Sulfamoylurea derivatives containing an alkyloxacycloalkyl moiety and their use

Abstract

The present disclosure relates to compounds of formula (I), and their pharmaceutically acceptable salts, pharmaceutical compositions, methods of use, and methods for their preparation. The compounds disclosed herein are useful for inhibiting the maturation of IL-1 family cytokines by inhibiting inflammasomes, and can be used in the treatment of disorders involving inflammasome activity, such as inflammatory, autoinflammatory, and autoimmune diseases, and cancer. TIFF2023540733000129.tif21128

Description

[Technical Field]

[0001] Related applications This application claims priority to U.S. Provisional Application No. 63 / 074,521, filed on 4 September 2020, the entire contents of which are incorporated herein by reference.

[0002] Areas of disclosure This disclosure relates to sulfamoylurea derivatives comprising an alkyloxacycloalkyl moiety, their prodrugs, and pharmaceutically acceptable salts thereof, which have inflammasome inhibitory activity and are therefore useful in methods of treating the human or animal body. This disclosure also relates to methods for preparing these compounds, pharmaceutical compositions comprising them, and their use in the treatment of disorders involving inflammasome activity, such as inflammatory diseases, autoinflammatory diseases, and autoimmune diseases, as well as oncological diseases. [Background technology]

[0003] background Autoimmune diseases are associated with the overproduction of inflammatory factors. One of these 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 (Non-patent Literature 1)).

[0004] In humans, the 22 NLR proteins are divided into four NLR subfamilies based on their N-terminal domains. NLRA contains a CARD-AT domain, NLRB (NAIP) contains a BIR domain, NLRC (including NOD1 and NOD2) contains a CARD domain, and NLRP contains a pyrin domain. Several NLR family members are involved in inflammasome formation.

[0005] While inflammasome activation appears to have evolved as a crucial component of host immunity against pathogens, the NLRP3 inflammasome is unique in that it has the ability to be activated in response to endogenous sterile risk signals. Many of these sterile signals have been elucidated, and their formation is associated with specific disease conditions. For example, uric acid crystals found in gout patients are a viable trigger for NLRP3 activation. Similarly, cholesterol crystals found in atherosclerosis patients can also promote NLRP3 activation. Recognizing the role of sterile risk signals as NLRP3 activators, IL-1 and IL-18 are involved in a wide range of pathophysiological signs, including metabolic disorders, physiological disorders, inflammatory disorders, hematological disorders, and immune disorders.

[0006] This disclosure arises from the need to provide further compounds for the specific modulation of NLRP3-dependent cellular processes. In particular, compounds having improved physicochemical, pharmacological, and pharmaceutical properties compared to existing compounds are desirable. [Prior art documents] [Non-patent literature]

[0007] [Non-Patent Document 1] Masters, SL, et. al., Annu. Rev. Immunol. 2009. 27:621-68 [Overview of the project]

[0008] overview In some aspects, this disclosure relates to formula (I): With respect to the compound TIFF0007865948000001.tif21128, or its prodrug, solvate, or pharmaceutically acceptable salt, During the ceremony, R1 is TIFF0007865948000002.tif29128, where n 1a and n 1b Each is independently either 0 or 1; R2 is -(CH2) n2 -R 2S where n2 is 1 or 2; R 2S is a 4- to 8-membered heterocycloalkyl in which at least one heteroatom is O, and the 4- to 8-membered heterocycloalkyl may be substituted with one or more R 2SS ; each R 2SS is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, halo, -CN, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, or oxo; R3 is a 5- or 6-membered heteroaryl which may be substituted with one or more R 3S ; each R 3S is independently halo, C1-C6 alkyl, or C1-C6 haloalkyl.

[0009] In some aspects, the disclosure provides compounds that can be obtained or have been obtained by a method for preparing a compound described herein (e.g., a method comprising one or more steps described in Schemes 1 and 2).

[0010] In some embodiments, the disclosure provides a pharmaceutical composition comprising a compound described herein and one or more pharmaceutically acceptable carriers or excipients.

[0011] In some aspects, the disclosure provides an intermediate described herein that is suitable for use in a method for preparing a compound described herein (e.g., the intermediate is selected from the intermediates described in Examples 1-12).

[0012] In some aspects, the disclosure provides a method of inhibiting inflammasome (e.g., NLRP3 inflammasome) activity (e.g., in vitro or in vivo), the method comprising contacting a cell with an effective amount of a compound of the disclosure.

[0013] In some aspects, the present disclosure provides a method for treating or preventing a disease or disorder disclosed herein in a subject that requires such treatment, comprising the step of administering to the subject a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition thereof.

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

[0015] In some aspects, this disclosure provides compounds of the disclosure for use in treating or preventing diseases or disorders disclosed herein.

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

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

[0018] In some aspects, this disclosure provides methods for compounding the compounds of the disclosure.

[0019] In some aspects, this disclosure provides a method for preparing a compound, comprising one or more steps described herein.

[0020] [Invention 1001] Equation (I): TIFF0007865948000003.tif20128 A compound thereof, or its prodrug, solvate, or pharmaceutically acceptable salt thereof, During the ceremony, R 1 but TIFF0007865948000004.tif28128 And here n 1a and n 1b However, each is independently either 0 or 1; R 2 However, -(CH 2 ) n2 -R 2S And here n 2 However, it is either 1 or 2; R 2S However, it is a 4-8 member heterocycloalkyl group in which at least one heteroatom is O, and the 4-8 member heterocycloalkyl group has one or more R 2SS It may also be replaced with; Each R 2SS However, independently, C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenil, C 2 ~C 6 Alkinyl, C 1 ~C 6 Haloalkyl, Halo, -CN, -OH, -O(C) 1 ~C 6 Alkyl), -NH 2 , -NH(C 1 ~C 6 Alkyl), -N(C 1 ~C 6 Alkyl) 2 , or oxo; R 3 However, one or more R 3S A 5-membered or 6-membered heteroaryl which may be substituted with; Each R 3S However, they became independent, Hello, C 1 ~C 6 Alkyl, or C 1 ~C 6 It is a haloalkyl, The aforementioned compound, or its prodrug, solvate, or pharmaceutically acceptable salt. [Invention 1002] R 1 but TIFF0007865948000005.tif28128 And here n 1a and n 1b However, each is independently either 0 or 1; R 2 However, -(CH 2 ) n2 -R 2S And here n 2 However, it is either 1 or 2; R 2S However, it is a 4- to 8-membered heterocycloalkyl group in which at least one heteroatom is O, and the 4- to 8-membered heterocycloalkyl group may be substituted with one or more -OH groups; R 3 However, one or more C 1 ~C 6 A 5-membered or 6-membered heteroaryl which may be substituted with an alkyl group. Any of the compounds of the present invention described above. [Invention 1003] n 1a and n 1b Any of the compounds of the present invention, wherein both of the following are 1. [Invention 1004] R 1 but TIFF0007865948000006.tif22128 A compound of the present invention, which is any of the above-mentioned compounds. [Invention 1005] R 1 but TIFF0007865948000007.tif22128 A compound of the present invention, which is any of the above-mentioned compounds. [Invention 1006] R 1 but TIFF0007865948000008.tif19128 A compound of the present invention, which is any of the above-mentioned compounds. [Invention 1007] R 2 However, -CH 2 -R 2S A compound of the present invention, which is any of the above-mentioned compounds. [Invention 1008] R 2 However, -CH 2 -R 2S And, R 2S The compound is tetrahydrofuranil or tetrahydropyranil, and the tetrahydrofuranil or tetrahydropyranil may be substituted with one or more -OH groups. Any of the compounds of the present invention described above. [Invention 1009] R 2 However, -(CH 2 ) 2 -R 2S A compound of the present invention, which is any of the above-mentioned compounds. [Invention 1010] R 2 However, -(CH 2 ) 2 -R 2S And, R 2S The compound is tetrahydrofuranil or tetrahydropyranil, and the tetrahydrofuranil or tetrahydropyranil may be substituted with one or more -OH groups. Any of the compounds of the present invention described above. [Invention 1011] R 2S However, it is a 5-6 member heterocycloalkyl group in which at least one heteroatom is O, and the 5-6 member heterocycloalkyl group has one or more R 2SS Any of the compounds of the present invention described above, which may be substituted with. [Invention 1012] R 2S However, it is a 5-6 member heterocycloalkyl having one heteroatom, and the heteroatom is O, and the 5-6 member heterocycloalkyl has one or more R 2SS Any of the compounds of the present invention described above, which may be substituted with. [Invention 1013] R 2S However, it is a 5-membered heterocycloalkyl having one heteroatom, and the heteroatom is O, and the 5-membered heterocycloalkyl has one or more R 2SS Any of the compounds of the present invention described above, which may be substituted with. [Invention 1014] R 2S However, it is a 6-membered heterocycloalkyl having one heteroatom, the heteroatom being O, and the 6-membered heterocycloalkyl having one or more R 2SS Any of the compounds of the present invention described above, which may be substituted with. [Invention 1015] at least one R 2SS Any of the compounds of the present invention described above, wherein the hydroxyl group is -OH. [Invention 1016] R 2S However, the tetrahydrofuranil or tetrahydropyranil is one or more R 2SS Any of the compounds of the present invention described above, which may be substituted with. [Invention 1017] R 2S The compound of the present invention is any of the above, wherein the compound is tetrahydrofuranil or tetrahydropyranil, and the tetrahydrofuranil or tetrahydropyranil may be substituted with one or more -OH groups. [Invention 1018] R 2S Any of the compounds of the present invention, wherein the compound is a tetrahydrofuranyl which may be substituted with one or more -OH groups. [Invention 1019] R 2S However, any of the compounds of the present invention, wherein the compound is tetrahydrofuranyl. [Invention 1020] R 2S The compound of the present invention is any of the above, wherein the compound is a tetrahydrofuranyl substituted with one or more -OH groups. [Invention 1021] R 2S However, any of the compounds of the present invention, wherein the compound is tetrahydropyranyl. [Invention 1022] R 2S The compound of the present invention is any of the above, wherein the compound is tetrahydropyranyl substituted with one or more -OH groups. [Invention 1023] R 3 However, one or more R 3S Any of the compounds of the present invention, which are five-membered or six-membered heteroaryl compounds substituted with . [Invention 1024] R 3 However, one or more C 1 ~C 6 Any of the compounds of the present invention, which are alkyl-substituted five-membered or six-membered heteroaryl compounds. [Invention 1025] R 3 However, one or more C 1 ~C 6 Any of the compounds of the present invention described above, which are alkyl-substituted pyrazolyl compounds. [Invention 1026] R 3 but TIFF0007865948000009.tif15128 A compound of the present invention, which is any of the above-mentioned compounds. [Invention 1027] R 3 but TIFF0007865948000010.tif11128 A compound of the present invention, which is any of the above-mentioned compounds. [Invention 1028] Equation (Ia-1) or (Ia-2): TIFF0007865948000011.tif56128 Any of the compounds of the present invention, which are compounds of, or their prodrugs, solvates, or pharmaceutically acceptable salts. [Invention 1029] Equation (Ib-1) or (Ib-2): TIFF0007865948000012.tif55128 Any of the compounds of the present invention, which are compounds of, or their prodrugs, solvates, or pharmaceutically acceptable salts. [Invention 1030] Equations (Ic-1), (Ic-2), or (Ic-3): TIFF0007865948000013.tif75128 Any of the compounds of the present invention, which are compounds of, or their prodrugs, solvates, or pharmaceutically acceptable salts. [Invention 1031] Equation (Id-1) or (Id-2): TIFF0007865948000014.tif58128 Any of the compounds of the present invention, which are compounds of, or their prodrugs, solvates, or pharmaceutically acceptable salts. [Invention 1032] Formulas (Ie-1), (Ie-2), (Ie-3), or (Ie-4): TIFF0007865948000015.tif140128 Any of the compounds of the present invention, which are compounds of, or their prodrugs, solvates, or pharmaceutically acceptable salts. [Invention 1033] Any of the compounds of the present invention, selected from compound numbers 1, 1A, 1B, 2, 2A, 2B, 3, 3A, 3B, 4, 4A, 4B, 5, 5A, 5B, 6, 6A, 6B, 7A, 7B, 8A, and 8B, as well as their prodrugs and pharmaceutically acceptable salts. [Invention 1034] A compound that is an isotopic derivative of any of the compounds of the present invention described above. [Invention 1035] Compounds that can be obtained or obtained by the methods described herein, Optionally, a compound wherein the method comprises one or more steps described in schemes 1 to 3. [Invention 1036] An intermediate obtained by a method for preparing any of the compounds of the present invention, Optionally, an intermediate selected from the intermediates described in Examples 1 to 12. [Invention 1037] A pharmaceutical composition comprising any of the compounds of the present invention described above and a pharmaceutically acceptable diluent or carrier. [Invention 1038] A method for inhibiting inflammasome activity, comprising the step of contacting cells with an effective amount of any of the compounds of the present invention, Optionally, a method in which the inflammasome is the NLRP3 inflammasome and the activity is in vitro or in vivo. [Invention 1039] A method for treating or preventing a disease or disorder in a person who needs to be treated or prevented, A method comprising the step of administering to a subject a therapeutically effective amount of any of the compounds or pharmaceutical compositions of the present invention described above. [Invention 1040] Any of the compounds or pharmaceutical compositions of the present invention for use in inhibiting inflammasome activity, Optionally, a compound or pharmaceutical composition in which the inflammasome is the NLRP3 inflammasome and the activity is in vitro or in vivo. [Invention 1041] Any of the compounds or pharmaceutical compositions of the present invention for use in treating or preventing a disease or disorder. [Invention 1042] The use of any of the compounds of the present invention in the manufacture of a pharmaceutical product for inhibiting inflammasome activity, Optionally, use if the inflammasome is the NLRP3 inflammasome and the activity is in vitro or in vivo. [Invention 1043] Use of any of the compounds of the present invention in the manufacture of a pharmaceutical product for treating or preventing a disease or disorder. [Invention 1044] Disease or disorder is associated with the involvement of inflammasome activity, Optionally, the disease or disorder is one in which inflammasome activity is involved. Any of the methods, compounds, pharmaceutical compositions, or uses of the present invention as described above. [Invention 1045] Any method, compound, pharmaceutical composition, or use of the present invention, wherein the disease or disorder is an inflammatory disorder, autoinflammatory disorder, autoimmune disorder, neurodegenerative disease, or cancer. [Invention 1046] The disease or disorder is an inflammatory disorder, autoinflammatory disorder, or autoimmune disorder. Optionally, the disease or disorder is selected from neuroinflammation occurring in cryopyrin-associated autoinflammatory syndromes (CAPS; e.g., familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurocutaneous arthritis (CINCA) syndrome / neonatal onset multiorgan inflammatory disease (NOMID)), familial Mediterranean fever (FMF), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), gout, rheumatoid arthritis, osteoarthritis, Crohn's disease, chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD), fibrosis, obesity, type 2 diabetes, multiple sclerosis, skin diseases (e.g., acne), and protein misfolding disorders (e.g., prion diseases). Any of the methods, compounds, pharmaceutical compositions, or uses of the present invention as described above. [Invention 1047] If the disease or disorder is a neurodegenerative disease, Optionally, if the disease or disorder is Parkinson's disease or Alzheimer's disease, Any of the methods, compounds, pharmaceutical compositions, or uses of the present invention as described above. [Invention 1048] If 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. Any of the methods, compounds, pharmaceutical compositions, or uses of the present invention as described above. [Invention 1049] Any method, compound, pharmaceutical composition, or use of the present invention wherein the disease or disorder is an inflammatory disease. [Invention 1050] Any method, compound, pharmaceutical composition, or use of the present invention relating to an inflammatory disease associated with infection. [Invention 1051] Any method, compound, pharmaceutical composition, or use of the present invention, wherein the infection is a viral infection. [Invention 1052] Any method, compound, pharmaceutical composition, or use of the present invention, wherein the viral infection is caused by a single-stranded RNA virus. [Invention 1053] Any method, compound, pharmaceutical composition, or use of the present invention, wherein the single-stranded RNA virus is a coronavirus. [Invention 1054] Any method, compound, pharmaceutical composition, or use of the present invention, wherein the coronavirus is severe acute respiratory syndrome coronavirus 2 (SARS-CoV 2). [Invention 1055] Any method, compound, pharmaceutical composition, or use of the present invention relating an inflammatory disease to infection by SARS-CoV 2, which leads to COVID-19. [Invention 1056] Any method, compound, pharmaceutical composition, or use of the present invention, wherein the inflammatory disease includes cytokine release syndrome (CRS). [Invention 1057] Any method, compound, pharmaceutical composition, or use of the present invention relating CRS to COVID-19. [Invention 1058] Any method, compound, pharmaceutical composition, or use of the present invention relating CRS to adoptive cell therapy. [Invention 1059] Any method, compound, pharmaceutical composition, or use of the present invention, wherein adoptive cell therapy includes chimeric antigen receptor T cell (CAR-T) therapy. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art in the field to which this disclosure belongs. In this specification, singular nouns also include plural nouns unless otherwise clearly indicated by the context. Methods and materials similar to or equivalent to those described herein may be used in the practice or testing of this disclosure, but preferred methods and materials are described below. All publications, patent applications, patents, and other references referenced herein are incorporated by reference. References cited herein are not considered prior art of the claimed invention. In case of any conflict, this specification, including definitions, shall prevail. Furthermore, materials, methods, and examples are illustrative only and are not intended to be limiting. In case of any conflict between a chemical structure and the name of a compound disclosed herein, the chemical structure shall prevail.

[0021] Other features and advantages of this disclosure will be apparent from the following detailed description and claims. [Modes for carrying out the invention]

[0022] Detailed explanation Autoimmune diseases are associated with the overproduction of inflammatory factors. One of these 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] Cytokines in the IL-1 family are highly active and, as important inflammatory mediators, are primarily associated with acute and chronic inflammation (Sims J. et al. Nature Reviews Immunology 10, 89-102 (February 2010)). Overproduction of IL-1 is thought to be a mediator in several autoimmune and autoinflammatory diseases. Autoinflammatory diseases are characterized by recurrent and idiopathic inflammation in the absence of autoantibodies, infections, or antigen-specific T lymphocytes.

[0024] The IL-1 superfamily of inflammatory cytokines includes IL-1α, IL-1β, IL-18, and IL-36α,β,λ, which are produced as part of the host innate immune response in response to pathogens and other cellular stressors. Unlike many other secretory cytokines that are processed and released by standard cellular secretory organelles consisting of the endoplasmic reticulum and Golgi apparatus, IL-1 family members lack the leader sequence required for endoplasmic reticulum translocation and are therefore retained intracellularly after translation. Furthermore, IL-1β, IL-18, and IL-36α,β,λ are synthesized as procytokines that require proteolytic activation to become optimal ligands for binding to their homologous receptors on target cells.

[0025] Currently, in the case of IL-1α, IL-1β, and IL-18, a multimeric protein complex known as the inflammasome is recognized as the cause of activation of the pro-forms of IL-1β and IL-18, as well as the extracellular release of these cytokines. Typically, the inflammasome complex consists of sensor molecules such as NLR (nucleotide oligomerization domain (NOD)-like receptor), an adapter molecule ASC (an apoptosis-related speck-like protein containing CARD (caspase mobilization domain)), and procaspase 1. In response to various "danger signals," including pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs), inflammasome subunits oligomerize to form supramolecular structures within the cell. Examples of PAMPs include molecules such as peptidoglycans, viral DNA or RNA, and bacterial DNA or RNA. On the other hand, DAMPs consist of a wide range of endogenous or exogenous sterile triggers, including monosodium urate crystals, silica, alum, asbestos, fatty acids, ceramides, cholesterol crystals, and β-amyloid peptide aggregates. The construction of an inflammasome platform enhances the autocatalytic activity of procaspase 1, leading to the generation of highly active cysteine ​​proteases responsible for the activation and release of pro-IL-1β and pro-IL-18. Therefore, the release of these highly inflammatory cytokines is achieved only in response to inflammasome sensors that detect and respond to specific molecular danger signals.

[0026] In humans, 22 NLR proteins are divided into four NLR subfamilies based on their N-terminal domains. NLRA contains a CARD-AT domain, NLRB (NAIP) contains a BIR domain, NLRC (including NOD1 and NOD2) contains a CARD domain, and NLRP contains a pyrin domain. Several NLR family members, including NLRP1, NLRP3, NLRP6, NLRP7, NLRP12, and NLRC4 (IPAF), are involved in inflammasome formation.

[0027] Two other structurally distinct inflammasome structures containing the PYHIN domain (pyrin and HIN domain-containing proteins), namely Absent in Melanoma 2 (AIM2) and IFNλ-inducible protein 16 (IFI16) (Latz et al., Nat Rev Immunol 2013 13(6) 397-311), serve as intracellular DNA sensors. Pyrin (encoded by the MEFV gene) is another type of inflammasome platform associated with proIL-1β activation (Chae et al., Immunity 34, 755-768, 2011).

[0028] Since the construction of an inflammasome platform is necessary to achieve the activation of IL-1β and IL-18 and their release from monocytes and macrophages, their production is undoubtedly carefully set up as a two-step process. First, NFκB-dependent transcription of NLRP3, pro-IL-1β, and pro-IL-18 occurs when the cell encounters a priming ligand (e.g., TLR4 receptor ligand LPS, or an inflammatory cytokine such as TNFα). 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 procaspase 1.

[0029] 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 the cleavage of gasdermin D. Pyroptosis exogenizes the mature forms of IL-1β and IL-18 along with the release of alarmin molecules such as high-mobility box 1 protein (HMGB1), IL-33, and IL-1α (compounds that promote inflammation and activate innate and adaptive immunity).

[0030] While inflammasome activation appears to have evolved as a crucial component of host immunity against pathogens, the NLRP3 inflammasome is unique in that it has the ability to be activated in response to endogenous and exogenous sterile risk signals. Many of these sterile signals have been elucidated, and their formation is associated with specific disease conditions. For example, uric acid crystals found in gout patients are a viable trigger for NLRP3 activation. Similarly, cholesterol crystals found in atherosclerosis patients can also promote NLRP3 activation. Recognizing the role of sterile risk signals as NLRP3 activators, IL-1β and IL-18 are involved in a wide range of pathophysiological signs, including metabolic disorders, physiological disorders, inflammatory disorders, hematological disorders, and immune disorders.

[0031] The association with human diseases is best exemplified by the discovery that mutations in the NLRP3 gene that result in gain-of-function lead to a range of autoinflammatory conditions collectively known as cryopyrin-associated periodic syndromes (CAPS), including familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multiorgan inflammatory disease (NOMID) (Hoffman et al., Nat Genet. 29(3) (2001) 301-305). Similarly, sterile mediator-induced activation of NLRP3 is involved in a wide range of disorders, including joint degeneration (gout, rheumatoid arthritis, osteoarthritis), cardiovascular metabolic disorders (type 2 diabetes, atherosclerosis, hypertension), central nervous system disorders (Alzheimer's disease, Parkinson's disease, multiple sclerosis), gastrointestinal disorders (Crohn's disease, ulcerative colitis), and pulmonary disorders (chronic obstructive pulmonary disease (COPD), asthma, idiopathic pulmonary fibrosis, and hepatic fibrosis, non-alcoholic steatohepatitis (NASH)). Furthermore, NLRP3 activation is thought to promote renal inflammation and therefore contribute to chronic kidney disease (CKD).

[0032] Current treatment options for diseases in which IL-1 is involved as a contributing factor to pathogenesis include the IL-1 receptor antagonist anakinra, an Fc-containing fusion construct of the extracellular domains of the IL-1 receptor and IL-1 receptor accessory protein (lilonacept), and the anti-IL-1β monoclonal antibody canakinumab. For example, canakinumab is approved for CAPS, tumor necrosis factor receptor-associated periodic syndromes (TRAPS), hyperimmune globulin D syndrome (HIDS) / mevalonate kinase deficiency (MKD), familial Mediterranean fever (FMF), and gout.

[0033] Several small molecules have been reported to inhibit the function of the NLRP3 inflammasome. For example, glybrid is a specific inhibitor of NLRP3 activation, even 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 impair NLRP3 activation, but their therapeutic utility is expected to be limited due to their shared structural characteristic of being composed of olefins activated by electron-withdrawing group substitution. This substitution can lead to the undesirable formation of covalent adducts with thiol groups containing proteins. Several natural products, such as β-hydroxybutyrate, sulforaphane, quercetin, and salvianolic acid, have also been reported to suppress NLRP3 activation. Similarly, numerous effectors / modulators targeting other molecular targets, including G protein-coupled receptor TGR5 agonists, sodium-glucose cotransport inhibitors such as empagliflozin, dopamine receptor antagonist A-68930, serotonin reuptake inhibitors such as fluoxetine, fenamic acid-based nonsteroidal anti-inflammatory drugs, and the β-adrenergic receptor blocker nevivolol, have been reported to impair NLRP3 activation. The efficacy of these molecules as therapeutic agents for the chronic treatment of NLRP3-dependent inflammatory disorders remains unestablished. A range of sulfonylurea-containing molecules have already been identified as potent and selective inhibitors of pro-IL-1β posttranslational processing (Perregaux et al., J Pharmacol. Exp. Ther. 299, 187-197, 2001). The exemplary molecules CP-456,773 in this study were characterized as specific inhibitors of NLRP3 activation (Coll et al., Nat Med 21.3 (2015): 248-255).

[0034] This disclosure relates to compounds useful for the specific modulation of NLRP3-dependent cellular processes. In particular, there is a need for compounds that have improved physicochemical, pharmacological, and pharmaceutical properties compared to existing NLRP3 modulating compounds.

[0035] definition Unless otherwise stated, the following terms used in this specification and in the claims shall have the meanings set forth below.

[0036] While we do not intend to limit ourselves by this statement, it will be understood that various options for the variable parts are described herein, and this disclosure encompasses functional embodiments having combinations of those options. This disclosure may be interpreted as excluding non-functional embodiments resulting from certain combinations of those options.

[0037] It should be understood that the compounds of this disclosure may be represented in neutral form, cationic form (e.g., having one or more positive charges), or anionic form (e.g., having one or more negative charges), and that all of these are included within the scope of this disclosure. For example, if a compound of this disclosure is represented in anionic form, it should be understood that such a description also refers to the various neutral, cationic, and anionic forms of that compound. As another example, if a compound of this disclosure is represented in anionic form, it should be understood that it also refers to the various salts (e.g., sodium salts) of the anionic form of that compound.

[0038] The "therapeutic dose" refers to the amount of a compound that, when administered to a mammal to treat a disease, is sufficient to achieve such treatment of that disease. The "therapeutic dose" will vary depending on the compound, the disease and its severity, as well as the age and weight of the mammal being treated.

[0039] As used herein, “alkyl,” “C1, C2, C3, C4, C5, or C6 alkyl,” or “C1-C6 alkyl” is intended to include a C1, C2, C3, C4, C5, or C6 linear saturated aliphatic hydrocarbon group and a C3, C4, C5, or C6 branched saturated aliphatic hydrocarbon group. For example, C1-C6 alkyl is intended to include C1, C2, C3, C4, C5, and C6 alkyl groups. Examples of alkyls include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, or n-hexyl, and include moieties having 1 to 6 carbon atoms. In some embodiments, linear or branched alkyls have 6 or fewer carbon atoms (e.g., C1-C6 in linear chains, C3-C6 in branched chains), and in other embodiments, linear or branched alkyls have 4 or fewer carbon atoms.

[0040] As used herein, the term "optionally substituted alkyl" means an unsubstituted alkyl or an alkyl having a predetermined substituent that replaces one or more hydrogen atoms on one or more carbons of a hydrocarbon skeleton. Examples of these substituents include 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, sulfonate, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, heterocyclyl, alkylaryl, or aromatic or heteroaromatic moieties.

[0041] As used herein, the term “alkenyl” includes unsaturated aliphatic groups that are similar to the alkyls described above in length and possible substitutions, but contain at least one double bond. For example, the term “alkenyl” includes linear alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl) and branched alkenyl groups. In certain embodiments, linear or branched alkenyl groups have six or fewer carbon atoms in their skeleton (e.g., C2-C6 for linear groups, C3-C6 for branched groups). The term “C2-C6” includes alkenyl groups containing two to six carbon atoms. The term “C3-C6” includes alkenyl groups containing three to six carbon atoms.

[0042] As used herein, the term "optionally substituted alkenyl" means an unsubstituted alkenyl or an alkenyl having a predetermined substituent that replaces one or more hydrogen atoms on one or more carbon atoms of a hydrocarbon skeleton. Examples of these substituents include 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, sulfonate, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, heterocyclyl, alkylaryl, or aromatic or heteroaromatic moieties.

[0043] As used herein, the term "alkynyl" includes unsaturated aliphatic groups that are similar to the alkyls described above in length and possible substitutions, but contain at least one triple bond. For example, "alkynyl" includes linear alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octinyl, noninyl, desynyl) and branched alkynyl groups. In certain embodiments, linear or branched alkynyl groups have six or fewer carbon atoms in their skeleton (e.g., C2-C6 for linear groups, C3-C6 for branched groups). The term "C2-C6" includes alkynyl groups containing two to six carbon atoms. The term "C3-C6" includes alkynyl groups containing three to six carbon atoms. As used herein, "C2-C6 alkenylene linker" or "C2-C6 alkynylene linker" is intended to contain a C2, C3, C4, C5, or C6 (straight-chain or branched-chain) diunsaturated aliphatic hydrocarbon group. For example, a C2-C6 alkenylene linker is intended to contain a C2, C3, C4, C5, and C6 alkenylene linker group.

[0044] As used herein, the term "optionally substituted alkynyl" means an unsubstituted alkynyl or an alkynyl having a predetermined substituent that replaces one or more hydrogen atoms on one or more carbon atoms of a hydrocarbon skeleton. Examples of these substituents include 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, sulfonate, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, heterocyclyl, alkylaryl, or aromatic or heteroaromatic moieties.

[0045] Other optionally substituted portions (e.g., optionally substituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl) include both an unsubstituted portion and a portion having one or more predetermined substituents. For example, substituted heterocycloalkyls include heterocycloalkyls 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.

[0046] As used herein, the term "cycloalkyl" refers to a molecule having 3 to 30 carbon atoms (e.g., C3-C3). 12 , C3~C 10This refers to saturated or partially unsaturated monocyclic or polycyclic (e.g., fused ring, crosslinked ring, or spiro-ring) hydrocarbon systems (C3-C8). Examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,2,3,4-tetrahydronaphthalenyl, and adamantyl. In the case of polycyclic cycloalkyls, only one of the rings in the cycloalkyl needs to be non-aromatic.

[0047] As used herein, the term "heterocycloalkyl" means, unless otherwise specified, one or more heteroatoms (e.g., O, N, S, P, or Se) independently selected from the group consisting of nitrogen, oxygen, and sulfur, e.g., one or one to two or one to three or one to four or one to five or one to six heteroatoms, or saturated or partially unsaturated 3- to 8-membered monocyclic systems, 7- to 12-membered bicyclic systems (fused, bridging, or spirocyclic systems), or 11- to 14-membered tricyclic systems (fused, bridging, or spirocyclic systems) having e.g., one, two, three, four, five, or six heteroatoms.Examples of heterocycloalkyl groups include piperidinyl, piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, isoindolinyl, indolinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, oxyranyl, 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'-fl[3,4-b]pyridine]-yl, 3'H-spiro[cyclohexane-1,1'-fl[3,4-c]pyridine]-yl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexane-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]pyrid Examples include, but are not limited to, nyl, 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-oxazaspiro[3.4]octanyl, and 2-oxazaspiro[3.4]octan-6-yl. In the case of polycyclic heterocycloalkyls, only one of the rings in the heterocycloalkyl needs to be non-aromatic (e.g., 4,5,6,7-tetrahydrobenzo[c]isoxazolyl).

[0048] As used herein, the term "aryl" includes aromatic groups that are conjugated or polycyclic, having one or more aromatic rings, and that do not contain 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, and naphthyl. Conveniently, aryl is phenyl.

[0049] As used herein, the term “heteroaryl” is intended to include stable 5-membered, 6-membered, or 7-membered monocyclic aromatic heterocycles or 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, or 12-membered bicyclic aromatic heterocycles, consisting of one or more heteroatoms independently selected from the group consisting of carbon atoms and nitrogen, oxygen, and sulfur, for example, one or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or for example, one, two, three, four, five, or six heteroatoms. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR, where R is H or another defined substituent). The nitrogen and sulfur heteroatoms may be oxidized (i.e., N → O and S(O)). p (where p=1 or 2). It should be noted that the total number of S and O atoms in the aromatic heterocycle does not exceed 1. Examples of heteroaryl groups include pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, pyridine, pyrazine, pyridazine, and pyrimidine. To form a polycyclic system, the heteroaryl group can be fused to or bridged with a non-aromatic alicyclic or heterocyclic ring (e.g., 4,5,6,7-tetrahydrobenzo[c]isoxazolyl).

[0050] Furthermore, the terms "aryl" and "heteroaryl" include polycyclic aryl and heteroaryl groups, such as tricyclic and bicyclic groups, such as naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzimidazole, benzothiophene, quinoline, isoquinoline, naphthyridine, indole, purine, benzofuran, deazapurine, and indoridine.

[0051] A cycloalkyl ring, heterocycloalkyl ring, aryl ring, or heteroaryl ring may have one or more substituents at ring positions (e.g., heteroatoms such as carbon atoms or N that form the ring), such as alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl They may be substituted with carbonyl, 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, sulfonate, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, heterocyclyl, alkylaryl, or aromatic or heteroaromatic moieties. Aryl and heteroaryl groups may be condensed or crosslinked with non-aromatic alicyclic or heterocyclic rings to form polycyclic systems (e.g., tetralin or methylenedioxyphenyl such as benzo[d][1,3]dioxol-5-yl).

[0052] As used herein, the term “substituted” means that any one or more hydrogen atoms on a given atom are replaced by selection from a specified group, provided that the substitution does not exceed the normal valence of the given atom and a stable compound is obtained. If the substituent is oxo or keto (i.e., =O), two hydrogen atoms on the atom are replaced. Keto substituents are not present on 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 intended to indicate a compound that is robust enough to withstand isolation from a reaction mixture in useful purity and formulation into an effective therapeutic agent.

[0053] If a bond to a substituent is indicated as crossing a bond connecting two atoms in a ring, the substituent may be bonded to any atom in the ring. If a substituent is enumerated without indicating which atoms of the substituent are bonded to the rest of the compound in a given formula, the substituent may be bonded through any atom in the formula. A combination of substituents and / or variants is permitted only if the combination results in a stable compound.

[0054] If any variable element (e.g., R) appears two or more times in any component or formula of a compound, the definition of that element for each occurrence is independent of the definition of that element for each other occurrence. Therefore, for example, if a group is indicated to be substituted with 0 to 2 R moieties, that group may be substituted with up to 2 R moieties, and the R for each occurrence is independently selected from the definition of R. Furthermore, combinations of substituents and / or variable elements are only permitted if the combination results in a stable compound.

[0055] As used herein, the terms "hydroxy" or "hydroxyl" refer to -OH or -O - It contains a group having a group.

[0056] As used herein, the terms "halo" or "halogen" mean fluoro, chloro, bromo, and iodine.

[0057] The terms "haloalkyl" or "haloalkoxyl" refer to alkyl or alkoxyl compounds substituted with one or more halogen atoms.

[0058] As used herein, the term "optionally substituted haloalkyl" means an unsubstituted haloalkyl or a haloalkyl having a predetermined substituent that replaces one or more hydrogen atoms on one or more carbon atoms of a hydrocarbon skeleton. Examples of these substituents include 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, sulfonate, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, heterocyclyl, alkylaryl, or aromatic or heteroaromatic moieties.

[0059] As used herein, the terms "alkoxy" or "alkoxyl" include substituted and unsubstituted alkyl groups, alkenyl groups, and alkynyl groups covalently bonded to an oxygen atom. Examples of alkoxy or alkoxyl groups include, but are not limited to, methoxy, ethoxy, isopropyloxy, propoxy, butoxy, and pentoxy groups. Examples of substituted alkoxy groups include halogenated alkoxy groups. The alkoxy group may be 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, sulfonate, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, heterocyclyl, alkylaryl, or aromatic or heteroaromatic moieties. Examples of halogen-substituted alkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, and trichloromethoxy.

[0060] Unless otherwise indicated, expressions used herein such as “one or more of A, B, or C,” “one or more A, B, or C,” “one or more of A, B, and C,” “one or more A, B, and C,” “selected from the group consisting of A, B, and C,” and “selected from A, B, and C” are interchangeable and all mean a selection from the group consisting of A, B, and / or C, i.e., one or more A, one or more B, one or more C, or any combination thereof.

[0061] As used herein, “Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV 2)” refers to the coronavirus that caused the 2019 novel coronavirus disease (COVID-19). COVID-19 was first identified in Wuhan, China in 2019 and has resulted in an ongoing global pandemic. By August 2020, more than 25 million cases had been reported worldwide, with 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, multiple organ failure, septic shock, and blood clots, likely due to cytokine release syndrome (CRS). The time from exposure to the virus to the onset of symptoms is typically around 5 days, but can range from 2 to 14 days. In some aspects, SARS-CoV 2 refers to a mutation of the coronavirus that caused the 2019 novel coronavirus disease (COVID-19).

[0062] In some embodiments, the coronavirus may be SARS-CoV (i.e., SARS), SARS-CoV-2, MERS-CoV (i.e., MERS), or a mutant and / or variant thereof. In some embodiments, the subject has a disease or lesion associated with MERS and / or its variant. In some embodiments, the subject has a disease or lesion associated with SARS and / or its variant. In some embodiments, the subject has a disease or lesion associated with SARS-CoV-2 and / or its variant. "Variant" refers to a genetic variant of a coronavirus in which a novel genetic mutation occurs with respect to one or more known strains of coronavirus. Mutations (e.g., substitutions or deletions) can occur at any nucleotide in the coronavirus genome. A variant may be a variant of note, a variant of concern, or a variant that is expected to cause significant harm. For example, B.1.1.7 (alpha), B.1.351 (beta), B.1.617 (delta), and P.1 (gamma), B.1.526 (iota), B.1.427 (epsilon), B.1.429 (epsilon), B.1.1.7 (alpha), P.2 (zeta), and their lineages are classified as variants of SARS-CoV-2. It will be understood that new variants of coronavirus with novel mutations or sets of mutations may arise, and these too will be included in the term "coronavirus" as used herein.

[0063] As used herein, “cytokine release syndrome (CRS)” refers to a systemic inflammatory response that can be triggered by a variety of factors, including, but not limited to, drugs, infections such as SARS-CoV-2, and immunotherapy such as chimeric antigen receptor T-cell (CAR-T) therapy. In CRS, numerous immune cells (e.g., T cells) are activated and release inflammatory cytokines, which in turn activate further immune cells. Symptoms include fever, fatigue, loss of appetite, myoarthralgia, nausea, vomiting, diarrhea, rash, respiratory failure, hypotension, seizures, headache, and confusion. CRS may respond to IL-6 receptor inhibition and high doses of steroids.

[0064] As used herein, “adoptive cell therapy” refers to a form of treatment that uses immune cells to treat diseases such as cancer. Immune cells, such as T cells, are collected from a subject or other source, multiplied in large numbers, and transplanted into the subject to help the immune system fight the disease. Types of adoptive cell therapy include chimeric antigen receptor T cell (CAR-T) therapy, tumor-infiltrating lymphocyte (TIL) therapy, and T cell receptor T cell (TCR-T) therapy.

[0065] 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 encompass engineered receptors that impart artificial specificity to specific immune effector cells. CARs can be used to confer the specificity of a monoclonal antibody to T cells, thereby enabling the generation of a large number of specific T cells, for example, for adoptive cell therapy. For example, a CAR can direct the specificity of cells expressing that CAR toward tumor-associated antigens. In some embodiments, a CAR comprises an intracellular activation domain, a transmembrane domain, and an extracellular domain including an antigen-binding domain, and optionally an extracellular hinge. The antigen-binding domain can be any antigen-binding domain known in the art, including antigen-binding domains derived from antibodies, Fab, F(ab')2, nanobodies, single-domain antigen-binding domains, scFv, VHH, etc. In certain aspects, a CAR comprises a fusion of a monoclonal antibody-derived single-chain variable fragment (scFv) fused to the transmembrane and endodomains of CD3. In certain cases, CARs include domains for additional co-stimulatory signaling, such as CD3, FcR, CD27, CD28, CD137, DAP10, and / or 0X40.

[0066] The T cell receptor (TCR) is a protein complex found on the surface of T cells, or T lymphocytes, which is responsible for recognizing antigen fragments as peptides bound to the major histocompatibility complex (MHC) molecule. The T cell receptor can be engineered to express an antigen-binding domain specific to a particular antigen and can be used in the adoptive cell therapy described herein.

[0067] It should be understood that this disclosure provides methods for the synthesis of compounds of any of the formulas described herein. This disclosure also provides detailed methods for the synthesis of various disclosed compounds of this disclosure, according to the schemes shown in the following schemes and examples.

[0068] Throughout this specification, when a composition is described as having, encompassing, or containing a particular component, it should be understood that the composition may essentially consist of or comprise the described component. Similarly, when a method or process is described as having, encompassing, or containing a particular step, the method may essentially consist of or comprise the described step. Furthermore, it should be understood that the order of the steps or the order in which a particular action is performed is not important, as long as the invention remains practicable. Moreover, two or more steps or actions may be performed simultaneously.

[0069] It should be understood that the synthesis method described herein is tolerant of a wide variety of functional groups, and therefore a variety of substituted starting materials can be used. While the method generally yields the desired final compound at or near the end of the entire process, in certain cases it may be desirable to further convert the compound to its pharmaceutically acceptable salts.

[0070] It should be understood that the compounds disclosed herein can be prepared in various ways using commercially available starting materials, using literature-known compounds, or from readily prepared intermediates, by using standard synthetic methods and procedures that are known to those skilled in the art or would be apparent to those skilled in the art in light of the teachings herein. Standard synthetic methods and procedures for the preparation of organic molecules, as well as standard transformations and manipulations of functional groups, can be obtained from relevant scientific literature or from standard textbooks in the art. Not limited to any one or more sources, but incorporated herein by reference, is Smith, MB, March, J., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5 th edition, John Wiley & Sons: New York, 2001; Greene, TW, Wuts, PGM, Protective Groups in Organic Synthesis, 3rd Classic textbooks such as 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 well-regarded reference texts for organic synthesis, known to those skilled in the art.

[0071] Those skilled in the art will note that the order of certain steps, such as the introduction and removal of protecting groups, can be modified within the reaction sequences and synthetic schemes described herein. Those skilled in the art will recognize that certain groups may require protection from reaction conditions by the use of protecting groups. Protecting groups may also be used to identify similar functional groups in a molecule. For a list of protecting groups, and how to introduce and remove them, see Greene, TW, Wuts, PGM, Protective Groups in Organic Synthesis, 3. rd This can be seen in the edition, John Wiley & Sons: New York, 1999.

[0072] Unless otherwise stated, any description of treatment methods should be understood to include the use of the Compound to perform the treatment or prevention described herein, and the use of the Compound to prepare a medicament for treating or preventing such condition. Treatment includes treatment of human or non-human animals, including rodents and other disease models.

[0073] As used herein, the term “subject” encompasses human and non-human animals, as well as cell lines, cell cultures, tissues, and organs. In some embodiments, the subject is a mammal. Mammals may be, for example, humans or suitable non-human mammals, such as primates, mice, rats, dogs, cats, cattle, horses, goats, camels, sheep, or pigs. The subject may also be a bird or poultry. In some embodiments, the subject is a human.

[0074] As used herein, the term “subjects in need” means subjects who have a disease or are at increased risk of disease progression. Subjects in need may be subjects who have already been diagnosed or identified as having a disease or disorder described herein. Alternatively, subjects in need may be subjects suffering from a disease or disorder described herein. Or, subjects in need may be subjects who are at increased risk of developing such a disease or disorder compared to the general population (i.e., subjects who are more likely to develop such a disorder compared to the general population). Subjects in need may have a refractory or resistant disease or disorder described herein (i.e., a disease or disorder described herein that does not respond to or has not yet responded to treatment). Subjects may exhibit resistance at the start of treatment or may develop resistance during treatment. In some embodiments, subjects in need have received all known effective treatments for the disease or disorder described herein, but without success. In some embodiments, subjects in need have received at least one conventional treatment.

[0075] As used herein, the terms “treating” or “treat” refer to the management and care of a patient to combat a disease, condition, or disorder, and include the administration of the compounds disclosed herein or their pharmaceutically acceptable salts, polymorphs, or solvates to alleviate the symptoms or complications of a disease, condition, or disorder, or to eliminate the disease, condition, or disorder. The term “treat” may also include the treatment of cells in vitro or the treatment of animal models.

[0076] It should be understood that the compounds of this disclosure or their pharmaceutically acceptable salts, polymorphs, or solvates may be used to prevent relevant diseases, conditions, or disorders, or to identify suitable candidates for such purposes.

[0077] As used herein, the terms “prevent,” “prevent,” or “protect against” describe reducing or eliminating the onset of symptoms or complications of the disease, condition, or disorder in question.

[0078] Those skilled in the art should understand that they can refer to general reference texts for a detailed description of the known techniques described herein or equivalent techniques. These texts include Ausubel et al., Current Protocols in Molecular Biology, John Wiley and Sons, Inc. (2005); Sambrook et al., Molecular Cloning, A Laboratory Manual (3 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 thThe (1990) edition can be cited. Of course, these texts may be referred to in creating or using one aspect of the present disclosure.

[0079] It should be understood that the present disclosure also provides a pharmaceutical composition comprising a combination of any of the compounds described herein and at least one pharmaceutically acceptable excipient or carrier.

[0080] As used herein, the term "pharmaceutical composition" refers to a formulation containing the compounds of the present disclosure in a form suitable for administration to a subject. In one aspect, the pharmaceutical composition is in bulk or unit dosage form. The unit dosage form can be any of various forms including, for example, capsules, infusion bags, tablets, a single pump on an aerosol inhaler, or vials. The amount of the active ingredient (e.g., a formulation of the disclosed compound or its salt, hydrate, solvate, or isomer) in the unit dosage form of the composition is an effective amount and varies depending on the particular treatment involved. Those skilled in the art will recognize that it is sometimes necessary to make routine modifications to the dosage according to the age and condition of the patient. The dosage also depends on the route of administration. Various routes are envisioned including oral, intralung, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalation, buccal, sublingual, intrapleural, intrathecal, intranasal, etc. Dosage forms for topical or transdermal administration of the compounds of the present disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. In one aspect, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any optional preservatives, buffers, or propellants as required.

[0081] As used herein, the term "pharmaceutically acceptable" means a compound, anion, cation, material, composition, carrier, and / or dosage form that is suitable for use in contact with human and animal tissues within the scope of sound medical judgment, without undue toxicity, irritation, allergic response, or other problems or complications, and commensurate with a reasonable benefit / risk ratio.

[0082] As used herein, the term "pharmaceutically acceptable excipient" means an excipient useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and not biologically or otherwise undesirable, and includes excipients acceptable for veterinary use and pharmaceutical use in humans. The "pharmaceutically acceptable excipient" used in this specification and the claims includes both one such excipient and two or more such excipients.

[0083] It should be understood that the pharmaceutical compositions of the present disclosure are formulated to be compatible with the intended route of administration. Examples of routes of administration include parenteral administration, such as intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (topical), and transmucosal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application may contain the following components: sterile diluents such as water for injection, saline, fixed oils, polyethylene glycol, glycerin, propylene glycol, or other synthetic solvents; antibacterial agents such as benzyl alcohol or methylparaben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetate, citrate, or phosphate, and agents for adjusting the osmotic pressure such as sodium chloride or glucose. The pH can be adjusted with an acid or base such as hydrochloric acid or sodium hydroxide. Parenteral formulations can be enclosed in ampoules, disposable syringes, or multi-dose vials made of glass or plastic.

[0084] It should be understood that the compounds or pharmaceutical compositions of this disclosure can be administered to a subject by many well-known methods currently used in chemotherapeutic treatments. For example, the compounds of this disclosure can be injected into the bloodstream or body cavities, taken orally, or applied through the skin by patch. The selected dose should be sufficient to constitute an effective treatment but not so high as to cause unacceptable side effects. It should be preferable to carefully monitor the condition of the disease (e.g., the disease or disorder described herein) and the patient's health during and for a considerable period after the treatment.

[0085] As used herein, the term “therapeutic effective dose” means the amount of a drug that treats, induces remission of, or prevents an identified disease or condition, or that exhibits a detectable therapeutic or inhibitory effect. The effect is detectable by any assay known in the art. The exact effective dose for a subject depends on the subject’s weight, size, and health; the nature and severity of the condition; and the therapeutic agent or combination of therapeutic agents selected for administration. The therapeutic effective dose in a given situation can be determined by routine experiments, within the scope of the clinician’s skill and judgment.

[0086] It should be understood that for any compound, the therapeutically effective dose can first be estimated, for example, in a cell culture assay of newly generated cells, or in an animal model, usually a rat, mouse, rabbit, dog, or pig. Animal models can also be used to determine appropriate concentration ranges and routes of administration. This 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 procedures in cell culture or experimental animals, e.g., ED. 50 (A therapeutically effective dose for 50% of the population) and LD 50 This can be determined by the lethal dose (for 50% of the population). The dose ratio between the toxic effect and the therapeutic effect is the therapeutic index, which is the LD50. 50 / ED 50It can be expressed as a ratio. Pharmaceutical compositions exhibiting a large therapeutic index are preferred. The dosage may vary within this range depending on the dosage form used, the patient's sensitivity, and the route of administration.

[0087] Dosage and administration are adjusted to deliver a sufficient level of active agent or to maintain the desired effect. Factors that may be taken into consideration include the severity of the disease state, the subject's overall health, age, weight, and sex, diet, administration time and frequency, drug combinations, sensitivity to response, and tolerance / response to treatment. Long-acting pharmaceutical compositions may be administered every 3-4 days, weekly, or every 2 weeks, depending on the half-life and clearance rate of the particular formulation.

[0088] Pharmaceutical compositions containing the active compounds of this disclosure can be prepared in generally known ways, for example, by conventional mixing, dissolution, granulation, sugar-coated tablet preparation, wet grinding, emulsification, encapsulation, encapsulation, or lyophilization processes. The pharmaceutical compositions can be formulated conventionally using a pharmaceutically acceptable carrier containing one or more excipients and / or adjuvants that facilitate the processing of the active compounds into pharmaceutically usable formulations. Naturally, appropriate formulation depends on the chosen route of administration.

[0089] Suitable pharmaceutical compositions for injection include sterile aqueous solutions (if water-soluble) or aqueous dispersions, and sterile powders for the immediate preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL® (BASF, Parsippany, New Jersey), or phosphate-buffered saline (PBS). In all cases, the composition must be sterile and fluid enough to allow for easy syringe injection. The composition must be stable under manufacturing and storage conditions and stored in a manner that resists contamination by microorganisms such as bacteria and fungi. The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyols (e.g., glycerin, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof. Appropriate fluidity can be maintained, for example, by the use of coatings such as lecithin, maintenance of the required particle size in the case of dispersions, and the use of surfactants. Inhibition of microbial activity can be achieved with various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, ascorbic acid, and thimerosal. In many cases, it is preferable to include isotonic agents, such as sugars, polyhydric alcohols such as mannitol and sorbitol, and sodium chloride in the composition. Long-term absorption of the injectable composition can be achieved by including absorption-delaying agents, such as aluminum monostearate and gelatin, in the composition.

[0090] Sterile injectable solutions can be prepared by incorporating the required amount of active compound into a suitable solvent, along with one or a combination of the components listed above as needed, and then performing sterilization by filtration. Generally, dispersions are prepared by incorporating the active compound into a sterile medium containing a basic dispersion medium and other necessary components listed above. For sterile powders used in the preparation of sterile injectable solutions, preparation methods include vacuum drying and freeze-drying, where the powder of the active ingredient and any further desired components is obtained from a solution that has already been sterile filtered.

[0091] Oral compositions generally contain an inert diluent or a pharmaceutically acceptable food carrier. Oral compositions may be encapsulated in gelatin capsules or compressed into tablets. For therapeutic oral administration, the active compound can be incorporated with excipients and used in the form of tablets, lozenges, or capsules. Oral compositions for use as mouthwashes can also be prepared using a fluid carrier. In a mouthwash, the compound in the fluid carrier is applied orally, rinsed, and then spat out or swallowed. Pharmaceutically compatible binders and / or auxiliary materials may be included as part of the composition. Tablets, pills, capsules, lozenges, etc., may contain any of the following ingredients or compounds of similar properties: binders such as crystalline cellulose, tragacanth gum, or gelatin; excipients such as starch or lactose; disintegrants such as alginic acid, Primogel, or corn starch; lubricants such as magnesium stearate or Sterotes; flow enhancers such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or flavorings such as peppermint, methyl salicylate, or orange flavor.

[0092] For inhalation administration, the compound is delivered in the form of an aerosol spray from a suitable nebulizer, such as a pressurized container or dispenser containing a gas like carbon dioxide, or from a nebulizer.

[0093] Systemic administration may be by mucosal or percutaneous means. For mucosal or percutaneous administration, a penetrating agent suitable for the barrier to be penetrated is used in the formulation. These penetrating agents are generally known in the art, and examples of those for mucosal administration include surfactants, bile salts, and fusidic acid derivatives. Mucosal administration can be achieved through the use of nasal sprays or suppositories. For percutaneous administration, the active compound is formulated as an ointment, rubbing agent, gel, or cream, which are generally known in the art.

[0094] The active compound can be prepared as a controlled-release formulation comprising a graft and a microencapsulated delivery system, along with a pharmaceutically acceptable carrier that protects the compound from rapid elimination from the body. Biodegradable and biocompatible polymers such as ethylene vinyl acetate, polyacid anhydride, polyglycolic acid, collagen, polyorthoesters, and polylactic acid can be used. Methods for preparing these formulations will be apparent to those skilled in the art. Materials may be commercially available from Alza Corporation and Nova Pharmaceuticals, Inc. Liposome suspensions (containing liposomes targeting infected cells together with monoclonal antibodies against viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, such as those described, for example, in U.S. Patent No. 4,522,811.

[0095] Formulating oral or parenteral compositions in unit dosage forms is particularly advantageous because it facilitates administration and ensures uniformity of the dose. As used herein, a unit dosage form means a physically separated unit suitable as a unit dosage form for the subject being treated, each unit comprising a combination of a predetermined amount of the active compound and the required pharmaceutically acceptable carrier, calculated to produce the desired therapeutic effect. The specifications of the unit dosage forms in this disclosure are determined by and directly depend upon the unique properties of the active compound and the specific therapeutic effect to be achieved.

[0096] For therapeutic use, the dosage of the pharmaceutical composition used in accordance with this disclosure will vary depending on factors influencing the selected dosage, particularly the agent, the age, weight, and clinical condition of the recipient patient, as well as the experience and judgment of the clinician or practitioner performing the treatment. Generally, the dose should be sufficient to delay, preferably regress, and preferably cause complete regression of the symptoms of the disease or disorder described herein. Dosages may range from about 0.01 mg / kg to about 5000 mg / kg per day. In preferred cases, doses may range from about 1 mg / kg to about 1000 mg / kg per day. In one phase, the dosage ranges from approximately 0.1 mg / day to approximately 50 g / day; approximately 0.1 mg / day to approximately 25 g / day; approximately 0.1 mg / day to approximately 10 g / day; approximately 0.1 mg to approximately 3 g / day; or approximately 0.1 mg to approximately 1 g / day, in single dose, divided dose, or sustained dose (this dosage is calculated based on the patient's body weight in kg, m 2 (Adjustable according to the body surface area of ​​the unit and age in years). An effective dose of a drug is the amount that produces an objectively identifiable improvement as recognized by a clinician or other certified observer. Improvements in survival and proliferation rate indicate regression. As used herein, the term “dosage effective manner” means the amount of active compound that produces the desired biological effect in the subject or cells.

[0097] It should be understood that pharmaceutical compositions can be contained in containers, packs, or dispensers along with instructions for administration.

[0098] It should be understood that, with respect to the compounds of this disclosure that can further form salts, all of these forms are also assumed to be within the scope of the claimed disclosure.

[0099] As used herein, the term “pharmaceutically acceptable salt” means a derivative of the compound of the disclosed which is modified by the parent compound to produce an acidic or basic salt thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic salts of basic residues such as amines, and alkali or organic salts of acidic residues such as carboxylic acids. Examples of pharmaceutically acceptable salts include ordinary non-toxic salts or quaternary ammonium salts of the parent compound, for example, formed from non-toxic inorganic or organic acids. For example, these common non-toxic salts include 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, 1,2-ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, glycolylarsanilic acid, hexylresorcinic acid, hydrabamic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxymaleic acid, hydroxynaphthoic acid, isethionic acid, lactic acid, lactobionic acid, and lauryl Examples include, but are not limited to, salts derived from inorganic and organic acids selected from sulfonic acids, 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 (subacetic acid), succinic acid, sulfamic acid, sulfanilic acid, sulfuric acid, tannic acid, tartaric acid, toluenesulfonic acid, and commonly occurring amine acids, such as glycine, alanine, phenylalanine, and arginine.

[0100] In some embodiments, pharmaceutically acceptable salts are sodium salts, potassium salts, calcium salts, magnesium salts, diethylamine salts, choline salts, meglumine salts, benzathine salts, trometamic acid salts, ammonia salts, arginine salts, or lysine salts.

[0101] Other examples of pharmaceutically acceptable salts include hexanoic acid, cyclopentanepropionic acid, pyruvate, 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]-octa-2-ene-1-carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, and muconic acid. The disclosure also includes salts formed when the acidic proton present in the parent compound is replaced by a metal ion, such as an alkali metal ion, an alkaline earth ion, or an aluminum ion, or when it coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, or N-methylglucamine. In salt form, the ratio of the compound to the cation or anion of the salt can be 1:1, or any other ratio, such as 3:1, 2:1, 1:2, or 1:3.

[0102] It should be understood that all references to pharmaceutically acceptable salts include the solvated (solvated) or crystalline (polymorphic) forms of the same salt as defined herein.

[0103] The compound or its pharmaceutically acceptable salts may be administered orally, nasally, transdermally, intrapulmonaryly, by inhalation, buccally, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, subarachnoidally, and parenterally. In one embodiment, the compound is administered orally. Those skilled in the art will recognize the advantages of specific routes of administration.

[0104] The administration regimen utilizing this compound is selected according to various factors, including the patient's type, breed, age, weight, sex, and medical condition; the severity of the condition being treated; the route of administration; the patient's renal and hepatic function; and the specific compound or its salts used. A physician or veterinarian of ordinary skill can easily determine and prescribe the effective dose of the drug necessary to prevent, counteract, or halt the progression of the condition.

[0105] Techniques for the formulation and administration of the disclosed compounds of the present disclosure can be found in Remington: the Science and Practice of Pharmacy, 19 th edition, Mack Publishing Co., Easton, PA (1995). In one aspect, the compounds described herein, and their pharmaceutically acceptable salts, are used in pharmaceutical formulations in combination with a pharmaceutically acceptable carrier or diluent. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents, and sterile aqueous or sterile organic solutions. The compounds are present in the appropriate pharmaceutical composition in an amount sufficient to provide the desired dosage within the ranges described herein.

[0106] All percentages and ratios used herein are by weight unless otherwise indicated. Other features and advantages of the present disclosure will become apparent from the different examples. The presented examples illustrate different components and methodologies useful in practicing the present disclosure. The examples are not intended to limit the claimed present disclosure. Those skilled in the art can identify and use other components and methodologies useful in practicing the present disclosure based on the present disclosure.

[0107] In the synthetic schemes described herein, compounds may be depicted in one specific configuration for the purpose of purification. These specific configurations should not be construed as limiting the present disclosure to one or another isomer, tautomer, positional isomer, or stereoisomer, nor as excluding mixtures of isomers, tautomers, positional isomers, or stereoisomers. However, it will be understood that a given isomer, tautomer, positional isomer, or stereoisomer may exhibit a higher level of activity than another isomer, tautomer, positional isomer, or stereoisomer.

[0108] All publications and patent documents cited herein are incorporated herein by reference as if each such publication or document were specifically and individually directed to be incorporated herein by reference. The citation of publications and patent documents is not intended to constitute an endorsement of any prior art, nor does it constitute an endorsement of their content or dates. Since the invention is described herein in writing, those skilled in the art will recognize that the invention is implementable in various embodiments, and that the foregoing description and the following examples are illustrative and not intended to limit the scope of subsequent claims.

[0109] As used herein, the term “compounds disclosed” means both compounds generally disclosed herein and compounds specifically disclosed herein.

[0110] Compounds of the Disclosure In some aspects, this disclosure relates to formula (I): With respect to the compound TIFF0007865948000016.tif21128, or its prodrug, solvate, or pharmaceutically acceptable salt, During the ceremony, R1 is TIFF0007865948000017.tif29128, where n 1a and n 1b Each is independently either 0 or 1; R2 is -(CH2) n2 -R 2S And here n2 is either 1 or 2; R 2S This is a 4- to 8-membered heterocycloalkyl group in which at least one heteroatom is O, and the 4- to 8-membered heterocycloalkyl group has one or more R 2SS It may also be replaced with; Each R 2SSThese are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, halo, -CN, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, or oxo; R3 is one or more R 3S A 5-membered or 6-membered heteroaryl which may be substituted with; Each R 3S These are independently halo, C1-C6 alkyl, or C1-C6 haloalkyl.

[0111] In some aspects, this compound, R1 TIFF0007865948000018.tif29128, where n 1a and n 1b However, each is independently either 0 or 1; R2 is -(CH2) n2 -R 2S And here n2 is either 1 or 2; R 2S However, it is a 4- to 8-membered heterocycloalkyl group in which at least one heteroatom is O, and the 4- to 8-membered heterocycloalkyl group may be substituted with one or more -OH groups; R3 is a 5-membered or 6-membered heteroaryl which may be substituted with one or more C1-C6 alkyl groups. The compound of formula (I), or its prodrug, solvate, or pharmaceutically acceptable salt.

[0112] For the compound of formula (I), R1, R2, R 2S , R3, and R 3S Each of these can be appropriately selected from the elements described herein, R1, R2, R 2S , R3, and R 3S Any of the groups described herein for any of R1, R2, R 2S , R3, and R 3SIt will be understood that any group described herein can be combined, as appropriate, with one or more of the remaining ones.

[0113] In some embodiments, n 1a is 0.

[0114] In some embodiments, n 1a is 1.

[0115] In some embodiments, n 1b is 0.

[0116] In some embodiments, n 1b is 1.

[0117] In some embodiments, n 1a and n 1b are both 0.

[0118] In some embodiments, n 1a and n 1b one of them is 0 and the other is 1.

[0119] In some embodiments, n 1a and n 1b are both 1.

[0120] In some embodiments, R1 is TIFF0007865948000019.tif22128.

[0121] In some embodiments, R1 is TIFF0007865948000020.tif21128.

[0122] In some embodiments, R1 is TIFF0007865948000021.tif19128.

[0123] In some embodiments, R2 is -CH2-R 2SIt is.

[0124] In some embodiments, R2 is -(CH2)2-R 2S It is.

[0125] In some embodiments, R 2S is a 4- to 8-member heterocycloalkyl having at least one heteroatom being O, and the 4- to 8-member heterocycloalkyl may be substituted with one or more R 2SS and may be substituted.

[0126] In some embodiments, R 2S is a 5- to 6-member heterocycloalkyl having at least one heteroatom being O, and the 5- to 6-member heterocycloalkyl may be substituted with one or more R 2SS and may be substituted.

[0127] In some embodiments, R 2S is a 4- to 8-member heterocycloalkyl having one heteroatom, the heteroatom being O, and the 4- to 8-member heterocycloalkyl may be substituted with one or more R 2SS and may be substituted.

[0128] In some embodiments, R 2S is a 5- to 6-member heterocycloalkyl having one heteroatom, the heteroatom being O, and the 5- to 6-member heterocycloalkyl may be substituted with one or more R 2SS and may be substituted.

[0129] In some embodiments, R 2S is a 5-member heterocycloalkyl having one heteroatom, the heteroatom being O, and the 5-member heterocycloalkyl may be substituted with one or more R 2SS and may be substituted.

[0130] In some embodiments, R 2S is a 6-member heterocycloalkyl having one heteroatom, the heteroatom being O, and the 6-member heterocycloalkyl may be substituted with one or more R2SS It may be replaced with .

[0131] In some embodiments, each R 2SS These are independently C1-C6 alkyl, halo, -CN, -OH, -NH2, or oxo.

[0132] In some embodiments, each R 2SS These are independently -OH or -NH2.

[0133] In some embodiments, at least one R 2SS It is -OH.

[0134] In some embodiments, each R 2SS It is -OH.

[0135] In some embodiments, R 2S This is a 4- to 8-membered heterocycloalkyl group in which at least one heteroatom is O, and this 4- to 8-membered heterocycloalkyl group may be substituted with one or more C1- to C6 alkyl groups, halos, -CN, -OH, -NH2, or oxos.

[0136] In some embodiments, R 2S This is a 5-6 member heterocycloalkyl group in which at least one heteroatom is O, and the 5-6 member heterocycloalkyl group may be substituted with one or more C1-C6 alkyl groups, halos, -CN, -OH, -NH2, or oxos.

[0137] In some embodiments, R 2S This is a 4- to 8-membered heterocycloalkyl group in which at least one heteroatom is O, and this 4- to 8-membered heterocycloalkyl group may be substituted with one or more -OH or -NH2 groups.

[0138] In some embodiments, R 2SThis is a 5-6 member heterocycloalkyl group in which at least one heteroatom is O, and the 4-8 member heterocycloalkyl group may be substituted with one or more -OH or -NH2 groups.

[0139] In some embodiments, R 2S This is a 4- to 8-membered heterocycloalkyl group in which at least one heteroatom is O, and this 4- to 8-membered heterocycloalkyl group may be substituted with one or more -OH groups.

[0140] In some embodiments, R 2S This is a 5-6 member heterocycloalkyl group in which at least one heteroatom is O, and the 4-8 member heterocycloalkyl group may be substituted with one or more -OH groups.

[0141] In some embodiments, R 2S This is a 4- to 8-membered heterocycloalkyl group having one heteroatom, wherein the heteroatom is oxygen, and the 4- to 8-membered heterocycloalkyl group may be substituted with one or more -OH groups.

[0142] In some embodiments, R 2S This is a 5-6 member heterocycloalkyl having one heteroatom, wherein the heteroatom is O, and the 5-6 member heterocycloalkyl may be substituted with one or more -OH groups.

[0143] In some embodiments, R 2S This is a five-membered heterocycloalkyl having one heteroatom, the heteroatom being oxygen, and the five-membered heterocycloalkyl may be substituted with one or more -OH groups.

[0144] In some embodiments, R 2S It is a 5-membered heterocycloalkyl having one heteroatom, and the heteroatom is oxygen (O).

[0145] In some embodiments, R 2SThis is a five-membered heterocycloalkyl having one heteroatom, the heteroatom being oxygen, and the five-membered heterocycloalkyl being substituted with one or more -OH groups.

[0146] In some embodiments, R 2S This is a six-membered heterocycloalkyl having one heteroatom, the heteroatom being oxygen, and the six-membered heterocycloalkyl may be substituted with one or more -OH groups.

[0147] In some embodiments, R 2S It is a six-membered heterocycloalkyl having one heteroatom, and the heteroatom is oxygen (O).

[0148] In some embodiments, R 2S This is a six-membered heterocycloalkyl having one heteroatom, the heteroatom being oxygen, and the six-membered heterocycloalkyl being substituted with one or more -OH groups.

[0149] In some embodiments, R 2S is tetrahydrofuranil or tetrahydropyranil, and the tetrahydrofuranil or tetrahydropyranil is one or more R 2SS It may be replaced with .

[0150] In some embodiments, R 2S is tetrahydrofuranil or tetrahydropyranil, which may be substituted with one or more -OH groups.

[0151] In some embodiments, R 2S It is tetrahydrofuranil or tetrahydropyranil.

[0152] In some embodiments, R 2SThis is tetrahydrofuranil or tetrahydropyranil, which is substituted with one or more -OH groups.

[0153] In some embodiments, R 2S This is one or more R 2SS It is a tetrahydrofuranyl which may be substituted with [another compound].

[0154] In some embodiments, R 2S This is a tetrahydrofuranyl which may be substituted with one or more -OH groups.

[0155] In some embodiments, R 2S It is tetrahydrofuranyl.

[0156] In some embodiments, R 2S This is tetrahydrofuranyl substituted with one or more -OH groups.

[0157] In some embodiments, R 2S teeth The filename is TIFF0007865948000022.tif10128.

[0158] In some embodiments, R 2S teeth The filename is TIFF0007865948000023.tif16143.

[0159] In some embodiments, R 2S teeth The filename is TIFF0007865948000024.tif16128.

[0160] In some embodiments, R 2S This is one or more R 2SS It is a tetrahydropyranyl which may be substituted with [another compound].

[0161] In some embodiments, R 2SThis is a tetrahydropyranyl which may be substituted with one or more -OH groups.

[0162] In some embodiments, R 2S It is tetrahydropyranyl.

[0163] In some embodiments, R 2S This is tetrahydropyranyl substituted with one or more -OH groups.

[0164] In some embodiments, R 2S teeth The filename is TIFF0007865948000025.tif13128.

[0165] In some embodiments, R 2S teeth The filename is TIFF0007865948000026.tif41128.

[0166] In some embodiments, R 2S teeth The filename is TIFF0007865948000027.tif19162.

[0167] In some embodiments, R3 is a 5-membered or 6-membered heteroaryl.

[0168] In some embodiments, R3 is one or more R 3S It is a 5-membered or 6-membered heteroaryl substituted with [the specified compound].

[0169] In some embodiments, R3 is a 5-membered or 6-membered heteroaryl substituted with one or more C1-C6 alkyl (e.g., methyl) atoms.

[0170] In some embodiments, R3 is one or more R 3S It is a 5-membered heteroaryl that may be substituted with [another compound].

[0171] In some embodiments, R3 is a five-membered heteroaryl which may be substituted with one or more C1-C6 alkyl groups (e.g., methyl groups).

[0172] In some embodiments, R3 is a five-membered heteroaryl.

[0173] In some embodiments, R3 is one or more R 3S It is a 5-membered heteroaryl substituted with [the specified compound].

[0174] In some embodiments, R3 is a five-membered heteroaryl substituted with one or more C1-C6 alkyl (e.g., methyl) atoms.

[0175] In some embodiments, R3 is one or more R 3S It is pyrazolyl which may be substituted with [another compound].

[0176] In some embodiments, R3 is a pyrazolyl which may be substituted with one or more C1-C6 alkyl (e.g., methyl) groups.

[0177] In some embodiments, R3 is pyrazolyl.

[0178] In some embodiments, R3 is one or more R 3S It is pyrazolyl substituted with [the specified compound].

[0179] In some embodiments, R3 is a pyrazolyl substituted with one or more C1-C6 alkyl (e.g., methyl) groups.

[0180] In some embodiments, each R 3S It is, independently, a halo.

[0181] In some embodiments, each R 3S These are independently C1-C6 alkyl or C1-C6 haloalkyl.

[0182] In some embodiments, each R 3S These are independently C1-C6 alkyl groups.

[0183] In some embodiments, each R 3S It is methyl.

[0184] In some embodiments, R3 is The filename is TIFF0007865948000028.tif12128.

[0185] In some embodiments, R3 is The filename is TIFF0007865948000029.tif17128.

[0186] In some embodiments, R3 is The filename is TIFF0007865948000030.tif15128.

[0187] In some embodiments, R3 is The filename is TIFF0007865948000031.tif11128.

[0188] In some embodiments, this compound is represented by formula (Ia-1): A compound of TIFF0007865948000032.tif28128, or a prodrug, solvate, or pharmaceutically acceptable salt thereof, wherein R2 and R3 are as described herein.

[0189] In some embodiments, the compound is represented by formula (Ia-2): A compound of TIFF0007865948000033.tif26128, or its prodrug, solvate, or pharmaceutically acceptable salt, wherein R 1S R2 and R3 are as described herein.

[0190] In some embodiments, this compound is represented by formula (Ib-1): A compound of TIFF0007865948000034.tif23128, or its prodrug, solvate, or pharmaceutically acceptable salt, wherein R1, R 2S、 And R3 are as described herein.

[0191] In some embodiments, this compound is represented by formula (Ib-2): A compound of TIFF0007865948000035.tif29128, or its prodrug, solvate, or pharmaceutically acceptable salt, wherein R1, R 2S , and R3 are as described herein.

[0192] In some embodiments, this compound is of formula (Ic-1): A compound of TIFF0007865948000036.tif24128, or its prodrug, solvate, or pharmaceutically acceptable salt, wherein R1, R2, and R 3S This is as described in this specification.

[0193] In some embodiments, the compound is of formula (Ic-2): A compound of TIFF0007865948000037.tif24128, or a prodrug, solvate, or pharmaceutically acceptable salt thereof, wherein R1 and R2 are as described herein.

[0194] In some embodiments, this compound is represented by formula (Ic-3): A compound of TIFF0007865948000038.tif23128, or a prodrug, solvate, or pharmaceutically acceptable salt thereof, wherein R1 and R2 are as described herein.

[0195] In some embodiments, this compound is represented by formula (Id-1): A compound of TIFF0007865948000039.tif24128, or its prodrug, solvate, or pharmaceutically acceptable salt, wherein R1 and R 2SThis is as described in this specification.

[0196] In some embodiments, this compound is represented by formula (Id-2): A compound of TIFF0007865948000040.tif30128, or its prodrug, solvate, or pharmaceutically acceptable salt, wherein R1 and R 2S This is as described in this specification.

[0197] In some embodiments, this compound is represented by formula (Ie-1): A compound of TIFF0007865948000041.tif32128, or its prodrug, solvate, or pharmaceutically acceptable salt, wherein R 2S This is as described in this specification.

[0198] In some embodiments, the compound is of formula (Ie-2): A compound of TIFF0007865948000042.tif37128, or its prodrug, solvate, or pharmaceutically acceptable salt, wherein R 2S This is as described in this specification.

[0199] In some embodiments, this compound is represented by formula (Ie-3): A compound of TIFF0007865948000043.tif30128, or its prodrug, solvate, or pharmaceutically acceptable salt, wherein R 2S This is as described in this specification.

[0200] In some embodiments, this compound is represented by formula (Ie-4): A compound of TIFF0007865948000044.tif36128, or its prodrug, solvate, or pharmaceutically acceptable salt, wherein R 2S This is as described in this specification.

[0201] For any compound of the formulas described herein, R1, R2, R 2S, R3, and R 3S Each of these can be appropriately selected from the elements described herein, R1, R2, R 2S , R3, and R 3S Any of the groups described herein for any of R1, R2, R 2S , R3, and R 3S It will be understood that one or more of the remaining elements can be combined as appropriate with any of the elements described herein.

[0202] In some embodiments, the compound is selected from the compounds listed in Table 1, as well as their prodrugs and pharmaceutically acceptable salts.

[0203] In some embodiments, the compound is selected from the compounds listed in Table 1 and their pharmaceutically acceptable salts.

[0204] In some embodiments, the compound is selected from the compounds listed in Table 1.

[0205] (Table 1) TIFF0007865948000045.tif20598TIFF0007865948000046.tif20298TIFF0007865948000047.tif19798TIFF0007865948000048.tif86128

[0206] In some aspects, the present disclosure provides compounds that are isotopic derivatives (e.g., isotope-labeled compounds) of any one of the compounds of the formulas disclosed herein.

[0207] In some embodiments, the compound is an isotopic derivative of any one of the compounds listed in Table 1, as well as their prodrugs and pharmaceutically acceptable salts.

[0208] In some embodiments, the compound is an isotopic derivative of any one of the compounds listed in Table 1 and their pharmaceutically acceptable salts.

[0209] In some embodiments, the compound is an isotopic derivative of any one of the compounds listed in Table 1.

[0210] It will be understood that isotopic derivatives can be prepared using any of the various techniques recognized in the art. For example, isotopic derivatives can generally be prepared by using isotopic labeling reagents instead of non-isotopic labeling reagents and following the procedures disclosed in the schemes and / or examples described herein.

[0211] In some embodiments, the isotopic derivative is a deuterium-labeled compound.

[0212] In some embodiments, the isotopic derivative is a deuterium-labeled compound of any one of the compounds of the formulas disclosed herein.

[0213] In some embodiments, the compound is a deuterium-labeled compound from any one of the compounds listed in Table 1, as well as its prodrug and pharmaceutically acceptable salt.

[0214] In some embodiments, the compound is any one deuterium-labeled compound from the compounds listed in Table 1, and a pharmaceutically acceptable salt thereof.

[0215] In some embodiments, the compound is one deuterium-labeled compound from among the compounds listed in Table 1.

[0216] It will be understood that deuterium-labeled compounds contain deuterium atoms that exhibit a deuterium abundance substantially exceeding the natural abundance of deuterium, which is 0.015%.

[0217] In some embodiments, the deuterium-labeled compound exhibits a deuterium enrichment factor of at least 3500 (52.5% deuterium uptake in each deuterium atom), at least 4000 (60% deuterium uptake), at least 4500 (67.5% deuterium uptake), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium uptake), at least 6000 (90% deuterium uptake), at least 6333.3 (95% deuterium uptake), at least 6466.7 (97% deuterium uptake), at least 6600 (99% deuterium uptake), or at least 6633.3 (99.5% deuterium uptake) for each deuterium atom. As used herein, the term “deuterium enrichment factor” means the ratio between the deuterium abundance and the naturally occurring abundance of deuterium.

[0218] It will be understood that deuterium-labeled compounds can be prepared using any of the various techniques recognized in the art. For example, deuterium-labeled compounds can generally be prepared by using a deuterium-labeled reagent instead of a non-deuterium-labeled reagent and following the procedures disclosed in the schemes and / or examples described herein.

[0219] Compounds of the present invention containing the above-mentioned deuterium atom, or pharmaceutically acceptable salts or solvates thereof, are within the scope of the present invention. Furthermore, deuterium (i.e. 2 Substitution with H) can result in certain therapeutic benefits obtained through increased metabolic stability, such as an increased in vivo half-life or a reduction in the required dose.

[0220] To avoid any ambiguity, when a group is referred to as “as described herein,” it should be understood that the group encompasses the unambiguous and broadest definition, as well as any specific definition of that group.

[0221] Suitable pharmaceutically acceptable salts of the compounds of this disclosure are, for example, acid addition salts of the compounds of this disclosure with sufficiently basic acids, such as inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, formic acid, citric acid, methanesulfonic acid, or maleic acid. Furthermore, suitable pharmaceutically acceptable salts of the compounds of this disclosure with sufficiently acidic acids are salts with alkali metal salts, such as sodium or potassium salts, alkaline earth metal salts, such as calcium or magnesium salts, ammonium salts, or organic bases that give pharmaceutically acceptable cations, such as methylamine, dimethylamine, diethylamine, trimethylamine, piperidine, morpholine, or tris-(2-hydroxyethyl)amine.

[0222] It will be understood that any one compound from the formulas disclosed herein, as well as any pharmaceutically acceptable salt thereof, includes stereoisomers, mixtures of stereoisomers, and polymorphs of all isomeric forms of the compound.

[0223] As used herein, the term "isomer" refers to compounds that have the same molecular formula but differ in the order of atomic bonding or the spatial arrangement of atoms. Isomers with different spatial arrangements of atoms are called "stereoisomers." Stereoiomers that are not mirror images of each other are called "diastereoisomers," and stereoisomers that are mirror images of each other but cannot be superimposed are called "enantiomers," or sometimes optical isomers. A mixture containing equal amounts of individual enantiomers with opposite chiralities is called a "racemic mixture."

[0224] As used herein, the term “chiral center” means a carbon atom bonded to four non-identical substituents.

[0225] As used herein, the term "chiral isomer" refers to a compound having at least one chiral center. Compounds having two or more chiral centers may exist as individual diastereomers or as a mixture of diastereomers called a "diastereomer mixture." When one chiral center is present, the stereoisomer may be characterized by the absolute configuration (R or S) of that chiral center. Absolute configuration refers to the spatial arrangement of substituents attached to the chiral center. Substituents attached to the chiral center under consideration are ranked according to the Cahn, Ingold, and Prelog priority 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).

[0226] As used herein, the term “geometric isomer” refers to diastereomers that exist due to rotational hindrance around a double bond or a cycloalkyl linker (e.g., 1,3-cyclobutyl). These arrangements are distinguished by the prefixes cis and trans or Z and E, which indicate that multiple groups are located on the same side or opposite side of the double bond in the molecule, according to the Cahn-Ingold-Prelog rule.

[0227] It should be understood that the compounds of this disclosure may be represented as different chiral or geometric isomers. Furthermore, it should be understood that, if a compound has chiral or geometric isomeric forms, all isomeric forms are intended to be included within the scope of this disclosure, and that the naming of such compounds does not exclude any isomeric form, and that not all isomers may exhibit the same level of activity.

[0228] It should be understood that the structures and other compounds described in this disclosure include all of their atropisomers. It should also be understood that not all atropisomers exhibit the same level of activity.

[0229] As used herein, the term “atropisomer” refers to a type of stereoisomer in which the atoms of two isomers are spatially arranged differently. Atropisomers exist due to rotational restrictions caused by rotational obstruction of large groups around a central bond. These atropisomers usually exist as a mixture, but as a result of recent advances in chromatography techniques, it has become possible to separate a mixture of two atropisomers in limited cases.

[0230] As used herein, the term “tautomer” refers to one of two or more structural isomers that exist in equilibrium and are readily convertible from one isomer to another. This conversion involves formal transfer of hydrogen atoms, with the switching of adjacent conjugated double bonds. Tautomers exist as a mixture of a set of tautomers in solution. In a solution where tautomerization is possible, chemical equilibrium of tautomers is reached. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. The concept that tautomers are interconvertible by tautomerization is called tautomerism. Two of the various types of tautomerism are commonly observed. Keto-enol tautomerism involves the simultaneous transfer of electrons and hydrogen atoms. Ring chain tautomerism, as demonstrated by glucose, occurs when an aldehyde group (-CHO) in a sugar chain molecule reacts with a hydroxyl group (-OH) in the same molecule, resulting in the molecule becoming cyclic (ring-shaped).

[0231] It should be understood that the compounds of this disclosure may be represented as different tautomers. Furthermore, it should be understood that, if a compound has tautomer forms, all tautomer forms are intended to be included within the scope of this disclosure, and that the naming of the compound does not exclude any tautomer form. It will be understood that certain tautomers may exhibit higher levels of activity than others.

[0232] Compounds that have the same molecular formula but differ in the properties of their atoms, the order of their bonding, or the spatial arrangement of their atoms are called "isomers." Isomers with different spatial arrangements of atoms are called "stereoisomers." Stereoisomers that are not mirror images of each other are called "diastereomers," and stereoisomers that are mirror images of each other but cannot be superimposed are called "enantiomers." For example, if a compound has a chiral center, the chiral center is bonded to four different groups, and a pair of enantiomers are possible. Enantiomers can be characterized by the absolute configuration of the chiral center, described by Cahn and Prelog's R- and S-order rules, or by the way the molecule rotates its plane of polarization, and are named dextrorotatory or levorotatory (i.e., (+) or (-)-isomers, respectively). Chiral compounds can exist as individual enantiomers or mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0233] The compounds of this disclosure may have one or more chiral centers. Therefore, the compounds can be produced as individual (R)- or (S)-stereoisomers or mixtures thereof. Unless otherwise indicated, the descriptions and nomenclature of specific compounds in this specification and claims are intended to include both individual enantiomers and their racemic or other mixtures. Methods for determining and separating the stereochemical configurations of stereoisomers, such as by synthesis from optically active starting materials or by resolution of racemates, are well known in the art (see Chapter 4 of "Advanced Organic Chemistry", 4th edition J. March, John Wiley and Sons, New York, 2001). Some of the compounds of this disclosure may have geometric isomers (E- and Z-isomers). It should be understood that this disclosure encompasses all optical isomers, diastereoisomers, and geometric isomers, as well as mixtures thereof, that possess inflammasome inhibitory activity.

[0234] This disclosure also includes compounds of the disclosure as defined herein, which include one or more isotopic substitutions.

[0235] It should be understood that any compound of any formula described herein may include the compound itself, as well as its salts and solvates as appropriate. For example, salts may be formed between an anion and a positively charged group (e.g., amino) on the substituted compounds disclosed herein. Suitable anions include chloride ions, bromide ions, iodide ions, sulfate ions, bisulfate ions, sulfamate ions, nitrate ions, phosphate ions, citrate ions, methanesulfonate ions, trifluoroacetate ions, glutamate ions, glucuronate ions, glutarate ions, malate ions, maleate ions, succinate ions, fumarate ions, tartrate ions, tosylate ions, salicylate ions, lactate ions, naphthalenesulfonate ions, and acetate ions (e.g., trifluoroacetate ions).

[0236] As used herein, the term “pharmaceutically acceptable anion” means an anion suitable for forming a pharmaceutically acceptable salt. Similarly, salts may also be formed between a cation and a negatively charged group (e.g., a carboxylate) on the substituted compounds disclosed herein. Suitable cations include sodium ions, potassium ions, magnesium ions, calcium ions, and ammonium cations such as tetramethylammonium ions or diethylamine inones. The substituted compounds disclosed herein also include salts containing a quaternary nitrogen atom.

[0237] It should be understood that the compounds disclosed herein, such as salts of these compounds, may exist in hydrated or unhydrated (anhydrous) forms, or as solvates with other solvent molecules. Non-limiting examples of hydrates include monohydrates and dihydrates. Non-limiting examples of solvates include ethanol solvate and acetone solvate.

[0238] As used herein, the term “solvate” means a solvative containing a stoichiometric or non-stoichiometric amount of solvent. Some compounds tend to form solvates by trapping solvent molecules in a fixed molar ratio within a crystalline solid. When the solvent is water, the solvate formed is a hydrate; when the solvent is alcohol, the solvate formed is an alcoholic dihydrate. Hydrates are formed by a combination of one or more water molecules and one molecule of a substance in which the water holds its molecular state as H2O.

[0239] As used herein, the term “analog” means a compound that is structurally similar to another compound but has a slightly different composition (for example, one atom is replaced by an atom of a different element, or a particular functional group is present, or one functional group is replaced by another functional group). Thus, an analog is a compound that is similar or equivalent in function and appearance to a reference compound, but not similar or equivalent in structure or origin.

[0240] As used herein, the term "derivative" means a compound having a common core structure but substituted with one of the various groups described herein.

[0241] As used herein, the term “biological equivalent” refers to a compound obtained by replacing one atom or group of atoms with another atom or group of atoms that is substantially similar. The purpose of biological equivalent substitution is to create novel compounds that have similar biological properties to the parent compound. Biological equivalent substitution can be physicochemical or morphological. Examples of carboxylic acid biological equivalents include, but are not limited to, acylsulfonimides, tetrazoles, sulfonates, and phosphonates. See, for example, Patani and LaVoie, Chem. Rev. 96, 3147-3176, 1996.

[0242] Furthermore, it should be understood that any one particular compound of the formulas disclosed herein may exist in both solvated and non-solvated forms, such as hydrated forms. For example, preferred pharmaceutically acceptable solvates are hydrates such as hemihydrate, monohydrate, dihydrate, or trihydrate. It should be understood that this disclosure encompasses all of these solvated forms that have inflammasome inhibitory activity.

[0243] Furthermore, it should be understood that any one particular compound among the formulas disclosed herein may exhibit pleomorphism, and that this disclosure encompasses all of these 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, differential scanning calorimetry, thermogravimetric analysis, diffuse reflectance infrared Fourier transform (DRIFT) spectroscopy, near-infrared (NIR) spectroscopy, and solution and / or solid-state nuclear magnetic resonance spectroscopy. The water content of these crystalline materials can be determined by Karl Fischer analysis.

[0244] Any one of the compounds of the formulas disclosed herein may exist in several different tautomerized forms, and references to the compound in formula (I) include all of these forms. For the avoidance of doubt, if a compound may exist in one of several tautomerized forms and only one is specifically described or illustrated, all other tautomerized forms are still encompassed in formula (I). Examples of tautomerized forms include keto, enol, and enolate forms, for example, the following tautomerized pairs: keto / enol (shown below), imine / enamine, amide / iminoalcohol, amidine / amidine, nitroso / oxime, thioketone / enthiol, and nitro / acy-nitro. TIFF0007865948000049.tif23128

[0245] Any one of the compounds of the formulas disclosed herein that contain an amine functional group may form an N-oxide. References herein to compounds of formula (I) containing an amine functional group also include N-oxides. If a compound contains several amine functional groups, one or more nitrogen atoms may be oxidized to form an N-oxide. Specific examples of N-oxides include nitrogen-containing heterocyclic tertiary amines or N-oxides of nitrogen atoms. N-oxides can be formed by treating the corresponding amine with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., a peroxycarboxylic acid). See, for example, Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages. More specifically, N-oxides can be prepared by the procedure of 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 dichloromethane.

[0246] Any one of the compounds of the formulas disclosed herein may be administered in the form of a prodrug, which is broken down in the body of a human or animal to release the compound disclosed herein. The physical and / or pharmacokinetic properties of the compound disclosed herein can be modified by using a prodrug. A prodrug may be formed if the compound disclosed herein contains a suitable group or substituent to which a character-modifying group can be bonded. Examples of prodrugs include derivatives of any one of the compounds of the formulas disclosed herein that contain an in vivo cleavable alkyl or acyl substituent at the sulfonylurea group.

[0247] Accordingly, this disclosure includes any one of the formulas disclosed herein as defined above, when made available by organic synthesis and when made available in the body of a human or animal by cleavage of its prodrug. Accordingly, this disclosure includes any one of the formulas disclosed herein produced by organic synthesis means, as well as such compounds produced in the body of a human or animal by metabolism of a precursor compound, i.e., any one of the formulas disclosed herein may be a compound produced by synthesis or a compound produced by metabolism.

[0248] A suitable pharmaceutically acceptable prodrug of any one compound of the formulas disclosed herein is a prodrug that is suitable for administration to the human or animal body, is free from undesirable pharmacological activity, and is free from excessive toxicity, based on reasonable medical judgment. Various forms of prodrugs are described in the following references, for example: 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.

[0249] A preferred pharmaceutically acceptable prodrug of any one compound of the formulas disclosed herein having a hydroxyl group is, for example, an in vivo cleavable ester or ether thereof. An in vivo cleavable ester or ether of any one compound of the formulas disclosed herein containing a hydroxyl group is, for example, a pharmaceutically acceptable ester or ether that cleaves in the body of a human or animal to produce a parent hydroxyl compound. Preferred pharmaceutically acceptable ester-forming groups for a hydroxyl group include inorganic esters such as phosphate esters (including phosphoroamidic acid cyclic esters). Further preferred pharmaceutically acceptable ester-forming groups for a hydroxyl group include C1-C groups such as acetyl, benzoyl, phenylacetyl, and substituted benzoyl and substituted phenylacetyl groups. 10 C1-C6 alkyl groups such as alkanoyl groups, ethoxycarbonyl groups, N,N-(C1-C6 alkyl)2-carbamoyl groups, 2-dialkylaminoacetyl groups, and 2-carboxyacetyl groups. 10 Examples of alkoxycarbonyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazine-1-ylmethyl, and 4-(C1-C4 alkyl)piperazine-1-ylmethyl. Suitable pharmaceutically acceptable ether-forming groups for the hydroxyl group include acetoxymethyl and α-acyloxyalkyl groups such as pivaloyloxymethyl.

[0250] A suitable pharmaceutically acceptable prodrug of any one compound of the formulas disclosed herein having a carboxyl group is an amide formed with an amine such as an in vivo cleavable amide, such as ammonia, a C1-C4 alkylamine such as methylamine, a (C1-C4 alkyl)2 amine such as dimethylamine, N-ethyl-N-methylamine, or diethylamine, a C1-C4 alkoxy-C2-C4 alkylamine such as 2-methoxyethylamine, a phenyl-C1-C4 alkylamine such as benzylamine, and an amino acid or its ester such as glycine.

[0251] A preferred pharmaceutically acceptable prodrug of any one of the compounds of the formulas disclosed herein having an amino group is, for example, an in vivo cleavable amide derivative thereof. Suitable pharmaceutically acceptable amides derived from an amino group include, for example, C1-C12 acetyl groups, benzoyl groups, phenylacetyl groups, and substituted benzoyl and substituted phenylacetyl groups. 10 Examples of amides formed with an alkanoyl group include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazine-1-ylmethyl, and 4-(C1-C4 alkyl)piperazine-1-ylmethyl.

[0252] The in vivo effect of any one of the compounds disclosed herein may be moderately exerted by one or more metabolites formed in the human or animal body after administration of any one of the compounds disclosed herein. Furthermore, as previously stated, the in vivo effect of any one of the compounds disclosed herein may be exerted by the metabolism of a precursor compound (prodrug).

[0253] Preferably, this disclosure excludes any individual compounds that do not have the biological activity defined herein.

[0254] Synthesis method In some aspects, this disclosure provides methods for preparing the compounds of this disclosure.

[0255] In some aspects, this disclosure provides a method for compounding a compound, comprising one or more steps described herein.

[0256] In some respects, this disclosure provides compounds that can be obtained, have been obtained, or are directly obtained by methods for preparing the compounds described herein.

[0257] In some aspects, this disclosure provides intermediates described herein that are suitable for use in methods for preparing the compounds described herein.

[0258] The compounds of this disclosure can be prepared by any suitable technique known in the art. Specific methods for preparing these compounds are further described in the accompanying examples.

[0259] In the descriptions of the synthesis methods described herein, and any mentioned synthesis methods used to prepare the starting materials, it should be understood that all presented reaction conditions, including the choice of solvent, reaction atmosphere, reaction temperature, experimental time, and work-up procedure, are selectable by those skilled in the art.

[0260] Those skilled in the field of organic synthesis will understand that the functional groups present on various parts of a molecule must be compatible with the reagents and reaction conditions used.

[0261] It will be recognized that during the synthesis of the compounds of this disclosure in the methods defined herein, or during the synthesis of certain starting materials, it may be desirable to protect certain substituents to prevent undesirable reactions. Experienced chemists will know when such protection is needed and how these protecting groups can be positioned and subsequently removed. For examples of protecting groups, see one of the many general texts on this subject, e.g., Theodora Green, *Protective Groups in Organic Synthesis* (publisher: John Wiley & Sons). Where appropriate, the protecting group in question may be removed by any convenient method described in the literature or known to experienced chemists, and these methods are chosen to perform the removal of the protecting group while minimizing interference with other groups in the molecule. Thus, when the reactants contain groups such as amino, carboxy, or hydroxy, it may be desirable to protect the groups in some of the reactions referred to herein.

[0262] As an example, suitable protecting groups for amino groups or alkylamino groups include, for example, acyl groups, such as alkanoyl groups, such as acetyl; alkoxycarbonyl groups, such as methoxycarbonyl groups, ethoxycarbonyl groups, or t-butoxycarbonyl groups; arylmethoxycarbonyl groups, such as benzyloxycarbonyl; or aroyl groups, such as benzoyl. The deprotection conditions for the above protecting groups will inevitably vary depending on the choice of protecting group. Therefore, for example, acyl groups such as alkanoyl groups, alkoxycarbonyl groups, or aroyl groups can be removed by hydrolysis with suitable bases, such as alkali metal hydroxides, such as lithium hydroxide or sodium hydroxide. Alternatively, acyl groups such as tert-butoxycarbonyl groups can be removed by treatment with suitable acids such as hydrochloric acid, sulfuric acid, phosphoric acid, or trifluoroacetic acid, and arylmethoxycarbonyl groups such as benzyloxycarbonyl groups can be removed by hydrogenation on a catalyst such as palladium carbon, or by treatment with a Lewis acid such as borontris (trifluoroacetate). A suitable alternative protecting group for primary amino groups is, for example, a phthaloyl group, which can be removed by treatment with an alkylamine such as dimethylaminopropylamine or hydrazine.

[0263] Suitable protecting groups for hydroxyl groups include, for example, acyl groups, such as alkanoyl groups, such as acetyl; alloyl groups, such as benzoyl; or arylmethyl groups, such as benzyl. The deprotection conditions for these protecting groups inevitably vary depending on the choice of protecting group. For example, acyl groups such as alkanoyl or alloyl groups can be removed by hydrolysis with suitable bases such as alkali metal hydroxides, such as lithium hydroxide, sodium hydroxide, or ammonia. Alternatively, arylmethyl groups such as benzyl groups can be removed by hydrogenation on a catalyst such as palladium-carbon.

[0264] Suitable protecting groups for the carboxyl group include, for example, esterifying groups such as methyl or ethyl groups, which can be removed by hydrolysis with a base such as sodium hydroxide; or, for example, tert-butyl groups, which can be removed by treatment with an acid such as an organic acid such as trifluoroacetic acid; or, for example, benzyl groups, which can be removed by hydrogenation on a catalyst such as palladium-carbon.

[0265] When a compound of formula (I) is synthesized by any one of the methods defined herein, the method may further include: (i) removing any protecting groups present; (ii) converting a compound of formula (I) to another compound of formula (I); (iii) forming a pharmaceutically acceptable salt, hydrate, or solvate thereof; and / or (iv) forming a prodrug thereof.

[0266] The resulting compound of formula (I) can be isolated and purified using techniques well known in the art.

[0267] Conveniently, the reaction of the compound is carried out under each reaction condition, preferably in the presence of a suitable solvent that is inert. Examples of suitable solvents include hydrocarbons such as hexane, petroleum ether, benzene, toluene, or xylene; chlorinated hydrocarbons such as trichloroethylene, 1,2-dichloroethane, tetrachloromethane, chloroform, or dichloromethane; alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol, or tert-butanol; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, cyclopentyl methyl ether (CPME), methyl tert-butyl ether (MTBE), or dioxane; glycol ethers such as ethylene glycol monomethyl or monoethyl ether or ethylene glycol dimethyl ether (diglyme); ketones such as acetone, methyl isobutyl ketone (MIBK), or butanone; amides such as acetamide, dimethylacetamide, dimethylformamide (DMF), or N-methylpyrrolidinone (NMP); nitriles such as acetonitrile; sulfoxides such as dimethyl sulfoxide (DMSO); and nitro compounds such as nitromethane or nitrobenzene. Examples include, but are not limited to, esters such as ethyl acetate or methyl acetate; or mixtures of the solvent or mixtures with water.

[0268] The reaction temperature is preferably about -100°C to 300°C, depending on the reaction process and conditions used.

[0269] Generally, reaction times range from less than one minute to several days, depending on the reactivity of each compound and the reaction conditions. A suitable reaction time can be easily determined by methods known to those skilled in the art, such as reaction monitoring. Based on the reaction temperatures shown above, a suitable reaction time is generally in the range of 10 minutes to 48 hours.

[0270] Furthermore, by utilizing the procedures described herein in combination with the ordinary skill in the art, further compounds of this disclosure can be readily prepared. Those skilled in the art will readily understand that these compounds can be prepared using known variations of the conditions and processes of the following preparation procedures.

[0271] As those skilled in the art will understand, the compounds of this disclosure are readily available through various synthetic routes, some of which are illustrated in the accompanying examples. Those skilled in the art will readily recognize, in any particular example, what kinds of reagents and reaction conditions should be used, and how they should be applied and utilized, whenever necessary or useful, to obtain the compounds of this disclosure. Furthermore, some of the compounds of this disclosure can be readily synthesized by reacting other compounds of this disclosure under suitable conditions, for example, by applying standard synthetic methods well known to those skilled in the art, such as reduction, oxidation, addition, or substitution reactions, to convert one specific functional group present in the compounds of this disclosure or their suitable precursor molecules to another functional group. Similarly, those skilled in the art will apply synthetic protecting groups whenever necessary or useful. Suitable protecting 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, PGM Wuts, TW Greene, "Greene's Protective Groups in Organic Synthesis", 4th edition (2006) (John Wiley & Sons).

[0272] The general route for preparing the compounds of this application is described in Schemes 1 and 2 of this specification.

[0273] Scheme 1 TIFF0007865948000050.tif80138

[0274] In Scheme 1, L1 is a suitable leaving group (e.g., Cl or another halide).

[0275] Reaction (i) can be carried out by reacting amine 1 with isocyanate 2 in a suitable solvent (e.g., diisopropyl ether or dichloromethane) at an optionally low temperature (e.g., 0°C or -15°C) to give intermediate 3. In some embodiments, intermediate 3 can be used directly as a solution and does not need to be isolated.

[0276] Reaction (ii) can be carried out by reacting amine 4 with acid 5 in a suitable solvent (e.g., DMF) in the presence of a coupling agent (e.g., HATU or EDCI) to give intermediate 6.

[0277] Reaction (iii) can be carried out by reacting amide 6 with a suitable reducing agent (e.g., LiAlH4) in a suitable solvent (e.g., THF) with optional heating (e.g., to 70°C). Intermediate 7 can be isolated by purification (e.g., by flash column chromatography or by preparative HPLC). In some embodiments, intermediate 7 is isolated as a free amine or as a salt (e.g., trifluoroacetate).

[0278] Reaction (iv) can be carried out by reacting intermediate 3 with intermediate 7 in a suitable solvent (e.g., tetrahydrofuran), in the presence of a base (e.g., sodium hydride or sodium hydroxide), and optionally in the presence of a catalyst (e.g., 4-(dimethylamino)-pyridine), to give the compound of formula (I). The compound of formula (I) can be isolated by purification (e.g., by flash column chromatography or by preparative HPLC). In some embodiments, the compound of formula (I) is isolated as a neutral compound or as a salt (e.g., a sodium salt).

[0279] Scheme 2 TIFF0007865948000051.tif155133

[0280] In Scheme 2, L1 is a suitable leaving group (e.g., Cl or another halide).

[0281] Reaction (i) can be carried out by reacting isocyanate 1 with tert-butanol in a suitable solvent (e.g., tetrahydrofuran) at an optionally low temperature (e.g., 0°C) to give intermediate 2. In some embodiments, intermediate 2 is then used directly as a solution and not directly isolated.

[0282] Reaction (ii) can be carried out by reacting amine 3 with acid 4 in a suitable solvent (e.g., DMF) in the presence of a coupling agent (e.g., HATU or EDCI) to give intermediate 5.

[0283] Reaction (iii) can be carried out by reacting amide 5 with a suitable reducing agent (e.g., LiAlH4) in a suitable solvent (e.g., THF) with optional heating (e.g., to 70°C). Intermediate 6 can be isolated by purification (e.g., by flash column chromatography or by preparative HPLC). In some embodiments, intermediate 7 is isolated as a free amine or as a salt (e.g., trifluoroacetate).

[0284] Reaction (iv) can be carried out by reacting intermediate 6 with intermediate 2 in a suitable solvent (e.g., tetrahydrofuran) in the presence of a base (e.g., diisopropylethylamine) to give intermediate 7. Intermediate 7 can be isolated by purification (e.g., by flash column chromatography or by preparative HPLC).

[0285] Reaction (v) can be carried out by reacting intermediate 7 with a suitable acid (e.g., hydrochloric acid or trifluoroacetic acid) in a suitable solvent (e.g., 1,4-dioxane or dichloromethane) at an optionally low temperature (e.g., 0°C) to give intermediate 8. Intermediate 8 can be isolated by purification (e.g., by flash column chromatography or by preparative HPLC). In some embodiments, intermediate 8 is isolated as a free amine or as a salt (e.g., trifluoroacetate).

[0286] Reaction (vi) can be carried out by reacting primary amine 9 with a suitable reagent (e.g., triphosgene) in the presence of a suitable base (e.g., diisopropylethylamine or triethylamine) and a suitable solvent (e.g., 1,4-dioxane) at an optional high temperature (e.g., 40°C) to give intermediate 10.

[0287] Reaction (vii) can be carried out by reacting intermediate 8 with intermediate 10 in a suitable solvent (e.g., tetrahydrofuran), in the presence of a base (e.g., sodium hydride or sodium hydroxide), and optionally in the presence of a catalyst (e.g., 4-(dimethylamino)-pyridine), to give the compound of formula (I). In some embodiments, reaction (vii) can be carried out at low temperatures (e.g., 0°C). The compound of formula (I) can be isolated by purification (e.g., by flash column chromatography or by preparative HPLC). In some embodiments, the compound of formula (I) can be isolated as a neutral compound or as a salt (e.g., a sodium salt).

[0288] In the descriptions and formulas shown above, it should be understood that the various groups are as defined herein unless otherwise indicated. Furthermore, for the purpose of synthesis, the compounds in the scheme are merely representative examples with selected substituents to illustrate the general synthetic methods disclosed herein.

[0289] It will be understood that the neutral compound of formula (I) can be converted to a salt (e.g., a sodium salt) using routine methods in the art (e.g., pH adjustment and optionally extraction (e.g., into an organic phase)). Furthermore, the salt (e.g., a sodium salt) of the compound of formula (I) can also be converted to a neutral compound using routine methods in the art (e.g., pH adjustment and optionally extraction (e.g., into an aqueous phase)).

[0290] If the compound contains a CH2CH2 spacer (i.e., R2 is -(CH2) n2 -R 2S And, in the formula, n2 is 2), intermediate 6 can be prepared using the reaction described above as shown in scheme 3.

[0291] Scheme 3 TIFF0007865948000052.tif22128

[0292] Biological assays Once compounds designed, selected, and / or optimized by the methods described above have been produced, they can be characterized using various assays known to those skilled in the art to determine whether they possess biological activity. For example, conventional assays, including, but not limited to, those described below, can be used to characterize molecules to determine whether they possess expected activity, binding activity, and / or binding specificity.

[0293] Furthermore, high-throughput screening can be used to speed up analysis using such assays. As a result, it may be possible to rapidly screen the molecules described herein using techniques known in the art. General methods for performing high-throughput screening are described, for example, in Devlin (1998) High Throughput Screening, Marcel Dekker, and U.S. Patent No. 5,763,263. High-throughput assays may use one or more different assay techniques, including, but not limited to, those described later.

[0294] Various in vitro or in vivo biological assays may be suitable for detecting the effects of the compounds disclosed herein. These in vitro or in vivo biological assays include, but are not limited to, enzyme activity assays, electrophoretic mobility shift assays, reporter gene assays, in vitro cell viability assays, and the assays described herein.

[0295] In some aspects, the biological assay is a biological assay that tests the inhibitory activity of NLRP3 activation on IL-1β release in peripheral blood mononuclear cells (PBMCs).

[0296] In some aspects, biological assays are performed using PBMC IC 50 This is a decisive assay. In some forms, the biological assay is PBMC IC 50 This is a decisive assay.

[0297] Pharmaceutical composition In some aspects, the present disclosure provides pharmaceutical compositions comprising the compounds of the present disclosure as active ingredients.

[0298] In some embodiments, the Disclosure provides a pharmaceutical composition comprising a compound described herein and one or more pharmaceutically acceptable carriers or excipients. In some embodiments, the Disclosure provides a pharmaceutical composition comprising at least one compound selected from Table 1.

[0299] As used herein, the term “composition” is intended to encompass products containing predetermined amounts of certain components, and any products obtained directly or indirectly by predetermined combinations of certain components.

[0300] The compounds of this disclosure can be formulated for oral administration in the form of tablets, capsules (including sustained-release and time-release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. Furthermore, the compounds of this disclosure can be formulated for intravenous (bolus or infusion), intraperitoneal, topical, subcutaneous, intramuscular, or transdermal (e.g., patch) administration, all of which are forms well known to those skilled in the pharmaceutical art.

[0301] The formulations of this disclosure may be in the form of aqueous solutions containing an aqueous medium. The aqueous medium components may include water and at least one pharmaceutically acceptable excipient. Suitable acceptable excipients include those selected from the group consisting of solubility enhancers, chelating agents, preservatives, isotonic agents, viscosity modifiers / suspending agents, buffers, and pH adjusters, as well as mixtures thereof.

[0302] Any solubility enhancer can be used. Examples of solubility enhancers include cyclodextrins, such as hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, randomly methylated β-cyclodextrin, ethylated β-cyclodextrin, triacetyl-β-cyclodextrin, peracetylated β-cyclodextrin, carboxymethyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, 2-hydroxy-3-(trimethylammonio)propyl-β-cyclodextrin, glucosyl-β-cyclodextrin, sulfated β-cyclodextrin (S-β-CD), maltosyl-β-cyclodextrin, β-cyclodextrin sulfobutyl ether, branched β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, randomly methylated γ-cyclodextrin, and trimethyl-γ-cyclodextrin, as well as cyclodextrins selected from the group consisting of these and mixtures thereof.

[0303] Any suitable chelating agent can be used. Examples of suitable chelating agents include those selected from the group consisting of ethylenediaminetetraacetic acid and its metal salts, disodium edetate, trisodium edetate, and tetrasodium edetate, and mixtures thereof.

[0304] Any suitable preservative can be used. Examples of preservatives include quaternary ammonium salts such as benzalkonium halide (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetylpyridinium chloride, benzyl bromide, phenylmercury nitrate, phenylmercury acetate, phenylmercury neodecanoate, methylthiolate, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethyl p-hydroxybenzoate, propylaminopropyl biguanide, butyl p-hydroxybenzoate, and sorbic acid, as well as mixtures thereof, selected from the group.

[0305] The aqueous medium may contain an isotonic agent to adjust the osmotic pressure. The isotonic agent can be selected from the group consisting of glycols (e.g., propylene glycol, diethylene glycol, triethylene glycol), glycerol, glucose, glycerin, mannitol, potassium chloride, and sodium chloride, as well as mixtures thereof.

[0306] The aqueous medium may contain viscosity modifiers / suspending agents. Suitable viscosity modifiers / suspending agents include those selected from the group consisting of cellulose derivatives, such as methylcellulose, ethylcellulose, hydroxyethylcellulose, polyethylene glycol (e.g., polyethylene glycol 300, polyethylene glycol 400), carboxymethylcellulose, hydroxypropylmethylcellulose, and crosslinked acrylic polymers (carbomers), such as acrylic polymers crosslinked with polyalkenyl ethers or divinyl glycol (Carbopol such as Carbopol 934, Carbopol 934P, Carbopol 971, Carbopol 974, and Carbopol 974P), and mixtures thereof.

[0307] To adjust the formulation to an acceptable pH (typically in the range of about 5.0 to about 9.0, more preferably about 5.5 to about 8.5, particularly about 6.0 to about 8.5, about 7.0 to about 8.5, about 7.2 to about 7.7, about 7.1 to about 7.9, or about 7.5 to about 8.0), the formulation may contain a pH adjuster. Typically, the pH adjuster is a mineral acid or a metal hydroxide base, selected from the group consisting of potassium hydroxide, sodium hydroxide, hydrochloric acid, and mixtures thereof, preferably sodium hydroxide and / or hydrochloric acid. Adding these acidic and / or basic pH adjusters adjusts the formulation to the target acceptable pH range. Therefore, it may not be necessary to use both an acid and a base. Depending on the formulation, it may be sufficient to add either an acid or a base to bring the mixture to the desired pH range.

[0308] The aqueous medium may contain a buffer to stabilize the pH. If used, the buffer is selected from the group consisting of phosphate buffers (e.g., sodium dihydrogen phosphate and disodium hydrogen phosphate), borate buffers (e.g., boric acid or salts thereof including disodium tetraborate), citrate buffers (e.g., citric acid or salts thereof including sodium citrate), and ε-aminocaproic acid, and mixtures thereof.

[0309] The formulation may further contain a wetting agent. A suitable class of wetting agents is selected from the group consisting of polyoxypropylene-polyoxyethylene block copolymers (poloxamers), polyethoxylated castor oil ethers, polyoxyethylene-sorbitan esters (polysorbates), oxyethylated octylphenol polymers (Tyloxapol), polyoxyl 40 stearate, fatty acid glycol esters, fatty acid glyceryl esters, sucrose fatty acid esters, and polyoxyethylene fatty acid esters, as well as mixtures thereof.

[0310] Oral compositions generally contain an inert diluent or a pharmaceutically acceptable food carrier. Oral compositions may be encapsulated in gelatin capsules or compressed into tablets. For therapeutic oral administration, the active compound can be incorporated with excipients and used in the form of tablets, lozenges, or capsules. Oral compositions for use as mouthwashes can also be prepared using a fluid carrier. In a mouthwash, the compound in the fluid carrier is applied orally, rinsed, and then spat out or swallowed. Pharmaceutically compatible binders and / or auxiliary materials may be included as part of the composition. Tablets, pills, capsules, lozenges, etc., may contain any of the following ingredients or compounds of similar properties: binders such as crystalline cellulose, tragacanth gum, or gelatin; excipients such as starch or lactose; disintegrants such as alginic acid, Primogel, or corn starch; lubricants such as magnesium stearate or Sterotes; flow enhancers such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or flavorings such as peppermint, methyl salicylate, or orange flavor.

[0311] Further aspects of this disclosure provide pharmaceutical compositions comprising a combination of a compound of the disclosure as defined above or a pharmaceutically acceptable salt, hydrate, or solvate thereof, and a pharmaceutically acceptable diluent or carrier.

[0312] The compositions of this disclosure may be in a form suitable for oral use (e.g., tablets, licks, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups, or elixirs), in a form suitable for topical use (e.g., creams, ointments, gels, or aqueous or oily solutions or suspensions), in a form suitable for inhalation (e.g., fine powders or liquid aerosols), in a form suitable for inhalation (e.g., fine powders), or in a form suitable for parenteral administration (e.g., sterile aqueous or oily solutions for intravenous, subcutaneous, intramuscular, intraperitoneal, or intramuscular administration, or suppositories for rectal administration).

[0313] The compositions of this disclosure can be obtained by conventional procedures using conventional pharmaceutical excipients that are well known in the art. Accordingly, compositions for oral use may include, for example, one or more colorants, sweeteners, flavorings, and / or preservatives.

[0314] An effective amount of the compounds of this disclosure for therapeutic use is an amount sufficient to treat or prevent, slow the progression of, and / or reduce the symptoms associated with, an inflammasome-associated condition as referred to herein.

[0315] The size of the dose of the compound of formula (I) for therapeutic or prophylactic purposes naturally varies according to well-known medical principles, depending on the nature and severity of the condition, the age and sex of the animal or patient, and the route of administration.

[0316] How to use In some aspects, the present disclosure provides a method for inhibiting inflammasome (e.g., NLRP3 inflammasome) activity (e.g., in vitro or in vivo), comprising the step of contacting a cell with an effective amount of the compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0317] In some aspects, the present disclosure provides a method for treating or preventing a disease or disorder disclosed herein in a subject that requires such treatment, comprising the step of administering to the subject a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition thereof.

[0318] In some embodiments, the disease or disorder involves inflammasome activity. In some embodiments, the disease or disorder is a disease or disorder in which inflammasome activity is involved.

[0319] In some embodiments, the disease or disorder is an inflammatory disease, autoinflammatory disorder, autoimmune disorder, neurodegenerative disease, or cancer.

[0320] In some embodiments, the disease or disorder is an inflammatory disease, an autoinflammatory disorder, and / or an autoimmune disorder.

[0321] In some aspects, the disease or disorder is cytokine release syndrome (CRS).

[0322] In some embodiments, the disease or disorder is selected from neuroinflammation occurring in cryopyrin-associated autoinflammatory syndromes (CAPS; e.g., familial cold autoinflammatory syndrome (FCAS)), Muckle-Wells syndrome (MWS), chronic infantile neurocutaneous arthritis (CINCA) syndrome, neonatal-onset multiorgan inflammatory disease (NOMID), familial Mediterranean fever (FMF), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), gout, rheumatoid arthritis, osteoarthritis, Crohn's disease, chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD), fibrosis, obesity, type 2 diabetes mellitus, multiple sclerosis, skin diseases (e.g., acne), and protein misfolding disorders (e.g., prion diseases).

[0323] In some aspects, the disease or disorder is a neurodegenerative disease.

[0324] In some embodiments, the disease or disorder is Parkinson's disease or Alzheimer's disease.

[0325] In some aspects, the disease or disorder is a skin disease.

[0326] In some aspects, the skin disease is acne.

[0327] In some aspects, the disease or disorder is cancer.

[0328] In some embodiments, cancer is metastatic cancer, gastrointestinal cancer, skin cancer, non-small cell lung cancer, brain cancer (e.g., glioblastoma), or colorectal adenocarcinoma.

[0329] In some aspects, cancer is breast cancer.

[0330] In some aspects, the Disclosure provides a method for treating or preventing an autoinflammatory disorder, autoimmune disorder, neurodegenerative disease, or cancer in a subject that requires such treatment, comprising the step of administering to the subject a therapeutically effective amount of a compound of the Disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition of the Disclosure.

[0331] In some aspects, the present disclosure provides a method for treating or preventing an inflammatory, autoinflammatory, and / or autoimmune disorder selected from neuroinflammation occurring in cryopyrin-associated autoinflammatory syndromes (CAPS; e.g., familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurocutaneous arthritis (CINCA) syndrome / neonatal onset multiorgan inflammatory disease (NOMID)), familial Mediterranean fever (FMF), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), gout, rheumatoid arthritis, osteoarthritis, Crohn's disease, chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD), fibrosis, obesity, type 2 diabetes mellitus, multiple sclerosis, skin diseases (e.g., acne), and protein misfolding disorders (e.g., prion diseases), the method comprising administering to the subject an effective amount of the compound of the present disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable composition of the present disclosure.

[0332] In some aspects, the present disclosure provides a method for treating or preventing cytokine release syndrome (CRS) in a subject that requires such treatment, comprising the step of administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable composition of the present disclosure.

[0333] In some aspects, CRS is associated with COVID-19. In some aspects, CRS is associated with adoptive cell therapy.

[0334] In some aspects, the present disclosure provides a method for treating or preventing a neurodegenerative disease (e.g., Parkinson's disease or Alzheimer's disease) in a subject that requires such treatment, comprising the step of administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable composition of the present disclosure.

[0335] In some aspects, the Disclosure provides a method for treating or preventing cancer in a subject that requires such treatment, comprising the step of administering to the subject a therapeutically effective amount of a compound of the Disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable composition of the Disclosure.

[0336] In some aspects, the present disclosure provides compounds of the present disclosure or pharmaceutically acceptable salts thereof for use in inhibiting inflammasome (e.g., NLRP3 inflammasome) activity (e.g., in vitro or in vivo).

[0337] In some respects, this disclosure provides compounds of the disclosure or pharmaceutically acceptable salts thereof for use in treating or preventing diseases or disorders disclosed herein.

[0338] In some aspects, the Disclosure provides compounds of the Disclosure or pharmaceutically acceptable salts thereof for use in subjects requiring treatment or prevention of inflammatory disorders, autoinflammatory disorders, autoimmune disorders, neurodegenerative diseases, or cancer.

[0339] In several aspects, the Disclosure provides compounds of the Disclosure or pharmaceutically acceptable salts thereof for use in subjects requiring treatment or prevention of inflammatory disorders, autoinflammatory disorders and / or autoimmune disorders selected from neuroinflammation occurring in cryopyrin-associated autoinflammatory syndromes (CAPS; e.g., familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurocutaneous arthritis (CINCA) syndrome / neonatal onset multiorgan inflammatory disease (NOMID)), familial Mediterranean fever (FMF), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), gout, rheumatoid arthritis, osteoarthritis, Crohn's disease, chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD), fibrosis, obesity, type 2 diabetes mellitus, multiple sclerosis and protein misfolding disorders (e.g., prion diseases).

[0340] In some aspects, the Disclosure provides compounds of the Disclosure or pharmaceutically acceptable salts thereof for use in doing so in subjects where it is necessary to treat or prevent CRS.

[0341] In some aspects, the Disclosure provides compounds of the Disclosure or pharmaceutically acceptable salts thereof for use in subjects where it is necessary to treat or prevent neurodegenerative diseases (e.g., Parkinson's disease or Alzheimer's disease).

[0342] In some aspects, the Disclosure provides compounds of the Disclosure or pharmaceutically acceptable salts thereof for use in subjects where it is necessary to treat or prevent cancer.

[0343] In some aspects, the present disclosure provides the use of the compounds of the present disclosure or pharmaceutically acceptable salts thereof in the manufacture of pharmaceuticals for inhibiting inflammasome (e.g., NLRP3 inflammasome) activity (e.g., in vitro or in vivo).

[0344] In some respects, the Disclosure provides the use of the Compounds of the Disclosure or pharmaceutically acceptable salts thereof in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0345] In some aspects, the Disclosure provides the use of the compounds of the Disclosure or pharmaceutically acceptable salts thereof in the manufacture of pharmaceuticals for treating or preventing inflammatory disorders, autoinflammatory disorders, autoimmune disorders, neurodegenerative diseases or cancer in subjects where such treatment or prevention is required.

[0346] In several aspects, the Disclosure provides the use of the compounds of the Disclosure or pharmaceutically acceptable salts thereof in the manufacture of pharmaceuticals for treating or preventing inflammatory, autoinflammatory, and / or autoimmune disorders selected from neuroinflammation occurring in cryopyrin-associated autoinflammatory syndromes (CAPS; e.g., familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurocutaneous arthritis (CINCA) syndrome / neonatal onset multiorgan inflammatory disease (NOMID)), familial Mediterranean fever (FMF), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), gout, rheumatoid arthritis, osteoarthritis, Crohn's disease, chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD), fibrosis, obesity, type 2 diabetes mellitus, multiple sclerosis, skin disorders (e.g., acne), and protein misfolding disorders (e.g., prion diseases).

[0347] In some aspects, the Disclosure provides the use of the compounds of the Disclosure or pharmaceutically acceptable salts thereof in the manufacture of a medicament for treating or preventing CRS in subjects that require such treatment or prevention.

[0348] In some aspects, the Disclosure provides the use of the compounds of the Disclosure or pharmaceutically acceptable salts thereof in the manufacture of pharmaceuticals for the purpose of treating or preventing neurodegenerative diseases (e.g., Parkinson's disease or Alzheimer's disease) in subjects where such treatment is required.

[0349] In some aspects, the Disclosure provides the use of the compounds of the Disclosure or pharmaceutically acceptable salts thereof in the manufacture of a medicament for treating or preventing cancer in subjects where such treatment or prevention is required.

[0350] This disclosure provides compounds that function as inhibitors of inflammasome activity. Therefore, this disclosure provides a method for inhibiting inflammasome activity in vitro or in vivo, comprising the step of contacting cells with an effective amount of a compound as defined herein or a pharmaceutically acceptable salt thereof.

[0351] The efficacy of the compounds disclosed herein can be determined by industry-accepted assays / disease models in accordance with standard practices that reveal efficacy, as described in the art and found in the latest general knowledge.

[0352] The disclosure also provides a method for treating a patient who requires treatment for a disease or disorder involving inflammasome activity, the method comprising administering to the patient a therapeutically effective amount of the compound described herein or a pharmaceutically acceptable salt or pharmaceutically acceptable composition thereof.

[0353] Generally, the compounds of this disclosure that inhibit the maturation of IL-1 family cytokines are effective in any therapeutic indication mediated by or associated with elevated levels of active cytokines belonging to the IL-1 cytokine family (Sims J. et al. Nature Reviews Immunology 10, 89-102 (February 2010)).

[0354] Exemplary diseases and corresponding references are listed below: inflammation, autoinflammatory and autoimmune diseases, e.g., CAPS (Dinarello, CAImmunity. 2004 Mar;20(3):243-4, Hoffman, HMet 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 (Coll, RC et al. Nat. Med. 2015 Mar;21(3):248-55, see EAE model), and many others (Martinon, F. et al. Immunol. 2009.27:229-65), for example, 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 several oncological disorders.

[0355] The compounds of this disclosure may be used as appropriate 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 diseases, autoinflammatory diseases, and autoimmune diseases may be appropriately selected from the group consisting of cryopyrin-associated autoinflammatory syndromes (CAPS; e.g., familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurocutaneous arthritis (CINCA) syndrome / neonatal onset multiorgan 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 mellitus, multiple sclerosis, skin diseases (e.g., acne), and neuroinflammation occurring in protein misfolding diseases, e.g., prion diseases. These neurodegenerative diseases include, but are not limited to, Parkinson's disease and Alzheimer's disease.

[0356] Accordingly, the compounds of this disclosure can be used to treat diseases selected from the group consisting of cryopyrin-associated autoinflammatory syndromes (CAPS; e.g., familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurocutaneous arthritis (CINCA) syndrome / neonatal onset multiorgan 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 mellitus, multiple sclerosis, skin diseases (e.g., acne), protein misfolding disorders, neuroinflammation occurring in prion diseases, neurodegenerative diseases (e.g., Parkinson's disease, Alzheimer's disease), and oncological disorders.

[0357] Inflammatory diseases associated with infection In some embodiments, the disease or disorder is an inflammatory disease.

[0358] In some aspects, inflammatory diseases are associated with infection.

[0359] In some aspects, inflammatory diseases are associated with viral infections.

[0360] In some embodiments, inflammatory diseases are associated with infection by RNA viruses. In some embodiments, RNA viruses are single-stranded RNA viruses. Single-stranded RNA viruses include group IV (positive-strand) and group V (negative-strand) single-stranded RNA viruses. In some embodiments, group IV viruses include coronaviruses.

[0361] In some aspects, inflammatory diseases are associated with coronavirus infection. In some aspects, the coronavirus is severe acute respiratory syndrome coronavirus 2 (SARS-CoV 2), SARS coronavirus (SARS-CoV), or Middle East respiratory syndrome-associated coronavirus (MERS).

[0362] In some aspects, inflammatory diseases are associated with infection by SARS-CoV 2. In some aspects, SARS-CoV 2 infection leads to COVID-19. In some aspects, SARS-CoV 2 infection leads to novel variants of COVID-19.

[0363] In some embodiments, inflammatory diseases are inflammatory diseases of the lungs.

[0364] In some ways, inflammatory lung diseases are associated with infection by SARS-CoV-2.

[0365] In some embodiments, inflammatory diseases include cytokine release syndrome (CRS).

[0366] In some ways, cytokine release syndrome (CRS) is associated with infection by SARS-CoV 2.

[0367] In some aspects, cytokine release syndrome (CRS) is associated with infection by variants of SARS-CoV 2.

[0368] In some aspects, a variant of SARS-CoV 2 is a variant of SARS-CoV 2 whose infection leads to a novel variant of COVID-19.

[0369] Cytokine release syndrome and immunotherapy In some embodiments, the disease or disorder is an inflammatory disease.

[0370] In some aspects, inflammatory diseases are associated with immunotherapy.

[0371] In some aspects, immunotherapy can cause cytokine release syndrome (CRS).

[0372] The effectiveness of immunotherapies such as CAR-T therapy is hindered by the frequency with which such treatments induce cytokine release syndrome (CRS). While we do not wish to be bound by theory, the severity of immunotherapy-induced CRS is thought to be mediated by IL-6, IL-1, and NO production (Giavridis et al. Nature Medicine 24, 731-738 (2018)). Alternatively, or in addition to the above, CRS can also occur when the 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 macrophage production of pro-inflammatory cytokines, which results in CRS (Liu et al. Science Immunology 5, eaax7969 (2020)).

[0373] In some embodiments, immunotherapy includes antibody or adoptive cell therapy.

[0374] In some aspects, adoptive cell therapy includes CAR-T or TCR-T cell therapy.

[0375] In some embodiments, adoptive cell therapy includes cancer therapy. In some embodiments, cancer therapy is the treatment of B-cell lymphoma or B-cell acute lymphoblastic leukemia. In some embodiments, adoptive cells may express CARs that target CD19+ B-cell acute lymphoblastic leukemia cells.

[0376] In some embodiments, adoptive cell therapy involves the administration of T cells, B cells, or NK cells.

[0377] In some embodiments, adoptive cell therapy includes the administration of T cells. In some embodiments, adoptive cell therapy includes the administration of B cells. In some embodiments, adoptive cell therapy includes the administration of NK cells.

[0378] In some embodiments, adoptive cell therapy is autologous.

[0379] In some forms, adoption therapy is homogeneous and heterogeneous.

[0380] Cancer treatment; association with inflammasomes Chronic inflammatory responses have long been observed to be associated with various types of cancer. Inflammasomes may be activated in response to danger signals during malignant transformation or cancer treatment, and this activation can be either beneficial or detrimental in cancer.

[0381] IL-1β expression is elevated in various cancers (including breast cancer, prostate cancer, colon cancer, lung cancer, head and neck cancer, and melanoma), and patients with IL-1β-producing tumors generally have a relatively poor 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).

[0382] Cancers originating from epithelial cells (carcinoma) or glandular epithelium (adenocarcinoma) are heterogeneous and comprise many different cell types. These may include fibroblasts, immune cells, adipocytes, endothelial cells, and pericytes, all of which can secrete cytokines / chemokines (Grivennikov, Sergei I., Florian R. Greten, and Michael Karin. "Immunity, inflammation, and cancer." Cell 140.6 (2010): 883-899). This can lead to cancer-associated inflammation through immune cell infiltration. While the presence of leukocytes in tumors is well known, it has only recently become clear that the inflammatory microenvironment is an essential component of all tumors. The majority of tumors (over 90%) are the result of somatic mutations or environmental factors rather than germline mutations, and many environmental causes of cancer are associated with chronic inflammation (20% of cancers are associated with chronic infections, 30% with smoking / inhalation pollutants, and 35% with dietary factors (20% of all cancers are associated with 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).

[0383] gastrointestinal cancer Gastrointestinal (GI) tract cancers are often associated with chronic inflammation. For example, Helicobacter pylori infection is linked to 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 IL-1β gene polymorphism 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).

[0384] In 19% of gastric cancer cases, caspase-1 expression is reduced, which correlates with stage, lymph node metastasis, and survival time (Jee et al., 2005). Mycoplasma hyorhinis is associated with the development of gastric cancer, and its activation of the NLRP3 inflammasome may be linked to the promotion of gastric cancer metastasis (Xu et al., 2013).

[0385] Skin cancer Ultraviolet radiation is the greatest environmental risk factor for skin cancer, which is promoted by causing DNA damage, immunosuppression, and inflammation. Melanoma, the most aggressive form of skin cancer, is characterized by the upregulation of inflammatory cytokines that can be controlled 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 enhanced metastasis and proliferation of melanoma cells via IL-1-dependent mechanisms in vivo. The use of thymoquinone has been shown to inhibit metastasis in the B16F10 mouse melanoma model, with the inhibition of the NLRP3 inflammasome being the key factor (Ahmad, Israr, et al. "Thymoquinone suppresses metastasis of melanoma cells by inhibition of NLRP3 inflammasome." Toxicology and applied pharmacology 270.1 (2013): 70-76).

[0386] Glioblastoma NLRP3 is a contributing factor to radiotherapy resistance in gliomas. Ionizing radiation can induce NLRP3 expression, but NLRP3 inhibition reduced tumor growth and extended mouse survival after radiotherapy. Therefore, NLRP3 inflammasome inhibition may be a viable therapeutic strategy for radiotherapy-resistant 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).

[0387] metastasis More broadly, the applicants believe that NLRP3 is involved in promoting metastasis, and therefore modulation of NLRP3 should likely block it. IL-1 is involved in tumorigenesis, tumor invasion, tumor metastasis, tumor-host interactions (Apte, Ron N., et al. "The involvement of IL-1 in tumorigenesis, tumor invasiveness, metastasis and tumor-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).

[0388] The IL-1 gene is frequently expressed in metastases from patients with several types of human cancer. For example, IL-1 mRNA was highly expressed in more than half of all tested metastatic human tumor samples, particularly those 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). IL-1RA inhibits xenograft growth in IL-1-producing tumors, but does not show antiproliferative effects in vitro.

[0389] Furthermore, IL-1 signaling serves as a biomarker to predict breast cancer patients at increased risk of developing bone metastases. In mouse models, IL-1β and its receptor are upregulated in breast cancer cells that metastasize to bone compared to cells that do not. In mouse models, the IL-1 receptor antagonist anakinra exerted a significant effect on the tumor environment by reducing the bone turnover markers IL-1β and TNFα, as well as reducing proliferation and angiogenesis (Holen, Ingunn, et al. "IL-1 drives breast cancer growth and bone metastasis in vivo." Oncotarget (2016)).

[0390] IL-18 promoted extracellular matrix degradation and cancer cell migration and invasion by inducing MMP-9 production in the human leukemia cell line HL-60 (Zhang, Bin, et al. "IL-18 increases invasiveness of HL-60 myeloid leukemia cells: up-regulation of matrix metalloproteinases-9 (MMP-9) expression." Leukemia Research 28.1 (2004): 91-95). Furthermore, IL-18 may support the development of tumor metastasis in the liver by inducing VCAM-1 expression on hepatic sinusoidal endothelium (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).

[0391] CD36 The fatty acid scavenger receptor CD36 plays a dual role: priming the gene transcription of pro-IL-1β and inducing the construction of the NLRP3 inflammasome complex. CD36 and the TLR4-TLR6 heterodimer recognize oxLDL, which initiates a signaling pathway that leads to the upregulation of NLRP3 and pro-IL-1β transcription (Signal 1). CD36 also mediates the internal translocation of oxLDL into the lysosomal compartment, where crystals are formed that induce lysosomal rupture and NLRP3 inflammasome activation (Signal 2) (Kagan, J. and Horng T., "NLRP3 inflammasome activation: CD36 serves double duty." Nature Immunology 14.8 (2013): 772-774).

[0392] A subpopulation of human oral cancer cells is unique in that it expresses high levels of the fatty acid scavenger receptor CD36 and has the ability to initiate metastasis. Palmitic acid or a high-fat diet boosted the transcriptional capacity of CD36+ cells. In an orthotopic mouse model of human oral cancer, metastasis was blocked by neutralizing an anti-CD36 antibody. The presence of CD36+ metastasis-initiating cells correlates with poor prognosis in numerous types of cancer. Dietary lipids are suggested to 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).

[0393] In hepatocellular carcinoma, exogenous palmitic acid activated an epithelial-mesenchymal transition (EMT)-like program and induced migration. This migration was reduced by the CD36 inhibitor sulfo-N-succinimidyloleate (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. This highlights that CD36 and free fatty acids are actually the key factors.

[0394] Cancer stem cells (CSCs) use CD36 to promote their maintenance. In glioblastoma, the presence of oxidized phospholipids, a ligand for CD36, and exposure to oxidized LDL increased CSC proliferation, but not non-CSC proliferation. Furthermore, CD36 was correlated with patient prognosis.

[0395] Chemotherapy resistance Chemotherapy agents utilize the host immune system, which contributes to their antitumor activity, in addition to their direct cytotoxic effects. However, gemcitabine and 5-FU have been shown to activate NLRP3 in bone marrow-derived suppressor cells, leading to the production of IL-1β, which reduces antitumor efficacy. Mechanistically, these agents activated NLRP3 by destabilizing lysosomes and releasing cathepsin B. IL-1β then promoted the production of IL-17 from CD4+ T cells, and IL-17 weakened the efficacy of chemotherapy. - / - Or Caps1 - / -Relatively high antitumor effects were observed in both gemcitabine and 5-FU when tumors were established in mice or WT mice treated with IL-1RA. Therefore, activation of NLRP3 in myeloid-derived suppressor cells limits the antitumor efficacy 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 tumor growth." Nature medicine 19.1 (2013): 57-64.). Accordingly, the compounds of this disclosure may be useful in chemotherapy for treating a range of cancers.

[0396] The compounds of this disclosure or their pharmaceutically acceptable salts may be administered alone as monotherapy, or in combination with one or more other substances and / or treatment agents. This combination therapy can be achieved by simultaneous, sequential, or individual administration of the individual components of the treatment.

[0397] For example, the administration of adjuvants can improve therapeutic efficacy (i.e., adjuvants may exhibit minimal therapeutic effect on their own, but when combined with other therapeutic agents, they can improve the overall therapeutic effect on the individual). Alternatively, as just one example, administering the compound of formula (I) together with another therapeutic agent (including a therapeutic regimen) that also exhibits therapeutic effect can increase the effect experienced by the individual.

[0398] When administering the compounds of this disclosure in combination with other therapeutic agents, the compounds of this disclosure do not necessarily have to be administered via the same route as the other therapeutic agents, and may be administered via different routes due to their differing physical and chemical properties. For example, the compounds of this disclosure can be administered orally to generate and maintain good blood levels, while the other therapeutic agents can be administered intravenously. Initial administration can be performed according to established protocols known in the art, and the dosage, mode of administration, and timing of administration can then be modified by a skilled physician based on the observed effects.

[0399] The specific selection of other therapeutic agents depends on the attending physician's diagnosis, as well as the physician's judgment regarding the individual's condition and appropriate treatment protocol. According to this aspect of the disclosure, combinations are provided for use in the treatment of diseases involving inflammasome activity, comprising the compounds of the disclosure as defined above or pharmaceutically acceptable salts thereof, and other suitable agents.

[0400] Further aspects of this disclosure provide pharmaceutical compositions comprising a combination of a compound of the disclosure or a pharmaceutically acceptable salt thereof with a suitable pharmaceutically acceptable diluent or carrier.

[0401] In addition to their use in therapeutic medicine, the compounds of formula (I) and their pharmaceutically acceptable salts are also useful as pharmacological tools in the development and standardization of in vitro and in vivo testing systems for evaluating the effects of inflammasome inhibitors in experimental animals such as dogs, rabbits, monkeys, rats, and mice as part of the search for novel therapeutic agents.

[0402] Any of the above-described pharmaceutical compositions, processes, methods, uses, pharmaceuticals, and manufacturing characteristics of this disclosure may also apply to any of the alternative embodiments of the macromolecules of this disclosure described herein.

[0403] Route of administration The compounds of this disclosure, or pharmaceutical compositions containing these compounds, can be administered to a subject by any convenient route of administration, whether systemic / peripheral or topical (i.e., the desired site of action).

[0404] Routes of administration include, but are not limited to, oral (e.g., oral ingestion); buccal; sublingual; transdermal (e.g., including patches and plasters); transmucosal (e.g., including patches and plasters); intranasal (e.g., nasal sprays); intraocular (e.g., eye drops); intrapulmonary (e.g., inhalation therapy or inhalation therapy, e.g., through the mouth or nose, e.g., using aerosols); rectal (e.g., suppositories or enemas); vaginal (e.g., pessaries); parenteral administration, e.g., injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, subarachnoid, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subepidermal, intraarticular, subarachnoid, and intrasternal; and subcutaneous or intramuscular depot or reservoir implantation. [Examples]

[0405] For illustrative purposes, the examples synthesize and test salts of the compound of formula (I). It will be understood that neutral compounds of formula (I) can also be similarly synthesized and tested using the exemplary procedures described in the examples. Furthermore, it will be understood that salts of the compound of formula (I) (e.g., sodium salts) can be converted to the corresponding neutral compounds using common methods in the art (e.g., pH adjustment and optionally extraction (e.g., into an aqueous phase)).

[0406] Nuclear magnetic resonance (NMR) spectra were recorded at 400 MHz or 300 MHz, as described, and at 300.3 K unless otherwise noted. Chemical shifts (δ) are reported in parts per million (ppm). Spectra were recorded using Bruker or Varian instruments with 8, 16, or 32 scans.

[0407] LC-MS chromatograms and spectra were recorded using an Agilent 1200 or Shimadzu LC-20 AD&MS 2020 instrument, with C-18 columns such as Luna-C18 2.0×30 mm or Xbridge Shield RPC18 2.1×50 mm. Injection volumes were 0.7–8.0 μL, and flow rates were typically 0.8 or 1.2 mL / min. Detection methods included diode array (DAD), evaporative light scattering (ELSD), and cation electrospray ionization. The MS range was 100–1000 Da. The solvent was a gradient of water and acetonitrile containing a modifier such as trifluoroacetic acid or ammonium carbonate (typically 0.01–0.04%).

[0408] Abbreviation: ACN Acetonitrile Acetic acid (ACOH) aq. Water-based DCM Dichloromethane DMF (N,N-dimethylformamide) DMSO-d6 Hexaduterodimethylsulfoxide eq. equivalent weight MS ES + Cational electrospray ionization mass spectrometry EDCI 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide ESI Electrospray Ionization HCl ethyl acetate FCC Flash Column Chromatography h time HATU N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridine-1-ylmethylene]-N-methylmethanaminonium hexafluorophosphate N-oxide HPLC (High-Performance Liquid Chromatography) LC-MS Liquid Chromatography-Mass Spectrometry MeOD methanol-d4 MeOH methanol Minutes MTBE methyl tert-butyl ether RM reaction mixture Rt room temperature sat. saturation SM Starting Material T3P Propylphosphonic Acid Anhydride TBSCl tert-butyldimethylsilyl chloride TFA (Trifluoroacetic Acid) THF (Tetrahydrofuran) Y yield

[0409] General Procedure A TIFF0007865948000053.tif18128 Add HATU (1.2 equivalents) to a 0.9 M DMF solution of carboxylic acid (1 equivalent) and stir the solution at 0°C for 1 hour. Add amine (1.1 equivalents) and DIPEA (2 equivalents) and stir the RM at 0°C for 2 hours. Stop the reaction of the RM (water) and extract the mixture (SiO2). Wash the combined organic layer (brine), dry it (Na2SO4), and concentrate it under reduced pressure. The residue was purified by column chromatography.

[0410] General Procedure B TIFF0007865948000054.tif18128 To a 1 M solution of amide (1 equivalent) in THF, 10 equivalents of LiAlH4 were added at 0°C and the mixture was stirred under N2 for 20 minutes. The mixture was then stirred under N2 at 70°C for 1 hour. The reaction was stopped at 0°C with RM (H2O and NaOH aqueous solution). The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the desired product.

[0411] General procedure C TIFF0007865948000055.tif20155 A 0.2M THF solution of sulfamoyl chloride (1 equivalent) and amine (1 equivalent) was mixed with either NaOH (1 equivalent) or NaH (4 equivalents) under N2 at 0°C. The mixture was stirred at 0°C for 2 hours. The reaction was evaporated under a stream of N2.

[0412] General Procedure D TIFF0007865948000056.tif18128 To a 0.4M solution (1 equivalent) of chlorosulfonyl isocyanate in isopropyl ether, cooled to -30°C under nitrogen, 0.4M of amine in isopropyl ether was added. The RM was stirred at -30°C for 0.5 to 2 hours and monitored by LC-MS (for the appearance of methylsulfonate). The product was used directly as an isopropyl ether solution (0.2M).

[0413] General Procedure E TIFF0007865948000057.tif20157 A 0.5 M solution of amine (1 equivalent) in THF was mixed with DIPEA (2 equivalents) and tert-butyl N-chlorosulfonyl carbamate (INT-C) (1.5 equivalents) at 0°C. The mixture was stirred at 0°C for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was diluted (H2O). The mixture was extracted (SiO₃). The combined organic layers were washed (brine), dried (Na₂SO₄), and concentrated under reduced pressure.

[0414] General Procedure F A mixture of tert-butyl sulfamoyl carbamate (1 equivalent) in ethyl phosphate and 4M HCl (0.2M) was stirred at 25°C for 1 hour. The RM was filtered, and the filter cake was dissolved in H2O at 25°C. An aqueous solution of Na2CO3 was added dropwise at 25°C until some solid precipitated and the pH reached 8. After 10 minutes, THF was added to dissolve the precipitate. The solution was dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the labeled compound as a free base.

[0415] General Procedure G TIFF0007865948000059.tif21146 A 0.23 M THF solution of sulfamoylamine (1 equivalent) and isocyanate (1 equivalent) was mixed with NaOH (1 equivalent) at 0°C. The mixture was stirred at 0°C for 12 hours.

[0416] General Procedure H TIFF0007865948000060.tif24128 A 0.1 M solution of amine (1 equivalent) in dioxane was mixed with triphosgene (1.1 equivalents) and a base. The mixture was stirred at 40°C for 1 hour until the RM was complete. The desired product was obtained by removing the solvent under reduced pressure.

[0417] Synthesis of intermediates Intermediate A: {[(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl]amino}sulfonyl chloride TIFF0007865948000061.tif24130

[0418] For the synthesis of 1,2,3,5,6,7-hexahydro-s-indacene-4-amine, patent application WO9832733A1 can be used as a direct reference. To a solution of chlorosulfonyl isocyanate (185 μL, 2.13 mmol) in isopropyl ether (20 mL), 1,2,3,5,6,7-hexahydro-s-indacene-4-amine (369 mg, 2.13 mmol) was added at -15°C. The mixture was stirred at -15°C for 0.5 hours. The reaction product was used directly in the next step. LC-MS (ESI) in MeOH: m / z: [MH] + =311.

[0419] Intermediate B: 4-Isocyanato-1,2,3,5,6,7-Hexahydro-s-Indacene TIFF0007865948000062.tif21128

[0420] For the synthesis of 1,2,3,5,6,7-hexahydro-s-indacene-4-amine, please refer to patent application WO9832733A1. To a mixture of triphosgene (1.71 g, 5.77 mmol) in DCM (5 mL) cooled to 0°C under nitrogen, 1,2,3,5,6,7-hexahydro-s-indacene-4-amine (1.00 g, 5.77 mmol) and triethylamine (1.69 mL, 12.12 mmol) were gradually added. The mixture was stirred at rt for 5 hours. The mixture was concentrated under reduced pressure to obtain the marked compound as a white solid. LC-MS (ESI) in MeOH: m / z: [M + MeOH + H] + =232

[0421] Intermediate C. tert-butyl N-(chlorosulfonyl)carbamate TIFF0007865948000063.tif20128

[0422] A 6 mL solution of DCM containing tert-butanol (338 μL, 3.53 mmol) was added to a 6 mL solution of DCM containing N-(oxomethylene)sulfamoyl chloride (307 μL, 3.53 mmol) cooled to 0°C. The mixture was stirred at 0°C for 2 hours. This solution was then used directly in the next step.

[0423] Intermediate D. 2-Isocyanatotricyclo[6.2.0.0 3,6 Deca-1,3(6),7-Trien The compound labeled TIFF0007865948000064.tif17128 was prepared as described in patent application WO2019023147A1 and used immediately. Y=98%. LCMS(ESI) in MeOH: m / z:[M+MeOH+H] + =204.0.

[0424] Intermediates E and F. TIFF0007865948000065.tif77165

[0425] Step 1. 1-Ethyl 3-methyl 2-(2,3-dihydroxypropyl)propanediate To a solution of 1,3-diethyl 2-(propanediol)propanediol (52.5 mL, 265 mmol) in formic acid (239 mL), H2O2 (27.3 mL, 28% solution, 265 mmol) was added at 0°C. RM was stirred under N2 at 0°C for 0.5 hours, then at 25°C for 23.5 hours. The reaction of the RM mixture was stopped by adding saturated Na2SO3 until iodine starch test paper indicated that all H2O2 had been consumed. RM was extracted (DCM, 100 mL x 3). The combined organic phase was washed (brine, 50 mL), dried (Na2SO4), and concentrated under reduced pressure to obtain the labeled compound as a colorless oil. Y = 89%. TIFF0007865948000066.tif19161

[0426] Step 2. 2-(2,3-dihydroxypropyl)propanediamide 1-ethyl 3-methyl 2-(2,3-dihydroxypropyl)propanedioate (54 g, 231 mmol) was dissolved in EtOH (500 mL) and NH3 (gas) was bubbling at 0°C. The RM was stirred at 0°C for 1 hour and filtered to obtain the marked compound as a white solid. Y = 86%. TIFF0007865948000067.tif12160

[0427] Step 3. 3-Bromo-5-(hydroxymethyl)-2-oxooxolane-3-carboxamide A solution of 2-(2,3-dihydroxypropyl)propanediamide (25 g, 142 mmol) in AcOH (500 mL) was stirred at 40°C for 2 hours. Br2 (7.32 mL, 41.9 mmol) was added at 0°C, and the mixture was stirred at 25°C for 26 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the labeled compound, which was used without further purification. TIFF0007865948000068.tif12148

[0428] Step 4. 4-Hydroxyoxolane-2,2-Dicarboxamide A solution of NH3 was bubbling at 0°C into a solution of 3-bromo-5-(hydroxymethyl)-2-oxotetrahydrofuran-3-carboxamide (33 g, 139 mmol) in EtOH (400 mL). The RM was stirred at 50°C for 6 hours. The RM was filtered, and the filtered cake was dried under reduced pressure to obtain the marked compound as a white solid (Y=79%), which was used directly in the next step.

[0429] Step 5. 4-Hydroxyoxolane-2,2-dicarboxylic acid A mixture of 4-hydroxyoxolane-2,2-dicarboxamide (10 g, 57.4 mmol) and 6 M HCl (105 mL) was stirred under N2 at 50°C for 4 hours. The RM was concentrated under reduced pressure to obtain the marked compound as a yellow solid, which was then used directly in the next step.

[0430] Step 6. 4-Hydroxyoxolane-2-carboxylic acid 4-hydroxyoxolane-2,2-dicarboxylic acid (2.0 g, 11.36 mmol) in H2O (12 mL) was heated in a sealed tube using microwave heating at 150°C for 1.5 hours. Four more batches were processed in parallel on the same scale. The reaction mixtures were combined and concentrated under reduced pressure to obtain the marked compound as a white solid, which was used without further purification. TIFF0007865948000069.tif19161

[0431] Step 7. 4-[(tert-butyldimethylsilyl)oxy]oxolane-2-carboxylic acid To a solution of 4-hydroxytetrahydrofuran-2-carboxylic acid (10 g, 75.7 mmol) cooled to 0°C in THF (300 mL), TBSCl (18.6 mL, 151 mmol) and imidazole (25.8 g, 378 mmol) were added. The RM was stirred at 25°C for 3 hours. The RM was concentrated under reduced pressure. The residue was diluted (water, 300 mL), and the resulting mixture was extracted (siRNA, 100 mL x 3). The combined organic layers were washed (brine, 100 mL), dried (Na2SO4), and concentrated under reduced pressure to obtain the marked compound as a brown oil, which was used without further purification.

[0432] Step 8. 4-[(tert-butyldimethylsilyl)oxy]-N-(1-methyl-1H-pyrazole-4-yl)oxolan-2-carboxamide To a solution of 4-[(tert-butyldimethylsilyl)oxy]oxolane-2-carboxylic acid (6.3 g, 25.6 mmol) in DMF (60 mL), HATU (11.7 g, 30.7 mmol) was added at 0°C and stirred for 1 hour. Then, DIPEA (8.91 mL, 51.1 mmol) and 1-methylpyrazole-4-amine (2.73 g, 28.1 mmol) were added. The mixture was stirred at 0°C for 1 hour. The reaction mixture was diluted (water, 100 mL), and the resulting mixture was extracted (siRNA, 100 mL x 3). The combined organic layers were washed (brine, 100 mL), dried (Na2SO4), and concentrated under reduced pressure to obtain a brown oily substance. This was purified with FCC (SiO2, 0-50% siRNA in petroleum ether) to obtain the marked compound as a yellow gum (Y=6%). TIFF0007865948000070.tif26161 (Note: Two sets of signals).

[0433] Step 9. syn-N-[[4-[tert-butyl(dimethyl)silyl]oxytetrahydrofuran-2-yl]methyl]-1-methylpyrazole-4-amine and anti-N-[[4-[tert-butyl(dimethyl)silyl]oxytetrahydrofuran-2-yl]methyl]-1-methylpyrazole-4-amine A mixture of 4-[tert-butyl(dimethyl)silyl]oxy-N-(1-methylpyrazole-4-yl)tetrahydrofuran-2-carboxamide (400 mg, 1.23 mmol) and 1 M BH3.THF (8.0 mL, 8.0 mmol) was stirred at 0°C for 0.5 hours. The RM was heated to 80°C for 1 hour. The reaction of the RM was stopped at 0°C (MeOH, 3 mL), and the mixture was concentrated under reduced pressure. Preparative HPLC (column: Phenomenex Gemini-NX C18, 3 μm, 75 × 30 mm; mobile phase: [water (0.04% NH3H2O ​​+ 10 mM NH4HCO3)-ACN]; B: 30-60%, 10 min) yielded syn-N-[[4-[tert-butyl(dimethyl)silyl]oxytetrahydrofuran-2-yl]methyl]-1-methylpyrazole-4-amine (Y=21%) and anti-N-[[4-[tert-butyl(dimethyl)silyl]-oxytetrahydrofuran-2-yl]methyl]-1-methylpyrazole-4-amine (Y=18%) as white solids.

[0434] syn-N-[[4-[tert-butyl(dimethyl)silyl]oxytetrahydrofuran-2-yl]methyl]-1-methylpyrazole-4-amine TIFF0007865948000071.tif26161

[0435] anti-N-[[4-[tert-butyl(dimethyl)silyl]oxytetrahydrofuran-2-yl]methyl]-1-methylpyrazole-4-amine TIFF0007865948000072.tif19161

[0436] Intermediate G. [({Tricyclo[6.2.0.0 3,6 Deca-1,3(6),7-trien-2-yl)carbamoyl)amino]-sulfonyl chloride TIFF0007865948000073.tif20128

[0437] The marked compound was obtained as a white solid (Y=63%) using tricyclo[6.2.0.03,6]deca-1(8),2,6-triene-2-amine according to general procedure D, and was immediately used. LC-MS(ESI):m / z:[M+MeOH-Cl] + = 283.2.

[0438] Example 1 (Compound 1). Sodium [(1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl][(1-methyl-1H-pyrazole-4-yl)[(oxolan-2-yl)methyl]sulfamoyl]azanide TIFF0007865948000074.tif23157

[0439] Step 1. N-(1-methyl-1H-pyrazole-4-yl)oxolan-2-carboxamide The general procedure A was followed using oxolane-2-carboxylic acid and 1-methyl-1H-pyrazole-4-amine. The marked compound was obtained as a yellow oil by FCC (SiO2, 50-100% phenylethylamine in petroleum ether). TIFF0007865948000075.tif19161

[0440] Step 2. 1-Methyl-N-[(oxolan-2-yl)methyl]-1H-pyrazole-4-amine The indicated compound was obtained as a yellow gum (Y=79%) by following general procedure B using N-(1-methyl-1H-pyrazole-4-yl)oxolan-2-carboxamide. TIFF0007865948000076.tif19161

[0441] Step 3. Sodium [(1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl][(1-methyl-1H-pyrazole-4-yl)[(oxolan-2-yl)methyl]sulfamoyl]azanide The general procedure C was followed using 1-methyl-N-(tetrahydrofuran-2-ylmethyl)pyrazole-4-amine, {[(1,2,3,5,6,7-hexahydro-s-indasen-4-yl)carbamoyl]amino}sulfonyl chloride (intermediate A) and NaH. The marked compound was obtained as a white solid by preparative HPLC (column: Agela DuraShell C18, 10 μm, 250 × 50 mm; mobile phase: [water (10 mM NH4HCO3)-can]; B: 2-35%, 23 min). Y = 5%. TIFF0007865948000077.tif26161

[0442] Example 2 (Compound 1A). Sodium [(1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl][(1-methyl-1H-pyrazole-4-yl)({[(2S)-oxolan-2-yl]methyl})sulfamoyl]azanide TIFF0007865948000078.tif48157

[0443] Step 1. (2S)-N-(1-methyl-1H-pyrazole-4-yl)oxolan-2-carboxamide (2S)-tetrahydrofuran-2-carboxylic acid and 1-methylpyrazole-4-amine were used according to general procedure A. The marked compound was obtained as a brown gum by preparative HPLC (column: Phenomenex Luna C18, 10 μm, 250 × 100 mm; mobile phase: [water (0.1% TFA)-ACN]; B: 0-14%, 40 min). Y = 74%. TIFF0007865948000079.tif13166

[0444] Step 2. 1-Methyl-N-{[(2S)-oxolan-2-yl]methyl}-1H-pyrazole-4-amine The indicated compound was used without further purification by following general procedure B with (2S)-N-(1-methyl-1H-pyrazole-4-yl)oxolan-2-carboxamide. Y = 55% TIFF0007865948000080.tif19161

[0445] Step 3. tert-butyl N-[(1-methyl-1H-pyrazole-4-yl)({[(2S)-oxolan-2-yl]methyl})sulfamoyl]carbamate The general procedure E was followed using 1-methyl-N-[[(2S)-tetrahydrofuran-2-yl]methyl]pyrazole-4-amine. The marked compound was obtained as a colorless gum by FCC (SiO2, 0-50% SiO2 in petroleum ether). Y = 76%. TIFF0007865948000081.tif19161

[0446] Step 4. N-(1-methyl-1H-pyrazole-4-yl)-N-{[(2S)-oxolan-2-yl]methyl}amino-sulfonamide The marked compound was obtained as a colorless gum by following general procedure F using N-[(1-methylpyrazole-4-yl)-[[(2S)-tetrahydrofuran-2-yl]methyl]sulfamoyl]carbamate. Y=85%. TIFF0007865948000082.tif19161

[0447] Step 5. Sodium [(1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl][(1-methyl-1H-pyrazole-4-yl)({[(2S)-oxolan-2-yl]methyl})sulfamoyl]azanide 1-methyl-4-[sulfamoyl-[[(2S)-tetrahydrofuran-2-yl]methyl]amino]pyrazole (1.2 g, 4.61 mmol) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (919 mg, 4.61 mmol) were dissolved in THF (20 mL) and NaOH (184 mg, 4.61 mmol) was added at 0°C. The mixture was stirred at 0°C for 12 hours. The reaction mixture was filtered to obtain a clear filtrate. MTBE (40 mL) was added, and the resulting solid was collected by filtration. The compound was freeze-dried with water to obtain the marked compound as a white solid. Y = 66%. TIFF0007865948000083.tif19161

[0448] Example 3 (Compound 3A). Sodium [(1-methyl-1H-pyrazole-4-yl)({[(2S)-oxolan-2-yl]methyl})sulfamoyl]-({tricyclo[6.2.0.0 3,6 Deca-1,3(6),7-trien-2-yl)carbamoyl)azanide TIFF0007865948000084.tif2912 1-methyl-4-[sulfamoyl-[[(2S)-tetrahydrofuran-2-yl]methyl]amino]pyrazole (85 mg, 286 μmol) at 80°C was mixed with NaOH (45.8 mg, 1.15 mmol) in a solution of THF (1 mL). After 15 minutes, 10-isocyanatotricyclodeca-(6),7(9),8(10)-triene (intermediate D) (49.0 mg, 286 μmol) was added, and the reaction mixture was stirred at 0°C for 1 hour. The reaction was concentrated under reduced pressure. The indicated compound was obtained as a white solid by preparative HPLC (column: Waters Xbridge BEH C18, 10 μm, 100 × 30 mm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B: 12-42%, 8 min). Y = 24%. TIFF0007865948000085.tif21167

[0449] Example 4 (Compound 1B). Sodium [(1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl][(1-methyl-1H-pyrazole-4-yl)({[(2R)-oxolan-2-yl]methyl})sulfamoyl]azanide TIFF0007865948000086.tif48157

[0450] Step 1. (2R)-N-(1-methyl-1H-pyrazole-4-yl)oxolan-2-carboxamide (2R)-oxolane-2-carboxylic acid (150 g, 1.29 mol) and 1-methyl-1H-pyrazole-4-aminium chloride (190 g, 1.42 mol) were dissolved in 900 mL of ethyl acetate (SiO2). DIPEA (501 g, 3.88 mol) and T3P (50% solution in ethyl acetate, 1.29 mol) were added dropwise at 0°C. The RM was stirred at 15-20°C for 12 hours. The RM was filtered, and the filtrate was concentrated under reduced pressure. The marked compound was obtained as a yellow solid by FCC (SiO2, 20-50% ethyl acetate in petroleum ether) (Y=78%). TIFF0007865948000087.tif19161

[0451] Step 2. 1-Methyl-N-{[(2R)-oxolan-2-yl]methyl}-1H-pyrazole-4-amine To a solution of (2R)-N-(1-methyl-1H-pyrazole-4-yl)oxolan-2-carboxamide (75.0 g, 384 mmol) in THF (450 mL), LiAlH4 (72.9 g, 1.92 mol) was added under N2 at 0°C. The mixture was stirred under N2 at 80°C for 1 hour. The RM was cooled to 0°C, and water (75 mL), NaOH (75 mL, 15% by weight, in water), and water (225 mL) were added dropwise in order at 0-5°C. The suspension was filtered, and the filter cake was washed (THF, 150 mL x 4). The filtrate was concentrated under reduced pressure to obtain the marked compound as an oil (Y = 77%). TIFF0007865948000088.tif19161

[0452] Step 3. tert-butyl N-[(1-methyl-1H-pyrazole-4-yl)({[(2R)-oxolan-2-yl]methyl})sulfamoyl]carbamate To a solution of 1-methyl-N-[[(2R)-tetrahydrofuran-2-yl]methyl]pyrazole-4-amine (115 g, 635 mmol) at 0°C in THF (690 mL), DIPEA (221 mL, 1.27 mol) and tert-butyl N-(chlorosulfonyl)carbamate (205 g, 952 mmol) in THF (880 mL) were added, and the RM was stirred at 0°C for 1 hour. The RM was diluted (water, 1.5 L) and extracted (SiO, 1 L x 2). The combined organic phases were washed with water (1.0 L) and brine (1.0 L), dried over Na2SO4, and concentrated under reduced pressure. Crude product was obtained by FCC (SiO2, 10-30% SiO in petroleum ether). The compound was ground in MTBE (600 mL) at 20°C for 2 hours, filtered, and dried under reduced pressure at 45°C for 4 hours to obtain the marked compound as a white solid. Y = 76%. TIFF0007865948000089.tif19161

[0453] Step 4. N-(1-methyl-1H-pyrazole-4-yl)-N-{[(2R)-oxolan-2-yl]methyl}amino-sulfonamide N-[(1-methylpyrazole-4-yl)-[[(2R)-tetrahydrofuran-2-yl]methyl]sulfamoyl]-carbamate (205 g, 569 mmol) was dissolved in 4 M HCl (1200 mL) in ethyl acetate and stirred at 15-20°C for 12 hours. The RM was concentrated under reduced pressure, and the residue was ground with ethyl acetate (500 mL) for 30 minutes at 20°C. The solid was collected by filtration. The solid was dissolved in water (600 mL), and the pH was adjusted to 8 with saturated Na2CO3 aqueous solution. The solution was extracted (ethyl acetate, 500 mL x 2). The combined organic phase was washed with water (500 mL) and brine (500 mL), dried over Na2SO4, and concentrated under reduced pressure to obtain the marked compound as a white solid. Y = 80%. TIFF0007865948000090.tif19161

[0454] Step 5. Sodium [(1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl][(1-methyl-1H-pyrazole-4-yl)({[(2R)-oxolan-2-yl]methyl})sulfamoyl]azanide To a solution of 1-methyl-4-[sulfamoyl-[[(2R)-tetrahydrofuran-2-yl]methyl]amino]pyrazole (59.5 g, 229 mmol) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (45.5 g, 229 mmol) in THF (900 mL) at 0°C, NaOH (9.14 g, 229 mmol) was added, and the RM was stirred at 15°C for 12 hours. The RM was filtered. MTBE (5.4 L) was added dropwise to the filtrate, and the solid was collected by filtration. The solid was washed with MTBE (500 mL x 2), dried under reduced pressure, and freeze-dried with water (1 L) to obtain the marked compound as an off-white solid. Y = 73%. TIFF0007865948000091.tif26161

[0455] Example 5 (Compound 3B). Sodium [(1-methyl-1H-pyrazole-4-yl)({[(2R)-oxolan-2-yl]methyl})sulfamoyl]-({tricyclo[6.2.0.0 3,6 Deca-1,3(6),7-trien-2-yl)carbamoyl)azanide The general procedure G was followed using 1-methyl-4-[sulfamoyl-[[(2R)-tetrahydrofuran-2-yl]methyl]amino]pyrazole and 10-isocyanatotricyclodeca-(6),7(9),8(10)-triene. The marked compounds were obtained as white solids by preparative HPLC (column: Waters Xbridge BEH C18, 10 μm, 100 × 30 mm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B: 12-42%, 8 min). Y = 14%. TIFF0007865948000093.tif20168

[0456] Example 6 (Compound 2A). Sodium ((1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)(N-((cis-4-hydroxytetrahydrofuran-2-yl)methyl)-N-(1-methyl-1H-pyrazole-4-yl)sulfamoyl)amide TIFF0007865948000094.tif22158

[0457] Step 1. 1-[[(2S,4S)-4-[tert-butyl(dimethyl)silyl]oxytetrahydrofuran-2-yl]methyl-(1-methylpyrazole-4-yl)sulfamoyl]-3-(1,2,3,5,6,7-hexahydro-s-indacene-4-yl)urea, sodium salt To a solution of syn-N-[[(2S,4S)-4-[tert-butyl(dimethyl)silyl]oxytetrahydrofuran-2-yl]methyl]-1-methylpyrazole-4-amine (60 mg, 192.62 μmol) in THF (1 mL), NaH (60% in mineral oil, 46.2 mg, 1.16 mmol) was added at 0°C for 15 minutes. Then, N-(1,2,3,5,6,7-hexahydro-s-indacene-4-ylcarbamoyl)sulfamoyl chloride (1.38 mL, 0.14 M in isopropyl ether, 193 μmol) was added. The RM was stirred at 0°C for 30 minutes and concentrated under reduced pressure to obtain the marked compound as a white solid. LCMS(ESI): m / z: [M+H] + = 590.3.

[0458] Step 2. 1-(1,2,3,5,6,7-hexahydro-s-indasen-4-yl)-3-[[(2S,4S)-4-hydroxytetrahydrofuran-2-yl]methyl-(1-methylpyrazole-4-yl)sulfamoyl]urea To a solution of 1-[[(2S,4S)-4-[tert-butyl(dimethyl)silyl]oxytetrahydrofuran-2-yl]methyl-(1-methylpyrazole-4-yl)sulfamoyl]-3-(1,2,3,5,6,7-hexahydro-s-indasen-4-yl)urea (50 mg, 81.6 μmol) in THF (1 mL) at 25°C, pyridine hydrogen fluoride (0.2 mL, 2.22 mmol) was added. The RM was stirred at 0°C for 30 minutes and treated with NaH (60% in mineral oil, 444 mg, 11.1 mmol). The RM was stirred at 0°C for 10 minutes and concentrated under reduced pressure. The indicated compound was obtained as a white solid by preparative HPLC (column: Waters Xbridge BEH C18, 10 μm, 100 × 30 mm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B: 5-35%, 8 min). Y = 4%. TIFF0007865948000095.tif26161

[0459] Example 7 (Compound 2B). 1-(1,2,3,5,6,7-hexahydro-s-indasen-4-yl)-3-[[(2R,4S)-4-hydroxytetrahydrofuran-2-yl]methyl-(1-methylpyrazole-4-yl)sulfamoyl]urea, sodium salt TIFF0007865948000096.tif21158

[0460] Step 1. 1-[[(2R,4S)-4-[tert-butyl(dimethyl)silyl]oxytetrahydrofuran-2-yl]methyl-(1-methylpyrazole-4-yl)sulfamoyl]-3-(1,2,3,5,6,7-hexahydro-s-indacene-4-yl)urea, sodium salt To a solution of anti-N-[[(2R,4S)-4-[tert-butyl(dimethyl)silyl]oxytetrahydrofuran-2-yl]methyl]-1-methylpyrazole-4-amine (60 mg, 192.62 μmol) in THF (1 mL) at 0°C, NaH (60% in mineral oil, 46.2 mg, 1.16 mmol) was added, and the RM was stirred for 15 minutes. N-(1,2,3,5,6,7-hexahydro-s-indacene-4-ylcarbamoyl)sulfamoyl chloride (0.14 M, 1.38 mL in isopropyl ether, 193 μmol) was added at 0°C, and the RM was stirred for 30 minutes. The RM was concentrated under reduced pressure to obtain the marked compound as a white solid, which was used without further purification. LCMS(ESI):m / z:[M+H] + = 590.3.

[0461] Step 2. 1-(1,2,3,5,6,7-hexahydro-s-indasen-4-yl)-3-[[(2R,4S)-4-hydroxytetrahydrofuran-2-yl]methyl-(1-methylpyrazole-4-yl)sulfamoyl]urea To a solution of 1-[[(2R,4S)-4-[tert-butyl(dimethyl)silyl]oxytetrahydrofuran-2-yl]methyl-(1-methylpyrazole-4-yl)sulfamoyl]-3-(1,2,3,5,6,7-hexahydro-s-indasen-4-yl)urea (60 mg, 97.9 μmol) in THF (1.5 mL) at 25°C, pyridine hydrogen fluoride (0.3 mL, 3.33 mmol) was added. After stirring at 25°C for 30 minutes, the reaction was cooled to 0°C and treated with NaH (133 mg, 60% in mineral oil, 3.33 mmol). The RM was stirred at 0°C for 10 minutes. The reaction mixture was concentrated under reduced pressure. The indicated compound was obtained as a white solid by preparative HPLC (column: Waters Xbridge BEH C18, 10 μm, 100 × 30 mm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B: 5-35%, 8 min). Y = 4%. TIFF0007865948000097.tif27167

[0462] Example 8 (Compound 4). Sodium [(1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl][(1-methyl-1H-pyrazole-4-yl)[(oxolan-2-yl)methyl]sulfamoyl]azanide TIFF0007865948000098.tif23156

[0463] Step 1. N-(1-methylpyrazole-4-yl)tetrahydrofuran-3-carboxamide The general procedure A was followed using tetrahydrofuran-3-carboxylic acid and 1-methylpyrazole-4-amine. The marked compound was obtained as a white solid (Y=59%) by FCC (5-50% MeOH in SiO2, ethylacetate). TIFF0007865948000099.tif19161

[0464] Step 2. N-(1-methyl-1H-pyrazole-4-yl)oxolan-2-carboxamide The compound was obtained as a colorless oil (Y=79%) using N-(1-methylpyrazole-4-yl)tetrahydrofuran-3-carboxamide according to general procedure B, and this was used directly in the next step without further purification.

[0465] Step 3. Sodium [(1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl][(1-methyl-1H-pyrazole-4-yl)[(oxolan-2-yl)methyl]sulfamoyl]azanide The general procedure C was followed using 1-methyl-N-(tetrahydrofuran-3-ylmethyl)pyrazole-4-amine, {[(1,2,3,5,6,7-hexahydro-s-indasen-4-yl)carbamoyl]amino}sulfonyl chloride (intermediate A) and NaH. The marked compound was obtained as a white solid by preparative HPLC (column: Waters Xbridge BEH C18, 5 μm, 100 × 25 mm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B: 10-40%, 10 min). Y = 16%. TIFF0007865948000100.tif32161

[0466] Example 9 (Compound 6) Sodium [(1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl][(1-methyl-1H-pyrazole-4-yl)[(oxan-2-yl)methyl]sulfamoyl]azanide TIFF0007865948000101.tif23157

[0467] Step 1. N-(1-methyl-1H-pyrazole-4-yl)oxan-2-carboxamide The general procedure A was followed using oxane-2-carboxylic acid and 1-methylpyrazole-4-amine. The marked compound was obtained as a yellow solid (Y=68%) by FCC (SiO2, 10-100% phenylethylamine in petroleum ether). TIFF0007865948000102.tif19161

[0468] Step 2. 1-Methyl-N-[(oxan-2-yl)methyl]-1H-pyrazole-4-amine The compound was obtained as a colorless oil (Y=82%) using N-(1-methyl-1H-pyrazole-4-yl)oxan-2-carboxamide according to general procedure B, and this was used directly in the next step without further purification. TIFF0007865948000103.tif19161

[0469] Step 3. Sodium [(1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl][(1-methyl-1H-pyrazole-4-yl)[(oxan-2-yl)methyl]sulfamoyl]azanide The general procedure C was followed using 1-methyl-N-[(oxan-2-yl)methyl]-1H-pyrazole-4-amine, {[(1,2,3,5,6,7-hexahydro-s-indasen-4-yl)carbamoyl]amino}sulfonyl chloride (intermediate A) and NaH. The marked compound was obtained as a white solid by preparative HPLC (column: Phenomenex Gemini-NX C18, 3 μm, 75 × 30 mm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B: 20-40%, 8 min). Y = 8%. TIFF0007865948000104.tif33161

[0470] Example 10 (Compound 5). Sodium [(1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl][(1-methyl-1H-pyrazole-4-yl)[2-(oxolan-2-yl)ethyl]sulfamoyl]azanide TIFF0007865948000105.tif69128

[0471] Step 1. 2-(oxolan-2-yl)acetic acid To a solution of ethyl 2-(oxolan-2-yl)acetate (500 mg, 3.16 mmol) at 0°C in H2O (2.5 mL) and MeOH (2.5 mL), LiOH,H2O (133 mg, 3.16 mmol) was added, and the RM was stirred at 0°C for 30 minutes. The RM was treated dropwise with 1 M HCl until the pH reached 5. The solution was extracted (HCl, 10 mL x 5). The resulting organic layer was concentrated under reduced pressure, and the marked compound was used without further purification. TIFF0007865948000106.tif19161

[0472] Step 2. N-(1-methyl-1H-pyrazole-4-yl)-2-(oxolan-2-yl)acetamide The general procedure A was followed using 2-(oxolan-2-yl)acetic acid and 1-methylpyrazole-4-amine. The marked compound was obtained by FCC (SiO2, 0-100% ethyl phosphate in petroleum ether). TIFF0007865948000107.tif19161

[0473] Step 3. 1-Methyl-N-[2-(oxolan-2-yl)ethyl]-1H-pyrazole-4-amine The indicated compound was obtained as a gum by following general procedure B using N-(1-methyl-1H-pyrazole-4-yl)-2-(oxolan-2-yl)acetamide, and this was used directly in the next step without further purification. TIFF0007865948000108.tif21169

[0474] Step 4. Sodium [(1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl][(1-methyl-1H-pyrazole-4-yl)[2-(oxolan-2-yl)ethyl]sulfamoyl]azanide The general procedure C was followed using 1-methyl-N-[2-(oxolan-2-yl)ethyl]-1H-pyrazole-4-amine, {[(1,2,3,5,6,7-hexahydro-s-indasen-4-yl)carbamoyl]amino}sulfonyl chloride (intermediate A) and NaH. The marked compound was obtained as a white solid by preparative HPLC (column: Waters Xbridge Prep OBD C18, 10 μm, 40 × 10 mm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B: 20-40%, 8 min). Y = 10%. TIFF0007865948000109.tif33161

[0475] Example 11 (Compound 7B). Sodium [(1-methyl-1H-pyrazole-4-yl)({[(2R)-oxan-2-yl]methyl})sulfamoyl]-({tricyclo[6.2.0.03,6]deca-1,3(6),7-trien-2-yl}carbamoyl)azanide) TIFF0007865948000110.tif24157

[0476] Step 1. (2R)-N-(1-methyl-1H-pyrazole-4-yl)oxan-2-carboxamide The general procedure A was followed using (2R)-oxane-2-carboxylic acid and 1-methylpyrazole-4-amine. The marked compound was obtained as a white solid by FCC (5-50% MeOH in SiO2, ethylacetate). Y = 83%. TIFF0007865948000111.tif26161

[0477] Step 2. 1-Methyl-N-{[(2R)-oxan-2-yl]methyl}-1H-pyrazole-4-amine The indicated compound was obtained as a colorless oil (Y=89%) using (2R)-N-(1-methyl-1H-pyrazole-4-yl)oxan-2-carboxamide according to general procedure B, and this was used in the next step without further purification. TIFF0007865948000112.tif19161

[0478] Step 3. Sodium [(1-methyl-1H-pyrazole-4-yl)({[(2R)-oxan-2-yl]methyl})sulfamoyl]-({tricyclo[6.2.0.0 3,6 Deca-1,3(6),7-trien-2-yl)carbamoyl)azanide Methyl-N-{[(2R)-oxan-2-yl]methyl}-1H-pyrazole-4-amine,({tricyclo[6.2.0.0 3,6 The general procedure C was followed using ]-deca-1,3(6),7-trien-2-yl)carbamoyl)aminosulfonyl chloride (intermediate G) and NaH. The marked compound was obtained as a white solid by preparative HPLC (column: Waters Xbridge Prep OBD C18, 10 μm, 150 × 40 mm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B: 15-45%, 8 min). Y = 12%. TIFF0007865948000113.tif26161

[0479] Example 12 (Compound 7A). Sodium [(1-methyl-1H-pyrazole-4-yl)({[(2S)-oxan-2-yl]methyl})sulfamoyl]-({tricyclo[6.2.0.0 3,6 Deca-1,3(6),7-trien-2-yl)carbamoyl)azanide TIFF0007865948000114.tif24157

[0480] Step 1. (2S)-N-(1-methyl-1H-pyrazole-4-yl)oxan-2-carboxamide (2S)-oxane-2-carboxylic acid and 1-methylpyrazole-4-amine were used in the general procedure A. The marked compound was obtained as a white solid by FCC (5-50% MeOH in SiO2, ethylacetate). Y = 69%. TIFF0007865948000115.tif19161

[0481] Step 2. 1-Methyl-N-{[(2S)-oxan-2-yl]methyl}-1H-pyrazole-4-amine The marked compound was obtained as an oily substance (Y=65%) using (2S)-N-(1-methyl-1H-pyrazole-4-yl)oxan-2-carboxamide according to general procedure B, and this was used in the next step without further purification. TIFF0007865948000116.tif19161

[0482] Step 3. Sodium [(1-methyl-1H-pyrazole-4-yl)({[(2S)-oxan-2-yl]methyl})sulfamoyl]-({tricyclo[6.2.0.0 3,6 Deca-1,3(6),7-trien-2-yl)carbamoyl)azanide Methyl-N-{[(2S)-oxan-2-yl]methyl}-1H-pyrazole-4-amine,({tricyclo[6.2.0.0 3,6 The general procedure C was followed using ]-deca-1,3(6),7-trien-2-yl}carbamoyl)aminosulfonyl chloride (intermediate G) and NaH.

[0483] The indicated compound was obtained as a white solid by preparative HPLC (column: Waters Xbridge Prep OBD C18, 5 μm, 100 × 25 mm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B: 10-50%, 10 min). Y = 21%. TIFF0007865948000117.tif54162

[0484] Example 13 (Compound 8A): 1-(1,2,3,5,6,7-hexahydro-s-indasen-4-yl)-3-[1H-pyrazole-4-yl-[[(2S)-tetrahydrofuran-2-yl]methyl]sulfamoyl]urea TIFF0007865948000118.tif57128

[0485] Step 1. tert-butyl 4-nitropyrazole-1-carboxylate To a solution of 4-nitro-1H-pyrazole (15 g, 132.7 mmol) in THF (150 mL), di-tert-butyl dicarbonate (33.5 mL, 145.9 mmol), DIPEA (23.1 mL, 132.7 mmol), and DMAP (1.62 g, 13.3 mmol) were added at 0°C. The mixture was stirred at 25°C for 2 hours. Water (100 mL) was added, and the resulting mixture was extracted with RINKAN (100 mL x 3). The combined organic layer was washed with brine (100 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO₂, 20-25% in petroleum ether) to obtain the marked compound as a white solid. Y = 50%. TIFF0007865948000119.tif5128

[0486] Step 2. tert-butyl 4-aminopyrazole-1-carboxylate To a solution of tert-butyl 4-nitropyrazole-1-carboxylate (5.0 g, 23.45 mmol) in MeOH (100 mL), 10% Pd carbon (50% wt., 1.0 g in water) was added under an N2 atmosphere. The suspension was degassed and purged three times with H2. The mixture was stirred at 25°C for 1 hour under H2 (15 psi). The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain the marked compound as a white solid. Y = 93%. TIFF0007865948000120.tif5141

[0487] Step 3. tert-butyl 4-[[(2S)-tetrahydrofuran-2-carbonyl]amino]pyrazole-1-carboxylate To a solution of (2S)-tetrahydrofuran-2-carboxylic acid (951 mg, 8.19 mmol) in DMF (30 mL), tert-butyl 4-aminopyrazole-1-carboxylate (1.5 g, 8.19 mmol), DIPEA (5.70 mL, 32.75 mmol), and T3P (50% solution in ethyl, 5.73 g, 9.01 mmol) were added. The RM was stirred at 25°C for 2 hours. Water (20 mL) was added, and the product was extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (10-30% ethyl in petroleum ether) to obtain the marked compound as a solid. Y = 91%.

[0488] Step 4. tert-butyl 4-[[(2S)-tetrahydrofuran-2-yl]methylamino]pyrazole-1-carboxylate To a solution of tert-butyl 4-[[(2S)-tetrahydrofuran-2-carbonyl]amino]pyrazole-1-carboxylate (1.8 g, 6.40 mmol) at 0°C in THF (100 mL), 10 M borane-dimethyl sulfide complex (2.56 ml, 25.6 mmol) was added. The RM was stirred at 80°C for 3 hours. The RM was cooled to 0°C and added dropwise to MeOH (50 mL). The mixture was concentrated under reduced pressure to obtain the marked compound as a yellow gum, which was used without purification. LCMS(ESI): m / z: [M+H] + = 268.2.

[0489] Step 5. 1-(1,2,3,5,6,7-hexahydro-s-indacene-4-yl)-3-[1H-pyrazole-4-yl-[[(2S)-tetrahydrofuran-2-yl]methyl]sulfamoyl]urea The general procedure C was followed using tert-butyl 4-[[(2S)-tetrahydrofuran-2-yl]methylamino]pyrazole-1-carboxylate, {[(1,2,3,5,6,7-hexahydro-s-indasen-4-yl)carbamoyl]amino}sulfonyl chloride (intermediate A) and NaH. Preparative HPLC (column: Phenomenex Titank C18 Bulk 250×70 mm 10 μm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B: 15-45%, 20 min) yielded 0.5 equivalents of the sodium salt of the labeled compound as a white solid. Y = 12%. TIFF0007865948000121.tif19161

[0490] In vitro profiling of the compounds of this disclosure The biological activity of the compounds disclosed herein was determined using the assays described herein.

[0491] PBMC IC 50 Determination assay. The compounds disclosed herein were tested for their inhibitory activity against IL-1β release upon NLRP3 activation in peripheral blood mononuclear cells (PBMCs).

[0492] Protocol A. PBMCs were isolated from the buffy coat by density gradient centrifugation using Histopaque-1077 (Sigma, catalog number 10771). Isolated cells were seeded in the wells of a 96-well plate and incubated with lipopolysaccharide (LPS) for 3 hours. After a medium change, the compounds of this disclosure were added (one compound per well), and the cells were incubated for 30 minutes. The cells were then stimulated with ATP (5 mM) or nigericin (10 μM) for 1 hour, and the cell culture medium was collected from the wells for further analysis. The release of IL-1β into the medium was determined by quantitative detection of IL-1β in the medium using the IL-1β enzyme-coupled immunosorbent assay (ELISA) Ready-SET-Go!, eBioscience catalog number 88-7261-88. Briefly, in the first step, a high affinity binding plate (Corning Costar 9018 or NUNC Maxisorp catalog number 44-2404) was coated overnight at 4°C using the kit-included specific capture antibody (anti-human IL-1β, product number 14-7018-68). Subsequently, the plate was blocked at room temperature (rt) for 1 hour using blocking buffer, washed with buffer (PBS containing 0.05% Tween-20), and incubated with protein standards and culture medium. After incubation at room temperature for 2 hours, the plate was washed and incubated at room temperature for 1 hour with the kit-included biotinylation detection antibody (anti-human IL-1β biotin, product number 33-7110-68). The plate was washed again and incubated at room temperature for 30 minutes with HRP-streptavidin, and then washed again. After adding 3,3',5,5'-tetramethylbenzidine peroxidase (TMB), the reaction was allowed to develop until a color change occurred, and then stopped with 2M H2SO4. The signal was detected at 450 nm using a microplate spectrometer (BioTek). The detection range for IL-1β ELISA was 2–150 ng / ml.

[0493] Protocol B. PBMCs were isolated from the buffy coat by density gradient centrifugation using Histopaque-1077 (Sigma, catalog number 10771). The isolated cells were seeded in the wells of a 96-well plate (280,000 cells / well) and incubated with lipopolysaccharide (LPS, 1 μg / ml, 1000-fold dilution from 1 mg / ml stock solution) for 3 hours. The compounds of this disclosure were added (1 compound per well), and the cells were incubated for 30 minutes. The cells were then stimulated with ATP (final concentration 5 mM, 20-fold dilution from 100 mM stock solution) for 1 hour, and cell culture medium was collected from the wells for further analysis. The release of IL-1β into the culture medium was determined by quantitative detection of IL-1β in the medium using HTRF®, CisBio catalog number 62HIL1BPEH. In short, cell culture supernatant was directly dispensed into assay plates containing antibodies labeled with HTRF® donor and HTRF® acceptor. A microplate spectrometer (BMG) was used to detect signals at 655 nm and 620 nm. The detection range for IL-1β HTRF® was 39–6500 pg / ml.

[0494] I C 50 The values ​​were determined using Graph Pad Prism software. The measured IC of the compounds of this disclosure 50 The values ​​are shown in Table A below ("++++" means <0.1 μM, "+++" means ≥0.1 and <1 μM, "++" means ≥1 and <3 μM, and "+" means ≥3 and <10 μM). These results indicate that the compounds of this disclosure can inhibit IL-1β release upon inflammasome activation.

[0495] (Table A) Activity in PBMC assay TIFF0007865948000122.tif74128

[0496] P-gp MDCK-MDR1 study. To evaluate whether the compounds of this disclosure are actively effluxed from cells by the efflux protein P-glycoprotein (P-gp), they were tested in an MDCK-MDR1 permeability assay.

[0497] Protocol. MDCK-MDR1 cells with passage numbers 6-30 were used. Cells were placed in Millipore Multiscreen Transwell plates in a 3.4 × 10⁶ configuration. 5 cells / cm 2 Cells were seeded. Cells were cultured in DMEM, and the medium was changed on day 3. P-gp inhibition studies were performed on day 4. Cell culture and assay incubation were carried out at 37°C under a 5% CO2 atmosphere, 95% relative humidity. On the day of the assay, a monolayer was prepared by rinsing both the apical and lateral / bottom surfaces with warmed (37°C) transport buffer (Hanks equilibrium salt solution [HBSS] at pH 7.4 containing 25 mM HEPES and 4.45 mM glucose). Next, cells were incubated at 37°C for 30 minutes with transport buffer containing the test compound or positive control inhibitor (eracridal) in both the apical and lateral / bottom compartments. Dosing solutions were prepared by diluting digoxin and, as appropriate, the test compound to a final digoxin concentration of 5 μM (final DMSO concentration of 1% v / v). Lucifer Yellow, a fluorescent integrity marker, was prepared in a receiver solution in a transport buffer containing the medium or test compound. After pre-incubation, the transport buffer was removed from both the apical and lateral compartments and replaced with a suitable dosing solution or receiver solution.

[0498] To evaluate BA permeability, the transport buffer was removed from the bottom companion plate and replaced with dosing solution. Fresh transport buffer (final DMSO concentration 1% v / v) containing Lucifer Yellow and, as appropriate, the test compound was added to the apical compartment insert, which was then placed in the companion plate. After 90 minutes of incubation, the apical compartment insert and companion plate were separated, and samples for analysis were taken from the compartment. Seven concentrations of the test compound (up to 100 μM) were evaluated in addition to the medium control (0 μM). Triple determination was performed for each concentration. Positive control inhibitors were evaluated in parallel. 3 [H]-digoxin was quantified by liquid scintillation counting, which provides decay rate per minute (dpm). The integrity of the monolayer throughout the experiment was checked by monitoring the transmission of Lucifer Yellow using fluorescence spectrometry.

[0499] BCRP and P-gp Caco-2 studies. The compounds of this disclosure were tested in Caco-2 permeability assays to evaluate whether they are actively effluxed from cells by the efflux protein P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP).

[0500] Protocol. Caco-2 cells with passages 40-60 were used. Cells were transferred to Millipore Multiscreen Transwell plates at a density of 105 cells / cm². 2Cells were seeded. Cells were cultured in DMEM, with the medium changed every 2 or 3 days. BCRP inhibition studies were performed on days 18–22. Cell culture and assay incubation were performed at 37°C under a 5% CO2 atmosphere, 95% relative humidity. On the day of the assay, monolayers were prepared by rinsing both the apical and lateral / basal surfaces with warmed (37°C) transport buffer (Hanks equilibrium salt solution [HBSS] at pH 7.4 containing 25 mM HEPES and 4.45 mM glucose). Cells were then incubated at 37°C for 30 minutes with transport buffer containing the test compound or positive control inhibitor (novobiocin) in both the apical and lateral / basal compartments. For inhibition studies, P-gp inhibitors or BCRP inhibitors were included on both sides of the monolayer during the equilibration period. The dosing solution was prepared by diluting estrone-3-sulfuric acid and, as appropriate, the test compound, until the final estrone-3-sulfuric acid concentration was 1 μM (final DMSO concentration 1% v / v). Lucifer Yellow, a fluorescent integrity marker, was prepared in a receiver solution in the medium or transport buffer containing the test compound. After pre-incubation, the transport buffer was removed from both the apical and bottom compartments and replaced with an appropriate dosing solution or receiver solution. To evaluate BA permeability, the transport buffer was removed from the bottom companion plate and replaced with the dosing solution. Fresh transport buffer (final DMSO concentration 1% v / v) containing Lucifer Yellow and, as appropriate, the test compound was added to the apical compartment insert, which was then placed in the companion plate. After 90 minutes of incubation, the apical compartment insert and the companion plate were separated, and samples for analysis were taken from the compartment. In addition to the media control (0 μM), seven concentrations of the compound (up to 100 μM) were evaluated. Triple determination was performed for each concentration. Positive control inhibitors were evaluated in parallel. 3[H]-estrone-3-sulfate was quantified by liquid scintillation counting, which gives decay rate per minute (dpm). The integrity of the monolayer throughout the experiment was checked by monitoring the transmission of Lucifer Yellow using fluorescence spectrophotometric analysis. The corrected apparent BA permeability (P) of the probe substrate was also measured. app ) was determined in the presence of the highest concentration of positive control inhibitor (giving 100% transporter inhibition), and its mean passive P app It was calculated by subtracting the average corrected BA P from the medium well (0 μM test compound). app We defined this as 100% transport activity, and then used this value to calculate the percentage control transport activity for all other test compound concentrations. We plotted the percentage control transport activity against the test compound concentration and performed fitting to obtain the IC score. 50 The value was calculated.

[0501] PAMPA research. To evaluate passive transcellular permeability, the compounds disclosed herein were tested in a PAMPA permeability assay.

[0502] Protocol. A 0.2 mM working solution was prepared by diluting a 10 mM stock solution with DMSO. A 10 μM donor solution (5% DMSO) was prepared by diluting 20 μL of the working solution with 380 μL of PBS. 150 μL of the 10 μM donor solution was added to each well of a donor plate with a PVDF membrane pre-coated with 5 μL of 1% lecithin / dodecane mixture. Replicates were prepared. 300 μL of PBS was added to each well of a PTFE acceptor plate. The donor and acceptor plates were combined and incubated at room temperature for 4 hours with shaking at 300 rpm. Preparation of T0 sample: 20 μL of donor solution was transferred to a new well, and then 250 μL of PBS (DF: 13.5) and 130 μL of ACN (containing internal standard) were added as the T0 sample. Preparation of acceptor sample: The plate was removed from the incubator. 270 μL of the solution was transferred to each acceptor well and mixed with 130 μL of ACN (containing an internal standard) as the acceptor sample. Donor sample preparation: 20 μL of the solution was transferred from each donor well and mixed with 250 μL of PBS (DF: 13.5) and 130 μL of ACN (containing an internal standard) as the donor sample. All acceptor and donor samples were analyzed by LC-MS / MS. The equation used to determine the transmittance (Pe) is shown below: VD=0.15mL; VA=0.30mL; Area=0.28cm 2 Time = 14400s; "[Drug] Acceptor = (Aa / Ai × DF) Acceptor; [Drug] Donor = (Aa / Ai*DF) Donor; Aa / Ai: Peak area ratio of analyte to internal standard; DF: Dilution ratio.

[0503] Thermodynamic solubility studies. The compounds disclosed herein were tested in equilibrium solubility assays.

[0504] Protocol. Appropriate amounts of the test compound and control compound were weighed into the lower chamber of a Whatman Mini-UniPrep vial. A supersaturated suspension was obtained by adding 450 μL of 50 mM pH 7.4 phosphate buffer. The samples were vortexed for at least 2 minutes. The Whatman Mini-UniPrep vials were shaken on a shaker at room temperature at 800 rpm for 24 hours. The vials were centrifuged for 20 minutes (e.g., 4000 rpm). The samples were pressurized, and filtrates were prepared for injection into an HPLC system, and the concentrations were calculated using standard curves. Table B shows the properties of selected compounds of the Disclosure. As shown in the table, the compounds of the Disclosure may exhibit improved properties (e.g., compared to prior art compounds), such as enhanced titer, solubility, membrane permeability, and transporter efflux.

[0505] The emission ratio (ER) values ​​of the compounds disclosed herein are shown in Table B below (where "****" means <3; "***" means 3≧ and <10; "**" means ≧10 and <30; and "*" means ≧30).

[0506] The PAMPA permeability measurements of the compounds disclosed herein are shown in Table B below (where "$$$$" means >10 nm / "$$$" means ≥3 and <10 nm / s / "$$" means ≥1 and <3 nm / s / "$" means <1 nm / s).

[0507] The measured values ​​of the thermodynamic stability of the compound of the present invention are shown in Table B below. TIFF0007865948000123.tif5128 means ≥3 and <10 mg / mL; TIFF0007865948000124.tif5128 means ≥1 and <3 mg / mL; TIFF0007865948000125.tif5128 means ≥0.3 and <1 mg / mL; TIFF0007865948000126.tif5128 means <0.3 mg / mL).

[0508] (Table B) TIFF0007865948000127.tif55142

[0509] Equivalents This specification provides details of one or more aspects of the present disclosure. Any methods and materials similar to or equivalent to those described herein may be used in the implementation or testing of the present disclosure, but preferred methods and materials are described here. Other features, purposes, and advantages of the present disclosure will become apparent from this specification and the claims. In this specification and the appended claims, the singular form encompasses multiple subjects unless the context makes this otherwise clear. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art to which this disclosure belongs. Any patents and publications referenced herein are incorporated herein by reference.

[0510] The above description is provided for illustrative purposes only and, except as limited by the attached claims, is not intended to limit this disclosure to the disclosed form itself.

Claims

1. Equation (I): A compound thereof, or its solvate, or a pharmaceutically acceptable salt thereof, During the ceremony, R 1 but And here n 1a and n 1b However, each is independently either 0 or 1; R 2 However, - (CH 2 ) n2 -R 2S And here n 2 However, it is either 1 or 2; R 2S is a 5- or 6-membered heterocycloalkyl having one heteroatom, the heteroatom being O, and further, the 5- or 6-membered heterocycloalkyl may be substituted with one or more R 2SS ; Each R 2SS However, independently, C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenil, C 2 ~C 6 Alkinyl, C 1 ~C 6 Haloalkyl, Halo, -CN, -OH, -O(C) 1 ~C 6 Alkyl), -NH 2 , -NH(C 1 ~C 6 Alkyl), -N (C 1 ~C 6 Alkyl) 2 , or oxo; R 3 However, one or more R 3S A 5-membered or 6-membered heteroaryl which may be substituted with; Each R 3S However, they became independent, Hello, C 1 ~C 6 Alkyl, or C 1 ~C 6 It is a haloalkyl, The aforementioned compound, its solvate, or a pharmaceutically acceptable salt thereof.

2. R 2S However, the heterocycloalkyl group is a five-membered or six-membered heterocycloalkyl group having one heteroatom, wherein the heteroatom is oxygen, and the five-membered or six-membered heterocycloalkyl group may be substituted with one or more -OH groups; R 3 However, one or more C 1 ~C 6 A 5-membered or 6-membered heteroaryl which may be substituted with an alkyl group. The compound according to claim 1.

3. R 1 but The compound according to claim 1 or 2.

4. R 2 However, -CH 2 -R 2S , or - (CH 2 ) 2 -R 2S The compound according to any one of claims 1 to 3.

5. R 2 However, -CH 2 -R 2S And, R 2S The compound is tetrahydrofuranil or tetrahydropyranil, and the tetrahydrofuranil or tetrahydropyranil may be substituted with one or more -OH groups. The compound according to any one of claims 1 to 4.

6. R 2 However, - (CH 2 ) 2 -R 2S And, R 2S The compound is tetrahydrofuranil or tetrahydropyranil, and the tetrahydrofuranil or tetrahydropyranil may be substituted with one or more -OH groups. The compound according to any one of claims 1 to 4.

7. R 2S However, it is a 5-membered or 6-membered heterocycloalkyl having one heteroatom, and the heteroatom is O, and the 5-membered or 6-membered heterocycloalkyl has one R 2SS The compound according to any one of claims 1 to 4, which may be substituted with

8. at least one R 2SS A compound according to any one of claims 1 to 7, wherein the compound is -OH.

9. R 2S However, the tetrahydrofuranil or tetrahydropyranil is one or more R 2SS The compound according to any one of claims 1 to 6 and 8, which may be substituted with

10. R 2S The compound according to any one of claims 1 to 6, 8 and 9, wherein the compound is tetrahydrofuranil or tetrahydropyranil, and the tetrahydrofuranil or tetrahydropyranil may be substituted with one or more -OH groups.

11. R 3 However, one or more R 3S The compound according to any one of claims 1 to 10, which is a 5-membered or 6-membered heteroaryl substituted with .

12. R 3 However, one or more C 1 ~C 6 The compound according to any one of claims 1 to 11, which is an alkyl-substituted five-membered or six-membered heteroaryl.

13. R 3 However, one or more C 1 ~C 6 The compound according to any one of claims 1 to 12, wherein the pyrazolyl is substituted with an alkyl group.

14. R 3 but The compound according to any one of claims 1 to 13.

15. Formula (Ia-1), (Ia-2), (Ib-1), (Ib-2), (Ic-1), (Ic-2), (Ic-3), (Id-1), (Id-2), (Ie-1), (Ie-2), (Ie-3), or (Ie-4): The compound according to claim 1, which is a compound of, a solvate thereof, or a pharmaceutically acceptable salt thereof.

16. the below described: The compound according to claim 1, selected from a compound selected from, a solvate thereof, or a pharmaceutically acceptable salt thereof.

17. A compound that is an isotopic derivative of the compound described in any one of claims 1 to 16.

18. A method for preparing the compound according to any one of claims 1 to 17, comprising one or more steps described in schemes 1 to 3 below; Scheme 1 ； Scheme 2 ； Scheme 3 ; In the formula, R 1 , R 2 , R 3 , R 2S L is the same as the definition in claim 1, 1 This is a leaving group.

19. A pharmaceutical composition comprising a compound according to any one of claims 1 to 17 and a pharmaceutically acceptable diluent or carrier.

20. A pharmaceutical composition for inhibiting inflammasome activity, comprising a compound according to any one of claims 1 to 17.

21. The pharmaceutical composition according to claim 20, wherein the inflammasome is an NLRP3 inflammasome and the activity is in vitro or in vivo.

22. A pharmaceutical composition for treating or preventing a disease or disorder, comprising a compound according to any one of claims 1 to 17.

23. The pharmaceutical composition according to claim 22, wherein the disease or disorder is associated with the involvement of inflammasome activity.

24. The pharmaceutical composition according to claim 23, wherein the disease or disorder is a disease or disorder in which inflammasome activity is involved.

25. The pharmaceutical composition according to any one of claims 22 to 24, wherein the disease or disorder is an inflammatory disorder, an autoinflammatory disorder, an autoimmune disorder, a neurodegenerative disease, or cancer.

26. The pharmaceutical composition according to any one of claims 22 to 25, wherein the disease or disorder is an inflammatory disorder, an autoinflammatory disorder, or an autoimmune disorder.

27. The pharmaceutical composition according to claim 26, wherein the disease or disorder is selected from cryopyrin-associated autoinflammatory syndrome (CAPS), familial Mediterranean fever (FMF), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), gout, rheumatoid arthritis, osteoarthritis, Crohn's disease, chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD), fibrosis, obesity, type 2 diabetes mellitus, multiple sclerosis, skin diseases, and neuroinflammation occurring in protein misfolding disorders.

28. The pharmaceutical composition according to claim 27, wherein the cryopyrin-related autoinflammatory syndrome is selected from familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurocutaneous arthral syndrome (CINCA), and neonatal onset multiorgan inflammatory disease (NOMID).

29. The pharmaceutical composition according to claim 27, wherein the skin disease is acne.

30. The pharmaceutical composition according to claim 27, wherein the protein misfolding disorder is a prion disease.

31. The pharmaceutical composition according to claim 25, wherein the disease or disorder is a neurodegenerative disease.

32. The pharmaceutical composition according to claim 31, wherein the disease or disorder is Parkinson's disease or Alzheimer's disease.

33. The pharmaceutical composition according to claim 25, wherein the disease or disorder is cancer.

34. The pharmaceutical composition according to claim 33, wherein 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.

35. If the disease or disorder is an inflammatory disorder, The inflammatory disorder is associated with infection. Inflammatory disorders are associated with infection by SARS-CoV-2, which leads to COVID-19, or A pharmaceutical composition according to any one of claims 22 to 26, wherein the inflammatory disorder includes cytokine release syndrome (CRS).

36. The pharmaceutical composition according to claim 35, wherein the CRS is associated with COVID-19 or adoptive cell therapy.

37. The pharmaceutical composition according to claim 35, wherein the infection is a viral infection.

38. The pharmaceutical composition according to claim 37, wherein the viral infection is caused by a single-stranded RNA virus.

39. The pharmaceutical composition according to claim 38, wherein the single-stranded RNA virus is a coronavirus.

40. The pharmaceutical composition according to claim 39, wherein the coronavirus is severe acute respiratory syndrome coronavirus 2 (SARS-CoV 2).

Images