2 CH 3 ), C(CH 2 OCH 3 ), C(cyclopropyl), C(NH(CH 2 CH 3 )), C(NH(i-propyl)), C(NH(CH 3 )), C(CH2 CF 3 ), C(NH(CH 2 CHF 2 )), C(NH(CH 2 CH 2 OCH 3 )), C(N(CH 3 )(CH 2 CH 3 )), C(i-propyl), C(NH 2 ), C(OCH 3 ), C(OCH 2 CH 3 ), or C(CH 2 NH 2 ).

[0057] In some embodiments, A 3 is NR 2a It is.

[0058] In some embodiments, A 3 is N(CH 3 ), N(CH 2 CH 3 ), N(i-propyl), N(cyclobutyl), and N(cyclopropyl).

[0059] In some embodiments, A 3 is N, O, or S.

[0060] In some embodiments, A 3 is N. In some embodiments, A 3 is O. In some embodiments, A 3 is S.

[0061] In some embodiments, A 2 is as long as the valence allows N(CH 3 ), N(CH 2 CH 3 ), N, N(i-propyl), N(cyclopropyl), N(cyclobutyl), C(Cl), C(Br), C(CN), C(CH 3 ), C(CH 2 CH 3 ), C(CH 2 OCH 3), C(cyclopropyl), C(NH(CH 2 CH 3 )), C(NH(i-propyl)), C(NH(CH 3 )), C(CH 2 CF 3 ), C(NH(CH 2 CHF 2 )), C(NH(CH 2 CH 2 OCH 3 )), C(N(CH 3 )(CH 2 CH 3 )), C(i-propyl), C(NH 2 ), C(OCH 3 ), C(OCH 2 CH 3 ), C(CH 2 NH 2 ), or CH.

[0062] In some embodiments, A 4 is as long as the valence allows. 2 , N, N.R. 2a , O, or S.

[0063] In some embodiments, A 4 is CR 2 , N, O, or S.

[0064] In some embodiments, A 4 is CR 2 It is.

[0065] In some embodiments, A 4 is CH.

[0066] In some embodiments, A 4 is NR 2a It is.

[0067] In some embodiments, A 4 is N(CH 3 ).

[0068] In some embodiments, A 4is N, O, or S.

[0069] In some embodiments, A 4 is N. In some embodiments, A 4 is O. In some embodiments, A 4 is S.

[0070] In some embodiments, A 4 is CH, N, N(CH 3 ), O, or S.

[0071] In some embodiments, A 2 , A 3 , or A 4 At least one of them is N, NR 2a , O, or S.

[0072] In some embodiments, A 2 , A 3 , or A 4 At least one of is N, O, or S.

[0073] In some embodiments, A 2 is S and A 3 is CR 2 And A 4 is CR 2 It is.

[0074] In some embodiments, A 2 is CR 2 And A 3 is CR 2 And A 4 is S.

[0075] In some embodiments, A 2 is N and A 3 is NR 2a And A 4 is CR 2 It is.

[0076] In some embodiments, A 2 is O and A 3is CR 2 And A 4 is CR 2 It is.

[0077] In some embodiments, A 2 is NR 2a And A 3 is N and A 4 is CR 2 It is.

[0078] In some embodiments, A 2 is N and A 3 is CR 2 And A 4 is NR 2a It is.

[0079] In some embodiments, A 2 is CR 2 And A 3 is N and A 4 is NR 2a It is.

[0080] In some embodiments, A 2 is CR 2 And A 3 is NR 2a And A 4 is N.

[0081] In some embodiments, A 2 is CR 2 And A 3 is CR 2 And A 4 is O.

[0082] In some embodiments, A 4 is as long as the valence allows CR 2 , N.R. 2a , O, or S.

[0083] In some embodiments, A 4 is not N.

[0084] In some embodiments, A 2 If S, then A4 is as long as the valence allows CR 2 , N.R. 2a , O, or S.

[0085] In some embodiments, A 2 If S, then A 4 is not N.

[0086] Variable symbol R 1 and R 1S In some embodiments, R 1 is H.

[0087] In some embodiments, R 1 -N(C 1 ~C 6 Alkyl) 2 , C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, or C 3 ~C 12 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 1S may be substituted with.

[0088] In some embodiments, R 1 -N(C 1 ~C 6 Alkyl) 2 , C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, or C 3 ~C 7 cycloalkyl, where -N(C 1 ~C 6 Alkyl) 2 , C 1 ~C6 Alkyl, C 2 ~C 6 Alkenyl, or C 3 ~C 7 Cycloalkyl is one or more R 1S may be substituted with.

[0089] In some embodiments, R 1 is one or more R 1S may be substituted with -N(C 1 ~C 6 Alkyl) 2 It is.

[0090] In some embodiments, R 1 -N(C 1 ~C 6 Alkyl) 2 It is.

[0091] In some embodiments, R 1 -N(CH 3 ) 2 It is.

[0092] In some embodiments, R 1 is one or more R 1S C which may be substituted with 1 ~C 6 It is an alkyl.

[0093] In some embodiments, R 1 is one or more R 1S C replaced with 1 ~C 6 It is an alkyl.

[0094] In some embodiments, R 1 is propyl (e.g., isopropyl).

[0095] In some embodiments, R 1 is one or more R 1S C replaced with 1 ~C 6 It is an alkyl.

[0096] In some embodiments, R 1 is one or more R 1S and propyl substituted with (eg, isopropyl).

[0097] In some embodiments, R 1 is one or more R 1S C which may be substituted with 2 ~C 6 It is alkenyl.

[0098] In some embodiments, R 1 is one or more R 1S C replaced with 2 ~C 6 It is alkenyl.

[0099] In some embodiments, R 1 is propenyl (e.g., isopropenyl).

[0100] In some embodiments, R 1 is one or more R 1S C replaced with 2 ~C 6 It is alkenyl.

[0101] In some embodiments, R 1 is one or more R 1S and propenyl substituted with (eg, isopropenyl).

[0102] In some embodiments, R 1 is one or more R 1S C which may be substituted with 3 ~C 12 It is cycloalkyl.

[0103] In some embodiments, R 1 is one or more R 1S C replaced with 3 ~C 12 It is cycloalkyl.

[0104] In some embodiments, R1 is C 3 ~C 12 It is cycloalkyl.

[0105] In some embodiments, R 1 is one or more R 1S C which may be substituted with 3 ~C 7 It is cycloalkyl.

[0106] In some embodiments, R 1 is one or more R 1S C replaced with 3 ~C 7 It is cycloalkyl.

[0107] In some embodiments, R 1 is C 3 ~C 7 It is cycloalkyl.

[0108] In some embodiments, R 1 is cyclopropyl.

[0109] In some embodiments, R 1 is one or more R 1S and cyclopropyl substituted with

[0110] In some embodiments, at least one R 1S is a halogen.

[0111] In some embodiments, at least one R 1S is F, Cl, or Br.

[0112] In some embodiments, at least one R 1S is F.

[0113] In some embodiments, at least one R 1S is Cl.

[0114] In some embodiments, at least one R 1Sis Br.

[0115] In some embodiments, at least one R 1S is cyano.

[0116] In some embodiments, at least one R 1S is -OH.

[0117] In some embodiments, at least one R 1S is C 1 ~C 6 It is an alkyl.

[0118] In some embodiments, R 1 is C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, or C 3 ~C 7 cycloalkyl, where C 1 ~C 6 Alkyl is one or more R 1S may be substituted with.

[0119] In some embodiments, R 1 is C 1 ~C 6 Alkyl (e.g., methyl, ethyl, or isopropyl), C 2 ~C 6 Alkenyl (e.g., isopropenyl), C 3 ~C 7 cycloalkyl (e.g., cyclopropyl) or C 6 Alkyl is one or more R 1S (eg, fluoromethyl).

[0120] In some embodiments, R 1 is methyl, ethyl, isopropyl, isopropenyl, cyclopropyl, or fluoromethyl.

[0121] Variable symbol R 2 , R 2S, and R 2a In some embodiments, each R 2 are independently H.

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

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

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

[0125] In some embodiments, each R 2 Independently - NO 2 It is.

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

[0127] In some embodiments, each R 2 is independently C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, or C 2 ~C 6 alkynyl, where C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, or C 2 ~C 6 Alkynyl can be one or more R 2S may be substituted with.

[0128] In some embodiments, each R 2 is independently one or more R 2S C which may be substituted with 1 ~C 6 It is an alkyl.

[0129] In some embodiments, each R 2 is independently C 1 ~C 6 It is an alkyl.

[0130] In some embodiments, each R 2 is independently one or more R 2S C replaced with 1 ~C 6 It is an alkyl.

[0131] In some embodiments, each R 2 is independently one or more R 2S C which may be substituted with 2 ~C 6 It is alkenyl.

[0132] In some embodiments, each R 2 is independently C 2 ~C 6 It is alkenyl.

[0133] In some embodiments, each R 2 is independently one or more R 2S C replaced with 2 ~C 6 It is alkenyl.

[0134] In some embodiments, each R 2 is independently one or more R 2S C which may be substituted with 2 ~C 6 It is alkynyl.

[0135] In some embodiments, each R 2 is independently C 2 ~C 6 It is alkynyl.

[0136] In some embodiments, each R 2 is independently one or more R 2S C replaced with 2 ~C 6 It is alkynyl.

[0137] In some embodiments, each R 2 are independently -O(C 1 ~C 6 alkyl), -NH(C 1 ~C 6 alkyl), or -N(C 1 ~C 6 Alkyl) 2 where -O(C 1 ~C 6 alkyl), -NH(C 1 ~C 6 alkyl), or -N(C 1 ~C 6 Alkyl) 2 is one or more R 2S may be substituted with.

[0138] In some embodiments, each R 2 is independently one or more R 2S -O(C 1 ~C 6 alkyl).

[0139] In some embodiments, each R 2 are independently -O(C 1 ~C 6 alkyl).

[0140] In some embodiments, each R 2 is independently one or more R 2S -NH(C 1 ~C 6 alkyl) or -N(C 1 ~C 6 Alkyl) 2 It is.

[0141] In some embodiments, each R 2 are independently -NH(C 1 ~C 6 alkyl) or -N(C 1 ~C 6 Alkyl) 2 It is.

[0142] In some embodiments, each R 2 is independently C 3 ~C 12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6 ~C 10 aryl, or 5-10 membered heteroaryl, where C 3 ~C 12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6 ~C 10 Aryl or 5- to 10-membered heteroaryl is one or more R 2S may be substituted with.

[0143] In some embodiments, each R 2 is independently C 3 ~C 7 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6 ~C 10 aryl, or 5-10 membered heteroaryl, where C 3 ~C 7 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6 ~C 10 Aryl or 5- to 10-membered heteroaryl is one or more R 2S may be substituted with.

[0144] In some embodiments, each R 2 is independently one or more R 2S C which may be substituted with 3 ~C 12 It is cycloalkyl.

[0145] In some embodiments, each R 2 is independently C 3 ~C 12 It is cycloalkyl.

[0146] In some embodiments, each R 2 is independently one or more R 2S C replaced with 3 ~C 12 It is cycloalkyl.

[0147] In some embodiments, each R 2 is independently one or more R 2S C which may be substituted with 3 ~C 7 It is cycloalkyl.

[0148] In some embodiments, each R 2 is independently C 3 ~C 7 It is cycloalkyl.

[0149] In some embodiments, each R 2 is independently one or more R 2S C replaced with 3 ~C 7 It is cycloalkyl.

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

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

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

[0153] In some embodiments, each R 2 is independently one or more R 2S C which may be substituted with 6 ~C 10 It is aryl.

[0154] In some embodiments, each R 2 is independently C 6 ~C 10 It is aryl.

[0155] In some embodiments, each R2 is independently one or more R 2S C replaced with 6 ~C 10 It is aryl.

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

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

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

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

[0160] In some embodiments, two R 2 together with the atoms to which they are attached, C 3 ~C 7 cycloalkyl or 3- to 12-membered heterocycloalkyl, where C 3 ~C 7 Cycloalkyl or 3- to 12-membered heterocycloalkyl may be one or more R 2S may be substituted with.

[0161] In some embodiments, two R 2 together with the atoms to which they are attached, C 3 ~C 12It forms a cycloalkyl or a 3- to 12-membered heterocycloalkyl.

[0162] In some embodiments, two R 2 together with the atoms to which they are attached, form one or more R 2S C which may be substituted with 3 ~C 12 Forms a cycloalkyl.

[0163] In some embodiments, two R 2 together with the atoms to which they are attached, C 3 ~C 12 Forms a cycloalkyl.

[0164] In some embodiments, two R 2 together with the atoms to which they are attached, C 3 ~C 7 It forms a cycloalkyl or a 3- to 12-membered heterocycloalkyl.

[0165] In some embodiments, two R 2 together with the atoms to which they are attached, form one or more R 2S C which may be substituted with 3 ~C 7 Forms a cycloalkyl.

[0166] In some embodiments, two R 2 together with the atoms to which they are attached, C 3 ~C 7 Forms a cycloalkyl.

[0167] In some embodiments, two R 2 together with the atoms to which they are attached, form one or more R 2S Forms an optionally substituted 3- to 12-membered heterocycloalkyl.

[0168] In some embodiments, two R 2together with the atom to which they are attached form a 3- to 12-membered heterocycloalkyl.

[0169] In some embodiments, R 2 are independently H, halogen, cyano, -NH 2 , 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 3 ~C 12 cycloalkyl, where C 1 ~C 6 Alkyl and -NH(C 1 ~C 6 alkyl) is one or more R 2S may be substituted with.

[0170] In some embodiments, R 2 are independently H, halogen (e.g., chlorine or bromine), cyano, -NH 2 , C 1 ~C 6 Alkyl (e.g., methyl, ethyl, or propyl), -O(C 1 ~C 6 alkyl) (e.g., -O-methyl or -O-ethyl), -NH(C 1 ~C 6 alkyl) (e.g., -NH-methyl, -NH-CD 3 , -NH-ethyl, or -NH-isopropyl), -N(C 1 ~C 6 Alkyl) 2 (e.g., (-N(Me)(Et)) or C 3 ~C 12 cycloalkyl (e.g., cyclopropyl), where C 1 ~C 6 Alkyl and -NH(C 1 ~C 6 alkyl) is one or more R 2S(e.g., -CH 2 -CF 3 , -NHCH 2 CHF 2 , -CH 2 -O-Methyl, -NHCH 2 CH 2 OMe, or -CH 2 -NH 2 ).

[0171] In some embodiments, R 2 are independently H, chlorine, bromine, cyano, -NH 2 , methyl, ethyl, propyl, -O-methyl, -O-ethyl, -NH-methyl, -NH-CD 3 , -NH-ethyl, -NH-isopropyl, -N(Me)(Et), cyclopropyl, -CH 2 -CF 3 , -NHCH 2 CHF 2 , -CH 2 -O-Methyl, -NHCH 2 CH 2 OMe, or -CH 2 -NH 2 It is.

[0172] In some embodiments, at least one R 2S is a halogen.

[0173] In some embodiments, at least one R 2S is F, Cl, or Br.

[0174] In some embodiments, at least one R 2S is F.

[0175] In some embodiments, at least one R 2S is Cl.

[0176] In some embodiments, at least one R 2S is Br.

[0177] In some embodiments, at least one R2S is -OH.

[0178] In some embodiments, at least one R 2S is -O(C 1 ~C 6 alkyl).

[0179] In some embodiments, at least one R 2S Ha-NH 2 It is.

[0180] In some embodiments, at least one R 2S -NH(C 1 ~C 6 alkyl) or -N(C 1 ~C 6 Alkyl) 2 It is.

[0181] In some embodiments, at least one R 2S is C 3 ~C 12 It is cycloalkyl.

[0182] In some embodiments, at least one R 2S is C 3 ~C 7 It is cycloalkyl.

[0183] In some embodiments, at least one R 2S is C 3 In some embodiments, at least one R 2S is C 4 In some embodiments, at least one R 2S is C 5 In some embodiments, at least one R 2S is C 6 In some embodiments, at least one R 2S is C 7 In some embodiments, at least one R 2S is C 8In some embodiments, at least one R 2S is C 9 In some embodiments, at least one R 2S is C 10 In some embodiments, at least one R 2S is C 11 In some embodiments, at least one R 2S is C 12 It is cycloalkyl.

[0184] In some embodiments, each R 2a are independently H.

[0185] In some embodiments, each R 2a are independently H, C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, C 1 ~C 6 Haloalkyl, -(CH 2 ) 0~3 -(C 3 ~C 12 cycloalkyl), or -(CH 2 ) 0~3 -(3 to 12 membered heterocycloalkyl).

[0186] In some embodiments, each R 2a is independently C 1 ~C 6 It is an alkyl.

[0187] In some embodiments, each R 2a is independently methyl, ethyl, or isopropyl.

[0188] In some embodiments, each R 2a is independently C 2 ~C 6 It is alkenyl.

[0189] In some embodiments, each R 2a is independently C 2 ~C 6 It is alkynyl.

[0190] In some embodiments, each R 2a is independently C 1 ~C 6 It is haloalkyl.

[0191] In some embodiments, each R 2a is independently -CF 3 It is.

[0192] In some embodiments, each R 2a is independently -(CH 2 ) 0~3 -(C 3 ~C 12 Cycloalkyl) or -(CH 2 ) 0~3 -(3 to 12 membered heterocycloalkyl).

[0193] In some embodiments, each R 2a is independently -(CH 2 ) 0~3 -(C 3 ~C 12 cycloalkyl).

[0194] In some embodiments, each R 2a is independently C 3 ~C 12 It is cycloalkyl.

[0195] In some embodiments, each R 2a is independently C 3 ~C 7 It is cycloalkyl.

[0196] In some embodiments, each R 2a is independently -(CH 2 ) 0~3 -(3 to 12 membered heterocycloalkyl).

[0197] In some embodiments, each R2a is independently -3 to 12 membered heterocycloalkyl.

[0198] In some embodiments, each R 2a is independently C 1 ~C 6 Alkyl or -(CH 2 ) 0~3 -C 3 ~C 12 It is cycloalkyl.

[0199] In some embodiments, each R 2a is independently C 1 ~C 6 Alkyl (e.g., methyl, ethyl, or isopropyl) or -(CH 2 ) 0~3 -C 3 ~C 12 It is cycloalkyl (eg, cyclopropyl or cyclobutyl).

[0200] In some embodiments, each R 2a is independently methyl, ethyl, isopropyl, cyclopropyl, or cyclobutyl.

[0201] Variable symbol R a In some embodiments, at least one R a is H.

[0202] In some embodiments, R a are both H.

[0203] In some embodiments, at least one R a is C 1 ~C 6 Alkyl (eg, methyl, ethyl, or propyl).

[0204] In some embodiments, at least one R a is C 1 ~C 4 Alkyl (eg, methyl, ethyl, or propyl).

[0205] In some embodiments, one R a is H, and the other R a is C 1 ~C 6 Alkyl (eg, methyl, ethyl, or propyl).

[0206] In some embodiments, one R a is H, and the other R a is C 1 ~C 4 Alkyl (eg, methyl, ethyl, or propyl).

[0207] In some embodiments, two R a together with the atoms to which they are attached, C 3 ~C 12 Forms a cycloalkyl.

[0208] In some embodiments, two R a together with the atoms to which they are attached, C 3 ~C 7 Forms a cycloalkyl.

[0209] In some embodiments, two R a together with the atoms to which they are attached, C 3 ~C 6 Forms a cycloalkyl.

[0210] In some embodiments, two R a together with the atom to which they are attached form cyclopropyl, cyclobutyl, or cyclopentyl, or cyclohexyl.

[0211] In some embodiments, two R a together with the atom to which they are attached form a cyclopropyl.

[0212] In some embodiments, both R a is H or two R atogether with the atoms to which they are attached, C 3 ~C 12 Cycloalkyl (e.g., C 3 ~C 7 Cycloalkyl or C 3 ~C 6 cycloalkyl).

[0213] In some embodiments, both R a is H or two R a together with the atom to which they are attached form a cyclopropyl.

[0214] Variable symbol R N2 , R Na , and R N2ab In some embodiments, 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), or -NH-(C 2 ~C 6 alkynyl), where 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 ~C6 alkyl), -NH-(C 2 ~C 6 alkenyl), or -NH-(C 2 ~C 6 alkynyl) can be one or more R N2a may be substituted with.

[0215] In some embodiments, R N2 is one or more R N2a C which may be substituted with 1 ~C 6 It is an alkyl.

[0216] In some embodiments, R N2 is C 1 ~C 6 It is an alkyl.

[0217] In some embodiments, R N2 is one or more R N2a C replaced with 1 ~C 6 It is an alkyl.

[0218] In some embodiments, R N2 is one or more R N2a C which may be substituted with 2 ~C 6 It is alkenyl.

[0219] In some embodiments, R N2 is C 2 ~C 6 It is alkenyl.

[0220] In some embodiments, R N2 is one or more R N2a C replaced with 2 ~C 6 It is alkenyl.

[0221] In some embodiments, R N2 is one or more R N2a C which may be substituted with 2 ~C 6It is alkynyl.

[0222] In some embodiments, R N2 is C 2 ~C 6 It is alkynyl.

[0223] In some embodiments, R N2 is one or more R N2a C replaced with 2 ~C 6 It is alkynyl.

[0224] In some embodiments, R N2 is one or more R N2a -O-(C 1 ~C 6 alkyl).

[0225] In some embodiments, R N2 is -O-(C 1 ~C 6 alkyl).

[0226] In some embodiments, R N2 is one or more R N2a -O-(C 1 ~C 6 alkyl).

[0227] In some embodiments, R N2 is one or more R N2a -O-(C 2 ~C 6 alkenyl).

[0228] In some embodiments, R N2 is -O-(C 2 ~C 6 alkenyl).

[0229] In some embodiments, R N2 is one or more R N2a -O-(C 2 ~C 6alkenyl).

[0230] In some embodiments, R N2 is one or more R N2a -O-(C 2 ~C 6 alkynyl).

[0231] In some embodiments, R N2 is -O-(C 2 ~C 6 alkynyl).

[0232] In some embodiments, R N2 is one or more R N2a -O-(C 2 ~C 6 alkynyl).

[0233] In some embodiments, R N2 is one or more R N2a -NH-(C 1 ~C 6 alkyl).

[0234] In some embodiments, R N2 -NH-(C 1 ~C 6 alkyl).

[0235] In some embodiments, R N2 is one or more R N2a -NH-(C 1 ~C 6 alkyl).

[0236] In some embodiments, R N2 is one or more R N2a -NH-(C 2 ~C 6 alkenyl).

[0237] In some embodiments, R N2 -NH-(C 2 ~C6 alkenyl).

[0238] In some embodiments, R N2 is one or more R N2a -NH-(C 2 ~C 6 alkenyl).

[0239] In some embodiments, R N2 is one or more R N2a -NH-(C 2 ~C 6 alkynyl).

[0240] In some embodiments, R N2 -NH-(C 2 ~C 6 alkynyl).

[0241] In some embodiments, R N2 is one or more R N2a -NH-(C 2 ~C 6 alkynyl).

[0242] In some embodiments, R N2 is C 3 ~C 12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6 ~C 10 aryl, or 5-10 membered heteroaryl, where C 3 ~C 12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6 ~C 10 Aryl or 5- to 10-membered heteroaryl is one or more R N2a may be substituted with.

[0243] In some embodiments, R N2 is C 3 ~C 7 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6 ~C 10aryl, or 5-10 membered heteroaryl, where C 3 ~C 7 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6 ~C 10 Aryl or 5- to 10-membered heteroaryl is one or more R N2a may be substituted with.

[0244] In some embodiments, R N2 is one or more R N2a C which may be substituted with 3 ~C 12 It is cycloalkyl.

[0245] In some embodiments, R N2 is C 3 ~C 12 It is cycloalkyl.

[0246] In some embodiments, R N2 is one or more R N2a C replaced with 3 ~C 12 It is cycloalkyl.

[0247] In some embodiments, R N2 is one or more R N2a C which may be substituted with 3 ~C 7 It is cycloalkyl.

[0248] In some embodiments, R N2 is C 3 ~C 7 It is cycloalkyl.

[0249] In some embodiments, R N2 is one or more R N2a C replaced with 3 ~C 7 It is cycloalkyl.

[0250] In some embodiments, R N2 is one or more R N2aand optionally substituted 3- to 12-membered heterocycloalkyl.

[0251] In some embodiments, R N2 is a 3- to 12-membered heterocycloalkyl.

[0252] In some embodiments, R N2 is one or more R N2a and 3-12 membered heterocycloalkyl substituted with

[0253] In some embodiments, R N2 is one or more R N2a C which may be substituted with 6 ~C 10 It is aryl.

[0254] In some embodiments, R N2 is C 6 ~C 10 It is aryl.

[0255] In some embodiments, R N2 is one or more R N2a C replaced with 6 ~C 10 It is aryl.

[0256] In some embodiments, R N2 is one or more R N2a is a 5- to 10-membered heteroaryl optionally substituted with

[0257] In some embodiments, R N2 is a 5-10 membered heteroaryl.

[0258] In some embodiments, R N2 is one or more R N2a is a 5-10 membered heteroaryl substituted with

[0259] In some embodiments, R N2 Ha-(C 1 ~C 6 Alkyl)-(C3 ~C 12 Cycloalkyl), -(C 1 ~C 6 alkyl)-(3 to 12 membered heterocycloalkyl), -(C 1 ~C 6 Alkyl)-(C 6 ~C 10 aryl), or -(C 1 ~C 6 alkyl)-(5-10 membered heteroaryl); 1 ~C 6 Alkyl)-(C 3 ~C 12 Cycloalkyl), -(C 1 ~C 6 alkyl)-(3 to 12 membered heterocycloalkyl), -(C 1 ~C 6 Alkyl)-(C 6 ~C 10 aryl), or -(C 1 ~C 6 alkyl)-(5-10 membered heteroaryl) is one or more R N2a may be substituted with.

[0260] In some embodiments, R N2 is one or more R N2a may be substituted with -(C 1 ~C 6 Alkyl)-(C 3 ~C 12 cycloalkyl).

[0261] In some embodiments, R N2 Ha-(C 1 ~C 6 Alkyl)-(C 3 ~C 12 cycloalkyl).

[0262] In some embodiments, R N2 is one or more R N2a -(C 1 ~C 6 Alkyl)-(C 3 ~C 12cycloalkyl).

[0263] In some embodiments, R N2 is one or more R N2a may be substituted with -(C 1 ~C 6 alkyl)-(3 to 12 membered heterocycloalkyl).

[0264] In some embodiments, R N2 Ha-(C 1 ~C 6 alkyl)-(3 to 12 membered heterocycloalkyl).

[0265] In some embodiments, R N2 is one or more R N2a -(C 1 ~C 6 alkyl)-(3 to 12 membered heterocycloalkyl).

[0266] In some embodiments, R N2 is one or more R N2a may be substituted with -(C 1 ~C 6 Alkyl)-(C 6 ~C 10 aryl).

[0267] In some embodiments, R N2 Ha-(C 1 ~C 6 Alkyl)-(C 6 ~C 10 aryl).

[0268] In some embodiments, R N2 is one or more R N2a -(C 1 ~C 6 Alkyl)-(C 6 ~C 10 aryl).

[0269] In some embodiments, R N2 is one or more RN2a may be substituted with -(C 1 ~C 6 alkyl)-(5-10 membered heteroaryl).

[0270] In some embodiments, R N2 Ha-(C 1 ~C 6 alkyl)-(5-10 membered heteroaryl).

[0271] In some embodiments, R N2 is one or more R N2a -(C 1 ~C 6 alkyl)-(5-10 membered heteroaryl).

[0272] In some embodiments, R N2 is C 3 ~C 12 cycloalkyl (e.g., cyclobutyl), 3- to 12-membered heterocycloalkyl (e.g., piperidinyl, octahydroindolizin-8-yl, or oxaspiro[3.3]heptan-6-yl), or 5- to 10-membered heteroaryl (e.g., oxazolyl, pyrimidinyl, or triazolylpyridinyl), where C 3 ~C 12 Cycloalkyl, 3- to 12-membered heterocycloalkyl, or 5- to 10-membered heteroaryl can be one or more R N2a may be substituted with.

[0273] In some embodiments, R N2 is cyclobutyl, piperidinyl, octahydroindolizin-8-yl, oxaspiro[3.3]heptan-6-yl), oxazolyl, pyrimidinyl, or triazolylpyridinyl, where cyclobutyl, piperidinyl, octahydroindolizin-8-yl, oxaspiro[3.3]heptan-6-yl), oxazolyl, pyrimidinyl, or triazolylpyridinyl is selected from one or more R N2a may be substituted with.

[0274] In some embodiments, at least one R N2a is oxo.

[0275] In some embodiments, at least two R N2a is oxo.

[0276] In some embodiments, at least one R N2a is a halogen.

[0277] In some embodiments, at least one R N2a is F, Cl, or Br.

[0278] In some embodiments, at least one R N2a is F.

[0279] In some embodiments, at least one R N2a is Cl.

[0280] In some embodiments, at least one R N2a is Br.

[0281] In some embodiments, at least one R N2a is cyano.

[0282] In some embodiments, at least one R N2a -OH, -NH 2 , -C(=O)H, or -C(=O)OH.

[0283] In some embodiments, at least one R N2a is -OH.

[0284] In some embodiments, at least one R N2a Ha-NH 2 It is.

[0285] In some embodiments, at least one R N2a is -C(=O)H.

[0286] In some embodiments, at least one R N2a is -C(=O)OH.

[0287] In some embodiments, at least one R N2a is C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, or C 2 ~C 6 alkynyl, where C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, or C 2 ~C 6 Alkynyl can be one or more R N2ab may be substituted with.

[0288] In some embodiments, at least one R N2a is one or more R N2ab C which may be substituted with 1 ~C 6 It is an alkyl.

[0289] In some embodiments, at least one R N2a is C 1 ~C 6 It is an alkyl.

[0290] In some embodiments, at least one R N2a is one or more R N2ab C replaced with 1 ~C 6 It is an alkyl.

[0291] In some embodiments, at least one R N2a is one or more R N2ab C which may be substituted with 2 ~C 6 It is alkenyl.

[0292] In some embodiments, at least one R N2a is C 2~C 6 It is alkenyl.

[0293] In some embodiments, at least one R N2a is one or more R N2ab C replaced with 2 ~C 6 It is alkenyl.

[0294] In some embodiments, at least one R N2a is one or more R N2ab C which may be substituted with 2 ~C 6 It is alkynyl.

[0295] In some embodiments, at least one R N2a is C 2 ~C 6 It is alkynyl.

[0296] In some embodiments, at least one R N2a is one or more R N2ab C replaced with 2 ~C 6 It is alkynyl.

[0297] In some embodiments, at least one R N2a is -O(C 1 ~C 6 alkyl), -NH(C 1 ~C 6 alkyl), or -N(C 1 ~C 6 Alkyl) 2 where -O(C 1 ~C 6 alkyl), -NH(C 1 ~C 6 alkyl), or -N(C 1 ~C 6 Alkyl) 2 is one or more R N2ab may be substituted with.

[0298] In some embodiments, at least one R N2ais one or more R N2ab -O(C 1 ~C 6 alkyl).

[0299] In some embodiments, at least one R N2a is -O(C 1 ~C 6 alkyl).

[0300] In some embodiments, at least one R N2a is one or more R N2ab -NH(C 1 ~C 6 alkyl) or -N(C 1 ~C 6 Alkyl) 2 It is.

[0301] In some embodiments, at least one R N2a -NH(C 1 ~C 6 alkyl) or -N(C 1 ~C 6 Alkyl) 2 It is.

[0302] In some embodiments, at least one R N2a is -C(=O)(C 1 ~C 6 alkyl), -C(=O)O(C 1 ~C 6 alkyl), or -NHC(=O)O(C 1 ~C 6 alkyl), where -C(=O)(C 1 ~C 6 alkyl), -C(=O)O(C 1 ~C 6 alkyl), or -NHC(=O)O(C 1 ~C 6 alkyl) is one or more R N2ab may be substituted with.

[0303] In some embodiments, at least one RN2a is one or more R N2ab -C(=O)(C 1 ~C 6 alkyl).

[0304] In some embodiments, at least one R N2a is -C(=O)(C 1 ~C 6 alkyl).

[0305] In some embodiments, at least one R N2a is one or more R N2ab -C(=O)(C 1 ~C 6 alkyl).

[0306] In some embodiments, at least one R N2a is one or more R N2ab -C(=O)O(C 1 ~C 6 alkyl).

[0307] In some embodiments, at least one R N2a is -C(=O)O(C 1 ~C 6 alkyl).

[0308] In some embodiments, at least one R N2a is one or more R N2ab -C(=O)O(C 1 ~C 6 alkyl).

[0309] In some embodiments, at least one R N2a is one or more R N2ab -NHC(=O)O(C 1 ~C 6 alkyl).

[0310] In some embodiments, at least one R N2ais -NHC(=O)O(C 1 ~C 6 alkyl).

[0311] In some embodiments, at least one R N2a is one or more R N2ab -NHC(=O)O(C 1 ~C 6 alkyl).

[0312] In some embodiments, at least one R N2a is -S(=O) 2 (C 1 ~C 6 Alkyl) or -S(=O) 2 N(C 1 ~C 6 Alkyl) 2 where -S(=O) 2 (C 1 ~C 6 Alkyl) or -S(=O) 2 N(C 1 ~C 6 Alkyl) 2 is one or more R N2ab may be substituted with.

[0313] In some embodiments, at least one R N2a is one or more R N2ab -S(=O) 2 (C 1 ~C 6 alkyl).

[0314] In some embodiments, at least one R N2a is -S(=O) 2 (C 1 ~C 6 alkyl).

[0315] In some embodiments, at least one R N2a is one or more R N2ab -S(=O) replaced with 2 (C 1 ~C6 alkyl).

[0316] In some embodiments, at least one R N2a is one or more R N2ab -S(=O) 2 N(C 1 ~C 6 Alkyl) 2 It is.

[0317] In some embodiments, at least one R N2a is -S(=O) 2 N(C 1 ~C 6 Alkyl) 2 It is.

[0318] In some embodiments, at least one R N2a is one or more R N2ab -S(=O) replaced with 2 N(C 1 ~C 6 Alkyl) 2 It is.

[0319] In some embodiments, at least one R N2a is C 3 ~C 12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6 ~C 10 aryl, or 5-10 membered heteroaryl, where C 3 ~C 12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6 ~C 10 Aryl or 5- to 10-membered heteroaryl is one or more R N2ab may be substituted with.

[0320] In some embodiments, at least one R N2a is C 3 ~C 7 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6 ~C 10aryl, or 5-10 membered heteroaryl, where C 3 ~C 7 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6 ~C 10 Aryl or 5- to 10-membered heteroaryl is one or more R N2ab may be substituted with.

[0321] In some embodiments, at least one R N2a is one or more R N2ab C which may be substituted with 3 ~C 12 It is cycloalkyl.

[0322] In some embodiments, at least one R N2a is C 3 ~C 12 It is cycloalkyl.

[0323] In some embodiments, at least one R N2a is one or more R N2ab C replaced with 3 ~C 12 It is cycloalkyl.

[0324] In some embodiments, at least one R N2a is one or more R N2ab C which may be substituted with 3 ~C 7 It is cycloalkyl.

[0325] In some embodiments, at least one R N2a is C 3 ~C 7 It is cycloalkyl.

[0326] In some embodiments, at least one R N2a is one or more R N2ab C replaced with 3 ~C 7 It is cycloalkyl.

[0327] In some embodiments, at least one R N2a is one or more R N2ab and optionally substituted 3- to 12-membered heterocycloalkyl.

[0328] In some embodiments, at least one R N2a is a 3- to 12-membered heterocycloalkyl.

[0329] In some embodiments, at least one R N2a is one or more R N2ab and 3-12 membered heterocycloalkyl substituted with

[0330] In some embodiments, at least one R N2a is one or more R N2ab C which may be substituted with 6 ~C 10 It is aryl.

[0331] In some embodiments, at least one R N2a is C 6 ~C 10 It is aryl.

[0332] In some embodiments, at least one R N2a is one or more R N2ab C replaced with 6 ~C 10 It is aryl.

[0333] In some embodiments, at least one R N2a is one or more R N2ab and optionally substituted 5-10 membered heteroaryl.

[0334] In some embodiments, at least one R N2a is a 5-10 membered heteroaryl.

[0335] In some embodiments, at least one R N2a is one or more R N2abis a 5-10 membered heteroaryl substituted with

[0336] In some embodiments, at least one R N2a Ha-(C 1 ~C 6 Alkyl)-(C 3 ~C 12 Cycloalkyl), -(C 1 ~C 6 alkyl)-(3 to 12 membered heterocycloalkyl), -(C 1 ~C 6 Alkyl)-(C 6 ~C 10 aryl), or -(C 1 ~C 6 alkyl)-(5-10 membered heteroaryl), where -(C 1 ~C 6 Alkyl)-(C 3 ~C 12 Cycloalkyl), -(C 1 ~C 6 alkyl)-(3 to 12 membered heterocycloalkyl), -(C 1 ~C 6 Alkyl)-(C 6 ~C 10 aryl), or -(C 1 ~C 6 alkyl)-(5-10 membered heteroaryl) is one or more R N2ab may be substituted with.

[0337] In some embodiments, at least one R N2a is one or more R N2ab may be substituted with -(C 1 ~C 6 Alkyl)-(C 3 ~C 12 cycloalkyl).

[0338] In some embodiments, at least one R N2a Ha-(C 1 ~C 6 Alkyl)-(C 3 ~C 12 cycloalkyl).

[0339] In some embodiments, at least one R N2a is one or more R N2ab -(C 1 ~C 6 Alkyl)-(C 3 ~C 12 cycloalkyl).

[0340] In some embodiments, at least one R N2a is one or more R N2ab may be substituted with -(C 1 ~C 6 alkyl)-(3 to 12 membered heterocycloalkyl).

[0341] In some embodiments, at least one R N2a Ha-(C 1 ~C 6 alkyl)-(3 to 12 membered heterocycloalkyl).

[0342] In some embodiments, at least one R N2a is one or more R N2ab -(C 1 ~C 6 alkyl)-(3 to 12 membered heterocycloalkyl).

[0343] In some embodiments, at least one R N2a is one or more R N2ab may be substituted with -(C 1 ~C 6 Alkyl)-(C 6 ~C 10 aryl).

[0344] In some embodiments, at least one R N2a Ha-(C 1 ~C 6 Alkyl)-(C 6 ~C 10 aryl).

[0345] In some embodiments, at least one R N2a is one or more R N2ab -(C 1 ~C 6 Alkyl)-(C 6 ~C 10 aryl).

[0346] In some embodiments, at least one R N2a is one or more R N2ab may be substituted with -(C 1 ~C 6 alkyl)-(5-10 membered heteroaryl).

[0347] In some embodiments, at least one R N2a Ha-(C 1 ~C 6 alkyl)-(5-10 membered heteroaryl).

[0348] In some embodiments, at least one R N2a is one or more R N2ab -(C 1 ~C 6 alkyl)-(5-10 membered heteroaryl).

[0349] In some embodiments, R N2a are independently halogen (e.g., F or Cl), cyano, -OH, C 1 ~C 6 Alkyl (e.g., methyl), C 3 ~C 12 Cycloalkyl (e.g., cyclopropyl or cyclobutyl), -C(=O)O(C 1 ~C 6 alkyl) (e.g., -COO-ethyl), where C 1 ~C 6 Alkyl (e.g., methyl) is one or more R N2ab (e.g., -C(=O)O(C 1 ~C 6 Alkyl).

[0350] In some embodiments, R N2a are independently halogen (e.g., F or Cl), cyano, -OH, C 1 ~C 6 Alkyl (e.g., methyl), C 3 ~C 12 Cycloalkyl (e.g., cyclopropyl or cyclobutyl), -C(=O)O(C 1 ~C 6 alkyl) (e.g., -COO-ethyl), where C 1 ~C 6 Alkyl (e.g., methyl) is one or more R N2ab (e.g., -C(=O)O(ethyl)).

[0351] In some embodiments, R N2a is independently F, Cl, cyano, -OH, methyl, cyclopropyl, cyclobutyl, or -COO-ethyl, where methyl may be optionally substituted with one or more -C(=O)O(ethyl).

[0352] In some embodiments, R N2a are independently F, Cl, cyano, -OH, methyl, cyclopropyl, cyclobutyl, or -COO-ethyl.

[0353] In some embodiments, at least one R N2ab is oxo.

[0354] In some embodiments, at least two R N2ab is oxo.

[0355] In some embodiments, at least one R N2ab is a halogen.

[0356] In some embodiments, at least one R N2ab is F, Cl, or Br.

[0357] In some embodiments, at least one R N2ab is F.

[0358] In some embodiments, at least one R N2ab is Cl.

[0359] In some embodiments, at least one R N2ab is Br.

[0360] In some embodiments, at least one R N2ab is cyano.

[0361] In some embodiments, at least one R N2ab -OH, -NH 2 , -C(=O)H, or -C(=O)OH.

[0362] In some embodiments, at least one R N2ab is -OH.

[0363] In some embodiments, at least one R N2ab Ha-NH 2 It is.

[0364] In some embodiments, at least one R N2ab is -C(=O)H.

[0365] In some embodiments, at least one R N2ab is -C(=O)OH.

[0366] In some embodiments, at least one R N2ab is -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), or -NHC(=O)O(C 1 ~C 6alkyl).

[0367] In some embodiments, at least one R N2ab is -O(C 1 ~C 6 alkyl).

[0368] In some embodiments, at least one R N2ab -NH(C 1 ~C 6 alkyl) or -N(C 1 ~C 6 Alkyl) 2 It is.

[0369] In some embodiments, at least one R N2ab is -C(=O)(C 1 ~C 6 alkyl).

[0370] In some embodiments, at least one R N2ab is -C(=O)O(C 1 ~C 6 alkyl) (e.g., —C(═O)O(ethyl)).

[0371] In some embodiments, at least one R N2ab is -NHC(=O)O(C 1 ~C 6 alkyl).

[0372] In some embodiments, at least one R N2ab is -S(=O) 2 (C 1 ~C 6 Alkyl) or -S(=O) 2 N(C 1 ~C 6 Alkyl) 2 It is.

[0373] In some embodiments, at least one R N2ab is -S(=O) 2 (C 1 ~C 6 alkyl).

[0374] In some embodiments, at least one R N2ab is -S(=O) 2 N(C 1 ~C 6 Alkyl) 2 It is.

[0375] Exemplary embodiments of the compounds In some embodiments, the compound is of formula (II) or a prodrug, solvate, or pharma- ceutically acceptable salt thereof: TIFF2025504374000011.tif26128.

[0376] In some embodiments, the compound is of formula (II-a) or a prodrug, solvate, or pharma- ceutically acceptable salt thereof: TIFF2025504374000012.tif26128.

[0377] In some embodiments, the compound is of formula (III-a), (III-b), (III-c), (III-d), (III-e), (III-f), or (III-g) or a prodrug, solvate, or pharma- ceutically acceptable salt thereof: TIFF2025504374000013.tif22282.

[0378] In some embodiments, the compound of formula (III) is selected from formula (III-b), formula (III-d), and formula (III-e).

[0379] In some embodiments, the compound of formula (III) is a compound of formula (III-e).

[0380] In some embodiments, the compound is selected from the compounds set forth in Table 1, and their prodrugs and pharma- ceutically acceptable salts.

[0381] In some embodiments, the compound is selected from the compounds set forth in Table 1 and their pharma- ceutically acceptable salts.

[0382] In some embodiments, the compound of formula (III) is selected from the compounds set forth in Table 1.

[0383] [Table 1] TIFF2025504374000015.tif23387TIFF2025504374000016.tif24187TIFF2025504374 000017.tif23487TIFF2025504374000018.tif24387TIFF2025504374000019.tif24187 TIFF2025504374000020.tif24387TIFF2025504374000021.tif23887TIFF20255043740 00022.tif22987TIFF2025504374000023.tif23787TIFF2025504374000024.tif156128

[0384] In some embodiments, the compound of formula (I) is selected from the compounds set forth in Table 2.

[0385] [Table 2] TIFF2025504374000026.tif23287TIFF2025504374000027.tif23687TIFF2025504374000028.tif60128

[0386] In some aspects, the disclosure provides compounds that are isotopic derivatives (eg, isotopically labeled compounds) of a compound of any one of the formulas disclosed herein.

[0387] In some embodiments, the compound is a protonated compound of any one of the formulas disclosed herein and pharma- ceutically acceptable salts thereof.

[0388] In some embodiments, the compound is a protonated compound of any one of the formulas disclosed herein.

[0389] In some embodiments, the compound is a protonated compound of any one of the compounds set forth in Table 1, and pharma- ceutically acceptable salts thereof.

[0390] In some embodiments, the compound is a protonated compound of any one of the compounds set forth in Table 1.

[0391] In some embodiments, the compound is an isotopic derivative of any one of the compounds set forth in Table 1, as well as prodrugs and pharma- ceutically acceptable salts thereof.

[0392] In some embodiments, the compound is an isotopic derivative of any one of the compounds set forth in Table 1, and pharma- ceutically acceptable salts thereof.

[0393] In some embodiments, the compound is an isotopic derivative of any one of the compounds set forth in Table 1.

[0394] It is understood that isotopic derivatives can be prepared using any of a variety of techniques recognized in the art. For example, isotopic derivatives can generally be prepared by carrying out the procedures disclosed in the schemes and / or examples described herein by substituting isotopic labeled reagents for nonisotopic labeled reagents.

[0395] In some embodiments, the isotopic derivatives are deuterium labeled compounds.

[0396] In some embodiments, an isotopic derivative is a deuterium-labeled compound of a compound of any one of the formulas disclosed herein.

[0397] In some embodiments, the compound is a deuterium-labeled compound of any one of the compounds set forth in Table 1, as well as prodrugs and pharma- ceutically acceptable salts thereof.

[0398] In some embodiments, the compound is a deuterium-labeled compound of any one of the compounds set forth in Table 1, and pharma- ceutically acceptable salts thereof.

[0399] In some embodiments, the compound is a deuterium-labeled compound of any one of the compounds set forth in Table 1.

[0400] A deuterium-labeled compound is understood to contain deuterium atoms at a deuterium abundance significantly greater than deuterium's natural abundance of 0.015%.

[0401] In some embodiments, the deuterium-labeled compound has a deuterium enrichment factor for each deuterium atom of at least 3500 (52.5% deuterium bonded at each deuterium atom), at least 4000 (60% deuterium bonded), at least 4500 (67.5% deuterium bonded), at least 5000 (75% deuterium bonded), at least 5500 (82.5% deuterium bonded), at least 6000 (90% deuterium bonded), at least 6333.3 (95% deuterium bonded), at least 6466.7 (97% deuterium bonded), at least 6600 (99% deuterium bonded), or at least 6633.3 (99.5% deuterium bonded). As used herein, the term "deuterium enrichment factor" refers to the ratio of the abundance of deuterium to the natural abundance of deuterium.

[0402] It is understood that deuterium-labeled compounds can be prepared using any of a variety of techniques recognized in the art. For example, deuterium-labeled compounds can generally be prepared by carrying out the procedures disclosed in the schemes and / or examples described herein by substituting deuterium-labeled reagents for non-deuterium-labeled reagents.

[0403] Compounds of the present invention or pharma- ceutically acceptable salts or solvates thereof containing said deuterium atom are within the scope of the present invention. 2H) may confer certain therapeutic advantages resulting from greater metabolic stability, for example an increased in vivo half-life or reduced dosage requirements.

[0404] For the avoidance of doubt, when a group meets the requirement herein of being "described herein," it is to be understood that the group encompasses the broadest definition first described and each and every specific definition of that group.

[0405] Suitable pharma- ceutically acceptable salts of the disclosed compounds are, for example, acid addition salts of the disclosed compounds that are sufficiently basic, such as 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. Additionally, suitable pharma- ceutically 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 a pharma- ceutically acceptable cation, such as methylamine, dimethylamine, diethylamine, trimethylamine, piperidine, morpholine, or tris-(2-hydroxyethyl)amine.

[0406] It will be understood that the compounds of any one of the formulas disclosed herein, and any pharma- ceutically acceptable salts thereof, include stereoisomers, mixtures of stereoisomers, and polymorphs of all isomeric forms of the compounds.

[0407] As used herein, the term "isomers" means compounds that have the same molecular formula but differ in the sequence of bonding of their atoms or the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are called "stereoisomers." Stereoisomers that are not mirror images of each other are called "diastereoisomers," and stereoisomers that are non-superimposable mirror images of each other are called "enantiomers" or sometimes optical isomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is called a "racemic mixture."

[0408] As used herein, the term "chiral center" refers to an atom bonded to four non-identical substituents.

[0409] As used herein, the term "chiral isomer" refers to 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, termed a "diastereomeric mixture." When one chiral center is present, a stereoisomer may be characterized by the absolute configuration (R or S) of that chiral center. Absolute configuration refers to the spatial arrangement of the substituents attached to the chiral center. The substituents attached to the chiral center under consideration are ranked according to the Cahn, Ingold and Prelog ranking 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).

[0410] As used herein, the term "geometric isomer" refers to diastereomers that exist due to hindered rotation about a double bond or a cycloalkyl linker (e.g., 1,3-cyclobutyl). These configurations are distinguished in their designations by the prefixes cis and trans or Z and E, which indicate that the groups are on the same or opposite sides of a double bond in the molecule according to the Cahn-Ingold-Prelog rules.

[0411] It is to be understood that the compounds of the present disclosure may be depicted as different chiral or geometric isomers. When a compound has chiral or geometric isomeric forms, it is also to be understood that all isomeric forms are intended to be included within the scope of the present disclosure, and that the name of the compound does not exclude any isomeric form, and it is to be understood that not all isomers have the same level of activity.

[0412] It is to be understood that the structures and other compounds discussed in this disclosure include all atropic isomers thereof. It is also to be understood that not all atropic isomers have the same level of activity.

[0413] As used herein, the term "atropic isomer" refers to a class of stereoisomers in which the atoms of two isomers are arranged differently in space. Atropic isomers owe their existence to restricted rotation caused by hindrance of rotation of large groups about a central bond. Such atropic isomers typically exist as mixtures, but as a result of recent advances in chromatographic techniques, it has become possible in certain cases to separate mixtures of two atropic isomers.

[0414] As used herein, the term "tautomer" refers to one of two or more structural isomers that exist in equilibrium and are easily converted from one isomeric form to another. This conversion results in the formal migration of a hydrogen atom accompanied by the switching of adjacent conjugated double bonds. Tautomers exist as a mixture of tautomeric sets in solution. In solutions 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 electrons and hydrogen atoms occurs. Ring-chain tautomerism occurs as a result of an aldehyde group (-CHO) in a sugar molecule reacting with one of the hydroxyl groups (-OH) in the same molecule to give a cyclic (ring-like) shape as shown by glucose.

[0415] It should be understood that the compounds of the present disclosure may be depicted as different tautomeric forms. When a compound has tautomeric forms, it should also be understood that all isomeric forms are intended to be included within the scope of the present disclosure, and the name of the compound does not exclude any tautomeric form. It will be understood that certain tautomeric forms may have a higher level of activity than others.

[0416] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or in the arrangement of their atoms in space are called "isomers". Isomers that differ in the arrangement of their atoms in space are called "stereoisomers". Stereoisomers that are not mirror images of each other are called "diastereoisomers" and those that are non-superimposable mirror images of each other are called "enantiomers". When a compound has an asymmetric center, e.g., 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, described by the R and S ordering rules of Cahn and Prelog, or the way in which the molecule rotates the plane of polarized light and is designated as dextrorotatory or levorotatory (i.e., (+) or (-) isomers, respectively). Chiral compounds can exist either as individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture".

[0417] The compounds of the present disclosure may have one or more asymmetric centers, and such compounds can therefore be produced as individual (R) or (S) stereoisomers or as mixtures thereof. Unless otherwise indicated, the description or name of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures such as racemic. Methods for determining stereochemistry and separating stereoisomers are well known in the art (see 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 racemic forms. Some of the compounds of the disclosure may have geometric isomeric centers (E and Z isomers). It is to be understood that the present disclosure encompasses all optical, diastereomeric and geometric isomers and mixtures thereof that have inflammasome inhibitory activity.

[0418] The present disclosure also encompasses compounds of the disclosure as defined herein that contain one or more isotopic substitutions.

[0419] Any formula compound described herein should be understood to include the compound itself, and if applicable, its salt and its solvate.For example, salt can be formed between a positively charged group (e.g., amino) on the substituted compound disclosed herein and an anion.Suitable anions include chloride, bromide, iodide, sulfate, bisulfate, sulfamate, nitrate, phosphate, citrate, methanesulfonate, glutamate, glucuronate, glutarate, maleate, maleate, succinate, fumarate, tartrate, tosylate, salicylate, lactate, naphthalenesulfonate and acetate.

[0420] The compound of any one of the formulas described herein can be protonated at physiological pH.Therefore, the compound can have a positive charge or partial positive charge at physiological pH.Such a compound may be called a cationic or ionizable compound.The compound of any one of the formulas described herein can also be zwitterionic, i.e., a neutral molecule that has both positive and negative charges.

[0421] 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 the substituted compounds disclosed herein and a cation.Suitable cations include sodium ion, potassium ion, magnesium ion, calcium ion, and ammonium cation such as tetramethylammonium ion or diethylamine ion.Substituted compounds disclosed herein also include those that contain a quaternary nitrogen atom.

[0422] It is understood that the compounds of the present disclosure, for example, 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 monohydrates, dihydrates, etc. Non-limiting examples of solvates include ethanol solvates, acetone solvates, etc.

[0423] As used herein, the term "solvate" refers to a solvent addition form that contains either stoichiometric or non-stoichiometric amounts of solvent. Some compounds tend to trap a certain molar ratio of solvent molecules in the crystalline solid state, thereby forming a solvate. When the solvent is water, the solvate formed is a hydrate, and when the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more water molecules with a molecule of a substance, where water is H 2 It retains its molecular state as O.

[0424] As used herein, the term "analog" refers to a chemical compound that is structurally similar to another but differs slightly in 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 is similar or equivalent in function and appearance, but not similar or equivalent in structure or origin to the reference compound.

[0425] As used herein, the term "derivative" refers to compounds that have a common core structure and are substituted with various groups as described herein.

[0426] As used herein, the term "bioisostere" 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 the bioisostere replacement is to create a new compound with similar biological properties as the parent compound. The bioisostere replacement may be physicochemical or morphologically based. Examples of carboxylic acid bioisosteres include, but are not limited to, acylsulfonamides, tetrazoles, sulfonates, and phosphonates. See, e.g., Patani and LaVoie, Chem. Rev. 96, 3147-3176, 1996.

[0427] It should also be understood that any one of the formulas disclosed herein may exist in solvated and non-solvated forms, such as hydrated forms.Suitable pharmaceutically acceptable solvates are hydrates, such as hemihydrate, monohydrate, dihydrate or trihydrate.It should be understood that the disclosure encompasses all such solvated forms that have inflammasome inhibitory activity.

[0428] It should also be understood that any one of the formulae disclosed herein may show polymorphism, and the disclosure encompasses all such forms or mixtures thereof that have 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, thermogravimetry, 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 materials can be determined by Karl Fischer analysis.

[0429] Compounds of any one of the formulas disclosed herein may exist in many different tautomeric forms, and reference to a compound of formula (III) includes all such forms.For the avoidance of doubt, if a compound may exist in one of several tautomeric forms, and only one is specifically described or shown, all others are still encompassed by formula (III).Examples of tautomeric forms include keto, enol, and enolate forms, such as, for example, the following tautomeric pairs: keto / enol (illustrated below), imine / enamine, amide / iminoalcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol, and nitro / acinitoro. TIFF2025504374000029.tif24128

[0430] Compounds of any one of the formulae disclosed herein that contain an amine functional group may also form N-oxides. Reference herein to compounds of formula (III) that contain an amine functional group also includes N-oxides. When a compound contains several amine functional groups, one or more nitrogen atoms may be oxidized to form N-oxides. Particular examples of N-oxides are the N-oxides of tertiary amines or nitrogen atoms of nitrogen-containing heterocycles. N-oxides can be formed by treating the corresponding amines with an oxidizing agent such as hydrogen peroxide or peracids (e.g., peroxycarboxylic acids), see, for example, Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages. More specifically, N-oxides can be made by the procedure of LW Deady (Syn. Comm. 1977, 7, 509-514), in which an amine compound is reacted with meta-chloroperoxybenzoic acid (mCPBA) in an inert solvent such as, for example, dichloromethane.

[0431] The compounds of any one of the formulas disclosed herein may be administered in the form of prodrugs, which are decomposed in the human or animal body to release the disclosed compounds.Prodrugs can be used to change the physical properties and / or pharmacokinetic properties of the disclosed compounds.Prodrugs can be formed when the disclosed compounds contain suitable groups or substituents to which the group that modifies the properties can be attached.Examples of prodrugs include derivatives that contain alkyl or acyl substituents that can be cleaved in vivo on the sulfonylurea group in the compounds of any one of the formulas disclosed herein.

[0432] Thus, the present disclosure includes the compound of any one of the formulas disclosed herein as defined above when it is made available by organic synthesis and when it is made available in the human or animal body by cleavage of its prodrug.Thus, the present disclosure includes the compound of any one of the formulas disclosed herein produced by organic synthesis means, and also the compound produced in the human or animal body by metabolism of a precursor compound, i.e., the compound of any one of the formulas disclosed herein may be a synthetically produced compound or a metabolically produced compound.

[0433] Suitable pharma- ceutically acceptable prodrugs of a compound of any one of the formulas disclosed herein are those that are based on sound medical judgment that 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", ACS Symposium Series, Volume 14; and H) E. Roche (editor), "Bioreversible Carriers in Drug Design", Pergamon Press, 1987.

[0434] Suitable pharma- ceutically acceptable prodrugs of the compounds of any one of the formulas disclosed herein that have a hydroxyl group are, for example, their esters or ethers that can be cleaved in vivo. The in vivo cleavable esters or ethers of the compounds of any one of the formulas disclosed herein that contain a hydroxyl group are, for example, pharma- ceutically acceptable esters or ethers that can be cleaved in the human or animal body to generate the parent hydroxyl compound. Suitable pharma-ceutically acceptable ester-forming groups for the hydroxyl group include inorganic esters such as phosphate esters (including phosphoramide cyclic esters). In addition, suitable pharma-ceutically acceptable ester-forming groups for the hydroxyl group include C esters such as acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups. 1 ~C 10 Alkanoyl group, ethoxycarbonyl, N,N-(C 1 ~C 6 Alkyl) 2 C such as carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl groups 1 ~C 10 Examples of ring substituents on the phenylacetyl and benzoyl groups are aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl, and 4-(C 1 ~C 4 Suitable pharma- ceutically acceptable ether forming groups at a hydroxyl group include α-acyloxyalkyl groups, such as acetoxymethyl and pivaloyloxymethyl groups.

[0435] Suitable pharma- ceutically acceptable prodrugs of a compound of any one of the formulae disclosed herein having a carboxy group include, for example, an in vivo cleavable amide thereof, e.g., an amide formed with an amine such as ammonia, a C-amino group such as a methylamine, etc. 1 ~ 4 (C) such as alkylamines, dimethylamine, N-ethyl-N-methylamine or diethylamine 1 ~C 4 Alkyl) 2Amines, such as 2-methoxyethylamine 1 ~C 4 Alkoxy-C 2 -C 4 Phenyl-C such as alkylamines and benzylamines 1 ~C 4 Alkylamines, and amino acids such as glycine or their esters.

[0436] Suitable pharma- ceutically acceptable prodrugs of the compounds of any one of the formulas disclosed herein having an amino group are, for example, in vivo cleavable amide derivatives thereof. Suitable pharma- ceutically acceptable amides from an amino group include, for example, C-type acetyl groups, such as acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups. 1 ~C 10 Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl, and 4-(C 1 ~C 4 alkyl)piperazin-1-ylmethyl.

[0437] The in vivo effect of the compound of any one of the formulas disclosed herein may be exerted in part by one or more metabolites formed in the human or animal body after administration of the compound of any one of the formulas disclosed herein.As mentioned above, the in vivo effect of the compound of any one of the formulas disclosed herein may also be exerted through the metabolism of a precursor compound (prodrug).

[0438] Preferably, the present disclosure excludes any individual compound that does not have biological activity as defined herein.

[0439] Synthesis method In some aspects, the disclosure provides methods of preparing the disclosed compounds.

[0440] In some aspects, the disclosure provides methods of preparing compounds comprising one or more of the steps described herein.

[0441] In some aspects, the disclosure provides compounds that are obtainable, obtained, or obtained directly by the methods for preparing the compounds described herein.

[0442] In some aspects, the disclosure provides intermediates described herein that are suitable for use in the methods for preparing the compounds described herein.

[0443] 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 illustrated in the accompanying examples.

[0444] In the description of synthetic methods described herein, and in any referenced synthetic methods used to prepare starting materials, it is understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of experiment and work-up procedures, can be selected by one of ordinary skill in the art.

[0445] It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reaction conditions used.

[0446] It will be recognized that during the synthesis of the disclosed compounds in the processes defined herein, or during the synthesis of certain starting materials, it may be desirable to protect certain substituents to prevent their undesired reactions. A skilled chemist will know when such protection is necessary and how such protecting groups can be placed and subsequently removed. For examples of protecting groups, see one of the many general texts on the subject, for example "Protective Groups in Organic Synthesis" by Theodora Green (Publisher: John Wiley & Sons). Protecting groups can be removed by any convenient method described in the literature or known to a skilled chemist to be suitable for removing the protecting group in question, and such methods are selected to provide for the removal of the protecting group while minimizing the disturbance of groups at other positions in the molecule. Thus, when a reactant contains a group such as, for example, amino, carboxy or hydroxy, it may be desirable to protect the group in some of the reactions described herein.

[0447] For example, suitable protecting groups for amino or alkylamino groups are, for example, acyl groups, such as alkanoyl groups, for example acetyl, alkoxycarbonyl groups, for example methoxycarbonyl, ethoxycarbonyl, or t-butoxycarbonyl groups, arylmethoxycarbonyl groups, for example benzyloxycarbonyl, or aroyl groups, for example benzoyl. The deprotection conditions for the above protecting groups necessarily vary depending on the choice of protecting group. Thus, for example, acyl groups, such as alkanoyl or alkoxycarbonyl groups or aroyl groups, can be removed by hydrolysis with a suitable base, for example an alkali metal hydroxide, for example lithium hydroxide or sodium hydroxide. Alternatively, acyl groups such as a tert-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid such as hydrochloric acid, sulfuric acid or phosphoric acid or trifluoroacetic acid, and arylmethoxycarbonyl groups such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium on carbon or by treatment with a Lewis acid, for example borontris(trifluoroacetate).A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.

[0448] Suitable protecting groups for hydroxyl groups are, for example, acyl groups, e.g., alkanoyl groups such as acetyl, aroyl groups, e.g., benzoyl, or arylmethyl groups, e.g., benzyl. The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, acyl groups such as alkanoyl or aroyl groups may be removed by hydrolysis with a suitable base, e.g., an alkali metal hydroxide, e.g., lithium hydroxide, sodium hydroxide, or ammonia. Alternatively, arylmethyl groups, e.g., benzyl groups, may be removed by hydrogenation, e.g., over a catalyst such as palladium on carbon.

[0449] Suitable protecting groups for carboxy groups are, for example, esterifying groups such as methyl or ethyl groups which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or, for example, a tert-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or, for example, a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium on carbon.

[0450] After a compound of formula (III) has been synthesised by any one of the processes defined herein, the process may further comprise the following additional steps: (i) removing any protecting groups present; (ii) converting the compound of formula (III) to another compound of formula (III); (iii) forming a pharma- ceutically acceptable salt, hydrate or solvate thereof; and / or (iv) forming a prodrug thereof.

[0451] The resulting compound of formula (III) can be isolated and purified using techniques well known in the art.

[0452] Conveniently, the reaction of the compounds is carried out in the presence of a suitable solvent, preferably inert under the respective reaction conditions. Examples of suitable solvents are hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as trichloroethylene, 1,2-dichloroethane, tetrachloromethane, chloroform or dichloromethane; alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, cyclopentyl methyl ether (CPME), methyl tert-butyl ether (MTBE) or dioxane; ethylene These include, but are not limited to, glycol ethers such as 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 dimethylsulfoxide (DMSO); nitro compounds such as nitromethane or nitrobenzene; esters such as ethyl acetate or methyl acetate, or mixtures of said solvents or with water.

[0453] The reaction temperature is preferably between about -100°C and 300°C depending on the reaction process and conditions used.

[0454] The reaction time generally ranges from a few minutes to several days, depending on the reactivity of each compound and each reaction condition. A suitable reaction time can be easily determined by methods known in the art, such as reaction monitoring. Based on the above reaction temperatures, a suitable reaction time generally ranges from 10 minutes to 48 hours.

[0455] Moreover, by utilizing the procedures described herein, in conjunction with ordinary skill in the art, additional compounds of the present disclosure can be readily prepared. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds.

[0456] As will be understood by those skilled in the art of organic synthesis, the compounds of the present disclosure are easily accessible by various synthetic routes, some of which are illustrated in the accompanying examples. Those skilled in the art will easily recognize what kind of reagents and reaction conditions should be used to obtain the compounds of the present disclosure, and how they should be applied and adapted in any particular case, if necessary or useful. Furthermore, some of the compounds of the present disclosure can be easily synthesized by reacting other compounds of the present disclosure under suitable conditions, for example by converting one specific functional group present in the compounds of the present disclosure or its appropriate precursor molecules into another by applying standard synthetic methods such as reduction, oxidation, addition or substitution reactions; these methods are well known to those skilled in the art. Similarly, those skilled in the art will apply synthetic protective (or blocking) groups, if necessary or useful; suitable protective groups and methods for introducing and removing them are well known to those skilled in the art of chemical synthesis and are described in more detail, for example, in PGM Wuts, TW Greene, "Greene's Protective Groups in Organic Synthesis", 4th edition (2006) (John Wiley & Sons).

[0457] General routes for the preparation of compounds of formulae (I)-(III) are depicted in Schemes 1-2.

[0458] Scheme 1 TIFF2025504374000030.tif85128 Scheme 1 shows the palladium catalyzed coupling of an appropriately substituted (2-halophenyl) carboxylic acid ester A1 with an aldehyde to form a dicarbonyl species A2. Step 2 cyclizes the dicarbonyl A2 to form a substituted phthalazin-1(2H)-one A3. Alkylation is achieved with a bromo or chloro acetate to give A4. Hydrolysis affords the acid A5, which can be treated directly with a suitable amine under amide coupling conditions using a coupling reagent such as azabenzotriazole tetramethyluronium hexafluorophosphate (HATU) and a suitable base, or with oxalyl chloride, thionyl chloride or POCl. 3 This can be converted to the acid chloride using a chlorinating agent such as, for example, followed by treatment with an amine to form a compound of formula (III).

[0459] Scheme 2 TIFF2025504374000031.tif104162 Compounds of formula (III) can be prepared according to Scheme 2. Bromoheteroaryl B1 can be treated with n-butyllithium followed by Weinreb amide to give B3. Alternatively, B3 can be synthesized from B2 by treatment with an organometallic base (e.g., LDA) followed by Weinreb amide. B3 can be treated with hot hydrazine hydrate in a suitable solvent (e.g., ethanol) to give B4. Compounds of formula (III) can be synthesized by treating B4 with a suitable alkylating agent in the presence of a base. B4 can also be alkylated with, for example, ethyl bromoacetate to give B5 (Alk represents an alkyl group). B5 can be hydrolyzed to give B6. Compounds of formula (III) can be synthesized from B6 using amide coupling conditions.

[0460] Biological assays The compounds designed, selected and / or optimized by the methods described above can be produced and then 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 expected activity, binding activity and / or binding specificity.

[0461] Furthermore, high-throughput screening can be used to speed up the analysis using such assays.As a result, it is possible to rapidly screen the activity of the molecules described herein using techniques known in the art.The general methodology for carrying out high-throughput screening is described, for example, in Devlin (1998) High Throughput Screening, Marcel Dekker and US Patent No. 5,763,263.High-throughput assays can use one or more different assay techniques, including but not limited to those described below.

[0462] Various in vitro or in vivo biological assays may be suitable for detecting the effects of the compounds of the present disclosure, including, but not limited to, enzyme activity assays, gel shift assays, reporter gene assays, in vitro cell viability assays, and assays described herein.

[0463] In some embodiments, the biological away is a biological away that tests inhibitory activity against IL-1β release upon NLRP3 activation in peripheral blood mononuclear cells (PBMCs).

[0464] In some embodiments, the biological assay comprises PBMC IC 50 In some embodiments, the biological assay is a PBMC IC 50 This is a determinative assay.

[0465] In some embodiments, compounds of the disclosure may be tested for inhibitory activity against IL-1β release upon NLRP3 activation in blood cells (e.g., peripheral blood mononuclear cells (PBMCs)).

[0466] In some embodiments, PBMCs can be isolated, seeded into wells of a plate, and cultured for a period of time (e.g., 3 hours with lipopolysaccharide). After culture, the medium can be replaced, a compound (e.g., a compound of the present disclosure) can be added to the well, and the cells can be cultured. The cells can then be stimulated (e.g., with ATP or nigericin) and the cell culture medium can be collected for further analysis.

[0467] In some embodiments, release of IL-1β into the medium may be determined by quantitative detection of IL-1β in the medium (eg, using an ELISA).

[0468] In some embodiments, PBMCs can be isolated (e.g., from buffy coats). The separated cells can be seeded into wells and cultured (e.g., with lipopolysaccharide for 3 hours). Compounds of the present disclosure can then be added and the cells cultured. The cells can then be stimulated and the medium collected from the wells for further analysis.

[0469] In some embodiments, release of IL-1β into the medium can be determined by quantitative detection (eg, of IL-1β in the medium using HTRF®).

[0470] Pharmaceutical Compositions In some aspects, the disclosure provides pharmaceutical compositions comprising a compound of the disclosure as an active ingredient.

[0471] In some embodiments, the disclosure provides pharmaceutical compositions comprising a compound described herein and one or more pharma- ceutically acceptable carriers or excipients. In some embodiments, the disclosure provides pharmaceutical compositions comprising at least one compound selected from Table 1.

[0472] As used herein, the term "composition" is intended to encompass a product comprising specified ingredients in specified amounts, as well as any product that results directly or indirectly from the combination of the specified ingredients in the specified amounts.

[0473] The compounds of the present disclosure can be formulated for oral administration in the form of tablets, capsules (each of which includes time-release or sustained release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, emulsions, and the like. 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, all using forms well known to those of ordinary skill in the pharmaceutical arts.

[0474] The formulation of the present disclosure may be in the form of an aqueous solution comprising an aqueous vehicle. The aqueous vehicle component may comprise water and at least one pharma- ceutically acceptable excipient. Suitable acceptable excipients include those selected from the group consisting of solubility enhancers, chelating agents, preservatives, tonicity agents, viscosity / suspension agents, buffers, and pH adjusters, and mixtures thereof.

[0475] Any suitable solubility enhancer may be used. Examples of solubility enhancers include cyclodextrins such as those selected from the group consisting of 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 mixtures thereof.

[0476] Any suitable chelating agent may 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.

[0477] Any suitable preservative may be used. Examples of preservatives include those selected from the group consisting of quaternary ammonium salts such as benzalkonium halides (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, propylaminopropyl biguanide, and butyl p-hydroxybenzoate, and sorbic acid, and mixtures thereof.

[0478] The aqueous vehicle may also contain an isotonicity agent to adjust the isotonicity (osmotic pressure), which may be selected from the group consisting of glycols (propylene glycol, diethylene glycol, triethylene glycol, etc.), glycerol, dextrose, glycerin, mannitol, potassium chloride, and sodium chloride, and mixtures thereof.

[0479] The aqueous vehicle may also contain a viscosity / suspending agent. Suitable viscosity / suspending agents include those selected from the group consisting of cellulose derivatives such as methylcellulose, ethylcellulose, hydroxyethylcellulose, polyethylene glycols (such as polyethylene glycol 300, polyethylene glycol 400), carboxymethylcellulose, hydroxypropylmethylcellulose, and crosslinked acrylic acid polymers (carbomers) such as polymers of acrylic acid crosslinked with polyalkenyl ethers or divinyl glycols (Carbopols such as Carbopol 934, Carbopol 934P, Carbopol 971, Carbopol 974 and Carbopol 974P), and mixtures thereof.

[0480] To adjust the formulation to an acceptable pH (typically 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 a mineral acid or metal hydroxide base selected from the group of potassium hydroxide, sodium hydroxide, and hydrochloric acid, and mixtures thereof, preferably sodium hydroxide and / or hydrochloric acid. These acidic and / or basic pH adjusters are added to adjust the formulation to a target acceptable pH range. Thus, depending on the formulation, it may not be necessary to use both an acid and a base, and the addition of either an acid or a base may be sufficient to bring the mixture to the desired pH range.

[0481] The aqueous vehicle may also contain a buffer to stabilize the pH. If used, the buffer 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 salts thereof including disodium tetraborate), citrate buffers (such as citric acid or salts thereof including sodium citrate), and ε-aminocaproic acid, and mixtures thereof.

[0482] The formulation may further comprise 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.

[0483] Oral compositions generally include an inert diluent or an edible pharma- ceutically acceptable carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with an excipient and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared with a fluid carrier for use as a mouthwash, and the compound in the fluid carrier is applied orally, swished, and expectorated or swallowed. Pharmaceutically compatible binding agents, and / or adjuvants can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

[0484] According to a further aspect of the present disclosure there is provided a pharmaceutical composition comprising a compound of the disclosure as defined above or a pharma- ceutically acceptable salt, hydrate or solvate thereof in combination with a pharma- ceutically acceptable diluent or carrier.

[0485] The compositions of the disclosure may be in a form suitable for oral use (e.g., as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), topical use (e.g., as creams, ointments, gels, or aqueous or oily solutions or suspensions), administration by inhalation (e.g., as a finely divided powder or liquid aerosol), administration by insufflation (e.g., as a finely divided powder) or parenteral administration (e.g., as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular administration, or as a suppository for rectal administration).

[0486] The compositions of the present disclosure 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 coloring agents, sweeteners, flavoring agents and / or preservatives.

[0487] An effective amount of a compound of the present disclosure for use in therapy is an amount sufficient to treat or prevent, slow the progression of, and / or reduce the symptoms associated with the inflammasome-associated conditions referred to herein.

[0488] The magnitude of a dose of a compound of formula (III) for therapeutic or prophylactic purposes will, of course, vary with 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 principles of medicine.

[0489] How to use In some aspects, the present disclosure provides a method of inhibiting inflammasome (e.g., NLRP3 inflammasome) activity (e.g., in vitro or in vivo), comprising contacting a cell with an effective amount of a compound of the present disclosure, or a pharma- ceutical acceptable salt thereof.

[0490] In some aspects, the present disclosure provides a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a compound of the present disclosure or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0491] In some aspects, the present disclosure provides a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0492] In some embodiments, the disease or disorder is associated with inflammasome activity. In some embodiments, the disease or disorder is a disease or disorder in which inflammasome activity is implicated.

[0493] In some embodiments, the disease or disorder is an inflammatory disorder, an autoinflammatory disorder, an autoimmune disorder, a neurodegenerative disease, or cancer.

[0494] In some embodiments, the disease or disorder is an inflammatory disorder, an autoinflammatory disorder, and / or an autoimmune disorder.

[0495] In some embodiments, the disease or disorder is cytokine release syndrome (CRS).

[0496] In some embodiments, the disease or disorder is selected from cryopyrin-associated autoinflammatory syndromes (CAPS; e.g., familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurological, cutaneous, and articular (CINCA) syndrome / neonatal-onset multisystem inflammatory disease (NOMID)), familial Mediterranean fever (FMF), nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), gout, rheumatoid arthritis, osteoarthritis, Crohn's disease, chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD), fibrosis, obesity, type 2 diabetes, multiple sclerosis, skin diseases (e.g., acne), and neuroinflammation occurring in protein misfolding diseases (e.g., prion diseases).

[0497] In some embodiments, the disease or disorder is a neurodegenerative disease.

[0498] In some embodiments, the disease or disorder is Parkinson's disease or Alzheimer's disease.

[0499] In some embodiments, the disease or disorder is a skin disease.

[0500] In some embodiments, the skin condition is acne.

[0501] In some embodiments, the disease or disorder is cancer.

[0502] 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.

[0503] 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 in need thereof, comprising administering to the subject a compound of the present disclosure or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0504] 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 in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0505] In some aspects, the present disclosure provides a method of treating or preventing an inflammatory, autoinflammatory and / or autoimmune disorder selected from cryopyrin-associated autoinflammatory syndromes (CAPS; e.g., familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurological, cutaneous and articular (CINCA) syndrome / neonatal-onset multisystem inflammatory disease (NOMID)), familial Mediterranean fever (FMF), nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), gout, rheumatoid arthritis, osteoarthritis, Crohn's disease, chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD), fibrosis, obesity, type 2 diabetes, multiple sclerosis, skin diseases (e.g., acne), and neuroinflammation occurring in protein misfolding diseases (e.g., prion diseases) in a subject in need thereof, comprising administering to the subject a compound of the present disclosure or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0506] In some aspects, the present disclosure provides a method of treating or preventing an inflammatory, autoinflammatory and / or autoimmune disorder selected from cryopyrin-associated autoinflammatory syndromes (CAPS; e.g., familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurological, cutaneous and articular (CINCA) syndrome / neonatal-onset multisystem inflammatory disease (NOMID)), familial Mediterranean fever (FMF), nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), gout, rheumatoid arthritis, osteoarthritis, Crohn's disease, chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD), fibrosis, obesity, type 2 diabetes, multiple sclerosis, skin diseases (e.g., acne), and neuroinflammation occurring in protein misfolding diseases (e.g., prion diseases) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0507] In some aspects, the present disclosure provides a method for treating or preventing cytokine release syndrome (CRS) in a subject in need thereof, comprising administering to the subject a compound of the present disclosure or a pharma- ceutically 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.

[0508] In some aspects, the present disclosure provides a method for treating or preventing cytokine release syndrome (CRS) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or its pharma- ceutically acceptable salt 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.

[0509] 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, comprising administering to the subject a compound of the present disclosure or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0510] 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, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0511] In some aspects, the present disclosure provides a method of treating or preventing cancer in a subject in need thereof, comprising administering to the subject a compound of the present disclosure or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0512] In some aspects, the present disclosure provides a method of treating or preventing cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0513] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharma- ceutically acceptable salt thereof, for use in inhibiting inflammasome (e.g., NLRP3 inflammasome) activity (e.g., in vitro or in vivo).

[0514] In some aspects, the disclosure provides a compound of the disclosure, or a pharma- ceutically acceptable salt thereof, for use in treating or preventing a disease or disorder disclosed herein.

[0515] In some aspects, the disclosure provides a compound of the disclosure, or a pharma- ceutically acceptable salt thereof, for use in treating or preventing an inflammatory disorder, an autoinflammatory disorder, an autoimmune disorder, a neurodegenerative disease, or cancer in a subject in need thereof.

[0516] In some aspects, the disclosure provides a compound of the disclosure or a pharma- ceutically acceptable salt thereof for use in treating or preventing an inflammatory, autoinflammatory and / or autoimmune disorder selected from cryopyrin-associated autoinflammatory syndromes (CAPS; e.g., familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurological, cutaneous and articular (CINCA) syndrome / neonatal-onset multisystem inflammatory disease (NOMID)), familial Mediterranean fever (FMF), nonalcoholic fatty liver disease (NAFLD), nonalcoholic 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.

[0517] In some aspects, the disclosure provides a compound of the disclosure, or a pharma- ceutically acceptable salt thereof, for use in treating or preventing CRS in a subject in need thereof.

[0518] In some aspects, the disclosure provides a compound of the disclosure, or a pharma- ceutically acceptable salt thereof, for use in treating or preventing a neurodegenerative disease (e.g., Parkinson's disease or Alzheimer's disease) in a subject in need thereof.

[0519] In some aspects, the disclosure provides a compound of the disclosure, or a pharma- ceutically acceptable salt thereof, for use in treating or preventing cancer in a subject in need thereof.

[0520] In some aspects, the disclosure provides the use of a compound of the disclosure, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting inflammasome (e.g., NLRP3 inflammasome) activity (e.g., in vitro or in vivo).

[0521] In some aspects, the disclosure provides the use of a compound of the disclosure, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0522] In some aspects, the disclosure provides the use of a compound of the disclosure, or a pharma- ceutically acceptable salt 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.

[0523] In some aspects, the disclosure provides use of a compound of the disclosure or a pharma- ceutical or pharma-ceutical acceptable salt thereof in the manufacture of a medicament for treating or preventing an inflammatory, autoinflammatory and / or autoimmune disorder selected from cryopyrin-associated autoinflammatory syndromes (CAPS; e.g., familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurological, cutaneous and articular (CINCA) syndrome / neonatal-onset multisystem inflammatory disease (NOMID)), familial Mediterranean fever (FMF), nonalcoholic fatty liver disease (NAFLD), nonalcoholic 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 neuroinflammation occurring in protein misfolding diseases (e.g., prion diseases) in a subject in need thereof.

[0524] In some aspects, the disclosure provides the use of a compound of the disclosure, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing CRS in a subject in need thereof.

[0525] In some aspects, the disclosure provides the use of a compound of the disclosure, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing a neurodegenerative disease (e.g., Parkinson's disease or Alzheimer's disease) in a subject in need thereof.

[0526] In some aspects, the disclosure provides the use of a compound of the disclosure, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing cancer in a subject in need thereof.

[0527] The present disclosure provides a compound that functions as an inhibitor of inflammasome activity.Accordingly, the present disclosure provides a method for inhibiting inflammasome activity in vitro or in vivo, comprising contacting a cell with an effective amount of a compound defined herein or a pharma-ceutically acceptable salt thereof.

[0528] The efficacy of the compounds of the present disclosure can be determined according to standard methods of elucidating this by industry-accepted assays / disease models described in the art and found in the current general knowledge.

[0529] The present disclosure also provides a method of treating a disease or disorder involving inflammasome activity in a patient in need of such treatment, comprising administering to the patient a compound defined herein or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0530] The present disclosure also provides a method of treating a disease or disorder involving inflammasome activity in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound defined herein or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0531] 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 related to increased levels of active cytokines belonging to the IL-1 family of cytokines (Sims J. et al. Nature Reviews Immunology 10, 89-102 (February 2010).

[0532] Exemplary diseases and corresponding references are given below: inflammatory, autoinflammatory and autoimmune diseases, such as CAPS (Dinarello, CA Immunity. 2004 Mar; 20(3):243-4; Hoffman, HM 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, CA et al. Curr. Opin. Endocrinol. Diabetes Obes. 2010 Aug; 17(4):314-21)), multiple sclerosis (see EAE model in Coll, RC et al. Nat. Med. 2015 Mar; 21(3):248-55) as well as 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.

[0533] Preferably, the compounds of the present disclosure can be used to treat 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 autoinflammatory syndromes (CAPS, e.g., familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurological, cutaneous, and articular (CINCA) syndrome / neonatal onset multisystem inflammatory disease (NOMID)), familial Mediterranean fever (FMF), nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), chronic kidney disease (CKD), gout, rheumatoid arthritis, osteoarthritis, Crohn's disease, COPD, fibrosis, obesity, type 2 diabetes, multiple sclerosis, skin diseases (e.g., acne), and neuroinflammation occurring in protein misfolding diseases, e.g., prion diseases. Neurodegenerative diseases include, but are not limited to, Parkinson's disease and Alzheimer's disease.

[0534] Thus, the compounds of the present disclosure can be used for the treatment of a disease selected from the group consisting of cryopyrin-associated autoinflammatory syndromes (CAPS, e.g., familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurological, cutaneous, and articular (CINCA) syndrome / neonatal onset multisystem inflammatory disease (NOMID)), familial Mediterranean fever (FMF), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), chronic kidney disease (CKD), gout, rheumatoid arthritis, osteoarthritis, Crohn's disease, COPD, fibrosis, obesity, type 2 diabetes, multiple sclerosis, skin diseases (e.g., acne), and neuroinflammation occurring in protein misfolding diseases, e.g., prion diseases, neurodegenerative diseases (e.g., Parkinson's disease, Alzheimer's disease), and neoplastic diseases.

[0535] Inflammatory disorders associated with infections In some embodiments, the disease or disorder is an inflammatory disease.

[0536] In some embodiments, the inflammatory disease is associated with an infection.

[0537] In some embodiments, the inflammatory disease is associated with a viral infection.

[0538] In some embodiments, the inflammatory disease is associated with an infection with an RNA virus. In some embodiments, the RNA virus is a single-stranded RNA virus. Single-stranded RNA viruses include group 4 (positive strand) and group 5 (negative strand) single-stranded RNA viruses. Group 4 viruses include coronaviruses.

[0539] In some embodiments, the inflammatory disease is associated with infection with 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).

[0540] In some embodiments, the inflammatory disease is associated with infection with SARS-CoV 2. In some embodiments, the SARS-CoV 2 infection results in novel coronavirus disease 2019 (COVID-19).

[0541] In some embodiments, the inflammatory disease is a pulmonary inflammatory disease.

[0542] In some embodiments, the pulmonary inflammatory disease is associated with infection with SARS-CoV 2.

[0543] In some embodiments, the inflammatory disease comprises cytokine release syndrome (CRS).

[0544] In some embodiments, cytokine release syndrome (CRS) is associated with infection with SARS-CoV 2.

[0545] Cytokine Release Syndrome and Immunotherapy In some embodiments, the disease or disorder is an inflammatory disease.

[0546] In some embodiments, the inflammatory disease is associated with immunotherapy.

[0547] In some embodiments, immunotherapy causes cytokine release syndrome (CRS).

[0548] The efficacy 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, it is believed that the severity of immunotherapy-induced CRS is 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 can occur when cells targeted by adoptive cell therapy undergo pyroptosis, a highly inflammatory form of programmed cell death. Pyroptosis leads to the release of factors that stimulate macrophages to produce inflammatory cytokines, resulting in CRS (Liu et al. Science Immunology (2020) V: eeax7969).

[0549] In some embodiments, the immunotherapy comprises an antibody or adoptive cell therapy.

[0550] In some embodiments, the adoptive cell therapy comprises CAR-T or TCR-T cell therapy.

[0551] In some embodiments, the adoptive cell therapy comprises cancer treatment.For example, the cancer treatment can be for treating B cell lymphoma or B cell acute lymphoblastic leukemia.For example, the adoptive cell can express CAR that targets CD19+ B cell acute lymphoblastic leukemia cells.

[0552] In some embodiments, the adoptive cell therapy involves the administration of T cells, B cells, or NK cells.

[0553] In some aspects, the adoptive cell therapy is autologous.

[0554] In some aspects, the adoptive therapy is allogeneic.

[0555] Cancer treatment: Linked to inflammasomes It has long been observed that chronic inflammatory responses are associated with various types of cancer. During malignant transformation or cancer therapy, inflammasomes can be activated in response to danger signals, and this activation can be either beneficial or detrimental to the cancer.

[0556] IL-1β expression is elevated in a variety of cancers (including breast, prostate, colon, lung, head and neck cancer, and melanoma), and patients with IL-1β-producing tumors generally have a poorer 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).

[0557] Cancers originating from epithelial cells (carcinomas) or from the glandular epithelium (adenocarcinomas) are heterogeneous and composed of many different cell types. They may include, among others, fibroblasts, immune cells, adipocytes, endothelial cells, and pericytes, all of which may secrete cytokines / chemokines (Grivennikov, Sergei I., Florian R. Greten, and Michael Karin. "Immunity, inflammation, and cancer." Cell 140.6 (2010): 883-899). This may lead to cancer-associated inflammation through the infiltration of immune cells. Although the presence of leukocytes in tumors is known, it has only recently become clear that an inflammatory microenvironment is an essential component of all tumors. Most tumors (>90%) are the result of somatic mutations or environmental factors rather than germline mutations, and many environmental causes of cancer are related to chronic inflammation (20% of cancers are related to chronic infections, 30% are related to smoking / inhaled pollutants, and 35% are related to dietary factors (20% of all cancers are related to obesity) (Aggarwal, Bharat B., RV 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).

[0558] GI cancer Cancers of the gastrointestinal (GI) tract 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 inflammation in the stomach 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).

[0559] 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 its promotion of gastric cancer metastasis (Xu et al., 2013).

[0560] Skin cancer UV radiation is the greatest environmental risk for skin cancer, which is promoted by causing DNA damage, immune suppression, and inflammation. Melanoma, the most aggressive form of skin cancer, is characterized by 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 in vivo through an IL-1-dependent mechanism. Using thymoquinone, inhibition of metastasis in the B16F10 mouse melanoma model was shown to be dependent on 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).

[0561] Glioblastoma NLRP3 contributes to radioresistance in gliomas. Ionizing radiation can induce NLRP3 expression, but NLRP3 inhibition reduced tumor growth and extended the survival of mice after radiation therapy. Therefore, NLRP3 inflammasome inhibition may provide a therapeutic strategy for radioresistant gliomas (Li, Lianling, and Yuguang Liu. "Aging-related gene signature regulated by Nlrp3 predicts glioma progression." American journal of cancer research 5.1 (2015): 442).

[0562] Metastasis More broadly, the applicants believe that NLRP3 is involved in promoting metastasis, and thus modulation of NLRP3 should credibly prevent it. 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).

[0563] IL-1 gene is frequently expressed in metastases from patients with several types of human cancer.For example, IL-1mRNA is highly expressed in more than half of all metastatic human tumor samples examined, 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 xenograft growth in IL-1-producing tumors, but has no antiproliferative effect in vitro.

[0564] Furthermore, IL-1 signaling is a biomarker for predicting breast cancer patients at increased risk of developing bone metastasis. In mouse models, IL-1β and its receptors are upregulated in breast cancer cells that metastasize to bone compared to non-metastatic cells. In mouse models, the IL-1 receptor antagonist anakinra reduced proliferation and angiogenesis in addition to exerting a significant effect on the tumor environment reducing the bone turnover markers IL-1β and TNF-alpha (Holen, Ingunn, et al. "IL-1 drives breast cancer growth and bone metastasis in vivo." Oncotarget (2016).

[0565] IL-18 induced the production of MMP-9 in the human leukemia cell line HL-60, which in turn 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). In addition, IL-18 may 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).

[0566] CD36 The fatty acid scavenger receptor CD36 plays a dual role in priming gene transcription of pro-IL-1β and inducing assembly of the NLRP3 inflammasome complex. CD36 and TLR4-TLR6 heterodimers recognize oxLDL, which initiates a signaling pathway that leads to transcriptional upregulation of NLRP3 and pro-IL-1β (signal 1). CD36 also mediates internalization of oxLDL into the lysosomal compartment, where crystals are formed that induce lysosomal rupture and 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).

[0567] A subpopulation of human oral cancer cells expresses high levels of the fatty acid scavenger receptor CD36 and is characterized by its ability to initiate metastasis. Palmitic acid or high-fat diets enhanced the metastatic potential of CD36+ cells. Neutralizing anti-CD36 antibodies prevented 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 has been 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).

[0568] In hepatocellular carcinoma, exogenous palmitic acid activated an epithelial-mesenchymal transition (EMT)-like program and induced migration that was reduced by the CD36 inhibitor sulfo-N-succinimidyl oleate (Nath, Aritro, et al. "Elevated free fatty acid uptake via CD36 promotes epithelial-mesenchymal transition in hepatocellular carcinoma." Scientific reports 5 (2015). Body mass index was not associated with the degree of EMT, emphasizing the importance of CD36 and free fatty acids.

[0569] Cancer stem cells (CSCs) use CD36 to promote their maintenance. Oxidized phospholipids, which are ligands for CD36, are present in glioblastoma, and exposure to oxidized LDL increased proliferation of CSCs, but not non-CSCs. CD36 also correlated with patient prognosis.

[0570] Chemotherapy resistance In addition to their direct cytotoxic effects, chemotherapeutic agents exploit the host immune system to contribute to antitumor activity. However, gemcitabine and 5-FU have been shown to activate NLRP3 in myeloid-derived suppressor cells, leading to the production of IL-1β, which suppresses antitumor effects. Mechanistically, these agents destabilize lysosomes to 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 cells 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 may therefore be useful in chemotherapy to treat a wide range of cancers.

[0571] The compounds of the present disclosure, or pharma- ceutically acceptable salts thereof, may be administered alone as the sole therapeutic agent or may be administered in combination with one or more other substances and / or treatments. Such co-treatment may be accomplished by simultaneous, sequential, or separate administration of the individual components of the treatment.

[0572] For example, the therapeutic effect may be enhanced by administration of an adjuvant (i.e., an adjuvant by itself may have minimal therapeutic effect, but when combined with another therapeutic agent, improves the overall therapeutic effect on the individual). Alternatively, and by way of example only, the benefit experienced by an individual may be increased by administering a compound of formula (III) with another therapeutic agent (which may also comprise a treatment regimen) that also has a therapeutic benefit.

[0573] When the compound of the present disclosure is administered in combination with other therapeutic agents, the compound of the disclosure does not need to be administered via the same route as the other therapeutic agents, and may be administered by different routes due to different physical and chemical properties.For example, the compound of the present disclosure may be administered orally to generate and maintain good blood levels, while the other therapeutic agents may be administered intravenously.The initial administration may be performed according to established protocols known in the art, and then the dosage, mode of administration, and time of administration may be modified by a skilled clinician based on the effects observed.

[0574] The specific choice of other therapeutic agents will depend on the diagnosis of the attending physician and their judgment of the individual's condition and the appropriate treatment protocol. According to this aspect of the disclosure, there is provided a combination comprising the disclosed compound as defined above or a pharma- ceutically acceptable salt thereof and other suitable agents for use in treating diseases involving inflammasome activity.

[0575] According to a further aspect of the present disclosure, there is provided a pharmaceutical composition comprising a disclosed compound, or a pharma- ceutically acceptable salt thereof, in combination with a suitable pharma- ceutically acceptable diluent or carrier.

[0576] In addition to their use in therapeutic medicine, the compounds of formula (III) and their pharma- ceutically acceptable salts are also useful as pharmacological tools in the development and standardization of in vitro and in vivo test systems for the evaluation of the effects of inflammasome inhibition in laboratory animals such as dogs, rabbits, monkeys, rats and mice as part of the search for new therapeutic agents.

[0577] In any of the above pharmaceutical compositions, processes, methods, uses, medicaments, and manufacturing features of the present disclosure, any of the alternative aspects of the macromolecules of the present disclosure described herein may be applied.

[0578] Route of administration The compounds of the present disclosure, or pharmaceutical compositions containing these compounds, may be administered to a subject by any convenient route of administration, whether systemic / peripheral or local (i.e., at the site of desired action).

[0579] Routes of administration include oral (e.g., by ingestion); buccal; sublingual; transdermal (including, e.g., by patches, plasters, etc.); transmucosal (including, e.g., by patches, plasters, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., through the mouth or nose, e.g., via 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, subcuticular, intraarticular, subarachnoid, and intrasternal; and implantation of a depot or reservoir, e.g., subcutaneously or intramuscularly.

[0580] definition Unless otherwise stated, the following terms used in the specification and claims have the following meanings set forth below.

[0581] Without wishing to be limited by this description, it is understood that although various options for each variable are described herein, the disclosure is intended to encompass operable embodiments having combinations of options, and the disclosure may be interpreted to exclude inoperable embodiments caused by specific combinations of options.

[0582] It is understood that the compounds of the present disclosure may be depicted in neutral, cationic (e.g., with one or more positive charges), or anionic (e.g., with one or more negative charges) forms, all of which are intended to be within the scope of the present disclosure. For example, when a compound of the present disclosure is depicted in anionic form, such depiction also refers to various neutral, cationic, and anionic forms of the compound. As another example, when a compound of the present disclosure is depicted in anionic form, such depiction also refers to various salts (e.g., sodium salts) of the anionic form of the compound. In some embodiments, the amines of the compounds of the present disclosure are protonated.

[0583] "Therapeutically effective amount" means the amount of a compound that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity, and the age, weight, etc., of the mammal being treated.

[0584] As used herein, “alkyl”, “C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 Alkyl" or "C 1 ~C 6 Alkyl" is C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 Straight-chain (linear) saturated aliphatic hydrocarbon groups and C 3 , C 4 , C 5 , or C 6 It is intended to include branched saturated aliphatic hydrocarbon groups. For example, C 1 ~C 6 Alkyl is C 1 , C 2 , C 3 , C 4 , C 5 , and C 6Alkyl groups are intended to include those having 1 to 6 carbon atoms, including, but not limited to, methyl (i.e., CH 3 ), ethyl (i.e., CH 2 CH 3 ), n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, or n-hexyl, etc. In some embodiments, a straight chain or branched alkyl has 6 or fewer carbon atoms (e.g., C for straight chain). 1 ~C 6 , C for branched chain 3 ~C 6 ) and in another embodiment, the straight chain or branched alkyl has 4 or fewer carbon atoms.

[0585] As used herein, the term "optionally substituted alkyl" refers to an unsubstituted alkyl or an alkyl having specified substituents replacing one or more hydrogen atoms on one or more carbons of the hydrocarbon backbone. Such substituents may 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, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or aromatic or heteroaromatic moieties.

[0586] As used herein, the term "alkenyl" includes unsaturated aliphatic groups similar in length and possible substitution to the alkyls described above, but 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, a straight-chain or branched alkenyl group has 6 or fewer carbon atoms in its backbone (e.g., C for straight chain). 2 ~C 6 , C for branched chain 3 ~C 6 ) has. 2 ~C 6 The term "alkenyl" includes alkenyl groups containing 2 to 6 carbon atoms. 3 ~C 6 The term includes alkenyl groups containing from 3 to 6 carbon atoms.

[0587] As used herein, the term "optionally substituted alkenyl" refers to an unsubstituted alkenyl or an alkenyl having specified substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents may 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, sulfonamido, nitro, trifluoromethyl, cyano, heterocyclyl, alkylaryl, or aromatic or heteroaromatic moieties.

[0588] As used herein, the term "alkynyl" includes unsaturated aliphatic groups similar in length and possible substitution to the alkyls described above, but which contain 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, a straight-chain or branched alkynyl group has 6 or fewer carbon atoms in its backbone (e.g., C for straight chain). 2 ~C 6 , C for branched chain 3 ~C 6 ) has. 2 ~C 6 The term "alkynyl" includes alkynyl groups containing 2 to 6 carbon atoms. 3 ~C 6As used herein, the term "alkynyl groups" includes alkynyl groups containing 3 to 6 carbon atoms. 2 ~C 6 alkenylene linker" or "C 2 ~C 6 Alkynylene linker" is C 2 , C 3 , C 4 , C 5 or C 6 It is intended to include chain (straight or branched) divalent unsaturated aliphatic hydrocarbon radicals. For example, C 2 ~C 6 The alkenylene linker is C 2 , C 3 , C 4 , C 5 and C 6 Alkenylene linker groups are intended to be included.

[0589] As used herein, the term "optionally substituted alkynyl" refers to an unsubstituted alkynyl or an alkynyl having specified substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents may 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, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or aromatic or heteroaromatic moieties.

[0590] Other optionally substituted moieties (such as optionally substituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl) include both unsubstituted moieties and moieties that have one or more of the 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.

[0591] As used herein, the term "cycloalkyl" refers to an alkyl group having 3 to 30 carbon atoms (e.g., C 3 ~C 12 , C 3 ~C 10 , or C 3 ~C 8 ) a saturated or partially unsaturated hydrocarbon monocyclic or polycyclic (e.g., fused, bridged, or spirocyclic) system having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 120, 132, 140, 141, 152, 163, 17

[0592] As used herein, the term "heterocycloalkyl," unless otherwise stated, refers to a saturated or partially unsaturated 3-8 membered monocyclic ring, 6-12 membered bicyclic ring (fused, bridged, or spirocyclic), or 11-14 membered tricyclic ring system (fused, bridged, or spirocyclic) having one or more heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur (such as O, N, S, P, or Se), e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or, e.g., 1, 2, 3, 4, 5, or 6 heteroatoms.Examples of heterocycloalkyl groups are 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-dioxa-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]pyridin]-yl, 3'H-spiro[cyclohexane-1,1'-furo[3,4-c]pyridin]-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, and the like. In the case of polycyclic heterocycloalkyls, only one of the rings in the heterocycloalkyl need be non-aromatic.

[0593] As used herein, the term "aryl" includes groups having aromaticity, including "conjugated" or polycyclic ring systems having one or more aromatic rings, and does not contain any 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, and the like. Conveniently, the aryl is phenyl.

[0594] As used herein, the term "heteroaryl" is intended to include a stable 5-, 6-, or 7-membered monocyclic or 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic aromatic heterocyclic ring consisting of carbon atoms and one or more heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or, e.g., 1, 2, 3, 4, 5, or 6 heteroatoms. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR, where R is H or other 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, and the like. Heteroaryl groups can also be fused or bridged with alicyclic or heterocyclic rings that are not aromatic so as to form polycyclic systems (e.g., 4,5,6,7-tetrahydrobenzo[c]isoxazolyl).

[0595] 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.

[0596] A cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring may have at one or more ring positions (e.g., a ring-forming carbon or heteroatom, e.g., N) a substituent 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, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or aromatic or heteroaromatic moieties. Aryl and heteroaryl groups may also be fused or bridged with alicyclic or heterocyclic rings which are not aromatic so as to form polycyclic systems (e.g., methylenedioxyphenyl, such as tetralin, benzo[d][1,3]dioxol-5-yl, etc.). As used herein, the term "substituted" means that any one or more hydrogen atoms on the designated atom are replaced with one selected from the indicated group, provided that the normal valence of the designated atom is not exceeded and the replacement results in a stable compound. If the substituent is oxo or keto (i.e., =O), then two hydrogen atoms on the atom are replaced. Keto substituents do not occur in aromatic moieties. As used herein, a ring double bond is a double bond formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N)."Stable compound" and "stable structure" are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

[0597] When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be attached to any atom in the ring. When a substituent is listed without indicating the atom to which such substituent is attached to the remainder of the compound of a given formula, then such substituent may be attached through any atom in such formula. Combinations of substituents and / or variables are permissible, but only if such combinations result in stable compounds.

[0598] When any variable (e.g., R) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R moieties, then that group may be substituted with up to 2 R moieties, and R at each occurrence is independently selected from the definitions of R. Also, combinations of substituents and / or variables are permissible, but only if such combinations result in stable compounds.

[0599] As used herein, the term "hydroxy" or "hydroxyl" refers to -OH or -O - The formula includes groups having the formula:

[0600] As used herein, the term "halo" or "halogen" refers to fluoro, chloro, bromo and iodo.

[0601] The terms "haloalkyl" or "haloalkoxyl" refer to an alkyl or alkoxyl substituted with one or more halogen atoms.

[0602] As used herein, the term "optionally substituted haloalkyl" refers to an unsubstituted haloalkyl having specified substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents may 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, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or aromatic or heteroaromatic moieties.

[0603] As used herein, the term "alkoxy" or "alkoxyl" includes substituted and unsubstituted alkyl, alkenyl, and alkynyl groups covalently linked to an oxygen atom. Examples of alkoxy groups or alkoxyl radicals include, but are not limited to, methoxy, ethoxy, isopropyloxy, propoxy, butoxy, and pentoxy groups. Examples of substituted alkoxy groups include halogenated alkoxy groups. Alkoxy groups can be optionally substituted 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, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Examples of halogen substituted alkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, and trichloromethoxy.

[0604] As used herein, phrases 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," and the like are used interchangeably and refer to all selected from the group consisting of A, B, and / or C, i.e., one or more A, one or more B, one or more C, or any combination thereof, unless otherwise indicated.

[0605] As used herein, "severe acute respiratory syndrome coronavirus 2 (SARS-CoV 2)" refers to the coronavirus that causes novel 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, over 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 experience mild symptoms, some develop acute respiratory distress syndrome, possibly due to cytokine release syndrome (CRS), multiple organ failure, septic shock, and blood clots. The time from exposure to the virus to the onset of symptoms is typically about 5 days, but can range from 2 to 14 days.

[0606] As used herein, "cytokine release syndrome (CRS)" refers to a systemic inflammatory response caused by a variety of factors, including but not limited to drugs, infectious diseases such as SARS-CoV 2, and immunotherapies such as chimeric antigen receptor T cell (CAR-T) therapy. In CRS, large numbers 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 high doses of steroids.

[0607] As used herein, "adoptive cell therapy" refers to a form of therapy 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 quantities, and transplanted into the subject to help the immune system fight 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.

[0608] As used herein, the term "chimeric antigen receptor (CAR)" refers to, for example, an artificial T cell receptor, a chimeric T cell receptor, or a chimeric immune receptor, and may include an engineered receptor that confers artificial specificity to a particular immune effector cell. CARs may be utilized to confer the specificity of a monoclonal antibody to a T cell, thereby making it possible to generate a large number of specific T cells for use in, for example, adoptive cell therapy. For example, CARs may direct the specificity of a cell expressing the CAR to a tumor-associated antigen. In some embodiments, a CAR comprises an intracellular activation domain, a transmembrane domain, an extracellular domain comprising an antigen-binding domain, and optionally an extracellular hinge. The antigen-binding domain may be any antigen-binding domain known in the art, including antigen-binding domains derived from antibodies, Fabs, F(ab')2, nanobodies, single-domain antigen-binding domains, scFvs, VHHs, and the like. In certain aspects, a CAR comprises a fusion of a single-chain variable region fragment (scFv) derived from a monoclonal antibody, fused to a CD3 transmembrane domain and endodomain. In some cases, the CAR comprises domains for additional costimulatory signaling, such as CD3, FcR, CD27, CD28, CD137, DAP10, and / or OX40.

[0609] A "T cell receptor (TCR)" is a protein complex found on the surface of T cells or T lymphocytes that is responsible for recognizing fragments of antigens as peptides bound to major histocompatibility complex (MHC) molecules. T cell receptors can be engineered to express antigen-binding domains specific for particular antigens and can be used in adoptive cell therapy as described herein.

[0610] It is to 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 of the present disclosure according to the following schemes and those shown in the Examples.

[0611] It should be understood that throughout the specification, when a composition is described as having, including, or comprising certain components, it is also contemplated that the composition consists essentially of or consists 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 processing steps. It should also be understood that the order of steps or order for performing certain actions is immaterial so long as the invention remains operable. Moreover, two or more steps or actions may be performed simultaneously.

[0612] It is to be understood that the synthetic processes of the present disclosure can tolerate a variety of functional groups, and thus variously substituted starting materials can be used. Although the processes generally provide the desired final compound at or near the end of the overall process, in certain cases it may be desirable to further convert the compound to its pharma-ceutically acceptable salt.

[0613] It should be understood that the compounds of the present disclosure can be prepared in a variety of ways, using compounds from commercially available starting materials, intermediates known in the literature or easily 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 functional group transformations and manipulations can be obtained from the relevant scientific literature or standard textbooks in the field. See, but are not limited to, any one or more sources, Smith, MB, March, J., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5, incorporated herein by reference. th edition, John Wiley & Sons: New York, 2001; Greene, TW, Wuts, PGM, Protective Groups in Organic Synthesis, 3 rd edition, John Wiley & Sons: New York, 1999; R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), are useful and are recognized references in organic synthesis known to those of skill in the art.

[0614] Those skilled in the art will recognize that the order of certain steps, such as the introduction and removal of protecting groups, may be altered during the reaction sequences and synthetic schemes described herein. Those skilled in the art will recognize that certain groups may require protection from reaction conditions through 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, TW, Wuts, PGM, Protective Groups in Organic Synthesis, 3 rd edition, John Wiley & Sons: New York, 1999.

[0615] Unless otherwise specified, any description of a method of treatment should be understood to include the use of the compounds to provide treatment or prophylaxis as described herein, as well as the use of the compounds to prepare a medicament for treating or preventing such conditions. Treatment includes the treatment of humans or non-human animals, including rodents and other disease models.

[0616] As used herein, the term "subject" includes human and non-human animals, cell lines, cell cultures, tissues, and organs. In some embodiments, the "subject" is a mammal. The mammal may be, for example, a human or a suitable non-human mammal, such as a primate, mouse, rat, dog, cat, cow, horse, goat, camel, sheep, or pig. The subject may also be a bird or poultry. In some embodiments, the subject is a human.

[0617] As used herein, the term "subject in need thereof" refers to a subject having a disease or at high risk of developing a disease. A subject in need thereof may be a subject previously diagnosed or identified as having a disease or disorder disclosed herein. A subject in need thereof may also be a subject suffering from the effects of a disease or disorder disclosed herein. Alternatively, a subject in need thereof may be a subject at high risk of developing such a disease or disorder compared to the population as a whole (i.e., a subject predisposed to developing such a disorder compared to the population as a whole). A subject in need thereof may 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, a subject in need thereof has undergone all known effective treatments for a disease or disorder disclosed herein and they have failed. In some embodiments, a subject in need thereof has undergone at least one prior treatment.

[0618] As used herein, the term "treating" or "treat" describes the management and care of a patient for the purpose of combating a disease, condition, or disorder, and includes the administration of a compound of the present disclosure, or a pharma- ceutically acceptable salt, polymorph, or solvate thereof, to alleviate the symptoms or complications of the disease, condition, or disorder, or to eliminate the disease, condition, or disorder. The term "treat" may also include the treatment of a cell in vitro, or an animal model.

[0619] It is to be understood that the compounds of the present disclosure, or pharma- ceutically acceptable salts, polymorphs or solvates thereof, can also be or may be used to prevent associated diseases, conditions or disorders, or to identify suitable candidates for such purposes.

[0620] As used herein, the terms "preventing," "prevent," or "protecting from" describe reducing or eliminating the onset of symptoms or complications of such a disease, condition, or disorder.

[0621] It is understood that those skilled in the art can refer to the general references for detailed descriptions of the known techniques discussed herein or equivalent techniques. 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, NY; Enna et al., Current Protocols in Pharmacology, John Wiley & Sons, NY; Fingl et al., The Pharmacological Basis of Therapeutics (1975), Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 18 th Of course, these references may be referenced when preparing or using aspects of the disclosure.

[0622] 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 pharma- ceutically acceptable excipient or carrier.

[0623] As used herein, the term "pharmaceutical composition" refers to a formulation containing the disclosed compound in a form suitable for administration to a subject. In one embodiment, the pharmaceutical composition is in bulk or unit dosage form. The unit dosage form is any of a variety of forms, including, for example, a capsule, an IV bag, a tablet, a single pump on an aerosol inhaler, or a vial. The amount of active ingredient (e.g., a formulation of the disclosed compound or its salt, hydrate, solvate, or isomer) in a unit dosage composition is an effective amount and varies according to the specific treatment involved. Those skilled in the art will recognize that routine modifications to dosage may be necessary depending on the age and condition of the patient. Dosage will also vary according to the route of administration. Various routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalation, buccal, sublingual, intrapleural, intraarachnoid, intranasal, and the like. Dosage forms for topical or transdermal administration of the disclosed compound include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. In one embodiment, the active compound is mixed under sterile conditions with a pharma- ceutically acceptable carrier, and with any preservatives, buffers, or propellants that are required.

[0624] As used herein, the term "pharmaceutically acceptable salt" refers to compounds, anions, cations, substances, compositions, carriers, and / or dosage forms that are suitable, within the scope of sound medical judgment, for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit-to-risk ratio.

[0625] As used herein, the term "pharmaceutically acceptable excipient" means an excipient that is generally safe, non-toxic, and not biologically or otherwise undesirable and useful in preparing pharmaceutical compositions, including excipients that are acceptable for veterinary and human pharmaceutical use. As used in the specification and claims, "a pharmaceutically acceptable excipient" includes both one and more than one such excipient.

[0626] It is understood that the pharmaceutical composition of the present disclosure is formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., ingested), inhalation, transdermal (topical), and transmucosal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application may contain the following components: a sterile diluent 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 acetates, citrates, or phosphates, and agents for adjusting isotonicity such as sodium chloride or dextrose. The pH can be adjusted with acids or bases such as hydrochloric acid or sodium hydroxide. Parenteral formulations can be placed into ampoules, disposable syringes, or multiple dose vials made of glass or plastic.

[0627] It should be understood that the compound or pharmaceutical composition of the present disclosure can be administered to a subject by many of the well-known methods currently used for chemotherapeutic treatment.For example, the disclosed compound can be injected into the bloodstream or body cavity, or taken orally, or applied through the skin using a patch.The dose selected should be sufficient to constitute effective treatment, but not so high as to cause unacceptable side effects.The condition (e.g., disease or disorder disclosed herein) status and the health of the patient should preferably be closely monitored during and for a reasonable period after treatment.

[0628] As used herein, the term "therapeutically effective amount" refers to an amount of a pharmaceutical agent to treat, ameliorate, or prevent an identified disease, disorder, or condition, or to exert a detectable therapeutic or suppressive effect. The effect can be detected by any analytical method known in the art. The exact effective amount for each subject will vary depending on the subject's weight, size, and health; the nature and extent of the condition; and the therapeutic agent or combination of therapeutic agents selected for administration. The therapeutically effective amount for a given situation can be determined by routine experimentation, which is within the skill and judgment of the clinician.

[0629] It is understood that for any compound, the therapeutically effective amount can be estimated first in cell culture assays, e.g., neoplastic cells, or in animal models, usually rats, mice, rabbits, dogs, or pigs. Animal models may also be used to determine appropriate concentration ranges and routes of administration. Such information can then be used to determine useful doses and routes of administration in humans. Therapeutic / prophylactic efficacy and toxicity can be determined using standard pharmaceutical techniques in cell cultures or experimental animals, e.g., ED 50 (therapeutically effective dose in 50% of the population) and LD 50 (the dose lethal to 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, and the LD 50 / ED 50 Pharmaceutical compositions that exhibit large therapeutic indices are preferred. The dosage may vary within this range depending on the dosage form employed, sensitivity of the patient, and the route of administration.

[0630] Dosage and administration are adjusted to provide sufficient levels of active agent or to maintain the desired effect. Factors that may be considered include the severity of the condition, the subject's general health, the subject's age, weight, and sex, diet, time and frequency of administration, drug combinations, reaction sensitivities, and tolerance / response to treatment. Long-acting pharmaceutical compositions may be administered every 3-4 days, every week, or once every two weeks, depending on the half-life and clearance rate of the particular formulation.

[0631] The pharmaceutical composition containing the active compound of the present disclosure may be prepared in a manner generally known in the art, for example, by conventional mixing, dissolving, granulating, dragee making, pulverizing, emulsifying, encapsulating, entrapping or lyophilizing process.The pharmaceutical composition may be formulated in a conventional manner using one or more pharma-ceutically acceptable carriers, including excipients and / or auxiliaries that facilitate the processing of the active compound into a pharma-ceutically usable preparation.Of course, the appropriate formulation varies according to the selected route of administration.

[0632] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions, and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL™ (BASF, Parsippany, NJ) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy filling / release into a syringe is possible. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. Prevention of microbial action can be achieved by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, etc. In many cases, it is preferable to include isotonic agents in the composition, such as sugars, polyalcohols such as mannitol and sorbitol, and sodium chloride. Prolonged absorption of the injectable composition can be achieved by including agents that delay absorption, such as aluminum monostearate and gelatin in the composition.

[0633] Sterile injectable solution can be prepared by incorporating the required amount of active compound into a suitable solvent containing one or a combination of the above-listed ingredients as required, and then sterilizing by filtration.Generally, dispersion is prepared by incorporating active compound into a sterile vehicle containing a basic dispersion medium and other ingredients required from the above-listed ones.In the case of sterile powder for preparing sterile injectable solution, the method of preparation is vacuum drying and freeze-drying, which obtains powder of active ingredient plus any additional desired ingredients from the previously sterile-filtered solution.

[0634] Oral compositions generally include an inert diluent or an edible pharma- ceutically acceptable carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with an excipient and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared with a fluid carrier for use as a mouthwash, and the compound in the fluid carrier is applied orally, swished, and expectorated or swallowed. Pharmaceutically compatible binding agents, and / or adjuvants can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

[0635] For administration by inhalation, the compounds are delivered in the form of an aerosol spray from pressured container or dispenser which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.

[0636] Systemic administration may also be by transmucosal or transdermal means. For transmucosal or transdermal administration, a penetrant appropriate to the barrier to be permeated is used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be achieved through the use of nasal sprays or suppositories. For transdermal administration, the active compound is formulated into ointments, salves, gels, or creams as generally known in the art.

[0637] The active compound can be prepared with a pharmaceutically acceptable carrier that protects the compound from rapid elimination from the body, such as controlled release formulations, including implants and microencapsulated delivery systems. Biodegradable biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparing such formulations will be clear to those skilled in the art. The materials can also be commercially obtained from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions can also be used as pharmaceutically acceptable carriers, including liposomes that target infected cells with monoclonal antibodies against viral antigens. These can be prepared according to methods known to those skilled in the art, for example, as described in US Pat. No. 4,522,811.

[0638] It is particularly advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage.Dosage unit form as used herein refers to a physically separate unit suitable as a single dose for the subject to be treated, each unit containing a predetermined amount of active compound calculated to produce desired therapeutic effect in association with required pharmaceutical carrier.The specification of each dosage unit form disclosed is determined by and directly varies according to the specific nature of active compound and the specific therapeutic effect to be achieved.

[0639] In therapeutic applications, dosages of pharmaceutical compositions used in accordance with the disclosure will vary depending on the agent, the age, weight, and clinical condition of the recipient patient, and the experience and judgment of the treating clinician or practitioner, among other factors that will affect the selected dosage. In general, the dosage should be sufficient to slow, preferably regress, the symptoms of the disease or disorder disclosed herein, and preferably cause complete regression of the disease or disorder. Dosages may range from about 0.01 mg / kg per day to about 5000 mg / kg per day. In preferred embodiments, dosages may range from about 1 mg / kg per day to about 1000 mg / kg per day. In certain aspects, the dosage will be in the range of 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 (the dosage is calculated based on the patient's weight in kg, m 2 (This may be adjusted for body surface area at birth, age, and age). An effective amount of a pharmaceutical agent is that amount that produces an objectively identifiable improvement as noted by a clinician or other qualified observer. Improved survival and growth indicate regression. As used herein, the term "dosage effective manner" refers to the amount of an active compound to produce a desired biological effect in a subject or cell.

[0640] It will be appreciated that the pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

[0641] Where the compounds of the present disclosure are capable of further forming salts, it is to be understood that all of those forms are contemplated within the scope of the claimed disclosure.

[0642] As used herein, the term "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds, where the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. Pharmaceutically acceptable salts include the 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 include 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, hexylresorcylic acid, hydrabamic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxymaleic acid, hydroxynaphthoic acid, isethionic acid, hydroxyphenyl trisulfate ... The preferred acids include, but are not limited to, those derived from inorganic and organic acids selected from acetic acid, lactic acid, lactobionic acid, laurylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, napsylic 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, toluenesulfonic acid, and naturally occurring amino acids, such as glycine, alanine, phenylalanine, arginine, and the like.

[0643] In some embodiments, the pharma- ceutically acceptable salt is a sodium salt, a potassium salt, a calcium salt, a magnesium salt, a diethylamine salt, a choline salt, a meglumine salt, a benzathine salt, a tromethamine salt, an ammonia salt, an arginine salt, or a lysine salt.

[0644] Other examples of pharma- ceutically 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, etc. The present disclosure also encompasses salts formed when an acidic proton present in the parent compound is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion, or when coordinated with an organic base, such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. In the salt form, it is understood that the ratio of the compound to the cation or anion of the salt can be 1:1, or any ratio other than 1:1, for example, 3:1, 2:1, 1:2, or 1:3.

[0645] All references to pharma- ceutically acceptable salts should be understood to include the solvent addition forms (solvates) or crystal forms (polymorphs) of the salt as defined herein.

[0646] Said compound or its pharmaceutically acceptable salt is administered orally, intranasally, transdermally, pulmonary, inhalation, buccal, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, intrarectally, intrapleurally, intrathecally and parenterally.In one embodiment, the compound is administered orally.Those skilled in the art will recognize the advantages of certain administration routes.

[0647] The dosing regimen using the compound is selected depending on a variety of 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 particular compound or salt thereof being employed. An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter or halt the progression of the condition.

[0648] Techniques for formulation and administration of the disclosed compounds of this disclosure are described in Remington: The Science and Practice of Pharmacy, 1999. th edition, Mack Publishing Co., Easton, PA (1995). In one embodiment, the compounds described herein and their pharmaceutically acceptable salts are used in pharmaceutical preparations in combination with pharmaceutically acceptable carriers or diluents. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions. The compound will be present in such pharmaceutical compositions in an amount sufficient to provide the desired dosage in the range described herein.

[0649] All percentages and ratios used herein are by weight unless otherwise specified. Other features and advantages of the present disclosure are apparent from different examples. The examples provided show different components and methodologies useful for implementing the present disclosure. The examples do not limit the claimed disclosure. Based on the present disclosure, a person skilled in the art can identify and adopt other components and methodologies useful for implementing the present disclosure.

[0650] In the synthesis schemes described herein, for the sake of simplicity, compounds may be illustrated in one specific configuration.Such specific configurations should not be interpreted as limiting the disclosure to one or another isomer, tautomer, positional isomer or stereoisomer, and do not exclude mixtures of isomers, tautomers, positional isomers or 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.

[0651] All publications and patent documents cited in this specification are incorporated herein by reference as if each such publication or document was specifically and individually indicated to be incorporated herein by reference. The citation of publications and patent documents is not intended as an admission that any is relevant prior art, and does not make any admission as to their contents or date. Although the present invention has been described above by written description, those skilled in the art will recognize that the present invention can be practiced in various embodiments, and that the above description and the following examples are intended to be illustrative and not limiting of the claims that follow.

[0652] As used herein, the phrase "disclosed compounds" refers to the compounds disclosed herein, both generally and specifically.

[0653] Exemplary embodiments Aspect 1. Formula (III): TIFF2025504374000032.tif30128 or a prodrug, solvate, or pharma- ceutically acceptable salt thereof, During the ceremony, each TIFF2025504374000033.tif7128 are independently single or double bonds, as valence permits; A 2 is as CR as the valence allows. 2 , N, N.R. 2a , O, or S; A 3 is as CR as the valence allows. 2 , N, N.R. 2a , O, or S; A 4 is as long as the valence allows. 2 , N, N.R. 2a , O, or S; Here, A 2 , A 3 , or A 4 At least one of them is N, NR 2a , O, or S, where A 2If S, then A 4 is CR 2 , N.R. 2a , O, or S; R 1 is H, -N(C 1 ~C 6 Alkyl) 2 , C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, or C 3 ~C 12 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 1S may be substituted with; Each R 1S are independently halogen, cyano, -OH, or C 1 ~C 6 is alkyl; Each R 2 are independently H, halogen, cyano, -OH, -NH 2 , -NO 2 , -C(=O)NH 2 , C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, -O(C 1 ~C 6 alkyl), -NH(C 1 ~C 6 alkyl), -N(C 1 ~C 6 Alkyl) 2 , C 3 ~C 12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6 ~C 10 aryl, or 5-10 membered heteroaryl, where C1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, -O(C 1 ~C 6 alkyl), -NH(C 1 ~C 6 alkyl), -N(C 1 ~C 6 Alkyl) 2 , C 3 ~C 12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6 ~C 10 Aryl or 5-10 membered heteroaryl is one or more R 2S or or two R's 2 together with the atoms to which they are attached, C 3 ~C 12 cycloalkyl or 3- to 12-membered heterocycloalkyl, where C 3 ~C 12 Cycloalkyl or 3- to 12-membered heterocycloalkyl may be one or more R 2S may be substituted with; Each R 2S are independently halogen, -OH, -O(C 1 ~C 6 alkyl), -NH 2 , -NH(C 1 ~C 6 alkyl), -N(C 1 ~C 6 Alkyl) 2 , or C 3 ~C 12 is cycloalkyl; Each R 2a are independently H, C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, C 1 ~C 6 Haloalkyl, -(CH 2 )0~3 -C 3 ~C 12 Cycloalkyl, or -(CH 2 ) 0~3 -(3 to 12 membered heterocycloalkyl); Each R a are independently H or C 1 ~C 6 alkyl; or two R a together with the atoms to which they are attached, C 3 ~C 12 Forming a cycloalkyl; 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, 3-12 membered heterocycloalkyl, C 6 ~C 10 Aryl, 5-10 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 6 Alkyl)-(C 6 ~C 10 aryl), or -(C 1 ~C 6alkyl)-(5-10 membered heteroaryl); 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, 3-12 membered heterocycloalkyl, C 6 ~C 10 Aryl, 5-10 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 6 Alkyl)-(C 6 ~C 10 aryl), or -(C 1 ~C 6 alkyl)-(5-10 membered heteroaryl) is one or more R N2a may be substituted with; Each R N2a are independently oxo, halogen, cyano, -OH, -NH 2 , -C(=O)H, -C(=O)OH, C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, -O(C 1 ~C 6 alkyl), -NH(C1 ~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 membered heterocycloalkyl, C 6 ~C 10 Aryl, 5-10 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 6 Alkyl)-(C 6 ~C 10 aryl), or -(C 1 ~C 6 alkyl)-(5-10 membered heteroaryl); 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, -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 ~C6 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 membered heterocycloalkyl, C 6 ~C 10 Aryl, 5-10 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 6 Alkyl)-(C 6 ~C 10 aryl), or -(C 1 ~C 6 alkyl)-(5-10 membered heteroaryl) is one or more R N2ab and Each R N2ab are independently oxo, halogen, cyano, -OH, -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) 2N(C 1 ~C 6 Alkyl) 2 That is, A compound or a prodrug, solvate, or pharma- ceutically acceptable salt thereof. Aspect 2.R 1 C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, or C 3 ~C 7 cycloalkyl, where C 1 ~C 6 The alkyl is selected from one or more R 1S may be substituted with; Each R 1S are independently halogen; Each R 2 are independently H, halogen, cyano, -NH 2 , 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 3 ~C 12 cycloalkyl, where C 1 ~C 6 Alkyl and -NH(C 1 ~C 6 alkyl) is one or more R 2S may be substituted with; Each R 2S are independently halogen, -O(C 1 ~C 6 Alkyl, or -NH 2 and; Each R 2a C 1 ~C 6 Alkyl or -(CH 2 ) 0~3 -C 3 ~C 12 is cycloalkyl; R N2C 3 ~C 12 cycloalkyl, 3- to 12-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, where C 3 ~C 12 Cycloalkyl, 3- to 12-membered heterocycloalkyl, or 5- to 10-membered heteroaryl can be one or more R N2a and Each R N2a are independently halogen, cyano, -OH, C 1 ~C 6 Alkyl, C 3 ~C 12 Cycloalkyl, -C(=O)O(C 1 ~C 6 alkyl), where C 1 ~C 6 The alkyl is selected from one or more R N2ab and Each R N2ab independently -C(=O)O(C 1 ~C 6 alkyl), The compound of embodiment 1. Aspect 3.A 2 is S and A 3 CR 2 And A 4 CR 2 or A 2 CR 2 And A 3 CR 2 And A 4 is S; or A 2 is N and A 3 NR 2a And A 4 CR 2 or A 2 is O and A 3 CR 2 And A 4 CR 2 or A 2 NR 2a And A3 is N and A 4 CR 2 or A 2 is N and A 3 CR 2 And A 4 NR 2a or A 2 CR 2 And A 3 is N and A 4 NR 2a or A 2 CR 2 And A 3 NR 2a And A 4 is N; or A 2 CR 2 And A 3 CR 2 And A 4 is O, A compound of embodiment 1 or embodiment 2. Aspect 4.R 2 are independently H, halogen, cyano, -NH 2 , 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 3 ~C 12 cycloalkyl, where C 1 ~C 6 Alkyl and -NH(C 1 ~C 6 alkyl) is one or more R 2S The compound of any one of the preceding embodiments, optionally substituted with Aspect 5.R 2 are independently H, halogen (e.g., chlorine or bromine), cyano, -NH 2 , C 1 ~C6 Alkyl (e.g., methyl, ethyl, or propyl), -O(C 1 ~C 6 alkyl) (e.g., -O-methyl or -O-ethyl), -NH(C 1 ~C 6 alkyl) (e.g., -NH-methyl, -NH-CD 3 , -NH-ethyl, or -NH-isopropyl), -N(C 1 ~C 6 Alkyl) 2 (e.g., (-N(Me)(Et)), C 3 ~C 12 cycloalkyl (e.g., cyclopropyl), where C 1 ~C 6 Alkyl and -NH(C 1 ~C 6 alkyl) is one or more R 2S (For example, -CH 2 -CF 3 , -NHCH 2 CHF 2 , -CH 2 -O-Methyl, -NHCH 2 CH 2 OMe, or -CH 2 -NH 2 4. The compound of any one of the preceding embodiments, optionally substituted with Aspect 6.R 2 are independently H, chlorine, bromine, cyano, -NH 2 , methyl, ethyl, propyl, -O-methyl, -O-ethyl, -NH-methyl, -NH-CD 3 , -NH-ethyl, -NH-isopropyl, -N(Me)(Et), cyclopropyl, -CH 2 -CF 3 , -NHCH 2 CHF 2 , -CH 2 -O-Methyl, -NHCH 2 CH 2 OMe, or -CH 2 -NH 2 The compound of any one of embodiments 1-4, wherein Aspect 7. Each R 2a C 1~C 6 Alkyl or -(CH 2 ) 0~3 -C 3 ~C 12 The compound of any one of the preceding embodiments, wherein the compound is cycloalkyl. Aspect 8. Each R 2a C 1 ~C 6 Alkyl (e.g., methyl, ethyl, isopropyl) or -(CH 2 ) 0~3 -C 3 ~C 12 The compound of any one of the embodiments 1-6, which is cycloalkyl (eg, cyclopropyl or cyclobutyl). Aspect 9. Each R 2a The compound of any one of embodiments 1-6, wherein is independently methyl, ethyl, isopropyl, cyclopropyl, or cyclobutyl. Aspect 10.R 1 C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, or C 3 ~C 7 cycloalkyl, where C 1 ~C 6 The alkyl is selected from one or more R 1S The compound of any one of the preceding embodiments, optionally substituted with Aspect 11.R 1 C 1 ~C 6 Alkyl (e.g., methyl, ethyl, or isopropyl), C 2 ~C 6 Alkenyl (e.g., isopropenyl), C 3 ~C 7 cycloalkyl (e.g., cyclopropyl) or C 6 Alkyl is one or more R 1S The compound of any one of embodiments 1-9, optionally substituted with (eg, fluoromethyl). Aspect 12.R 1The compound of any one of embodiments 1-9, wherein is methyl, ethyl, isopropyl, isopropenyl, cyclopropyl, or fluoromethyl. Aspect 13. Both R a is H or two R a together with the atoms to which they are bonded, C 3 ~C 12 The compound of any one of the preceding embodiments, which forms a cycloalkyl. Aspect 14. Both R a is H or two R a together with the atoms to which they are bonded, C 3 ~C 7 The compound of any one of embodiments 1 to 12, which forms a cycloalkyl. Aspect 15. Both R a is H or two R a together with the atoms to which they are bonded, C 3 ~C 6 The compound of any one of embodiments 1 to 12, which forms a cycloalkyl. Aspect 16. Both R a is H or two R a The compound of any one of embodiments 1-12, wherein together with the atom to which they are attached form a cyclopropyl. Aspect 17.R N2 But, C 3 ~C 12 cycloalkyl (e.g., cyclobutyl), 3- to 12-membered heterocycloalkyl (e.g., piperidinyl, octahydroindolizin-8-yl, or oxaspiro[3.3]heptan-6-yl), or 5- to 10-membered heteroaryl (e.g., oxazolyl, pyrimidinyl, or triazolylpyridinyl), where C 3 ~C 12 Cycloalkyl, 3- to 12-membered heterocycloalkyl, or 5- to 10-membered heteroaryl is selected from one or more R N2a The compound of any one of the preceding embodiments, optionally substituted with Aspect 18.R N2is cyclobutyl, piperidinyl, octahydroindolizin-8-yl, oxaspiro[3.3]heptan-6-yl), oxazolyl, pyrimidinyl, or triazolylpyridinyl, each of which is selected from one or more of R N2a The compound of any one of embodiments 1-16, optionally substituted with Aspect 19.R N2a are independently halogen (e.g., F or Cl), cyano, -OH, C 1 ~C 6 Alkyl (e.g., methyl), C 3 ~C 12 Cycloalkyl (e.g., cyclopropyl or cyclobutyl), -C(=O)O(C 1 ~C 6 alkyl) (e.g., -COO-ethyl), where C 1 ~C 6 Alkyl (e.g., methyl) can be present in one or more R N2ab (e.g., -C(=O)O(C 1 ~C 6 alkyl), particularly -C(=O)O(ethyl), according to any one of the preceding embodiments. Embodiment 20. A compound of formula (III-a), (III-b), (III-c), (III-d), (III-e), (III-f), or (III-g): The compound of any one of the preceding embodiments, which is a compound of TIFF2025504374000034.tif127153 or a prodrug, solvate, or pharma- ceutically acceptable salt thereof. Embodiment 21. The compound of any one of embodiments 1-19, which is a compound of formula (III-b), formula (III-d), or formula (III-e). Aspect 22. The compound of any one of aspects 1 to 19, which is a compound of formula (III-e). Embodiment 23. The compound of any one of the preceding embodiments, selected from the compounds set forth in Table 1, and prodrugs and pharma- ceutically acceptable salts thereof. Aspect 24. A compound which is an isotopic derivative of the compound of any one of the preceding aspects. Aspect 25. A method for preparing a compound of formula (III) of any one of the preceding embodiments, comprising: TIFF2025504374000035.tif104162. Embodiment 26. A pharmaceutical composition comprising a compound of any one of embodiments 1 to 24 and a pharma- ceutically acceptable diluent or carrier. 27. A method for inhibiting inflammasome activity, comprising: A method comprising contacting a cell with an effective amount of a compound of any one of embodiments 1-24, wherein optionally, the inflammasome is the NLRP3 inflammasome, and the activity is in vitro or in vivo. Embodiment 28. A method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of any one of embodiments 1 to 24 or a pharmaceutical composition of embodiment 26. 29. Optionally, the inflammasome is the NLRP3 inflammasome, and the inflammasome activity is in vitro or in vivo. A compound of any one of embodiments 1 to 24 or a pharmaceutical composition of embodiment 26 for use in inhibiting inflammasome activity. Embodiment 30. A compound of any one of embodiments 1 to 24 or a pharmaceutical composition of embodiment 26 for use in treating or preventing a disease or disorder. 31. Optionally, the inflammasome is the NLRP3 inflammasome, and the inflammasome activity is in vitro or in vivo. Use of a compound according to any one of embodiments 1 to 24 in the manufacture of a medicament for inhibiting inflammasome activity. Embodiment 32. Use of a compound according to any one of embodiments 1 to 24 in the manufacture of a medicament for treating or preventing a disease or disorder. 33. The disease or disorder is associated with inflammasome activity, and optionally the disease or disorder is a disease or disorder involving inflammasome activity; The method, compound for use, pharmaceutical composition, or use of any one of embodiments 27 to 32. Embodiment 34. The method, compound for use, pharmaceutical composition, or use of any one of embodiments 27 to 32, wherein the disease or disorder is an inflammatory disorder, an autoinflammatory disorder, an autoimmune disorder, a neurodegenerative disease, or cancer. Embodiment 35. The method, compound for use, pharmaceutical composition, or use of any one of embodiments 27-34, 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 autoinflammatory syndromes (CAPS; e.g., familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurological, cutaneous, and articular (CINCA) syndrome / neonatal-onset multisystem inflammatory disease (NOMID)), familial Mediterranean fever (FMF), nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), gout, rheumatoid arthritis, osteoarthritis, Crohn's disease, chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD), fibrosis, obesity, type 2 diabetes, multiple sclerosis, skin diseases (e.g., acne), and neuroinflammation occurring in protein misfolding diseases (e.g., prion diseases). Embodiment 36. The method, compound for use, pharmaceutical composition, or use of any one of embodiments 27 to 34, wherein the disease or disorder is a neurodegenerative disease; optionally, the disease or disorder is Parkinson's disease or Alzheimer's disease. Embodiment 37. The method, compound for use, pharmaceutical composition, or use of any one of embodiments 27 to 34, wherein the disease or disorder is cancer; and optionally, the cancer is metastatic cancer, brain tumor, gastrointestinal cancer, skin cancer, non-small cell lung cancer, head and neck squamous cell carcinoma, or colorectal adenocarcinoma. Embodiment 38. The method, compound for use, pharmaceutical composition, or use of any one of embodiments 27 to 34, wherein the disease or disorder is an inflammatory disease. Embodiment 39. The method, compound for use, pharmaceutical composition, or use of embodiment 38, wherein the inflammatory disease is associated with an infectious disease. Embodiment 40. The method, compound for use, pharmaceutical composition, or use of embodiment 39, wherein the infectious disease is a viral infection. Embodiment 41. The method, compound for use, pharmaceutical composition, or use of embodiment 40, wherein the viral infection is caused by a single-stranded RNA virus. Embodiment 42. The method, compound for use, pharmaceutical composition, or use of embodiment 41, wherein the single-stranded RNA virus is a coronavirus. Embodiment 43. The method, compound for use, pharmaceutical composition, or use of embodiment 42, wherein the coronavirus is severe acute respiratory syndrome coronavirus 2 (SARS-CoV 2). Embodiment 44. The method, compound for use, pharmaceutical composition, or use of embodiment 38, wherein the inflammatory disease is associated with infection with SARS-CoV 2, which causes novel coronavirus disease 2019 (COVID-19). Embodiment 45. The method, compound for use, pharmaceutical composition, or use of embodiment 38, wherein the inflammatory disease comprises cytokine release syndrome (CRS). Embodiment 46. The method, compound for use, pharmaceutical composition, or use of embodiment 45, wherein CRS is associated with COVID-19. Embodiment 47. The method, compound for use, pharmaceutical composition, or use of embodiment 45, wherein CRS is associated with adoptive cell therapy. Embodiment 48. The method, compound for use, pharmaceutical composition, or use of embodiment 47, wherein the adoptive cell therapy comprises chimeric antigen receptor T cell (CAR-T) therapy. EXAMPLES

[0654] For illustrative purposes, salts of the compound of formula (III) are synthesized and tested in the examples.It is understood that neutral compounds of formula (III) can be similarly synthesized and tested using the exemplary procedures described in the examples.Furthermore, it is understood that salts of the compound of formula (III) (e.g., sodium salts) can be converted to corresponding neutral compounds using techniques common in the art (e.g., pH adjustment and, optionally, extraction (e.g., into aqueous phase)).

[0655] Compound synthesis Compounds of formula (III) can be prepared using the methods detailed herein. Those skilled in the art can envision alternative synthetic routes using different starting materials and reagents to prepare and further modify the disclosed compounds of formula (III). For illustrative purposes, several salts of compounds of formula (III) are synthesized and tested in the examples. It is understood that neutral compounds of formula (III) can be similarly synthesized and tested using the exemplary procedures described in the examples. Furthermore, it is understood that salts of compounds of formula (III) (e.g., hydrochloride salts) can be converted to corresponding neutral compounds using techniques common in the art (e.g., pH adjustment and, optionally, extraction (e.g., into aqueous phase)).

[0656] 1 H, 13 C and 19 F nuclear magnetic resonance (NMR) spectra were recorded at 400 MHz or 300 MHz as indicated, and at 300.3 K unless otherwise noted; chemical shifts (δ) are reported in parts per million (ppm) relative to the residual solvent peak, and multiplicities are reported with associated coupling constants (J) where applicable. Spectra were recorded using Bruker or Varian instruments with 8, 16, 32 or 64 scans.

[0657] LC-MS chromatograms and spectra were recorded using an Agilent 1200 or Shimadzu LC-20 AD&MS 2020 instrument using C-18 columns such as Luna-C18 2.0×30 mm or Xbridge Shield RPC18 2.1×50 mm. Injection volumes ranged from 0.7 to 8.0 μL, and flow rates were typically 0.8 or 1.2 mL / min. Detection methods were diode array (DAD) or evaporative light scattering (ELSD) or positive ion electrospray ionization. MS range was 100–1000 Da. Solvents were gradients of water and acetonitrile, both containing modifiers such as trifluoroacetic acid or ammonium carbonate (typically 0.01–0.04%).

[0658] UPLC-MS analysis was performed on 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 performed using an Acquity UPLC PDA detector (scanning from 210 to 400 nm), while mass detection was achieved using an Acquity QDa detector (mass scan from 100 to 1250 Da; positive and negative modes simultaneously) and ELS detection was achieved using an Acquity UPLC ELS detector. Analytes were separated using a Waters Acquity UPLC BEH C18 column (2.1 × 50 mm, 1.7 mm).

[0659] 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 before analysis. All solvents, including formic acid and 36% ammonia solution, were purchased as HPLC grade. The solvent was a gradient of water and acetonitrile, both containing modifiers such as formic acid or ammonium (typically 0.01-0.04%).

[0660] Abbreviation Ac Acetate ACN, MeCN Acetonitrile AcOH Acetic acid CAN Ammonium Cerium Nitrate CDCl 3 Chloroform-d DCM Dichloromethane DIPEA N,N-Diisopropylethylamine DME Dimethyl Ether DMEDA 1,2-Dimethylethylenediamine DMF N,N-Dimethylformamide DMSO-d 6 Dimethylsulfoxide-d6 dppf 1,1'-bis(diphenylphosphino)ferrocene dtbbpy 4,4'-Di-tert-butyl-2,2'-bipyridine eq. equivalent weight ESI Electrospray Ionization EtOAc Ethyl acetate EtOH Ethanol FCC Flash Column Chromatography h time HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, azabenzotriazole tetramethyluronium hexafluorophosphate HPLC High Performance Liquid Chromatography LCMS Liquid Chromatography-Mass Spectrometry LiHMDS Lithium bis(trimethylsilyl)amide MeOH-d 4 Deuterated Methanol MeOH Methanol min n-BuLi n-Butyl lithium MTBE Methyl tert-butyl ether NMR nuclear magnetic resonance RM reaction mixture RP Reverse Phase rt room temperature s-Phos 2-Dicyclohexylphosphino-2',6'-dimethoxybiphenyl TBHP tert-butyl hydroperoxide TEA Triethylamine TFA Trifluoroacetic acid THF Tetrahydrofuran TMS Trimethylsilyl TTMSS Tris-(trimethylsilyl)silane, Y Yield

[0661] Schematic routes for the preparation of compounds of the present disclosure are depicted in Schemes 1-3.

[0662] Intermediate A1. (3R)-tert-Butyl 3-[(2-chloroacetyl)amino]piperidine-1-carboxylate TIFF2025504374000036.tif15128To a mixture of tert-butyl (3R)-3-aminopiperidine-1-carboxylate (10 g, 49.9 mmol) in THF (150 mL) at 25°C was added TEA (10.4 mL, 74.9 mmol). The solution was stirred for 30 min and then 2-chloroacetyl chloride (3.97 mL, 49.93 mmol) was added. The RM was stirred for 1 h, diluted with water (100 mL) and extracted with ethyl acetate (3 x 150 mL). The combined organic phase was washed with Na 2 SO 4 It was dried at 40° C., filtered, and the filtrate was concentrated under reduced pressure to give the title compound as a solid (Y=98%). TIFF2025504374000037.tif19160

[0663] Intermediate A2. 2-Chloro-N-[(3R)-1-cyclopropyl-3-piperidyl]acetamide TIFF2025504374000038.tif17163 Step 1. 2-Chloro-N-[(3R)-3-piperidyl]acetamide hydrochloride. (3R)-3-[(2-chloroacetyl)amino]piperidine-1-carboxylate tert-Butyl (1.5 g, 5.42 mmol) was stirred in 4N HCl in EtOAc (50 mL) at 25° C. for 1 h. The RM was concentrated in vacuo to give the title compound as a yellow solid (quantitative), which was used without purification.

[0664] Step 2. tert-Butyl (3R)-3-[(2-chloroacetyl)amino]piperidine-1-carboxylate. 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) was treated with AcOH (0.25 mL, 4.35 mmol) and NaBH 3CN (1.37 g, 21.8 mmol) was added. The reaction was stirred at 45° C. for 8 h. The reaction was run a total of three times and 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 phase was washed with brine (3×10 mL) and diluted with anhydrous Na 2 SO 4 Drying at 40° C., filtration and concentration in vacuo afforded the title compound as a yellow solid which was used in the next reaction without purification (5.4 g, crude).

[0665] Intermediate A3. 2-Chloro-N-[(3R)-1-methyl-3-piperidyl]acetamide TIFF2025504374000039.tif17128To a solution of (3R)-1-methylpiperidin-3-amine (1.0 g, 8.76 mmol) in DCM (10 mL) at 25 °C was added TEA (1.83 mL, 13.1 mmol) and 2-chloroacetyl chloride (836 μL, 10.5 mmol) dropwise. 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 resulting residue was purified by preparative HPLC (column: Phenomenex Luna C18, 80 × 40 mm, 3 μm; mobile phase: [water (0.04% HCl) to ACN]; B: 1 to 5%, 4 min). ACN was removed from the fractions under reduced pressure. The aqueous phase was washed with saturated aqueous Na 2 CO 3 The solution was basified to pH 8 with DCM (3×10 mL) and the solution was extracted with DCM (3×10 mL). The combined organic layers were washed with brine (10 mL) and diluted with Na 2 SO 4 Drying at rt and concentration afforded the title compound as a yellow oil. Y=60%.

[0666] Intermediate A4 TIFF2025504374000040.tif13162 Step 1. tert-Butyl N-[(3R)-1-cyclobutyl-3-piperidyl]carbamate. To a mixture of tert-butyl N-[(3R)-3-piperidyl]carbamate (100 g, 499 mmol) and cyclobutanone (48.5 mL, 649 mmol) in DCE (500 mL) at 25 °C was added AcOH (71.4 mL, 1.25 mol). After stirring for 30 min, NaBH(OAc) 3 (265 g, 1.25 mol) was added and the mixture was stirred at 25° C. for 1 h. Saturated aqueous Na 2 CO 3 (500 mL) was added and the resulting mixture was stirred for 5 min. The solution was extracted with DCM (3×300 mL). The combined organic phase was washed with brine (300 mL) and anhydrous Na 2 SO 4 It was dried at rt, filtered and concentrated in vacuo to give the title compound as a yellow solid. Y=95%.

[0667] Step 2. (3R)-1-Cyclobutylpiperidin-3-amine hydrochloride. tert-Butyl N-[(3R)-1-cyclobutyl-3-piperidyl]carbamate (120 g, 472 mmol) was stirred in 4N HCl (1 L) in EtOAc at 25° C. for 30 min. The reaction was concentrated in vacuo to give the title compound as an oil, which was used without further purification.

[0668] Step 3. 2-Chloro-N-[(3R)-1-cyclobutyl-3-piperidyl]acetamide. To a mixture of (3R)-1-cyclobutylpiperidin-3-amine hydrochloride (90 g, 1.42 mol) in THF (1 L) at 25° C. was added TEA (197 mL, 1.42 mol) and 2-chloroacetyl chloride (37.5 mL, 472 mmol). The RM was stirred at 25° C. for 1 h and then concentrated in vacuo. The residue was poured into water (300 mL) and the resulting mixture was extracted with ethyl acetate (3×300 mL). The combined organic phase was washed with brine (300 mL) and diluted with anhydrous Na 2 SO 4 It was dried at rt, filtered and concentrated in vacuo to give the title compound as a solid. Y=66%.

[0669] Intermediate B1. 2-Chloro-N-(5-fluoropyrimidin-4-yl)acetamide TIFF2025504374000041.tif16128N 2 CHCl at 25 °C 3 5-Fluoropyrimidin-4-amine (1.0 g, 8.84 mmol) in (10 mL) and Et 3 N (1.84 mL, 13.2 mmol) and a solution of CHCl 3 A solution of 2-chloroacetyl chloride (773 μL, 9.72 mmol) in 1,2-dichloroethane (4 mL) was added. The mixture was stirred at 25° C. for 4 h. Water (15 mL) was added and the resulting mixture was extracted with DCM (3×15 mL). The combined organic layers were washed with brine (15 mL) and diluted with Na 2 SO 4 The mixture was dried over 1000 ml of FCC (SiO 2 , 50% EtOAc in petroleum ether) to afford the title compound as a yellow solid. Y=48%. TIFF2025504374000042.tif5140

[0670] Intermediate B2. 2-Chloro-N-(5-fluoropyrimidin-2-yl)acetamide TIFF2025504374000043.tif16128CHCl 3 To a solution of 5-fluoropyrimidin-2-amine (2.0 g, 17.7 mmol) in RM (20 mL) was added TEA (3.69 mL, 26.5 mmol). The RM was stirred at 0° C. for 30 min and then CHCl 3 A solution of 2-chloroacetyl chloride (2.11 mL, 26.5 mmol) in 1,2-dichloroethane (8 mL) was added. The mixture was stirred at 25° C. for 4 h, diluted with water (20 mL) and extracted with DCM (20 mL×3). The combined organic layers were washed with brine (20 mL) and diluted with Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered and concentrated under reduced pressure. 2 , 100% EtOAc) to afford the title compound as a white solid. Y=54%. TIFF2025504374000044.tif5128

[0671] Intermediate B3. Chloro-N-pyrimidin-2-yl-acetamide TIFF2025504374000045.tif1512To a solution of pyrimidin-2-amine (50 g, 526 mmol) in DCM (500 mL) at 80° C. was added TEA (110 mL, 789 mmol) and a solution of 2-chloroacetyl chloride (62.7 mL, 789 mmol) in DCM (50 mL). The RM was stirred at 25° C. for 2 h, then diluted with water (500 mL) and DCM (500 mL), filtered and the solid dried under vacuum to give the title compound as a grey solid. Y=61%. TIFF2025504374000046.tif12128

[0672] Intermediate B4. 2-Chloro-N-(5-chloropyrimidin-2-yl)acetamide TIFF2025504374000047.tif17128N 2 CHCl below 0 °C 3 To a stirred solution of 5-chloropyrimidin-2-amine (10.0 g, 77.2 mmol) in Et 3 N (16.1 mL, 115 mmol) followed by CHCl at 0 °C 3 A solution of 2-chloroacetyl chloride (116 mmol, 9.2 mL) in 10 mL of H 2 O was added. The mixture was stirred at 25° C. for 12 h and then H 2 The mixture was diluted with 2×O (150 mL) and the resulting mixture was extracted with DCM (3×150 mL). The combined organic layers were washed with brine (150 mL) and 2 SO 4 The crude material was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=1 / 1) to give the title compound as a yellow solid, Y=50%. TIFF2025504374000048.tif5128

[0673] Intermediate B5. 2-Chloro-N-(5-methylpyrimidin-2-yl)acetamide TIFF2025504374000049.tif16128CHCl 3 To a solution of 5-methylpyrimidin-2-amine (0.30 g, 2.75 mmol) in 1 mL of N 2 Et below 0°C 3 N (572 μL, 4.11 mmol) was added, followed by CHCl at 0 °C. 3 The mixture was stirred at 25° C. for 12 h and then treated with a solution of 2-chloroacetyl chloride (328 μL, 4.12 mmol) in 1 mL of H 2 The mixture was diluted with 2×O (5 mL) and extracted with DCM (3×5 mL). The combined organic layers were washed with brine (5 mL) and 2 SO 4 The crude material was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=1 / 1) to give the title compound as a yellow solid, Y=39%.

[0674] Intermediate B6. 2-Chloro-N-((1s,3s)-3-hydroxy-3-methylcyclobutyl)acetamide TIFF2025504374000050.tif15128CHCl 3 To a solution of cis-3-amino-1-methyl-cyclobutanol (1.4 g, 13.8 mmol) in 100 mL of 10 ... 3 A solution of 2-chloroacetyl chloride (1.21 mL, 15.2 mmol) in hexanes (30 mL) was added. The mixture was stirred at 25° C. for 4 h. The reaction mixture was concentrated under reduced pressure. The crude material was analyzed by preparative TLC (SiO 2 , 100% ethyl acetate) to afford the title compound as a white solid, Y=45%. TIFF2025504374000051.tif12165

[0675] Intermediate B7. 2-Chloro-N-(oxazol-2-yl)acetamide TIFF2025504374000052.tif14128To a mixture of oxazol-2-amine (9.5 g, 113 mmol) in DCM (100 mL) was added TEA (226 mmol, 31 mL) and 2-chloroacetyl chloride (9.89 mL, 124 mmol) at 0° C. The mixture was stirred at 25° C. for 2 h. The reaction mixture was stirred at H 2 The crude material was purified by column chromatography (SiO 2 , 0-100% ethyl acetate in petroleum ether) to afford the title compound as a yellow solid, Y=22%. TIFF2025504374000053.tif5149

[0676] Intermediate C1. 4-Isopropyl-1-methyl-1,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one TIFF2025504374000054.tif59147Step 1. Methyl 5-methyl-2,4-dioxo-hexanoate. A solution of dimethyl oxalate (5.0 g, 42.3 mmol) and 3-methylbutan-2-one (4.98 mL, 46.6 mmol) in toluene (50 mL) was diluted with KO in THF (20 mL). t A solution of Bu (5.70 g, 50.8 mmol) was added dropwise. The mixture was stirred at 25° C. for 2 h. Water (50 mL) was added and the resulting mixture was extracted with ethyl acetate (3×35 mL). The combined organic layers were washed with brine (35 mL) and diluted with Na 2 SO 4 It was dried at rt, filtered and concentrated under reduced pressure to give the title compound as a white solid. Y=71%.

[0677] Step 2. (3Z)-3-(Dimethylaminomethylene)-5-methyl-2,4-dioxo-hexanoate methyl ester. A mixture of 1,1-dimethoxy-N,N-dimethyl-methanamine (10.4 g, 11.6 mL, 87.1 mmol) and 5-methyl-2,4-dioxo-hexanoate methyl ester (15 g, 87.1 mmol) was stirred at 25° C. for 6 h. Water (125 mL) was added and the resulting mixture was extracted with DCM (125 mL×3). The combined organic layers were washed with brine (100 mL) and concentrated to give a crude product. 2 SO 4 It was dried at 40° C., filtered and concentrated under reduced pressure to give the title compound as a yellow liquid. Y=79%.

[0678] Step 3. Methyl 2-methyl-4-(2-methylpropanoyl)pyrazole-3-carboxylate. To a solution of methyl (3Z)-3-(dimethylaminomethylene)-5-methyl-2,4-dioxohexanoate (3.0 g, 13.2 mmol) in EtOH (80 mL) at 25° C. was added acetic acid (1.3 mL, 22.7 mmol) and a solution of methylhydrazine (40% in water, 3.13 mL) in EtOH (80 mL). The mixture was heated to 60° C. and stirred for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue which was suspended in water (50 mL) and extracted with EtOAc (3×60 mL). The combined organic layers were washed with brine (60 mL) and diluted with Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered, and concentrated under reduced pressure to give a residue. 2 , petroleum ether:EtOAc, 25:1 to 20:1) to give the title compound as a yellow solid. Y=22%. TIFF2025504374000055.tif19160

[0679] Step 4. 4-Isopropyl-1-methyl-6H-pyrazolo[3,4-d]pyridazin-7-one. To a solution of methyl 2-methyl-4-(2-methylpropanoyl)pyrazole-3-carboxylate (300 mg, 1.43 mmol) in EtOH (3 mL) was added hydrazine hydrate (1.42 mL, 28.5 mmol) at 25° C. The mixture was stirred at 80° C. for 2 h. The reaction mixture was filtered and the filter cake was dried under vacuum to give the title compound as a white solid. Y=80%. TIFF2025504374000056.tif12147

[0680] Intermediate C2. 7-Isopropyl-1-methyl-5H-pyrazolo[3,4-d]pyridazin-4-one TIFF2025504374000057.tif23158 Step 1. Ethyl 1-methyl-5-(2-methylpropanoyl)pyrazole-4-carboxylate. A solution of ethyl 1-methylpyrazole-4-carboxylate (1.0 g, 6.49 mmol) in THF (10 mL) at -78 °C was added with N 2 A solution of LDA (2M in THF, 4.86 mL, 9.72 mmol) was added under atmosphere. After stirring for 30 min, a solution of N-methoxy-N,2-dimethyl-propanamide (1.02 g, 7.78 mmol) in THF (10 mL) was added at −78° C. The resulting mixture was stirred at −78° C. for 30 min. 2 The mixture was stirred at 25° C. for 30 min under agitation. 4 Aqueous Cl (5 mL) and water (10 mL) were added and the resulting mixture was extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (3×10 mL) and Na 2 SO 4 The mixture was dried over 1000 ml of FCC (SiO 2 Purification by elution with 10% EtOAc in petroleum ether (10-25% EtOAc) afforded the title compound as a colorless oil. Y=25%. TIFF2025504374000058.tif19159

[0681] Step 2. 7-Isopropyl-1-methyl-5H-pyrazolo[3,4-d]pyridazin-4-one. To a solution of ethyl 1-methyl-5-(2-methylpropanoyl)pyrazole-4-carboxylate (150 mg, 669 μmol) in EtOH (1 mL) was added hydrazine hydrate (331 μL, 6.69 mmol) at 25° C. The mixture was stirred at 80° C. for 12 h. The reaction mixture was filtered and dried under reduced pressure to give the title compound as a white solid. Y=86%. TIFF2025504374000059.tif12130

[0682] Intermediate C3. 7-Isopropyl-2-methyl-5H-pyrazolo[3,4-d]pyridazin-4-one TIFF2025504374000060.tif22165 Step 1. 2-Methyl-1-(1-methylpyrazol-3-yl)propan-1-one. To a 1M solution of isopropylmagnesium chloride (6.25 mL, 6.25 mmol) in THF (13 mL) at 0° C. was added a solution of 3-iodo-1-methylpyrazole (1.3 g, 6.25 mmol) in THF (5 mL). After stirring for 1 h at 25° C., a solution of N-methoxy-N,2-dimethyl-propanamide (574 mg, 4.38 mmol) in THF (3 mL) was added and the RM was stirred at 25° C. for 12 h. Saturated NH 4 Aqueous Cl (5 mL) was added and the resulting mixture was extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (3×10 mL) and Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered, and concentrated under reduced pressure to give a residue. 2 , 25% EtOAc in petroleum ether) to afford the title compound as a red solid. Y=63%. TIFF2025504374000061.tif20159

[0683] Step 2. 1-(4-iodo-1-methyl-pyrazol-3-yl)-2-methyl-propan-1-one. To a solution of 2-methyl-1-(1-methylpyrazol-3-yl)propan-1-one (550 mg, 3.61 mmol) in AcOH (5.7 mL) at 25° C. was added N-iodosuccinimide (1.22 g, 5.42 mmol). The mixture was stirred at 25° C. for 12 h, diluted with water (6 mL) and extracted with EtOAc (3×6 mL). The combined organic layers were washed with brine (3×6 mL) and concentrated to 100° C. with 100% NaCl. 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered, and concentrated under reduced pressure. 2 Purification by elution with 10-25% EtOAc in petroleum ether) afforded the title compound as a red solid. Y=85%. TIFF2025504374000062.tif12128

[0684] Step 3. Methyl 1-methyl-3-(2-methylpropanoyl)pyrazole-4-carboxylate. A solution of 1-(4-iodo-1-methyl-pyrazol-3-yl)-2-methyl-propan-1-one (0.40 g, 1.44 mmol) in MeOH (12.8 mL) at 25 °C was treated with TEA (1.0 mL, 7.19 mmol) and PdCl 2 (dppf) (105 mg, 144 μmol) was added. The suspension was degassed and flushed with CO (gas) three times. The mixture was stirred at 70° C. under CO (gas, 50 Psi) for 12 h. The reaction mixture was filtered through a pad of Celite. The filtrate was diluted with water (5 mL) and extracted with EtOAc (3×5 mL). The combined organic layers were washed with brine (3×5 mL) and diluted with Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered, and concentrated under reduced pressure. 2 , 10-50% EtOAc in petroleum ether) to afford the title compound as a yellow oil. TIFF2025504374000063.tif12140

[0685] Step 4. 7-Isopropyl-2-methyl-5H-pyrazolo[3,4-d]pyridazin-4-one. To a solution of methyl 1-methyl-3-(2-methylpropanoyl)pyrazole-4-carboxylate (150 mg, 714 μmol) in EtOH (1.5 mL) was added hydrazine hydrate (354 μL, 7.14 mmol) at 25° C. The resulting mixture was stirred at 80° C. for 12 h. The RM was concentrated under reduced pressure to give the title compound as a white solid. Y=88%. TIFF2025504374000064.tif12128

[0686] Intermediate C4. 2-(cyclopropylmethyl)-7-isopropyl-5H-pyrazolo[3,4-d]pyridazin-4-one TIFF2025504374000065.tif57158 Step 1. 1-(Cyclopropylmethyl)-3-iodo-pyrazole. To a solution of 3-iodo-1H-pyrazole (4.0 g, 20.6 mmol) in DMF (40 mL) at 25 °C was added bromomethylcyclopropane (1.97 mL, 20.6 mmol) and K 2 CO 3 (8.55 g, 61.9 mmol) was added. The RM was stirred for 12 h, diluted with water (40 mL) and extracted with EtOAc (3×40 mL). The combined organic layers were washed with brine (3×40 mL) and diluted with Na 2 SO 4 The mixture was dried over 1000 ml of FCC (SiO 2 Purification by elution with 10-20% EtOAc in petroleum ether) afforded the title compound as a yellow oil. Y=92%. TIFF2025504374000066.tif12159

[0687] Step 2. 1-[1-(cyclopropylmethyl)pyrazol-3-yl]-2-methyl-propan-1-one. To a solution of 1M isopropylmagnesium chloride lithium chloride (8.06 mL, 8.06 mmol) in THF (20 mL) was added a solution of 1-(cyclopropylmethyl)-3-iodo-pyrazole (2.0 g, 8.06 mmol) in THF (8 mL) at 0° C. The mixture was stirred at 25° C. for 1 h, then a solution of N-methoxy-N-(2-dimethyl)-propanamide (740 mg, 5.64 mmol) in THF (3 mL) was added at 25° C. The RM was stirred at 25° C. for 12 h. The RM was diluted with saturated NH 4 It was quenched with aqueous Cl (10 mL), diluted with water (20 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (3×20 mL) and diluted with Na 2 SO 4 The mixture was dried over 1000 ml of FCC (SiO 2 Purification by elution with 10-25% EtOAc in petroleum ether) afforded the title compound as a yellow oil. Y=65%. TIFF2025504374000067.tif20159

[0688] Step 3. 1-[1-(cyclopropylmethyl)-4-iodo-pyrazol-3-yl]-2-methyl-propan-1-one. To a solution of 1-[1-(cyclopropylmethyl)pyrazol-3-yl]-2-methyl-propan-1-one (500 mg, 2.60 mmol) in AcOH (5 mL) at 25° C. was added N-iodosuccinimide (878 mg, 3.90 mmol). The RM was stirred for 12 h. The reaction mixture was diluted with water (6 mL) and extracted with EtOAc (3×6 mL). The combined organic layers were washed with brine (3×6 mL) and diluted with Na 2 SO 4 The mixture was dried over 1000 ml of FCC (SiO 2 Purification by elution with 10-30% EtOAc in petroleum ether) afforded the title compound as a yellow solid. Y=60%. TIFF2025504374000068.tif12165

[0689] Step 4. Methyl 1-(cyclopropylmethyl)-3-(2-methylpropanoyl)pyrazole-4-carboxylate. A solution of 1-[1-(cyclopropylmethyl)-4-iodo-pyrazol-3-yl]-2-methyl-propan-1-one (420 mg, 1.32 mmol) in MeOH (5 mL) was treated with TEA (919 μL, 6.60 mmol) and PdCl at 25 °C. 2 (dppf) (96 mg, 132 μmol) was added. The suspension was degassed and flushed with CO (gas) three times. The mixture was stirred under CO (gas, 50 Psi) at 70 °C for 12 h. The reaction mixture was filtered through a pad of Celite. The filtrate was diluted with water (5 mL) and extracted with EtOAc (3 x 5 mL). The combined organic layers were washed with brine (3 x 5 mL) and diluted with Na 2 SO 4 The mixture was dried over 1000 ml of FCC (SiO 2 Purification by elution with 10% EtOAc in petroleum ether (10-50% EtOAc) afforded the title compound as a red oil. Y=88%. TIFF2025504374000069.tif19159

[0690] Step 5. 2-(cyclopropylmethyl)-7-isopropyl-5H-pyrazolo[3,4-d]pyridazin-4-one. To a solution of methyl 1-(cyclopropylmethyl)-3-(2-methylpropanoyl)pyrazole-4-carboxylate (290 mg, 1.16 mmol) in EtOH (1.5 mL) was added hydrazine hydrate (575 μL, 11.6 mmol) at 25° C. The resulting mixture was stirred at 80° C. for 12 hours. The reaction mixture was filtered and dried in vacuum to give the title compound as a white solid. Y=74%. TIFF2025504374000070.tif19159

[0691] Intermediate C5. 2-Ethyl-7-isopropyl-5H-pyrazolo[3,4-d]pyridazin-4-one TIFF2025504374000071.tif57158Step 1. 1-Ethyl-3-iodo-pyrazole. A solution of 3-iodo-1H-pyrazole (6.0 g, 30.9 mmol) in DMF (60 mL) was added with Cs2 CO 3 (30.2 g, 92.8 mmol) was added. The mixture was stirred at 25° C. for 10 min, then iodoethane (4.95 mL, 61.9 mmol) was added. The RM was stirred for 2 h, diluted with water (60 mL) and extracted with EtOAc (3×60 mL). The combined organic layers were washed with brine (3×60 mL) and diluted with Na 2 SO 4 The mixture was dried over 1000 ml of FCC (SiO 2 Purification by elution with 10-20% EtOAc in petroleum ether) afforded the title compound as a colorless oil. Y=41%. TIFF2025504374000072.tif12132

[0692] Step 2. 1-(1-Ethylpyrazol-3-yl)-2-methyl-propan-1-one. To a solution of 1M isopropylmagnesium chloride lithium chloride (8.33 mL, 8.33 mmol) in THF (20 mL) at 0° C. was added a solution of 1-ethyl-3-iodo-pyrazole (1.85 g, 8.33 mmol) in THF (7 mL) and the resulting mixture was stirred at 0° C. for 1 h. A solution of N-methoxy-N-(2-dimethyl)propanamide (765 mg, 5.83 mmol) in THF (10 mL) was added. RM was converted to N 2 The mixture was stirred at 25 °C for 12 h and then saturated aqueous NH 4 The mixture was quenched with Cl (5 mL) and water (20 mL). The mixture was extracted with EtOAc (3×20 mL) and the combined organic layers were washed with brine (3×20 mL) and diluted with Na 2 SO 4 The mixture was dried over 1000 ml of FCC (SiO 2 Purification by elution with 10-16% EtOAc in petroleum ether) afforded the title compound as a red solid. Y=72%. TIFF2025504374000073.tif12145

[0693] Step 3. 1-(1-Ethyl-4-iodo-pyrazol-3-yl)-2-methyl-propan-1-one. To a solution of 1-(1-ethylpyrazol-3-yl)-2-methyl-propan-1-one (900 mg, 5.41 mmol) in AcOH (9 mL) at 25° C. was added N-iodosuccinimide (1.83 g, 8.12 mmol). The RM was stirred at 25° C. for 12 h, diluted with water (10 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (3×10 mL) and concentrated to 100° C. with 10% NaCl. 2 SO 4 The mixture was dried over 1000 ml of FCC (SiO 2 Purification by elution with 10-25% EtOAc in petroleum ether) afforded the title compound as a yellow oil. Y=89%. TIFF2025504374000074.tif12137

[0694] Step 4. Methyl 1-ethyl-3-(2-methylpropanoyl)pyrazole-4-carboxylate. To a solution of 1-(1-ethyl-4-iodo-pyrazol-3-yl)-2-methyl-propan-1-one (1.4 g, 4.79 mmol) in MeOH (15 mL) at 25 °C was added TEA (3.34 mL, 24.0 mmol) and PdCl 2 (dppf) (351 mg, 479 μmol) was added. The suspension was degassed and flushed with CO (gas) three times. The mixture was stirred at 70° C. under CO (gas, 50 psi) for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was filtered through a pad of Celite, diluted with water (15 mL) and extracted with EtOAc (3×15 mL). The combined organic layers were washed with brine (3×15 mL) and diluted with Na 2 SO 4 The mixture was dried over 1000 ml of FCC (SiO 2 Purification by elution with 10% EtOAc in petroleum ether (10-50% EtOAc in petroleum ether) afforded the title compound as a red oil. Y=93%. TIFF2025504374000075.tif19159

[0695] Step 5. 2-Ethyl-7-isopropyl-5H-pyrazolo[3,4-d]pyridazin-4-one. To a solution of methyl 1-ethyl-3-(2-methylpropanoyl)pyrazole-4-carboxylate (1.0 g, 4.46 mmol) in EtOH (5 mL) at 25° C. was added hydrazine hydrate (2.28 g, 44.6 mmol). The resulting mixture was stirred at 80° C. for 12 h. The reaction mixture was filtered and the solid was dried under reduced pressure to give the title compound as a white solid. Y=87%. TIFF2025504374000076.tif19159

[0696] Intermediate C6. 2-(2-Ethyl-7-isopropyl-4-oxo-pyrazolo[3,4-d]pyridazin-5-yl)acetic acid TIFF2025504374000077.tif24162 Step 1. Ethyl 2-(2-ethyl-7-isopropyl-4-oxo-pyrazolo[3,4-d]pyridazin-5-yl)acetate. To a solution of ethyl 2-bromoacetate (121 μL, 1.09 mmol) in DMF (2 mL) at 25 °C, 2 CO 3 (302 mg, 2.18 mmol) and 2-ethyl-7-isopropyl-5H-pyrazolo[3,4-d]pyridazin-4-one (150 mg, 727 μmol) were added. The RM was stirred at 80° C. for 5 h, diluted with water (3 mL) and extracted with EtOAc (3×3 mL). The combined organic layers were washed with brine (3×3 mL) and diluted with Na 2 SO 4 The mixture was dried over 1000 ml of FCC (SiO 2 Purification by elution with 10% EtOAc in petroleum ether (10-100% EtOAc) afforded the title compound as a yellow oil. Y=80%. TIFF2025504374000078.tif20165

[0697] Step 2. 2-(2-Ethyl-7-isopropyl-4-oxo-pyrazolo[3,4-d]pyridazin-5-yl)acetic acid. A solution of 2-(2-ethyl-7-isopropyl-4-oxo-pyrazolo[3,4-d]pyridazin-5-yl)ethyl acetate (170 mg, 582 μmol) in THF (2 mL) and water (0.5 mL) at 25 °C was added with LiOH.H 2 2M HCl was added dropwise until the pH was 4-5. The resulting mixture was extracted with EtOAc (3×1 mL). The combined organic layers were washed with brine (3×1 mL) and diluted with NaCl. 2 SO 4 It was dried at rt, filtered and concentrated under reduced pressure to give the title compound as a white solid. Y=78%. TIFF2025504374000079.tif19159

[0698] Intermediate C7. 4-Isopropyl-2-methyl-2,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one TIFF2025504374000080.tif20164 Step 1. Methyl 3-(ethoxymethylene)-5-methyl-2,4-dioxohexanoate. Ac at 25°C 2 To a solution of methyl 5-methyl-2,4-dioxo-hexanoate (2.0 g, 11.6 mmol) in 2O (2.18 mL, 23.2 mmol) was added diethoxymethoxyethane (2.32 mL, 13.9 mmol). 2 The mixture was stirred at 120° C. for 4 h and then concentrated in vacuo to give the title compound as a brown oil. Y=quantitative.

[0699] Step 2. Methyl 4-isobutyryl-1-methyl-1H-pyrazole-3-carboxylate. To a solution of methyl 3-(ethoxymethylene)-5-methyl-2,4-dioxohexanoate (2.6 g, 11.4 mmol) in THF (30 mL) at 0° C. was added methylhydrazine (1.50 mL, 40% in THF, 11.4 mmol). RM was converted to N 2The mixture was stirred at 0 °C for 4 h under reduced pressure and then concentrated in vacuo. Preparative HPLC (column: Agela DuraShell C18, 250 × 70 mm, 10 μm; mobile phase: [water (10 mM NH 4 HCO 3 )~ACN]; B: 12~42%, 20 min) afforded the title compound as a white solid. Y=40%. TIFF2025504374000081.tif19159

[0700] Step 3. 4-Isopropyl-2-methyl-6H-pyrazolo[3,4-d]pyridazin-7-one. To a solution of methyl 4-isobutyryl-1-methyl-1H-pyrazole-3-carboxylate (300 mg, 1.43 mmol) in EtOH (3 mL) at 25° C. was added hydrazine hydrate (1.42 mL, 28.5 mmol). RM was converted to N 2 The mixture was stirred at 80° C. for 4 h and then concentrated in vacuo to give the title compound as a brown oil. Y=quantitative.

[0701] Intermediate C8. 2-Chloro-7-isopropyl-5H-thieno[2,3-d]pyridazin-4-one TIFF2025504374000082.tif27158 Step 1. 2-(2-Methylpropanoyl)thiophene-3-carboxylic acid. To a solution of thiophene-3-carboxylic acid (1.0 g, 7.80 mmol) in THF (10 mL) at 0 °C, add N 2 2M LDA in THF (8.59 mL, 17.18 mmol) was added dropwise with stirring under reduced pressure. The resulting mixture was stirred for 15 min. A solution of N-methoxy-N,2-dimethylpropanamide (1.13 g, 8.58 mmol) in THF (5 mL) was added dropwise at 0° C. The RM was stirred at 25° C. for 2 h. The mixture was adjusted to pH 4 with 2M HCl. The resulting mixture was extracted with EtOAc (3×10 mL). The combined organic phase was washed with brine (5 mL) and anhydrous Na 2 SO 4 It was dried at rt, filtered and concentrated in vacuo to give the title compound as a red solid. TIFF2025504374000083.tif12164

[0702] Step 2. 7-Isopropyl-5H-thieno[2,3-d]pyridazin-4-one. To a solution of 2-(2-methylpropanoyl)thiophene-3-carboxylic acid (650 mg, 3.28 mmol) in EtOH (8 mL) was added hydrazine hydrate (1.63 mL, 32.8 mmol) and the RM was stirred at 80° C. for 1 h. The mixture was concentrated under reduced pressure to give the title compound as a white solid. Y=71%.

[0703] Step 3. 2-Chloro-7-isopropyl-5H-thieno[2,3-d]pyridazin-4-one. To a solution of 7-isopropyl-5H-thieno[2,3-d]pyridazin-4-one (90 mg, 463 μmol) in DMF (1 mL) at 25° C. was added N-chlorosuccinimide (124 mg, 927 μmol). The RM was stirred at 25° C. for 1 h. Saturated aqueous Na 2 S 2 O 3 Solution (2 mL) was added and the mixture was stirred at 0° C. for 10 min. The mixture was extracted with ethyl acetate (3×2 mL). The combined organic phase was washed with brine (2 mL) and anhydrous Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered and concentrated in vacuo. 2 , 100% ethyl acetate) to afford the title compound as a white solid. Y=66%.

[0704] Intermediate C9. 2-Chloro-4-isopropyl-6H-thieno[2,3-d]pyridazin-7-one TIFF2025504374000084.tif23129 Step 1. 3-(2-Methylpropanoyl)thiophene-2-carboxylic acid. To a solution of 3-bromothiophene-2-carboxylic acid (1.6 g, 7.73 mmol) in THF (16 mL) at -78 °C was added n-BuLi (2.5 M, 6.18 mL, 15.5 mmol) and the resulting mixture was stirred for 0.5 h. N-Methoxy-N,2-dimethyl-propanamide (1.22 g, 9.27 mmol) was added to N 2 The reaction mixture was stirred at 25° C. for 1 h. The reaction mixture was diluted with saturated aqueous NH4 The mixture was quenched by the addition of 10 mL of Cl and then diluted with 1M HCl (8 mL). The mixture was extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (15 mL) and Na 2 SO 4 The mixture was dried over 1000 ml of FCC (SiO 2 Purification by elution with 50-100% EtOAc in petroleum ether) afforded the title compound as a yellow solid. Y=78%.

[0705] Step 2. 4-Isopropyl-6H-thieno[2,3-d]pyridazin-7-one. To a solution of 3-(2-methylpropanoyl)thiophene-2-carboxylic acid (500 mg, 2.52 mmol) in EtOH (6 mL) at 25° C. was added hydrazine hydrate (2.58 g, 50.4 mmol). The solution was stirred at 80° C. for 12 h. The reaction was filtered and the filter cake was dried in vacuum to give the title compound as a yellow solid. Y=80%. TIFF2025504374000085.tif12128

[0706] Step 3. 2-Chloro-4-isopropyl-6H-thieno[2,3-d]pyridazin-7-one. To a solution of 4-isopropyl-6H-thieno[2,3-d]pyridazin-7-one (180 mg, 927 μmol) in THF (3 mL) at −78° C. was added LDA (2 M in THF, 1.16 mL, 2.32 mmol). After 30 min, hexachloroethane (105 μL, 927 μmol) was added at −25° C. The RM was stirred at 0° C. for 2 h. The reaction mixture was quenched by the addition of water (2 mL) at 0° C. and extracted with EtOAc (3×2 mL). The combined organic layers were washed with brine (2×2 mL) and diluted with Na 2 SO 4 It was dried at 40° C., filtered and concentrated under reduced pressure. Purification by FCC (20-50% EtOAc in petroleum ether) afforded the title compound as a white solid. Y=71%.

[0707] Intermediate C10. 2-Ethyl-7-isopropyl-5H-thieno[2,3-d]pyridazin-4-one TIFF2025504374000086.tif20128 Step 1. 5-Ethyl-2-(2-methylpropanoyl)thiophene-3-carboxylic acid. To a solution of 5-ethylthiophene-3-carboxylic acid (500 mg, 3.20 mmol) in THF (6 mL) at -78 °C was added N 2 LDA (2M in THF, 3.20 mL, 6.40 mmol) was added under reduced pressure and the mixture was stirred for 1 h. N-Methoxy-N,2-dimethylpropanamide (420 mg, 3.20 mmol) was added. After stirring for 2 h, water (5 mL) was added and the resulting mixture was extracted with ethyl acetate (3×5 mL). The combined organic layers were washed with brine (5 mL) and anhydrous Na 2 SO 4 The mixture was dried over 1000 ml of FCC (SiO 2 , 50% EtOAc in petroleum ether) to give the title compound as a white solid. Y=73%. TIFF2025504374000087.tif19160

[0708] Step 2. 2-Ethyl-7-isopropyl-5H-thieno[2,3-d]pyridazin-4-one. To a solution of 5-ethyl-2-(2-methylpropanoyl)thiophene-3-carboxylic acid (230 mg, 1.02 mmol) in EtOH (2 mL) at 25° C. was added hydrazine hydrate (1.04 g, 20.3 mmol) and the mixture was stirred at 80° C. for 2 h. The solution was concentrated under vacuum. The residue was triturated with petroleum ether at 25° C. for 5 min and the solid was collected by filtration and dried in vacuum to give the title compound as a white solid. Y=31%.

[0709] Intermediate C11. 1-Methyl-7-(prop-1-en-2-yl)-1H,4H,5H-imidazo[4,5-d]pyridazin-4-one TIFF2025504374000088.tif24168Step 1. Diethyl 1-methylimidazole-4,5-dicarboxylate. To a solution of diethyl 1H-imidazole-4,5-dicarboxylate (10 g, 47.1 mmol) in DMF (150 mL) at 25 °C, add 2 CO 3(13.0 g, 94.3 mmol) and CH 3 I (2.93 mL, 47.1 mmol) was added. The RM was stirred for 2 h. Water (50 mL) was added and the resulting mixture was extracted with EtOAc (3×50 mL). The combined organic phase was washed with brine (50 mL) and anhydrous Na 2 SO 4 It was dried at rt, filtered and concentrated in vacuo to give the title compound as a brown oil. TIFF2025504374000089.tif12136

[0710] Step 2. 3-Methyl-5,6-dihydroimidazo[4,5-d]pyridazine-4,7-dione. To a solution of diethyl 1-methylimidazole-4,5-dicarboxylate (10 g, 44.2 mmol) in EtOH (250 mL) at 25° C. was added hydrazine hydrate (13.2 mL, 265 mmol). The RM was stirred at 80° C. for 2 h, then cooled and the resulting solid was collected by filtration to give the title compound as a white solid.

[0711] Step 3. 4,7-Dichloro-3-methyl-imidazo[4,5-d]pyridazine. 3-Methyl-5,6-dihydroimidazo[4,5-d]pyridazine-4,7-dione (600 mg, 3.61 mmol) and POCl 3 (10 mL) was stirred for 12 h at 100° C. The solution was concentrated in vacuo and azeotroped with chloroform (3×20 mL) to give the title compound as a yellow gum.

[0712] Step 4. 4-Chloro-7-isopropenyl-1-methyl-imidazo[4,5-d]pyridazine. To a solution of 4,7-dichloro-3-methyl-imidazo[4,5-d]pyridazine (700 mg, 3.45 mmol) in water (3 mL) and THF (15 mL) at 25 °C was added 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (579 mg, 3.45 mmol), Na 2 CO 3 (1.83 g, 17.2 mmol) and Pd(PPh 3 ) 4(398 mg, 345 μmol) was added. RM was 2 The mixture was stirred at 90° C. for 12 h, then diluted with water (10 mL) and extracted with ethyl acetate (3×10 mL). The combined organic phase was washed with brine (10 mL) and diluted with anhydrous Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered and concentrated in vacuo. Preparative HPLC (column: Kromasil C18 (250 × 50 mm, 10 μm); mobile phase: [water (10 mM NH 4 HCO 3 )~ACN]; B: 1~20%, 10 min) to give the title compound as a white solid. Y=9% TIFF2025504374000090.tif12128

[0713] Step 5. 1-Methyl-7-(prop-1-en-2-yl)-1H,4H,5H-imidazo[4,5-d]pyridazin-4-one. To a solution of 4-chloro-7-isopropenyl-1-methyl-imidazo[4,5-d]pyridazine (65 mg, 312 μmol) in AcOH (2 mL) at 25° C. was added NaOAc (76.7 mg, 934 μmol). The RM was stirred at 50° C. for 12 h and then concentrated in vacuo to give the title compound as a white solid (y=quantitative).

[0714] Intermediate C12. 2,7-Diisopropyl-2,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one TIFF2025504374000091.tif50164 Step 1. 3-Iodo-1-isopropyl-pyrazole. To a solution of 3-iodo-1H-pyrazole (5.0 g, 25.8 mmol) in DMF (1 mL) at 0 °C was added NaHMDS (1 M in THF, 30.9 mL, 30.9 mmol). After stirring for 30 min, 2-iodopropane (3.09 mL, 30.9 mmol) was added and the resulting mixture was stirred at 25 °C for 12 h. RM was dissolved in saturated NH 4 The mixture was quenched with Cl (10 mL), diluted with water (40 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (3×50 mL) and diluted with Na 2 SO 4The mixture was dried over 1000 ml of ethyl acetate, filtered and concentrated under reduced pressure. Preparative HPLC (column: Phenomenex C18, 250 × 70 mm, 10 μm; mobile phase: [water (NH 3 H 2 O+NH 4 HCO 3 )~ACN]; B: 35~60%, 20 min) afforded the title compound as a colorless oil. Y=41%. TIFF2025504374000092.tif12128

[0715] Step 2. 1-(1-Isopropylpyrazol-3-yl)-2-methyl-propan-1-one. To isopropylmagnesium chloride lithium chloride (1M in THF, 10.2 mL, 10.2 mmol) in THF (10 mL) at 0° C. was added a solution of 3-iodo-1-isopropyl-pyrazole (2.4 g, 10.2 mmol) in THF (10 mL). After 1 h, a solution of N-methoxy-N,-(2-dimethyl)propanamide (934 mg, 7.12 mmol) in THF (10 mL) was added at 25° C. The mixture was stirred at 25° C. for 12 h and saturated NH 4 The mixture was quenched with Cl (10 mL), diluted with water (20 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (3×20 mL) and diluted with Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered and concentrated under reduced pressure. 2 , 25% EtOAc in petroleum ether) to afford the title compound as a yellow oil. Y=60%. TIFF2025504374000093.tif19159

[0716] Step 3. 1-(4-Iodo-1-isopropyl-pyrazol-3-yl)-2-methyl-propan-1-one. To a solution of 1-(1-isopropylpyrazol-3-yl)-2-methyl-propan-1-one (1.0 g, 5.55 mmol) in AcOH (10 mL) at 25° C. was added N-iodosuccinimide (1.87 g, 8.32 mmol). The RM was stirred at 25° C. for 12 h, diluted with water (10 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (3×10 mL) and concentrated to 100° C. with 10 mL of NaCl. 2 SO 4 The mixture was dried over 1000 ml of FCC (SiO 2 Purification by elution with 10-25% EtOAc in petroleum ether) afforded the title compound as a yellow oil. Y=88%. TIFF2025504374000094.tif12139

[0717] Step 4. Methyl 1-isopropyl-3-(2-methylpropanoyl)pyrazole-4-carboxylate. To a solution of 1-(4-iodo-1-isopropyl-pyrazol-3-yl)-2-methyl-propan-1-one (1.47 g, 4.80 mmol) in MeOH (8 mL) at 25 °C was added TEA (2.43 g, 24.0 mmol, 3.34 mL) and PdCl 2 (dppf) (351 mg, 480 μmol) was added. The suspension was degassed and flushed with CO gas three times. The mixture was stirred under CO (50 Psi) at 70 °C for 12 h. The reaction mixture was filtered through a pad of Celite. The filtrate was diluted with water (15 mL) and extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with brine (3 x 15 mL) and diluted with Na 2 SO 4 The mixture was dried over 1000 ml of FCC (SiO 2 Purification with 10-50% EtOAc in petroleum ether afforded the title compound as a yellow oil. Y=87%. TIFF2025504374000095.tif20160

[0718] Step 5. 2,7-Diisopropyl-5H-pyrazolo[3,4-d]pyridazin-4-one. To methyl 1-isopropyl-3-(2-methylpropanoyl)pyrazole-4-carboxylate (1.0 g, 4.20 mmol) in EtOH (10 mL) at 25° C. was added hydrazine hydrate (2.08 mL, 42.0 mmol). The resulting mixture was stirred at 80° C. for 12 h. The reaction mixture was filtered and the filter cake was dried in vacuum to give the title compound as a white solid. Y=65%. TIFF2025504374000096.tif19159

[0719] Intermediate C13. 2-Cyclopropyl-7-isopropyl-5H-pyrazolo[3,4-d]pyridazin-4-one TIFF2025504374000097.tif41128Step 1. 1-Cyclopropyl-3-iodo-pyrazole. A solution of 3-iodo-1H-pyrazole (5.0 g, 25.8 mmol) and cyclopropylboronic acid (4.43 g, 51.6 mmol) in DCE (50 mL) was added with Na 2 CO 3 (5.46 g, 51.6 mmol), 2-(2-pyridyl)pyridine (4.03 g, 25.8 mmol) and copper(II) diacetate (4.68 g, 25.8 mmol) were added. The RM was stirred at 70° C. for 8 h. The reaction was cooled to 25° C. and AcOH (5 mL) was added. The resulting mixture was concentrated in vacuo. The residue was diluted with water (50 mL) and extracted with EtOAc (3×50 mL). The organic layer was washed with Na 2 SO 4 The mixture was dried over 1000 ml of FCC (SiO 2 Purification by elution with 15% EtOAc in petroleum ether) afforded the title compound as a colorless oil. Y=83%. TIFF2025504374000098.tif19159

[0720] Step 2. 1-(1-Cyclopropylpyrazol-3-yl)-2-methyl-propan-1-one. To a solution of isopropylmagnesium chloride and lithium chloride (1M, 21.4 mL, 21.4 mmol) in THF (50 mL) at 0° C. was added 1-cyclopropyl-3-iodo-pyrazole (5.0 g, 21.4 mmol). After 1 h, N-methoxy-N-(2-dimethyl)-propanamide (2.80 g, 21.4 mmol) in THF (50 mL) was added and the RM was stirred at 25° C. for 12 h. The reaction mixture was diluted with saturated NH 4 The mixture was quenched with Cl (30 mL), diluted with water (20 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (3×30 mL) and diluted with Na 2 SO 4 The mixture was dried over 1000 ml of FCC (SiO 2 Purification by elution with 25% EtOAc in petroleum ether) afforded the title compound as a colorless liquid. Y=91%. TIFF2025504374000099.tif12135

[0721] Step 3. 1-(1-Cyclopropyl-4-iodo-pyrazol-3-yl)-2-methyl-propan-1-one. To 1-(1-cyclopropylpyrazol-3-yl)-2-methyl-propan-1-one (3.4 g, 19.1 mmol) in AcOH (35 mL) was added N-iodosuccinimide (6.44 g, 28.6 mmol). The RM was stirred at 25° C. for 8 h, diluted with water (30 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (30 mL) and concentrated to 100° C. with 100% NaCl. 2 SO 4 The mixture was dried over 1000 ml of FCC (SiO 2 , 25% EtOAc in petroleum ether) to afford the title compound as a brown oil. TIFF2025504374000100.tif12133

[0722] Step 4. Methyl 1-cyclopropyl-3-(2-methylpropanoyl)pyrazole-4-carboxylate. A solution of 1-(1-cyclopropyl-4-iodo-pyrazol-3-yl)-2-methyl-propan-1-one (2.0 g, 6.58 mmol) in MeOH (50 mL) at 25 °C was treated with TEA (4.58 mL, 32.9 mmol) and PdCl 2 (dppf) (481 mg, 658 μmol) was added. The RM was stirred under CO (gas, 50 psi) at 70° C. for 12 h. The reaction was filtered and the filtrate was concentrated in vacuo. FCC (SiO 2 , 20% EtOAc in petroleum ether) to afford the title compound as a brown solid. Y=84%. TIFF2025504374000101.tif20159

[0723] Step 5. 2-Cyclopropyl-7-isopropyl-5H-pyrazolo[3,4-d]pyridazin-4-one. To methyl 1-cyclopropyl-3-(2-methylpropanoyl)pyrazole-4-carboxylate (800 mg, 3.39 mmol) in EtOH (4 mL) at 25° C. was added hydrazine hydrate (1.68 mL, 33.9 mmol). The RM was stirred at 80° C. for 12 h. The reaction mixture was filtered and dried under reduced pressure to give the title compound as a green solid. Y=81% yield. TIFF2025504374000102.tif12159

[0724] Intermediate C14. 2-(7-Cyclopropyl-1-isopropyl-4-oxo-pyrido[3,4-d]pyridazin-3-yl)acetic acid TIFF2025504374000103.tif44128 Step 1. 6-Chloro-4-(2-methylpropanoyl)pyridine-3-carboxylic acid. To a solution of n-BuLi (2.5 M, 50.8 mL, 127 mmol) in THF (130 mL) at -78 °C was added 2,2,6,6-tetramethylpiperidine (16.2 mL, 95.2 mmol) and the RM was stirred at 0 °C for 30 min. A solution of 6-chloropyridine-3-carboxylic acid (5 g, 31.7 mmol) in THF (10 mL) was added dropwise at -78 °C. After addition, the mixture was stirred at this temperature for 1.5 h. N-Methoxy-N-(2-dimethyl)propanamide (16.7 g, 127 mmol) was added and the mixture was stirred at -78 °C for 3.5 h. The reaction mixture was quenched by the addition of water (100 mL) at 0° C. and extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (2×100 mL) and diluted with Na 2 SO 4 The mixture was dried over 1000 ml of FCC (SiO 2 , 25-100% EtOAc in petroleum ether) to give the title compound as a white solid. Y=14%.

[0725] Step 2. 6-Cyclopropyl-4-(2-methylpropanoyl)pyridine-3-carboxylic acid. A mixture of 6-chloro-4-(2-methylpropanoyl)pyridine-3-carboxylic acid (1.0 g, 4.39 mmol), cyclopropylboronic acid (1.13 g, 13.2 mmol) and K 3 PO 4 (1.96 g, 9.22 mmol) and PdCl 2 (dppf) (161 mg, 220 μmol) was mixed with N 2 The mixture was stirred at 100° C. for 8 h under reduced pressure. The RM was concentrated under reduced pressure, then diluted with water (30 mL) and extracted with DCM (3×30 mL). The combined organic layers were washed with brine (2×30 mL) and diluted with Na 2 SO 4 The mixture was dried over 1000 ml of FCC (SiO 2 Purification by elution with 25% EtOAc in petroleum ether (25-100% EtOAc in petroleum ether) afforded the title compound as a yellow oil. Y=98%.

[0726] Step 3. 7-Cyclopropyl-1-isopropyl-3H-pyrido[3,4-d]pyridazin-4-one. To 6-cyclopropyl-4-(2-methylpropanoyl)pyridine-3-carboxylic acid (0.43 g, 1.84 mmol) in EtOH (3 mL) at 25° C. was added hydrazine hydrate (1.83 mL, 36.9 mmol). The mixture was stirred at 80° C. for 12 h. The reaction was cooled to 25° C., filtered and dried to give the title compound as a white solid. Y=47%. TIFF2025504374000104.tif12132

[0727] Step 4. 2-(7-Cyclopropyl-1-isopropyl-4-oxo-pyrido[3,4-d]pyridazin-3-yl)acetic acid. A solution of 2-bromoacetic acid (80.1 μL, 155 mg) in THF (1 mL) was added to LiO t Bu (267 μL, 2.97 mmol) and 7-cyclopropyl-1-isopropyl-3H-pyrido[3,4-d]pyridazin-4-one (0.17 g, 741 μmol) were added. The RM was stirred at 80° C. for 3 h, cooled, and 2 M HCl was added until pH was 4. The resulting mixture was diluted with water (2 mL) and extracted with EtOAc (3×3 mL). The combined organic layers were washed with brine (2×3 mL) and diluted with Na 2 SO 4 It was dried at rt, filtered and concentrated under reduced pressure to give the title compound as a white solid. Y=94%. TIFF2025504374000105.tif12165

[0728] Intermediate C15. 2-(2,7-Diethyl-4-oxo-pyrazolo[3,4-d]pyridazin-5-yl)acetic acid TIFF2025504374000106.tif40135Step 1. 1-Ethyl-3-iodo-pyrazole. A solution of 3-iodo-1H-pyrazole (19 g, 98.0 mmol) in DMF (100 mL) was added with Cs 2 CO 3(95.7 g, 294 mmol) was added. After stirring at 25° C. for 30 min, iodoethane (15.7 mL, 196 mmol) was added and the RM was stirred for 2 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (3×100 mL) and diluted with Na 2 SO 4 The mixture was dried over 1000 ml of FCC (SiO 2 Purification by elution with 10-20% EtOAc in petroleum ether) afforded the title compound as a pale yellow oil. Y=52%. TIFF2025504374000107.tif20160

[0729] Step 2. 1-(1-Ethylpyrazol-3-yl)-2-methyl-propan-1-one. To a solution of isopropylmagnesium chloride and lithium chloride (1M, 13.5 mL, 13.5 mmol) in THF (20 mL) was added 1-ethyl-3-iodo-pyrazole (3.0 g, 13.5 mmol) in THF (7 mL) at 0° C. The RM was stirred at 25° C. for 1 h, then a solution of N-methoxy-N,2-dimethyl-propanamide (1.24 g, 9.46 mmol) in THF (10 mL) was added. The RM was reacted with N 2 Stir at 25°C for 12 hours in a 35°C bath and add saturated NH 4 The mixture was quenched with Cl (10 mL), diluted with water (30 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (3×20 mL) and diluted with Na 2 SO 4 The mixture was dried over 1000 ml of FCC (SiO 2 Purification by elution with 10-20% EtOAc in petroleum ether) afforded the title compound as a yellow oil. Y=58%. TIFF2025504374000108.tif19160

[0730] Step 3. 1-(1-Ethyl-4-iodo-pyrazol-3-yl)-2-methyl-propan-1-one. To a solution of 1-(1-ethylpyrazol-3-yl)-2-methyl-propan-1-one (1.3 g, 7.82 mmol) in AcOH (15 mL) at 25° C. was added NIS (2.64 g, 11.7 mmol). The RM was stirred for 12 h, diluted with water (15 mL) and extracted with EtOAc (3×15 mL). The combined organic layers were washed with brine (3×15 mL) and concentrated to 100° C. with 100% NaCl. 2 SO 4 The mixture was dried over 1000 ml of FCC (SiO 2 Purification by elution with 10-25% EtOAc in petroleum ether) afforded the title compound as a yellow solid. Y=92%. TIFF2025504374000109.tif12145

[0731] Step 4. Methyl 1-ethyl-3-propanoyl-pyrazole-4-carboxylate. A solution of 1-(1-ethyl-4-iodo-pyrazol-3-yl)propan-1-one (1.0 g, 3.60 mmol) in MeOH (10 mL) at 25 °C was treated with TEA (2.50 mL, 18.0 mmol) and PdCl 2 (dppf) (263 mg, 360 μmol) was added. The RM was stirred under CO (gas, 50 Psi) at 70° C. for 12 h and then concentrated under reduced pressure. The residue was filtered through a pad of Celite, then the filtrate was diluted with water (15 mL) and extracted with EtOAc (3×15 mL). The combined organic layers were washed with brine (3×15 mL) and diluted with Na 2 SO 4 The mixture was dried over 1000 ml of FCC (SiO 2 Purification by elution with 10-50% EtOAc in petroleum ether) afforded the title compound as a yellow oil. Y=93%. TIFF2025504374000110.tif12149

[0732] Step 5. 2,7-Diethyl-5H-pyrazolo[3,4-d]pyridazin-4-one. To a solution of 1-ethyl-3-propanoyl-pyrazole-4-methyl carboxylate (0.70 g, 3.33 mmol) in EtOH (7 mL) at 25° C. was added hydrazine hydrate (1.65 mL, 33.3 mmol). The RM was stirred at 80° C. for 12 h, filtered and dried under reduced pressure to give the title compound as a white solid. Y=78%. TIFF2025504374000111.tif12165

[0733] Step 6. 2-(2,7-Diethyl-4-oxo-pyrazolo[3,4-d]pyridazin-5-yl)acetic acid. To a solution of 2,7-diethyl-5H-pyrazolo[3,4-d]pyridazin-4-one (175 mg, 910 μmol) in THF (3 mL) at 25° C. was added lithium tert-butoxide (328 μL, 3.64 mmol) and 2-bromoacetic acid (98.3 μL, 1.37 mmol). RM was converted to N 2 The mixture was stirred at 80° C. for 3 h under reduced pressure, then diluted with water (1 mL) and washed with EtOAc (3×1 mL). 2M HCl was added dropwise until the pH was 4-5, and the aqueous phase was extracted with EtOAc (3×1 mL). The combined organic layers were washed with brine (3×1 mL) and diluted with Na 2 SO 4 It was dried at rt, filtered and concentrated under reduced pressure to give the title compound as a white solid. Y=79%. TIFF2025504374000112.tif19159

[0734] Intermediate C16. 2-Ethyl-7-isopropyl-5H-furo[2,3-d]pyridazin-4-one TIFF2025504374000113.tif19165Step 1. 5-Vinylfuran-3-carboxylic acid. To a solution of 5-bromofuran-3-carboxylic acid (500 mg, 2.62 mmol) in dioxane (10 mL) and water (2 mL) at 25 °C was added Na 2 CO 3 (555mg, 5.24mmol), PdCl 2(dppf) (383 mg, 524 μmol) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (666 μL, 3.93 mmol) were added. The mixture was stirred at 80° C. for 3 h. The pH was adjusted to about 3 by addition of 1 M HCl. Water (3 mL) was added and the solution was extracted with ethyl acetate (3×3 mL). The combined organic layers were washed with brine (5 mL) and diluted with Na 2 SO 4 Drying at rt, filtration and concentration under reduced pressure afforded the title compound as a white solid: Y=83% yield.

[0735] Step 2. 5-Ethylfuran-3-carboxylic acid. 2 To a solution of 5-vinylfuran-3-carboxylic acid (270 mg, 1.95 mmol) in MeOH (5 mL) at 25° C. under reduced pressure was added Pd / C (200 mg, 10% on carbon, 50% in water). 2 The reaction was stirred under (15 psi) for 1 h. The reaction was filtered and the filtrate was washed with saturated NaHCO 3 (2 mL) to adjust the pH to 8. The mixture was washed with ethyl acetate (2 mL). The aqueous phase was adjusted to pH 2 with 1 M HCl and extracted with ethyl acetate (3 x 1 mL). The organic layer was washed with brine (1 x 1 mL) and diluted with Na 2 SO 4 It was dried at 40° C., filtered and concentrated under reduced pressure to give the title compound as a brown solid. Y=91%. TIFF2025504374000114.tif12128

[0736] Step 3. 5-Ethyl-2-(2-methylpropanoyl)furan-3-carboxylic acid. 2 To a solution of 5-ethylfuran-3-carboxylic acid (50 mg, 357 μmol) in THF (1 mL) at −70° C. below was added LDA (2 M in THF, 535 μL, 1.07 mmol). The mixture was stirred at −70° C. for 30 min, then N-methoxy-N-(2-dimethyl)propanamide (93.6 mg, 714 μmol) was added. The RM was stirred at −70° C. for 1 h and then diluted with saturated NH 4The mixture was quenched with Cl (3 mL) and adjusted to pH 3 with 1M HCl. The resulting mixture was diluted with water (1 mL) and extracted with ethyl acetate (3×1 mL). The combined organic layers were washed with brine (3 mL) and diluted with Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered and concentrated under reduced pressure. 2 , 1:1 petroleum ether:ethyl acetate) to afford the title compound as a white solid. Y=20%. TIFF2025504374000115.tif19159

[0737] Step 4. 2-Ethyl-7-isopropyl-5H-furo[2,3-d]pyridazin-4-one. To a solution of 5-ethyl-2-(2-methylpropanoyl)furan-3-carboxylic acid (110 mg, 523 μmol) in EtOH (3 mL) at 25° C. was added hydrazine hydrate (519 μL, 10.5 mmol). The mixture was stirred at 70° C. for 2 h and then concentrated under reduced pressure to give the title compound as a white solid. Y=93%.

[0738] Intermediate C17. 2-Ethyl-4-isopropyl-6H-thieno[2,3-d]pyridazin-7-one TIFF2025504374000116.tif49128 Step 1. 3-(2-Methylpropanoyl)thiophene-2-carboxylic acid. To a solution of 3-bromothiophene-2-carboxylic acid (2.0 g, 9.66 mmol) in THF (20 mL) at -78 °C was added n-BuLi (2.5 M, 7.73 mL, 19.3 mmol). After 30 min, N-methoxy-N-(2-dimethyl)propanamide (1.52 g, 11.6 mmol) in THF (3 mL) was added and the RM was stirred at 25 °C for 1 h. The pH of the RM was adjusted to 4-5 by the addition of 2 M HCl (10 mL). The resulting mixture was diluted with water (5 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (30 mL) and diluted with anhydrous Na 2 SO 4 The mixture was dried over 1000 ml of FCC (SiO 2Purification by elution with 10-25% EtOAc in petroleum ether) afforded the title compound as a white solid. Y=52%.

[0739] Step 2. 4-Isopropyl-6H-thieno[2,3-d]pyridazin-7-one. To a solution of 3-(2-methylpropanoyl)thiophene-2-carboxylic acid (0.50 g, 2.52 mmol) in EtOH (5 mL) at 25° C. was added hydrazine hydrate (2.50 mL, 50.4 mmol). The mixture was stirred at 80° C. for 2 h, concentrated in vacuo, then filtered and dried to give the title compound as a white solid. Y=71%.

[0740] Step 3. 2-Chloro-4-isopropyl-6H-thieno[2,3-d]pyridazin-7-one. To 4-isopropyl-6H-thieno[2,3-d]pyridazin-7-one (350 mg, 1.80 mmol) in THF (4 mL) at -78 °C was added 2M LDA in THF (2.25 mL, 4.50 mmol). After stirring for 30 min, 1,1,1,2,2,2-hexachloroethane (204 μL, 1.80 mmol) was added at -25 °C. The RM was stirred at 0 °C for 2 h, quenched with water (3 mL) at 0 °C, and the resulting mixture was concentrated under reduced pressure. The residue was diluted with water (3 mL) and extracted with EtOAc (3 x 2 mL). The combined organic layers were washed with brine (2 x 2 mL) and diluted with Na 2 SO 4 The mixture was dried over 1000 ml of FCC (SiO 2 , 20% EtOAc in petroleum ether) to afford the title compound as a white solid. Y=39%. TIFF2025504374000117.tif12128

[0741] Step 4. 4-Isopropyl-2-vinyl-6H-thieno[2,3-d]pyridazin-7-one. To a solution of 2-chloro-4-isopropyl-6H-thieno[2,3-d]pyridazin-7-one (200 mg, 875 μmol) in THF (4 mL) and water (0.8 mL) at 25 °C was added 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (445 μL, 2.62 mmol), Na2 CO 3 (463 mg, 4.37 mmol) and Pd(PPh 3 ) 4 (101 mg, 87.5 μmol) was added. The RM was stirred at 80° C. for 12 h, diluted with water (5 mL) and extracted with ethyl acetate (3×5 mL). The combined organic layers were washed with brine (5 mL) and anhydrous Na 2 SO 4 The mixture was dried over 1000 ml of FCC (SiO 2 , 25% EtOAc in petroleum ether) to afford the title compound as a white solid. Y=57%.

[0742] Step 5. 2-Ethyl-4-isopropyl-6H-thieno[2,3-d]pyridazin-7-one. To a solution of 4-isopropyl-2-vinyl-6H-thieno[2,3-d]pyridazin-7-one (70 mg, 318 μmol) in EtOH (2 mL) was added Pd / C (70 mg, 10% Pd on carbon, 50% in water) and the mixture was cooled to 5° C. 2 (15 psi) at 25° C. for 1 h. The solution was filtered and the filtrate was concentrated in vacuo to give the title compound as a yellow oil. Y=quantitative.

[0743] Intermediate C18. 2-(2-cyclopropyl-8-isopropyl-5-oxo-pyrido[2,3-d]pyridazin-6-yl)acetic acid TIFF2025504374000118.tif35165Step 1. Ethyl 6-cyclopropylpyridine-3-carboxylate. Ethyl 6-bromopyridine-3-carboxylate (13.4 g, 58.1 mmol), cyclopropylboronic acid (12.5 g, 145 mmol) in dioxane (150 mL), and K 3 PO 4 (25.9 g, 122 mmol) and PdCl 2 (dppf) (2.13 g, 2.91 mmol) was mixed with N 2 The mixture was stirred at 100° C. for 8 h under reduced pressure. The RM was concentrated under reduced pressure, diluted with water (100 mL) and extracted with DCM (3×100 mL). The combined organic layers were washed with brine (100 mL) and concentrated under reduced pressure. FCC (SiO2 Purification by elution with 0% EtOAc in petroleum ether (0-30% EtOAc in petroleum ether) afforded the title compound as a yellow oil. Y=45%. TIFF2025504374000119.tif19159

[0744] Step 2. Ethyl 6-cyclopropyl-1-oxide-pyridin-1-ium-3-carboxylate. To a solution of ethyl 6-cyclopropylpyridine-3-carboxylate (5.0 g, 26.1 mmol) in DCM (50 mL) at 25° C. was added m-CPBA (10.6 g, 52.3 mmol). The mixture was stirred at 25° C. for 1 h and then diluted with saturated Na 2 S 2 O 3 (50 mL). Water (50 mL) was added and the solution was extracted with DCM (3×100 mL). The combined organic layers were washed with brine (2×100 mL) and diluted with Na 2 SO 4 The mixture was dried over 1000 ml of FCC (SiO 2 Purification by elution with 10% EtOAc in petroleum ether (10-100% EtOAc in petroleum ether) afforded the title compound as a white solid. Y=92%.

[0745] Step 3. Ethyl 2-chloro-6-cyclopropyl-pyridine-3-carboxylate. POCl 3 Ethyl 6-cyclopropyl-1-oxide-pyridin-1-ium-3-carboxylate (4.8 g, 23.2 mmol) in ethyl 6-cyclopropyl-1-oxide-pyridin-1-ium-3-carboxylate (50 mL, 538 mmol) was stirred at 100° C. for 12 h. The mixture was cooled to 25° C. and then poured into water (200 mL). The resulting mixture was extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine (2×100 mL) and diluted with Na 2 SO 4 The mixture was dried over 1000 ml of FCC (SiO 2 Purification by elution with 10-30% EtOAc in petroleum ether) afforded the title compound as a yellow oil. Y=93%. TIFF2025504374000120.tif20159

[0746] Step 4. Ethyl 2-cyano-6-cyclopropyl-pyridine-3-carboxylate. To a solution of ethyl 2-chloro-6-cyclopropyl-pyridine-3-carboxylate (2.0 g, 8.86 mmol) in DMA (16 mL) at 25 °C was added Zn(CN) 2 (1.13 mL, 17.72 mmol), zinc (69.5 mg, 1.06 mmol), Pd 2 (dba) 3 (81.2 mg, 88.6 μmol) and DPPF (98.3 mg, 177 μmol) were added. 2 The mixture was stirred at 120° C. for 2 h, diluted with water (30 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (2×30 mL) and diluted with Na 2 SO 4 The mixture was dried over 1000 ml of FCC (SiO 2 Purification by elution with 10-25% EtOAc in petroleum ether) afforded the title compound as a yellow oil. Y=94%. TIFF2025504374000121.tif19159

[0747] Step 5. 2-Cyano-6-cyclopropyl-pyridine-3-carboxylic acid. A solution of ethyl 2-cyano-6-cyclopropyl-pyridine-3-carboxylate (1.8 g, 8.32 mmol) in water (3 mL) and THF (15 mL) at 25 °C was treated with LiOH.H 2 0 (699 mg, 16.7 mmol) was added. The mixture was stirred at 25° C. for 2 h, concentrated under reduced pressure, diluted with water (10 mL) and lyophilized to give the Li salt of the title compound as a white solid. Y=quantitative. LCMS (ESI): m / z: [M+H] + = 189.1.

[0748] Step 6. 6-Cyclopropyl-2-(2-methylpropanoyl)pyridine-3-carboxylic acid. To 2-cyano-6-cyclopropyl-pyridine-3-carboxylic acid (0.80 g, 4.10 mmol) in THF (8 mL) at 0° C. was added isopropylmagnesium chloride (2M in THF, 2.05 mL, 4.1 mmol). The RM was stirred at 25° C. for 5 h, quenched with water (5 mL) at 0° C., and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (10 mL) and diluted with Na 2 SO 4 The mixture was dried over 1000 ml of FCC (SiO 2 Purification by elution with 5% EtOAc in petroleum ether (5-50% EtOAc in petroleum ether) afforded the title compound as a white solid. Y=52%.

[0749] Step 7. 2-Cyclopropyl-8-isopropyl-6H-pyrido[2,3-d]pyridazin-5-one. To 6-cyclopropyl-2-(2-methylpropanoyl)pyridine-3-carboxylic acid (0.50 g, 2.14 mmol) in EtOH (5 mL) at 25° C. was added hydrazine hydrate (2.13 mL, 42.9 mmol). The RM was stirred at 80° C. for 12 h, gradually cooled to 25° C., filtered and dried to give the title compound as a white solid. Y=37%. TIFF2025504374000122.tif20159

[0750] Step 8. 2-(2-Cyclopropyl-8-isopropyl-5-oxo-pyrido[2,3-d]pyridazin-6-yl)acetic acid. To 2-cyclopropyl-8-isopropyl-6H-pyrido[2,3-d]pyridazin-5-one (0.17 g, 741 μmol) in THF (1.7 mL) at 25° C. was added lithium tert-butoxide (267 μL, 2.97 mmol) and 2-bromoacetic acid (80.1 μL, 1.11 mmol). The RM was stirred at 80° C. for 3 h, cooled and adjusted to pH 4 with aqueous 2M HCl. The solution was diluted with water (3 mL) and extracted with EtOAc (3×3 mL). The combined organic layers were washed with brine (2×3 mL) and concentrated to 100° C. with 100% NaCl. 2 SO 4It was dried at rt, filtered and concentrated under reduced pressure to give the title compound as a white solid. Y=94%. TIFF2025504374000123.tif19160

[0751] Intermediate C19. 2-Bromo-4-isopropyl-6H-thieno[2,3-d]pyridazin-7-one TIFF2025504374000124.tif22128 Step 1. 3-(2-Methylpropanoyl)thiophene-2-carboxylic acid. To a solution of 3-bromothiophene-2-carboxylic acid (3.0 g, 14.5 mmol) in THF (30 mL) at -78 °C was added n-BuLi (2.5 M in THF, 11.6 mL). After stirring for 30 min, N-methoxy-N-(2-dimethyl)propanamide (2.28 g, 17.4 mmol) was added to the N 2 The RM was stirred at 25° C. for 1 h and then added with saturated NH 4 The mixture was quenched with Cl (20 mL). Water (20 mL) was added and the solution was extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (15 mL) and diluted with Na 2 SO 4 The mixture was dried over 1000 ml of FCC (SiO 2 Purification by elution with 50-100% EtOAc in petroleum ether) afforded the title compound as a yellow solid. Y=97%. TIFF2025504374000125.tif12152

[0752] Step 2. 4-Isopropyl-6H-thieno[2,3-d]pyridazin-7-one. To a solution of 3-(2-methylpropanoyl)thiophene-2-carboxylic acid (2.8 g, 14.1 mmol) in EtOH (30 mL) at 25° C. was added hydrazine hydrate (14.0 mL, 282 mmol). The RM was stirred at 80° C. for 12 h, then cooled and filtered to give the title compound as a white solid. Y=55%. TIFF2025504374000126.tif19159

[0753] Step 3. 2-Bromo-4-isopropyl-6H-thieno[2,3-d]pyridazin-7-one. To a solution of 4-isopropyl-6H-thieno[2,3-d]pyridazin-7-one (1.3 g, 6.69 mmol) in THF (15 mL) at -78 °C was added LDA (2 M in THF, 8.37 mL, 16.7 mmol). After stirring for 30 min, 1,2-dibromo-1,1,2,2-tetrachloro-ethane (965 μL, 8.03 mmol) was added at -78 °C. RM was converted to N 2 The mixture was stirred at 25° C. for 2 h. The RM was quenched by addition of water (15 mL) at 0° C. and extracted with EtOAc (3×25 mL). The combined organic layers were washed with brine (8 mL) and diluted with Na 2 SO 4 The mixture was dried over 1000 ml of FCC (SiO 2 Purification by elution with 30-100% EtOAc in petroleum ether) afforded the title compound as a yellow solid. Y=82%.

[0754] Intermediate C20. 2-Cyclopropyl-8-ethyl-6H-pyrido[2,3-d]pyridazin-5-one TIFF2025504374000127.tif38158Step 1. Ethyl 6-cyclopropylpyridine-3-carboxylate. Ethyl 6-bromopyridine-3-carboxylate (13.4 g, 58.1 mmol), cyclopropylboronic acid (12.5 g, 145 mmol) in dioxane (150 mL), and K 3 PO 4 (25.9 g, 122 mmol) and PdCl 2 (dppf) (2.13 g, 2.91 mmol) was mixed with N 2 The mixture was stirred at 100° C. for 8 h under reduced pressure. The RM was concentrated under reduced pressure, diluted with water (100 mL) and the resulting mixture was extracted with DCM (3×100 mL). The combined organic layers were washed with brine (100 mL) and concentrated under reduced pressure. FCC (SiO 2 Purification by elution with 0% EtOAc in petroleum ether (0-30% EtOAc in petroleum ether) afforded the title compound as a yellow oil. Y=45%. TIFF2025504374000128.tif20160

[0755] Step 2. Ethyl 6-cyclopropyl-1-oxidopyridinium-3-carboxylate. To a solution of ethyl 6-cyclopropylpyridine-3-carboxylate (5 g, 26.15 mmol) in DCM (50 mL) was added m-CPBA (10.62 g, 52.29 mmol) at 25° C. The mixture was stirred at 25° C. for 1 h. The reaction mixture was diluted with saturated Na 2 S 2 O 3 (50 mL). The resulting mixture was quenched with H 2 The mixture was diluted with 2×O (50 mL) and extracted with DCM (100 mL×3). The combined organic layers were washed with brine (100 mL×2) and 2 SO 4 The mixture was dried over 1000 ml of FCC (SiO 2 10-100% EtOAc in petroleum ether gave the title compound as a white solid. Y=92%.

[0756] Step 3. Ethyl 2-chloro-6-cyclopropyl-pyridine-3-carboxylate. POCl 3 Ethyl 6-cyclopropyl-1-oxide-pyridinium-3-carboxylate (4.8 g, 23.2 mmol) in ethyl 6-cyclopropyl-1-oxide-pyridinium-3-carboxylate (50 mL, 538 mmol) was stirred at 100° C. for 12 h. The mixture was cooled to 25° C. and then poured into water (200 mL). The resulting mixture was extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine (2×100 mL) and diluted with Na 2 SO 4 The mixture was dried over 1000 ml of FCC (SiO 2 Purification by elution with 10-30% EtOAc in petroleum ether) afforded the title compound as a yellow oil. Y=93%. TIFF2025504374000129.tif19159

[0757] Step 4. Ethyl 2-cyano-6-cyclopropyl-pyridine-3-carboxylate. A solution of ethyl 2-chloro-6-cyclopropylpyridine-3-carboxylate (2.0 g, 8.86 mmol) in DMA (16 mL) was treated with Zn(CN) 2(1.13mL, 17.7mmol), Zn (69.5mg, 1.06mmol), Pd 2 (dba) 3 (81.2 mg, 88.6 μmol) and DPPF (98.3 mg, 177 μmol) were added. The mixture was then cooled to 37° C. for 24 hours. 2 The mixture was stirred at 120° C. for 2 h under reduced pressure. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (2×30 mL) and diluted with Na 2 SO 4 The mixture was dried over 1000 ml of FCC (SiO 2 Purification by elution with 10-25% EtOAc in petroleum ether) afforded the title compound as a yellow oil. Y=94%. TIFF2025504374000130.tif20160

[0758] Step 5. 2-Cyano-6-cyclopropylpyridine-3-carboxylic acid. A solution of ethyl 2-cyano-6-cyclopropylpyridine-3-carboxylate (1.8 g, 8.32 mmol) in water (3 mL) and THF (15 mL) was added to LiOH.H at 25 °C. 2 2H2O (699 mg, 16.7 mmol) was added and stirred for 2 h. The reaction mixture was concentrated under reduced pressure to remove THF and H 2 0 (10 mL) and the resulting mixture was lyophilized to give the title compound as a white solid. Y=100%, Li salt. LCMS (ESI): m / z: [M+H] + = 189.1.

[0759] Step 6. 6-Cyclopropyl-2-propanoylpyridine-3-carboxylic acid. To a solution of 2-cyano-6-cyclopropylpyridine-3-carboxylic acid (0.5 g, 2.56 mmol) in THF (5 mL) was added ethylmagnesium bromide (3 M in diethyl ether, 1.28 mL, 3.84 mmol) at 0° C. The mixture was stirred at 25° C. for 5 h, quenched with water (5 mL) at 0° C., and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (10 mL) and diluted with Na 2 SO 4The mixture was dried over 1000 ml of FCC (SiO 2 Puri...

Claims

1. Formula (III): or a prodrug, solvate, or pharma- ceutically acceptable salt thereof, During the ceremony, each are independently, where valences permit, a single bond or a double bond; A 2 is as long as the valence allows. 2 , N, N.R. 2a , O, or S; A 3 is as long as the valence allows. 2 , N, N.R. 2a , O, or S; A 4 is as long as the valence allows. 2 , N, N.R. 2a , O, or S; Here, A 2 , A 3 , or A 4 At least one of them is N, NR 2a , O, or S, where A 2 If S, then A 4 is CR 2 , N.R. 2a , O, or S; R 1 is H, -N(C 1 ~C 6 Alkyl) 2 , C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, or C 3 ~C 12 cycloalkyl, wherein the -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 1S may be substituted with; Each R 1S are independently halogen, cyano, -OH, or C 1 ~C 6 is alkyl; Each R 2 are independently H, halogen, cyano, -OH, -NH 2 , -NO 2 , -C(=O)NH 2 , C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, -O(C 1 ~C 6 alkyl), -NH(C 1 ~C 6 alkyl), -N(C 1 ~C 6 Alkyl) 2 , C 3 ~C 12 Cycloalkyl, 3- to 12-membered heterocycloalkyl, C 6 ~C 10 aryl, or 5- to 10-membered heteroaryl, 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, -O(C 1 ~C 6 alkyl), -NH(C 1 ~C 6 alkyl), -N(C 1 ~C 6 Alkyl) 2 , C 3 ~C 12 Cycloalkyl, 3- to 12-membered heterocycloalkyl, C 6 ~C 10 Aryl or 5- to 10-membered heteroaryl is one or more R 2S may be substituted with or two R's 2 together with the atoms to which they are attached, C 3 ~C 12 cycloalkyl or 3- to 12-membered heterocycloalkyl, wherein the C 3 ~C 12 Cycloalkyl or 3- to 12-membered heterocycloalkyl may be one or more R 2S may be substituted with; Each R 2S are independently halogen, -OH, -O(C 1 ~C 6 alkyl), -NH 2 , -NH(C 1 ~C 6 alkyl), -N(C 1 ~C 6 Alkyl) 2 , or C 3 ~C 12 is cycloalkyl; Each R 2a are independently H, C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, C 1 ~C 6 Haloalkyl, -(CH 2 ) 0～3 -C 3 ~C 12 Cycloalkyl, or -(CH 2 ) 0～3 -(3 to 12 membered heterocycloalkyl); Each R a are independently H or C 1 ~C 6 alkyl; or two R a together with the atoms to which they are attached, C 3 ~C 12 Forming a cycloalkyl; R N2 is C 3 ~C 12 cycloalkyl, 3- to 12-membered heterocycloalkyl, or 5- to 10-membered heteroaryl; 3 ~C 12 Cycloalkyl, 3- to 12-membered heterocycloalkyl, or 5- to 10-membered heteroaryl can be one or more R N2a may be substituted with; Each R N2a are independently oxo, halogen, cyano, -OH, -NH 2 , -C(=O)H, -C(=O)OH, C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, -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- 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 6 Alkyl)-(C 6 ~C 10 aryl), or -(C 1 ~C 6 alkyl)-(5- to 10-membered heteroaryl); 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, -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- 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 6 Alkyl)-(C 6 ~C 10 aryl), or -(C 1 ~C 6 alkyl)-(5- to 10-membered heteroaryl) is one or more R N2ab and Each R N2ab are independently oxo, halogen, cyano, -OH, -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 That is, The compound or a prodrug, solvate, or pharma- ceutically acceptable salt thereof.

2. R 1 C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, or C 3 ~C 7 cycloalkyl, wherein the C 1 ~C 6 The alkyl is selected from one or more R 1S may be substituted with; Each R 1S are independently halogen; Each R 2 are independently H, halogen, cyano, -NH 2 , 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 3 ~C 12 cycloalkyl, wherein the C 1 ~C 6 Alkyl and -NH(C 1 ~C 6 alkyl) is one or more R 2S may be substituted with; Each R 2S are independently halogen, -O(C 1 ~C 6 Alkyl, or -NH 2 and Each R 2a C 1 ~C 6 Alkyl or -(CH 2 ) 0～3 -C 3 ~C 12 is cycloalkyl; Each R N2a are independently halogen, cyano, -OH, C 1 ~C 6 Alkyl, C 3 ~C 12 Cycloalkyl, -C(=O)O(C 1 ~C 6 alkyl), wherein the C 1 ~C 6 The alkyl is selected from one or more R N2ab and Each R N2ab independently -C(=O)O(C 1 ~C 6 alkyl), 2. The compound of claim 1.

3. A 2 is S and A 3 CR 2 And A 4 CR 2 or A 2 CR 2 And A 3 CR 2 And A 4 is S; or A 2 is N and A 3 NR 2a And A 4 CR 2 or A 2 is O and A 3 CR 2 And A 4 CR 2 or A 2 NR 2a And A 3 is N and A 4 CR 2 or A 2 is N and A 3 CR 2 And A 4 NR 2a or A 2 CR 2 And A 3 is N and A 4 NR 2a or A 2 CR 2 And A 3 NR 2a And A 4 is N; or A 2 CR 2 And A 3 CR 2 And A 4 is O, 3. A compound according to claim 1 or claim 2.

4. R 2 are independently H, halogen, cyano, -NH 2 , 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 3 ~C 12 cycloalkyl, wherein the C 1 ~C 6 Alkyl and -NH(C 1 ~C 6 alkyl) is one or more R 2S 4. The compound of claim 1, optionally substituted with

5. R 2 are independently H, halogen (e.g., chlorine or bromine), cyano, -NH 2 , C 1 ~C 6 Alkyl (e.g., methyl, ethyl, or propyl), -O(C 1 ~C 6 alkyl) (e.g., -O-methyl or -O-ethyl), -NH(C 1 ~C 6 alkyl) (e.g., -NH-methyl, -NH-CD 3 , -NH-ethyl, or -NH-isopropyl), -N(C 1 ~C 6 Alkyl) 2 (e.g., (-N(Me)(Et)), C 3 ~C 12 cycloalkyl (e.g., cyclopropyl), 1 ~C 6 Alkyl and -NH(C 1 ~C 6 alkyl) is one or more R 2S (For example, -CH 2 -CF 3 , -NHCH 2 CHF 2 , -CH 2 -O-Methyl, -NHCH 2 CH 2 OMe, or -CH 2 -NH 2 5. The compound of claim 1, wherein the compound is optionally substituted with .

6. R 2 are independently H, chlorine, bromine, cyano, -NH 2 , methyl, ethyl, propyl, -O-methyl, -O-ethyl, -NH-methyl, -NH-CD 3 , -NH-ethyl, -NH-isopropyl, -N(Me)(Et), cyclopropyl, -CH 2 -CF 3 , -NHCH 2 CHF 2 , -CH 2 -O-Methyl, -NHCH 2 CH 2 OMe, or -CH 2 -NH 2 The compound according to any one of claims 1 to 4,

7. Each R 2a C 1 ~C 6 Alkyl or -(CH 2 ) 0～3 -C 3 ~C 12 2. The compound of any one of the preceding claims, which is cycloalkyl.

8. Each R 2a C 1 ~C 6 Alkyl (e.g., methyl, ethyl, isopropyl) or -(CH 2 ) 0～3 -C 3 ~C 12 The compound of any one of claims 1 to 6, which is cycloalkyl (e.g., cyclopropyl or cyclobutyl).

9. Each R 2a 7. The compound of any one of claims 1-6, wherein is independently methyl, ethyl, isopropyl, cyclopropyl, or cyclobutyl.

10. R 1 C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, or C 3 ~C 7 cycloalkyl, where C 1 ~C 6 The alkyl is selected from one or more R 1S 4. The compound of claim 1, optionally substituted with

11. R 1 C 1 ~C 6 Alkyl (e.g., methyl, ethyl, or isopropyl), C 2 ~C 6 Alkenyl (e.g., isopropenyl), C 3 ~C 7 cycloalkyl (e.g., cyclopropyl) or C 6 Alkyl is one or more R 1S The compound of any one of claims 1 to 9, optionally substituted with (eg, fluoromethyl).

12. R 1 10. The compound of any one of claims 1-9, wherein is methyl, ethyl, isopropyl, isopropenyl, cyclopropyl, or fluoromethyl.

13. Both R a is H or two R a together with the atoms to which they are bonded, C 3 ~C 12 2. A compound according to any one of the preceding claims which forms a cycloalkyl.

14. Both R a is H or two R a together with the atoms to which they are bonded, C 3 ~C 7 The compound of any one of claims 1 to 12, which forms a cycloalkyl.

15. Both R a is H or two R a together with the atoms to which they are bonded, C 3 ~C 6 The compound of any one of claims 1 to 12, which forms a cycloalkyl.

16. Both R a is H or two R a 13. The compound of any one of claims 1-12, wherein: together with the atom to which they are attached form a cyclopropyl.

17. R N2 But, C 3 ~C 12 cycloalkyl (e.g., cyclobutyl), 3- to 12-membered heterocycloalkyl (e.g., piperidinyl, octahydroindolizin-8-yl, or oxaspiro[3.3]heptan-6-yl), or 5- to 10-membered heteroaryl (e.g., oxazolyl, pyrimidinyl, or triazolylpyridinyl), wherein the C 3 ~C 12 Cycloalkyl, 3- to 12-membered heterocycloalkyl, or 5- to 10-membered heteroaryl is selected from one or more R N2a 4. The compound of claim 1, optionally substituted with

18. R N2 is cyclobutyl, piperidinyl, octahydroindolizin-8-yl, oxaspiro[3.3]heptan-6-yl), oxazolyl, pyrimidinyl, or triazolylpyridinyl, each of which is selected from one or more of R N2a The compound of any one of claims 1 to 16, optionally substituted with

19. R N2a are independently halogen (e.g., F or Cl), cyano, -OH, C 1 ~C 6 Alkyl (e.g., methyl), C 3 ~C 12 Cycloalkyl (e.g., cyclopropyl or cyclobutyl), -C(=O)O(C 1 ~C 6 alkyl) (e.g., -COO-ethyl), where 1 ~C 6 Alkyl (e.g., methyl) can be present in one or more R N2ab (e.g., -C(=O)O(C 1 ~C 6 4. A compound according to any one of the preceding claims, wherein the aryl group is -C(=O)O(alkyl), in particular -C(=O)O(ethyl).

20. Formula (III-a), (III-b), (III-c), (III-d), (III-e), (III-f), or (III-g):

2. The compound of claim 1, wherein the compound is:

21. 20. The compound of any one of claims 1 to 19, which is a compound of formula (III-b), formula (III-d), or formula (III-e).

22. The compound according to any one of claims 1 to 19, which is a compound of formula (III-e).

23. A compound according to any one of the preceding claims selected from: and prodrugs and pharma- ceutically acceptable salts thereof.

24. A compound which is an isotopic derivative of a compound according to any one of the preceding claims.

25. A process for preparing a compound of formula (III) according to any one of the preceding claims, comprising:

26. 25. A pharmaceutical composition comprising a compound according to any one of claims 1 to 24 and a pharma- ceutically acceptable diluent or carrier.

27. 1. A method for inhibiting inflammasome activity, comprising: The method comprising contacting a cell with an effective amount of a compound according to any one of claims 1 to 24, wherein optionally, the inflammasome is the NLRP3 inflammasome, and the activity is in vitro or in vivo.

28. A method of treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound according to any one of claims 1 to 24 or a pharmaceutical composition according to claim 26.

29. Optionally, the inflammasome is the NLRP3 inflammasome and the inflammasome activity is in vitro or in vivo. A compound according to any one of claims 1 to 24 or a pharmaceutical composition according to claim 26 for use in inhibiting said inflammasome activity.

30. A compound according to any one of claims 1 to 24 or a pharmaceutical composition according to claim 26 for use in treating or preventing a disease or disorder.

31. Optionally, the inflammasome is the NLRP3 inflammasome and the inflammasome activity is in vitro or in vivo. Use of a compound according to any one of claims 1 to 24 in the manufacture of a medicament for inhibiting said inflammasome activity.

32. 25. Use of a compound according to any one of claims 1 to 24 in the manufacture of a medicament for treating or preventing a disease or disorder.

33. The method, compound for use, pharmaceutical composition or use according to any one of claims 27 to 32, wherein the disease or disorder is associated with inflammasome activity, and optionally the disease or disorder is a disease or disorder in which inflammasome activity is involved.

34. 33. The method, compound for use, pharmaceutical composition or use according to any one of claims 27 to 32, wherein said disease or disorder is an inflammatory disorder, an autoinflammatory disorder, an autoimmune disorder, a neurodegenerative disease, or cancer.

35. 35. The method, compound for use, pharmaceutical composition or use of any one of claims 27 to 34, 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 autoinflammatory syndromes (CAPS; e.g., familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurological, cutaneous, articular (CINCA) syndrome / neonatal-onset multisystem inflammatory disease (NOMID)), familial Mediterranean fever (FMF), nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), gout, rheumatoid arthritis, osteoarthritis, Crohn's disease, chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD), fibrosis, obesity, type 2 diabetes, multiple sclerosis, skin diseases (e.g., acne), and neuroinflammation occurring in protein misfolding diseases (e.g., prion diseases).

36. 35. The method, compound for use, pharmaceutical composition or use according to any one of claims 27 to 34, wherein the disease or disorder is a neurodegenerative disease; optionally, the disease or disorder is Parkinson's disease or Alzheimer's disease.

37. 35. The method, compound for use, pharmaceutical composition or use of any one of claims 27 to 34, wherein the disease or disorder is cancer; 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.

38. The method, compound for use, pharmaceutical composition or use according to any one of claims 27 to 34, wherein said disease or disorder is an inflammatory disease.

39. 39. The method, compound for use, pharmaceutical composition or use of claim 38, wherein the inflammatory disease is associated with an infectious disease.

40. 40. The method, compound for use, pharmaceutical composition or use of claim 39, wherein the infectious disease is a viral infection.

41. 41. The method, compound for use, pharmaceutical composition or use of claim 40, wherein the viral infection is caused by a single-stranded RNA virus.

42. 42. The method, compound for use, pharmaceutical composition, or use of claim 41, wherein the single-stranded RNA virus is a coronavirus.

43. 43. The method, compound for use, pharmaceutical composition, or use of claim 42, wherein the coronavirus is severe acute respiratory syndrome coronavirus 2 (SARS-CoV 2).

44. 39. The method, compound for use, pharmaceutical composition, or use of claim 38, wherein the inflammatory disease is associated with infection with SARS-CoV 2, which leads to novel coronavirus disease 2019 (COVID-19).

45. 39. The method, compound for use, pharmaceutical composition, or use of claim 38, wherein the inflammatory disease comprises cytokine release syndrome (CRS).

46. 46. ​​The method, compound for use, pharmaceutical composition, or use of claim 45, wherein the CRS is associated with COVID-19.

47. 46. ​​The method, compound for use, pharmaceutical composition or use of claim 45, wherein said CRS is associated with adoptive cell therapy.

48. 48. The method, compound for use, pharmaceutical composition, or use of claim 47, wherein said adoptive cell therapy comprises chimeric antigen receptor T cell (CAR-T) therapy.

Images