Sulfonylurea derivatives and uses thereof

Abstract

The present disclosure relates to compounds of formula (I) and their prodrugs, pharmaceutically acceptable salts, pharmaceutical compositions, methods of use and methods of preparation. The compounds disclosed herein can be used to inhibit the maturation of cytokines of the IL-1 family by inhibiting inflammasomes, and can be used to treat conditions in which inflammasome activity is involved, such as inflammatory, autoinflammatory and autoimmune diseases and cancer.

Description

[0001] Related applications

[0002] This application claims priority to and the benefit of U.S. Provisional Application No. 62 / 860,664, filed on June 12, 2019, the contents of which are hereby incorporated by reference in their entirety. Technical Field

[0003] The present disclosure relates to sulfonylurea derivatives, prodrugs, and pharmaceutically acceptable salts thereof, which may have inflammasome inhibitory activity and, therefore, may be used in methods of treating the human or animal body. The present disclosure also relates to methods of preparing these compounds, pharmaceutical compositions containing them, and their use in treating conditions involving inflammasome activity, such as inflammatory diseases, autoinflammatory diseases, autoimmune diseases, and neoplastic diseases. Background Art

[0004] Autoimmune diseases are associated with excessive production of proinflammatory cytokines. 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 participates in a variety of cellular processes, including cell proliferation, differentiation, and apoptosis (Seth L. al. Rev. Immunol. 2009. 27:621–68).

[0005] In humans, 22 NLR proteins are divided into four NLR subfamilies based on their N-terminal domains. NLRAs contain a CARD-AT domain, NLRBs (NAIPs) contain a BIR domain, NLRCs (including NOD1 and NOD2) contain a CARD domain, and NLRPs contain a pyrin domain. Several NLR family members are associated with inflammasome formation.

[0006] Although inflammasome activation appears to have evolved as an important component of host immunity to pathogens, the NLRP3 inflammasome is unique in its ability to activate in response to endogenous sterile danger signals. Many of these sterile signals have been elucidated, and their formation is associated with specific disease states. For example, uric acid crystals found in gout patients are effective triggers for NLRP3 activation. Similarly, cholesterol crystals found in patients with atherosclerosis can also promote NLRP3 activation. Recognizing the role of sterile danger signals as NLRP3 activators has led to the involvement of IL-1 and IL-18 in a wide range of pathophysiological indications, including metabolic, physiological, inflammatory, hematological and immunological disorders.

[0007] The present disclosure arises from the need to provide further compounds for specifically modulating NLRP3-dependent cellular processes. In particular, there is a need for compounds having improved physicochemical, pharmacological, and pharmaceutical properties relative to existing compounds. Summary of the Invention

[0008] In some aspects, the present disclosure provides, inter alia, compounds of formula (I):

[0009]

[0010] or a prodrug, solvate or pharmaceutically acceptable salt thereof, wherein:

[0011] R1 is optionally replaced by one or more R 1S substituted 5- to 12-membered heterocycloalkyl or 5- to 12-membered heteroaryl;

[0012] Each R 1S are independently C1-C6 alkyl, C1-C6 haloalkyl, -O(C1-C6 alkyl), -O(C1-C6 haloalkyl), -(C1-C6 alkyl)-O(C1-C6 alkyl), cyano, halo, C3-C8 cycloalkyl, C3-C8 aryl, 3- to 8-membered heterocycloalkyl, or 3- to 8-membered heteroaryl;

[0013] R2 is -(CX2X2) n -R 2S , wherein n is 0, 1 or 2, and each X2 is independently H, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl, wherein the C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl is optionally substituted with one or more halo, -CN, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2 or oxo;

[0014] R 2S It is C1-C6 alkyl, C3-C 16 Cycloalkyl or 4 to 8 membered heterocycloalkyl, wherein the C1-C6 alkyl, C3-C 16 The cycloalkyl or 4- to 8-membered heterocycloalkyl is optionally substituted with one or more 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; and

[0015] R3 is optionally replaced by one or more R 3S substituted 5- to 12-membered heterocycloalkyl or 5- or 6-membered heteroaryl, wherein each R 3SIt is independently C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halo or C3-C8 heterocycloalkyl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl or C3-C8 heterocycloalkyl is optionally substituted with -O(C1-C6 alkyl), -N(C1-C6 alkyl)2, halo or -CN.

[0016] In some aspects, the present disclosure provides compounds obtainable by a process for preparing a compound as described herein or by a process for preparing a compound as described herein (e.g., a process comprising one or more steps described in Schemes 1-6).

[0017] In some aspects, the present disclosure provides pharmaceutical compositions comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.

[0018] In some aspects, the disclosure provides intermediates as described herein, which are useful in methods of preparing compounds as described herein (eg, the intermediates are selected from the intermediates described in Examples 1-17).

[0019] In some aspects, the present disclosure provides methods of inhibiting inflammasome (e.g., NLRP3 inflammasome) activity (e.g., in vitro or in vivo) comprising contacting a cell with an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0020] In some aspects, the present disclosure provides methods of treating or preventing a disease or condition disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0021] In some aspects, the present disclosure provides methods of treating a disease or condition disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0022] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in inhibiting inflammasome (eg, NLRP3 inflammasome) activity (eg, in vitro or in vivo).

[0023] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating or preventing a disease or condition disclosed herein.

[0024] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating a disease or condition disclosed herein.

[0025] In some aspects, the present disclosure provides use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for inhibiting inflammasome (eg, NLRP3 inflammasome) activity (eg, in vitro or in vivo).

[0026] In some aspects, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating or preventing a disease or condition disclosed herein.

[0027] In some aspects, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating a disease or condition disclosed herein.

[0028] In some aspects, the present disclosure provides methods of preparing the compounds of the present disclosure.

[0029] In some aspects, the present disclosure provides methods of making a compound comprising one or more of the steps described herein.

[0030] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those of ordinary skill in the art to which this disclosure belongs. In the specification, the singular also includes the plural, unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. All publications, patent applications, patents and other references mentioned herein are incorporated herein by reference. The references cited herein are not admitted to be prior art of the claimed invention. In the event of a conflict, this specification (including definitions) shall prevail. In addition, the substances, methods and examples are illustrative only and are not intended to be limiting. In the event of a conflict between the chemical structure and the name of the compound disclosed herein, the chemical structure shall prevail.

[0031] Other features and advantages of the disclosure will be apparent from the following detailed description and from the claims. DETAILED DESCRIPTION

[0032] Autoimmune diseases are associated with excessive production of proinflammatory cytokines, one of which is interleukin-1 (IL-1), which is produced by activated macrophages, monocytes, fibroblasts, and other components of the innate immune system, such as dendritic cells, and participates in a variety of cellular activities, including cell proliferation, differentiation, and apoptosis (Seth L. al. Rev. Immunol. 2009. 27: 621–68).

[0033] Autoimmune diseases are associated with excessive production of proinflammatory cytokines, one of which is interleukin-1 (IL-1), which is produced by activated macrophages, monocytes, fibroblasts, and other components of the innate immune system, such as dendritic cells, and participates in a variety of cellular activities, including cell proliferation, differentiation, and apoptosis (Seth L. al. Rev. Immunol. 2009. 27: 621–68).

[0034] Cytokines from the IL-1 family are highly active and, as important mediators of inflammation, are primarily associated with acute and chronic inflammation (Sims J. et al., Nature Reviews Immunology 10, 89-102 (February 2010)). Excessive production of IL-1 is considered a mediator of some autoimmune and autoinflammatory diseases. Autoinflammatory diseases are characterized by recurrent and unprovoked inflammation in the absence of autoantibodies, infection, or antigen-specific T lymphocytes.

[0035] The IL-1 superfamily of proinflammatory cytokines includes IL-1α, IL-1β, IL-18, and IL-36α, β, and λ, and is produced in response to pathogens and other cellular stressors as part of the host innate immune response. Unlike many other secreted cytokines that are processed and released via the standard cellular secretory apparatus consisting of the endoplasmic reticulum and the Golgi apparatus, IL-1 family members lack the leader sequence required for endoplasmic reticulum entry and are therefore retained intracellularly after translation. In addition, IL-1β, IL-18, and IL-36α, β, and λ are synthesized as procytokines that require proteolytic activation to become optimal ligands for binding to their cognate receptors on target cells.

[0036] In the case of IL-1α, IL-1β and IL-18, it is now recognized that a multimeric protein complex called inflammasome is responsible for activating the precursors of IL-1β and IL-18 and releasing these cytokines extracellularly. The inflammasome complex is typically composed of sensor molecules such as NLR (nucleotide-oligomerization domain (NOD)-like receptors), adapter molecules ASC (apoptosis-associated speck-like proteins containing CARD (caspase recruitment domain)) and pro-caspase-1. In response to a variety of "danger signals", including pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs), the subunits of the inflammasome oligomerize within the cell to form supramolecular structures. PAMPs include molecules such as peptidoglycan, viral DNA or RNA, and bacterial DNA or RNA. On the other hand, DAMPs are composed of many endogenous or exogenous sterile triggers, including aggregates of monosodium urate crystals, silica, alum, asbestos, fatty acids, ceramides, cholesterol crystals, and β-amyloid peptides. Assembly of the inflammasome platform promotes the autocatalysis of pro-caspase-1, generating highly active caspases responsible for the activation and release of pro-IL-1β and pro-IL-18. Thus, the release of these highly inflammatory cytokines occurs only in response to the detection and action of specific molecular danger signals by inflammasome sensors.

[0037] 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 are associated with inflammasome formation, including NLRP1, NLRP3, NLRP6, NLRP7, NLRP12, and NLRC4 (IPAF).

[0038] Two other structurally distinct inflammasome structures containing a PYHIN domain (pyrin and HIN domain-containing proteins), melanoma deficiency factor 2 (AIM2) and IFNλ-inducible protein 16 (IFI16) (Latz et al., Nat Rev Immunol 2013 13(6)397-311), act as intracellular DNA sensors. Pyrin (encoded by the MEFV gene) represents another type of inflammasome platform associated with pro-IL-1β activation (Chae et al., Immunity 34, 755-768, 2011).

[0039] The need to assemble an inflammasome platform to achieve activation and release of IL-1β and IL-18 from monocytes and macrophages ensures that their production is carefully coordinated via a two-step process. First, the cell must encounter a triggering ligand (such as the TLR4 receptor ligand LPS or an inflammatory cytokine such as TNFα), which leads to NFkB-dependent transcription of NLRP3, pro-IL-1β, and pro-IL-18. The newly translated pro-cytokines remain intracellular and inactive unless the producing cell encounters a second signal that leads to activation of the inflammasome scaffold and maturation of pro-caspase-1.

[0040] In addition to proteolytic activation of pro-IL-1β and pro-IL-18, active caspase-1 triggers a form of inflammatory cell death called pyroptosis through cleavage of gasdermin-D. Pyroptosis externalizes mature forms of IL-1β and IL-18, accompanied by the release of alarmin molecules (compounds that promote inflammation and activate innate and adaptive immunity), such as high-mobility group box 1 protein (HMGB1), IL-33, and IL-1α.

[0041] Although inflammasome activation appears to have evolved as an important component of host immunity to pathogens, the NLRP3 inflammasome is unique in its ability to activate in response to endogenous and exogenous sterile danger signals. Many of these sterile signals have been elucidated, and their formation is associated with specific disease states. For example, uric acid crystals found in gout patients are a potent trigger for NLRP3 activation. Similarly, cholesterol crystals found in patients with atherosclerosis can also promote NLRP3 activation. Recognition of the role of sterile danger signals as NLRP3 activators has led to the involvement of IL-1β and IL-18 in a wide range of pathophysiological indications, including metabolic, physiological, inflammatory, hematological, and immunological disorders.

[0042] The best example of its connection to human disease is the discovery that gain-of-function mutations in the NLRP3 gene confer a series of autoinflammatory conditions, collectively known as the cold and heat protein-associated periodic syndromes (CAPS), including familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease (NOMID) (Hoffman et al., Nat Genet. 29(3)(2001)301-305). Similarly, activation of NLRP3 induced by sterile mediators has been implicated in a wide variety of disorders, including joint degeneration (gout, rheumatoid arthritis, osteoarthritis), cardiovascular metabolism (type 2 diabetes, atherosclerosis, hypertension), central nervous system (Alzheimer's disease, Parkinson's disease, multiple sclerosis), gastrointestinal (Crohn's disease, ulcerative colitis), lung (chronic obstructive pulmonary disease (COPD), asthma, idiopathic pulmonary fibrosis), and liver (fibrosis, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis (NASH)). NLRP3 activation is further believed to promote renal inflammation and thereby contribute to chronic kidney disease (CKD).

[0043] Current treatment options for diseases in which IL-1 is implicated in the pathogenesis include the IL-1 receptor antagonist anakinra (an Fc-containing fusion construct of the extracellular domains of the IL-1 receptor and the IL-1 receptor accessory protein (rilonacept)) and the anti-IL-1β monoclonal antibody canakinumab. For example, canakinumab is licensed for use in CAPS, tumor necrosis factor receptor-associated periodic syndrome (TRAPS), hyperimmunoglobulin D syndrome (HIDS) / mevalonate kinase deficiency (MKD), familial Mediterranean fever (FMF), and gout.

[0044] Several small molecules have been reported to inhibit the function of the NLRP3 inflammasome. For example, glibenclamide is a specific inhibitor of NLRP3 activation, albeit at micromolar concentrations unlikely to be achieved in vivo. Nonspecific agents such as parthenolide, Bay 11-7082, and 3,4-methylenedioxy-β-nitrostyrene have been reported to attenuate NLRP3 activation but are expected to have limited therapeutic utility because they share a common structural feature consisting of an olefin activated by substitution with an electron-withdrawing group; this can lead to the formation of undesirable covalent adducts with thiol groups on proteins. A number of natural products, such as β-hydroxybutyrate, sulforaphane, quercetin, and salvianolic acid, have also been reported to inhibit NLRP3 activation. Similarly, a number of effectors / modulators of other molecular targets have been reported to attenuate NLRP3 activation, including agonists of the G-protein coupled receptor TGR5, inhibitors of sodium-glucose co-transport epigliflozin, dopamine receptor antagonist A-68930, serotonin reuptake inhibitor fluoxetine, fenamates nonsteroidal anti-inflammatory drugs, and beta-adrenergic receptor blockers nebivolol. The utility of these molecules as therapeutic agents for the long-term treatment of NLRP3-dependent inflammatory disorders remains to be established. A series of sulfonylurea-containing molecules were previously identified as potent and selective inhibitors of post-translational processing of pro-IL-1β (Perregaux et al., J Pharmacol. Exp. Ther. 299, 187-197, 2001). An exemplary molecule from this work, CP-456,773, was recently characterized as a specific inhibitor of NLRP3 activation (Coll et al., Nat Med 21.3 (2015): 248-255).

[0045] The present disclosure relates to compounds that can be used to specifically modulate NLRP3-dependent cellular processes. In particular, there is a need for compounds that have improved physicochemical, pharmacological, and pharmaceutical properties relative to existing NLRP3 modulating compounds.

[0046] definition

[0047] Unless otherwise stated, the following terms used in the specification and claims have the following meanings given below.

[0048] As used herein, "alkyl," "C1, C2, C3, C4, C5, or C6 alkyl," or "C1-C6 alkyl" is intended to include C1, C2, C3, C4, C5, or C6 straight-chain (linear) saturated aliphatic hydrocarbon groups and C3, C4, C5, or C6 branched-chain saturated aliphatic hydrocarbon groups. For example, C1-C6 alkyl is intended to include C1, C2, C3, C4, C5, and C6 alkyl groups. Examples of alkyl groups include moieties having from one to six carbon atoms, such as, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, or n-hexyl. In some embodiments, a straight-chain or branched alkyl group has six or fewer carbon atoms (e.g., C1-C6 for straight-chain, C3-C6 for branched), and in another embodiment, a straight-chain or branched alkyl group has four or fewer carbon atoms.

[0049] As used herein, the term "optionally substituted alkyl" refers to unsubstituted alkyl or alkyl having the specified substituents replacing one or more hydrogen atoms on one or more carbons of the hydrocarbon backbone. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonato, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0050] As used herein, the term "alkenyl" is included in unsaturated aliphatic groups similar to the above-mentioned alkyl groups in terms of length and possible substitution but containing at least one double bond. For example, the term "alkenyl" includes straight-chain alkenyl (e.g., vinyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl) and branched alkenyl. In certain embodiments, straight or branched alkenyl has six or less carbon atoms (e.g., for straight chain C2-C6, for branched chain C3-C6) in its backbone. The term "C2-C6" includes alkenyl containing two to six carbon atoms. The term "C3-C6" includes alkenyl containing three to six carbon atoms.

[0051] As used herein, the term "optionally substituted alkenyl" refers to unsubstituted alkenyl or alkenyl having the specified substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonato, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0052] As used herein, the term "alkynyl" is included in unsaturated aliphatic groups similar to the above-mentioned alkyl groups in terms of length and possible substitution but containing at least one triple bond. For example, "alkynyl" includes straight chain alkynyl (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl) and branched chain alkynyl. In certain embodiments, straight or branched chain alkynyl has six or less carbon atoms in its backbone (e.g., for straight chain C2-C6, for branched chain C3-C6). 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 linking group" or "C2-C6 alkynylene linking group" is intended to include C2, C3, C4, C5 or C6 chain (straight or branched) divalent unsaturated aliphatic hydrocarbon groups. For example, a C2-C6 alkenylene linker is intended to include C2, C3, C4, C5, and C6 alkenylene linking groups.

[0053] As used herein, the term "optionally substituted alkynyl" refers to unsubstituted alkynyl groups or alkynyl groups having designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonato, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0054] Other optionally substituted moieties (such as optionally substituted cycloalkyl, heterocycloalkyl, aryl or heteroaryl) include both unsubstituted moieties and moieties with one or more specified substituents. For example, substituted heterocycloalkyl includes those substituted with one or more alkyl groups, such as 2,2,6,6-tetramethyl-piperidinyl and 2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridinyl.

[0055] As used herein, the term "cycloalkyl" refers to a group having 3 to 30 carbon atoms (e.g., C3-C 12 、C3-C 10 or C3-C8) of a saturated or partially unsaturated hydrocarbon monocyclic or polycyclic (e.g., fused, bridged, or spirocyclic) system. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,2,3,4-tetrahydronaphthyl, and adamantyl. In the case of polycyclic cycloalkyl groups, only one ring in the cycloalkyl group needs to be non-aromatic.

[0056] As used herein, unless otherwise specified, the term "heterocycloalkyl" refers to a saturated or partially unsaturated 3-8 membered monocyclic, 7-12 membered bicyclic (fused, bridged or spiro) or 11-14 membered tricyclic ring system (fused, bridged or spiro) having one or more heteroatoms (such as O, N, S, P or Se), e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or e.g., 1, 2, 3, 4, 5 or 6 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur. Examples of heterocycloalkyl include, but are not limited to, piperidinyl, piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, isoindolinyl, indolinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, oxirane, azetidinyl, oxetanyl, thietanyl, 1,2,3,6-tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, pyranyl, morpholinyl, tetrahydrothiopyranyl, 1,4-diazepanyl, 1,4-oxazepanyl, 2-oxa-5-azacycloheptanyl, Heterobicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.1]heptyl, 2-oxa-6-azaspiro[3.3]heptyl, 2,6-diazaspiro[3.3]heptyl, 1,4-dioxa-8-azaspiro[4.5]decyl, 1,4-dioxaspiro[4.5]decyl, 1-oxaspiro[4.5]decyl, 1-azaspiro[4.5]decyl, 3'H-spiro[cyclohexane-1,1'-isobenzofuran]-yl, 7'H-spiro[cyclohexane-1,5 '-furo[3,4-b]pyridinyl]-yl, 3'H-spiro[cyclohexane-1,1'-furo[3,4-c]pyridinyl]-yl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexan-3-yl, 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolyl, 3,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidinyl, 4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridinyl, 5,6,7,8 -tetrahydropyrido[4,3-d]pyrimidinyl, 2-azaspiro[3.3]heptyl, 2-methyl-2-azaspiro[3.3]heptyl, 2-azaspiro[3.5]nonyl, 2-methyl-2-azaspiro[3.5]nonyl, 2-azaspiro[4.5]decyl, 2-methyl-2-azaspiro[4.5]decyl, 2-oxa-azaspiro[3.4]octanyl, 2-oxa-azaspiro[3.4]octan-6-yl, 5,6-dihydro-4H-cyclopenta[b]thienyl, and the like. In the case of polycyclic heterocycloalkyls, only one ring in the heterocycloalkyl needs to be non-aromatic (e.g., 4,5,6,7-tetrahydrobenzo[c]isoxazolyl). In some embodiments, the heterocycloalkyl is 5,6-dihydro-4H-cyclopenta[b]thienyl (e.g., In some embodiments, the heterocycloalkyl group is 4,5,6,7-tetrahydrobenzofuranyl (eg, In some embodiments, the heterocycloalkyl group is 4,5,6,7-tetrahydrobenzo[b]thienyl (e.g., ).

[0057] As used herein, the term "aryl" includes groups having aromatic properties, including "conjugated" or polycyclic ring systems having one or more aromatic rings, and does not contain any heteroatoms in the ring structure. The term aryl includes both monovalent and divalent species. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, and the like. Conveniently, aryl is phenyl.

[0058] As used herein, the term "heteroaryl" is intended to include stable 5-, 6-, or 7-membered monocyclic or 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic aromatic heterocyclic rings consisting of carbon atoms and one or more heteroatoms, such as 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or such as 1, 2, 3, 4, 5, or 6 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR, where R is H or other substituents as defined). The nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., N→O and S(O)). p , wherein 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, isothiazole, pyridine, pyrazine, pyridazine, pyrimidine, and the like. Heteroaryl groups can also be fused or bridged with non-aromatic alicyclic or heterocyclic rings to form polycyclic ring systems (e.g., 4,5,6,7-tetrahydrobenzo[c]isoxazolyl). In some embodiments, the heteroaryl group is thienyl or benzothienyl. In some embodiments, the heteroaryl group is thienyl. In some embodiments, the heteroaryl group is benzothienyl.

[0059] In addition, the terms "aryl" and "heteroaryl" include polycyclic aromatic and heteroaryl groups, such as tricyclic and bicyclic rings, for example, naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzimidazole, benzothiophene, quinoline, isoquinoline, naphthyridine, indole, benzofuran, purine, benzofuran, deazapurine, indolizine.

[0060] The cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring can be substituted at one or more ring positions (e.g., a ring carbon or heteroatom such as N) with substituents such as those described above, for example, alkyl, alkenyl, alkynyl, halogen, hydroxy, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthio The aryl and heteroaryl groups may also be fused or bridged with non-aromatic alicyclic or heterocyclic rings to form polycyclic ring systems (e.g., tetralin, methylenedioxyphenyl, such as benzo[d][1,3]dioxol-5-yl).

[0061] As used herein, the term "substituted" means that any one or more hydrogen atoms on a designated atom are replaced by a selected designated group, provided that the normal valence of the designated atom is not exceeded and that the replacement produces a stable compound. When the substituent is an oxo or keto (i.e., =O), 2 hydrogen atoms on the atom are replaced. There is no keto substituent on the aromatic moiety. 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" mean that the compound is sufficiently stable to withstand being separated by RM to a useful degree of purity and formulated into an effective therapeutic agent.

[0062] When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, such substituent may be bonded to any atom in the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, such substituent may be bonded to any atom in such formula. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0063] When any variable (e.g., R) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at all other occurrences. Thus, for example, if a group is shown to be substituted with 0-2 R moieties, then that group may optionally be substituted with up to two R moieties, with R at each occurrence being independently selected from the definition of R. Furthermore, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0064] As used herein, the term "hydroxy" (hydroxyl) includes groups having -OH or -O - group.

[0065] As used herein, the term "halo" or "halogen" refers to fluoro, chloro, bromo, and iodo.

[0066] The term "haloalkyl" or "haloalkoxy" refers to an alkyl or alkoxy group substituted with one or more halogen atoms.

[0067] As used herein, the term "optionally substituted haloalkyl" refers to unsubstituted haloalkyl groups having the specified substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonato, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0068] As used herein, the term "alkoxy" (alkoxyl) includes substituted and unsubstituted alkyl, alkenyl, and alkynyl groups covalently linked to an oxygen atom. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy, propoxy, butoxy, and pentoxy. Examples of substituted alkoxy groups include haloalkoxy. The alkoxy group can be substituted with groups such as alkenyl, alkynyl, halogen, hydroxyalkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonato, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Examples of halogen-substituted alkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, and trichloromethoxy.

[0069] As used herein, unless otherwise indicated, the expressions "one or more of A, B or C", "one or more A, B or C", "one or more of A, B and C", "one or more A, B and C", "selected from the group consisting of A, B and C", "selected from A, B and C", etc. are used interchangeably and all refer to selected from the group consisting of A, B and / or C, i.e., one or more A, one or more B, one or more C or any combination thereof.

[0070] It is to be understood that the present disclosure provides methods for synthesizing compounds of any formula described herein.The present disclosure also provides detailed methods for synthesizing various disclosed compounds of the present disclosure according to the following schemes as well as those shown in the Examples.

[0071] It is to be understood that throughout this specification, where a composition is described as having, including or comprising a particular component, it is intended that the composition also consists essentially of, or consists of, the enumerated components. Similarly, where a method or process is described as having, including or comprising a particular process step, the process also consists essentially of or consists of the enumerated processing steps. Further, it is to be understood that the order of the steps or the order in which certain actions are performed is immaterial so long as the present invention remains operable. In addition, two or more steps or actions may be performed simultaneously.

[0072] It is to be understood that the synthetic methods of the present disclosure can tolerate a wide variety of functional groups and therefore can use various substituted starting materials. The methods generally provide the desired final compound at or near the end of the overall method, although in some cases it may be desirable to convert the compound into a pharmaceutically acceptable salt thereof.

[0073] It is to be understood that the compounds of the present disclosure can be prepared in a variety of ways using commercially available starting materials, compounds known in the literature, or from readily prepared intermediates by employing standard synthetic methods and procedures known to those skilled in the art or which will be apparent to those skilled in the art in light of the teachings herein. Standard synthetic methods and procedures for the preparation of organic molecules and for the transformation and manipulation of functional groups can be obtained from the relevant scientific literature or from standard textbooks in the field. Although classic textbooks are not limited to any one or a few sources, textbooks such as the following are reference textbooks on organic synthesis that are known and recognized by those skilled in the art and are incorporated herein by reference: Smith, MB, March, J., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th Edition, John Wiley & Sons: New York, 2001; Greene, TW, Wuts, PGM, Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons: New York, 1999; R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquett, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995)

[0074] Those of ordinary skill in the art will note that during reaction sequence as herein described and synthesis scheme, the order of some steps can be changed, such as introducing and removing blocking groups. Those of ordinary skill in the art will recognize that some groups may need to be protected from the impact of reaction conditions via the use of blocking groups. Blocking groups can also be used to distinguish similar functional groups in molecules. The list of blocking groups and how to introduce and remove these groups can be found in Greene, TW, Wuts, PGM, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons: New York, 1999.

[0075] It is to be understood that, unless otherwise indicated, any description of a method of treatment or prevention includes the use of the compounds to provide such treatment or prevention as described herein. It is further to be understood that, unless otherwise indicated, any description of a method of treatment or prevention includes the use of the compounds to prepare a medicament for treating or preventing such a condition. Treatment or prevention includes treatment or prevention in humans and non-human animals, including rodents and other disease models.

[0076] It is to be understood that, unless otherwise indicated, any description of a method of treatment includes the use of the compound to provide such treatment as described herein. It is further to be understood that, unless otherwise indicated, any description of a method of treatment includes the use of the compound to prepare a medicament for treating such a condition. Treatment includes treatment of humans or non-human animals, including rodents and other disease models. As used herein, the term "subject" is interchangeable with the term "subject in need thereof," both of which refer to a subject suffering from a disease or at increased risk of developing a disease. "Subject" includes mammals. The mammal can be, for example, a human or an appropriate non-human mammal, such as a primate, mouse, rat, dog, cat, cow, horse, goat, camel, sheep, or pig. The subject can also be a bird or fowl. In one embodiment, the mammal is a human. The subject in need can be a subject who has previously been diagnosed or confirmed to have a disease or condition disclosed herein. The subject in need can also be a subject suffering from a disease or condition disclosed herein. Alternatively, the subject in need can be a subject at increased risk of developing such a disease or condition relative to the majority of the population (i.e., a subject who is susceptible to such a condition relative to the majority of the population). A subject in need may have a refractory or drug-resistant disease or condition disclosed herein (i.e., a disease or condition disclosed herein that has not responded or has not yet responded to treatment). The subject may be drug-resistant at the start of treatment, or may become drug-resistant during treatment. In some embodiments, the subject in need has received all known effective therapies for the disease or condition disclosed herein and has not been successful. In some embodiments, the subject in need has received at least one prior therapy.

[0077] As used herein, the terms "treating" and "treat" describe the management and care of a patient for the purpose of combating a disease, condition, or disorder, and include the administration of a compound of the present disclosure, or a pharmaceutically acceptable salt, polymorph, or solvate thereof, to alleviate the symptoms or complications of, or to eliminate, the disease, condition, or disorder. The term "treat" may also include the treatment of in vitro cells or animal models. It is to be understood that references to "treating" include alleviating established symptoms of a condition. "Treating" a condition, disorder, or disorder thus includes: (1) preventing or delaying the onset of clinical symptoms of the condition, disorder, or disorder in a person who may be susceptible to or susceptible to the condition, disorder, or disorder but has not yet experienced or displayed clinical or subclinical symptoms of the condition, disorder, or disorder, (2) inhibiting the condition, disorder, or disorder, i.e., preventing, reducing, or delaying the onset of the disease or its recurrence (in the case of maintenance therapy) or at least one clinical or subclinical symptom thereof, or (3) alleviating or attenuating the disease, i.e., resolving the condition, disorder, or disorder or at least one clinical or subclinical symptom thereof.

[0078] It is to be understood that the compounds of the present disclosure, or pharmaceutically acceptable salts, polymorphs or solvates thereof, may be or may also be used to prevent related diseases, conditions or disorders, or to identify suitable candidates for such purposes.

[0079] As used herein, the terms "preventing," "prevent," or "protection" describe reducing or eliminating the onset of symptoms or complications of such a disease, condition, or disorder.

[0080] It is understood that those skilled in the art can refer to general reference materials for detailed descriptions of known techniques or equivalent techniques discussed herein. Such materials include Ausubel et al., Current Protocols in Molecular Biology, John Wiley and Sons, Inc. (2005); Sambrook et al., Molecular Cloning, A Laboratory Manual (3rd ed.), Cold Spring Harbor Press, Cold Spring Harbor, New York (2000); Coligan et al., Current Protocols in Immunology, John Wiley & Sons, NY; Enna et al., Current Protocols in Pharmacology, John Wiley & Sons, NY; Fingl et al., The Pharmacological Basis of Therapeutics (1975), Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 18th ed. (1990). Of course, these materials can also be consulted in the preparation or use of certain aspects of the present disclosure.

[0081] It is to be understood that the present disclosure also provides pharmaceutical compositions comprising any of the compounds described herein in combination with at least one pharmaceutically acceptable excipient or carrier.

[0082] As used herein, the term "pharmaceutical composition" is a preparation of a compound of the present disclosure in a form suitable for administration to a subject. In one embodiment, the pharmaceutical composition is in bulk or in unit dosage form. A unit dosage form is any of a variety of forms, including, for example, a capsule, an IV bag, a tablet, a single pump or a vial on an aerosol inhaler. The amount of the active ingredient (e.g., a preparation of a disclosed compound or its salt, hydrate, solvate, or isomer) in a unit dose of the composition is an effective amount and varies according to the specific treatment involved. Those skilled in the art will recognize that it is sometimes necessary to make conventional changes to the dosage according to the age and condition of the patient. The dosage will also depend on the route of administration. Various routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalation, buccal, sublingual, intrapleural, intrathecal, intranasal, etc. Dosage forms for topical or transdermal administration of compounds of the present disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. In one embodiment, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that are required.

[0083] As used herein, the term "pharmaceutically acceptable" refers to those compounds, anions, cations, substances, compositions, carriers and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0084] As used herein, the term "pharmaceutically acceptable excipient" means an excipient that can be used to prepare a pharmaceutical composition that is generally safe, non-toxic, and has no biological or other adverse effects, and includes excipients that are acceptable for veterinary use as well as human pharmaceutical use. As used in the specification and claims, "pharmaceutically acceptable excipient" includes one or more such excipients.

[0085] It is to be understood that the pharmaceutical compositions of the present disclosure are formulated to be compatible with their intended route of administration. Examples of route of administration include parenteral, such as intravenous, intradermal, subcutaneous, oral (e.g., ingestion), inhalation, transdermal (external) and transmucosal administration. Solutions or suspensions for parenteral, intradermal or subcutaneous application may include the following components: a sterile diluent, such as water for injection, saline solution, fixed oil, polyethylene glycol, glycerol, propylene glycol or other synthetic solvents; antibacterial agents, such as benzyl alcohol or methyl paraben; antioxidants, such as ascorbic acid or sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid; buffers, such as acetates, citrates or phosphates, and agents for regulating tension, such as sodium chloride or dextrose. pH can be adjusted with acid or alkali, such as with hydrochloric acid or sodium hydroxide. Parenteral formulations can be packaged in ampoules, disposable syringes or multidose bottles made of glass or plastic.

[0086] It is to be understood that the compounds or pharmaceutical compositions of the present invention can be administered to a subject in many well-known methods currently used for chemotherapeutic treatments. For example, the compounds of the present invention can be injected into the bloodstream or body cavity or taken orally or applied through a skin patch. The selected dose should be sufficient to constitute an effective treatment, but not so high as to cause unacceptable side effects. The state and health status of the patient's disease condition (e.g., a disease or disorder disclosed herein) should preferably be closely monitored within a reasonable period of time during and after treatment.

[0087] As used herein, the term "therapeutically effective amount" refers to an amount of a pharmaceutical agent that is used to treat, ameliorate or prevent a confirmed disease or condition or to exhibit a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. The precise effective amount for a subject will depend on the subject's weight, size, and health; the nature and extent of the condition; and the therapeutic agent or combination of therapeutic agents selected for administration. The therapeutically effective amount for a given situation can be determined by routine experimentation within the skill and judgment of the clinician.

[0088] As used herein, the term "therapeutically effective amount" refers to an amount of a pharmaceutical agent that is effective to treat or ameliorate a confirmed disease or condition or to exhibit a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. The precise effective amount for a subject will depend on the subject's weight, size, and health; the nature and extent of the condition; and the therapeutic agent or combination of therapeutic agents selected for administration. The therapeutically effective amount for a given situation can be determined by routine experimentation within the skill and judgment of the clinician.

[0089] It is understood that for any compound, the therapeutically effective amount can be estimated initially in cell culture assays (e.g., of neoplastic cells) or in animal models (typically rats, mice, rabbits, dogs, or pigs). Animal models can also be used to determine appropriate concentration ranges and routes of administration. This information can then be used to determine a dose and route of administration that can be used in humans. Therapeutic / prophylactic efficacy and toxicity, such as ED, can be determined by standard pharmaceutical procedures in cell cultures or experimental animals. 50 (the dose therapeutically effective in 50% of the population) and LD 50 (the dose that is lethal to 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD 50 / ED 50 Pharmaceutical compositions that exhibit large therapeutic indices are preferred. The dosage may vary within this range depending on the dosage form employed, sensitivity of the patient, and the route of administration.

[0090] Dosage and administration are adjusted to provide adequate levels of the active agent or to maintain the desired effect. Factors that may be considered include the severity of the disease state; the subject's general health; the subject's age, weight, and sex; diet; time and frequency of administration; drug combination; reaction sensitivity; and tolerance / response to therapy. Long-acting pharmaceutical compositions may be administered every 3 to 4 days, weekly, or biweekly, depending on the half-life and clearance rate of the particular formulation.

[0091] Pharmaceutical compositions containing the active compound of the present disclosure can be prepared in a generally known manner, for example by means of conventional mixing, dissolving, granulating, making dragees, fine grinding, emulsifying, encapsulating, embedding or lyophilizing methods. Pharmaceutical compositions can be prepared in a conventional manner using one or more pharmaceutically acceptable carriers comprising excipients and / or adjuvants that contribute to processing the active compound into a pharmaceutically useful preparation. Of course, the appropriate formulation depends on the route of administration selected.

[0092] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL TM(BASF, Parsippany, NJ) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be a fluid that is easy to realize the degree of injectability. It must be stable under preparation and storage conditions and must be preserved to prevent the contamination of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyols (for example, glycerol, propylene glycol and liquid polyethylene glycol, etc.) and a suitable mixture thereof. Suitable fluidity can be maintained, for example, by using a coating such as lecithin, by maintaining the required particle size and by using a surfactant in the case of a dispersion. The effect of microorganisms can be prevented by various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, etc. In many cases, it is preferred to include isotonic agents in the composition, for example sugar, polyols such as mannitol and sorbitol and sodium chloride. The extended absorption of the injectable composition can be achieved by including in the composition an agent that delays absorption, such as aluminum monostearate and gelatin.

[0093] Sterile injectable solutions can be prepared by incorporating the desired amount of the active compound into an appropriate solvent, as needed, along with one or a combination of the ingredients listed above, followed by filtration sterilization. Typically, dispersions are prepared by incorporating the active compound into a sterile vehicle containing a basic dispersion medium and other ingredients desired from those listed above. In the case of sterile powders for the preparation of sterile injectable solutions, the preparation methods can be vacuum drying and freeze drying, which produce a powder of the active ingredient plus any additional desired ingredients from its previously sterile-filtered solution.

[0094] Oral compositions typically include an inert diluent or an edible pharmaceutically acceptable carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be combined with excipients and used in the form of tablets, lozenges, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and gargled and expectorated or swallowed. Pharmaceutically compatible binding agents and / or adjuvant substances can 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 microcrystalline cellulose, tragacanth gum, or gelatin; excipients such as starch or lactose; disintegrants such as alginic acid, Primogel, or corn starch; lubricants such as magnesium stearate or Sterotes; glidants such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or flavorings such as peppermint, methyl salicylate, or orange flavor.

[0095] For administration by inhalation, the compounds are delivered in the form of an aerosol spray from pressured container or dispenser which contains a suitable propellant, eg, a gas such as carbon dioxide, or from a nebulizer.

[0096] Systemic administration can also be performed through mucosal or transdermal means. For transmucosal or transdermal administration, penetrants suitable for the barrier to be penetrated are used in the formulation. Such penetrants are generally known in the art and include, for example, detergents, bile salts, and fusidic acid derivatives for transmucosal administration. Transmucosal administration can be achieved by using nasal sprays or suppositories. For transdermal administration, the active compound is formulated into an ointment, salves, gel, or cream commonly known in the art.

[0097] The active compound can be prepared together with a pharmaceutically acceptable carrier that will protect the compound to prevent it from being rapidly eliminated from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid can be used. Methods for preparing such preparations will be apparent to those skilled in the art. The substances can also be commercially available from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Patent No. 4,522,811.

[0098] It is particularly advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. As used herein, dosage unit form refers to physically discrete units suitable as unitary dosages for the subject to be treated; each unit contains a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specifications for the dosage unit forms of the present disclosure are dictated by and directly dependent on the unique characteristics of the active compound and the specific therapeutic effect to be achieved.

[0099] In therapeutic applications, the dosage of the pharmaceutical composition used according to the present disclosure varies according to the experience and judgment of the medicament, the age, weight and clinical condition of the patient, and the clinician or practitioner administering the therapy, as well as other factors affecting the selected dosage. Generally, the dosage should be sufficient to cause the symptoms of the disease disclosed herein or the condition to slow down and preferably disappear, and the disease or condition is also preferably completely eliminated. The dosage can vary from about 0.01 mg / kg per day to about 5000 mg / kg per day. In preferred aspects, the dosage can vary from about 1 mg / kg per day to about 1000 mg / kg per day. On the one hand, the dosage can be administered in single doses, divided doses, or continuous doses (which can be directed to the patient's weight (kg), body surface area (m2)), or both. 2) and age (years) (the dosage is adjusted), the dosage will be in the range of about 0.1 mg / day to about 50 g / day; about 0.1 mg / day to about 25 g / day; about 0.1 mg / day to about 10 g / day; about 0.1 mg to about 3 g / day; or about 0.1 mg to about 1 g / day. An effective amount of a medicament is an amount that provides an objectively identifiable improvement as noted by a clinician or other qualified observer. Improvements in survival and growth indicate regression. As used herein, the term "dosage effective manner" refers to the amount of active compound used to produce a desired biological effect in a subject or cell.

[0100] It will be understood that the pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

[0101] It is to be understood that for the compounds of the present disclosure that are capable of further forming salts, all such forms are also encompassed within the scope of the claimed disclosure.

[0102] As used herein, the term "pharmaceutically acceptable salt" refers to derivatives of the compounds of the present disclosure wherein the parent compound is modified by forming acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali metal or organic salts of acidic residues such as carboxylic acids, and the like. Pharmaceutically acceptable salts include, for example, conventional non-toxic salts or quaternary ammonium salts of the parent compound formed from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from the group consisting of 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonic acid, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, 1,2-ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, glycollyarsanilic acid, hexylresorcinolic acid, hydrabamic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxymaleic acid, hydroxynaphthoic acid, isethionic acid, lactic acid, lactobionic acid, laurylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, napsylic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, subacetic acid acid), succinic acid, sulfamic acid, sulfanilic acid, sulfuric acid, tannic acid, tartaric acid, toluenesulfonic acid and common amino acids such as glycine, alanine, phenylalanine, arginine, etc.

[0103] In some embodiments, the pharmaceutically acceptable salt is a sodium salt, potassium salt, calcium salt, magnesium salt, diethylamine salt, choline salt, meglumine salt, benzathine penicillin salt, tromethamine salt, ammonium salt, arginine salt, or lysine salt.

[0104] Other examples of pharmaceutically acceptable salts include hexanoic acid, cyclopentanepropionic acid, pyruvic acid, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo-[2.2.2]-oct-2-ene-1-carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, muconic acid, and the like. The present disclosure also encompasses salts formed when an acidic proton present in the parent compound is replaced by a metal ion (e.g., an alkali metal ion, an alkaline earth metal ion, or an aluminum ion); or coordinated with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. In salt form, it is understood that the ratio of the compound to the cation or anion of the salt can be 1:1, or any ratio different from 1:1, such as 3:1, 2:1, 1:2, or 1:3.

[0105] It is to be understood that all references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystal forms (polymorphs) as defined herein, of the same salt.

[0106] The compound or its pharmaceutically acceptable salt is administered orally, nasally, transdermally, pulmonary, by inhalation, buccal, sublingual, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally, and parenterally. In one embodiment, the compound is administered orally. Those skilled in the art will recognize the advantages of certain routes of administration.

[0107] The dosage regimen for using the compound is selected based on a variety of factors, including the type, species, age, weight, sex, and medical condition of the patient; the severity of the condition to be treated; the route of administration; the patient's renal and liver function; and the specific compound or salt thereof used. A physician or veterinarian can readily determine and prescribe the effective amount of the drug needed to prevent, counter, or arrest the progression of the condition. A physician or veterinarian can readily determine and prescribe the effective amount of the drug needed to counter or arrest the progression of the condition.

[0108] Techniques for formulating and administering the compounds disclosed herein can be found in Remington: the Science and Practice of Pharmacy, 19th ed., Mack Publishing Co., Easton, PA (1995). In one embodiment, the compounds described herein and pharmaceutically acceptable salts thereof are combined with a pharmaceutically acceptable carrier or diluent for use in pharmaceutical formulations. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions. The compound is present in such pharmaceutical compositions in an amount sufficient to provide the desired dosage within the range described herein.

[0109] Unless otherwise indicated, all percentages and ratios used herein are by weight. Other features and advantages of the present disclosure will be apparent from the various examples. The examples provided illustrate the various components and methods that can be used to practice the present disclosure. The examples do not limit the claimed disclosure. Based on the present disclosure, a skilled person can identify and use other components and methods that can be used to practice the present disclosure.

[0110] In the synthetic schemes described herein, for the sake of simplicity, compounds may be depicted as having a particular configuration. Such a particular configuration should not be construed as limiting the disclosure to one or another isomer, tautomer, regioisomer, or stereoisomer, nor does it exclude mixtures of isomers, tautomers, regioisomers, or stereoisomers; however, it will be understood that a given isomer, tautomer, regioisomer, or stereoisomer may have a higher level of activity than another isomer, tautomer, regioisomer, or stereoisomer.

[0111] All publications and patent documents cited herein are incorporated herein by reference, to the same extent as if each such publication or document was specifically and individually indicated to be incorporated herein by reference. Citation of publications and patent documents is not intended to be an admission that any of them is relevant prior art, nor does it constitute any admission of their content or date. Having now described the invention by way of a written description, those skilled in the art will recognize that the invention can be implemented in various embodiments, and the foregoing description and the following examples are for illustrative purposes only and do not limit the claims that follow.

[0112] As used herein, the phrase "compounds of the present disclosure" refers to those compounds disclosed both generically and specifically herein.

[0113] Compounds of the present disclosure

[0114] In some aspects, the present disclosure provides, inter alia, compounds of formula (I):

[0115]

[0116] or a prodrug, solvate or pharmaceutically acceptable salt thereof, wherein:

[0117] R1 is optionally replaced by one or more R 1S substituted 5- to 12-membered heterocycloalkyl or 5- to 12-membered heteroaryl;

[0118] Each R 1Sare independently C1-C6 alkyl, C1-C6 haloalkyl, -O(C1-C6 alkyl), -O(C1-C6 haloalkyl), -(C1-C6 alkyl)-O(C1-C6 alkyl), cyano, halo, C3-C8 cycloalkyl, C3-C8 aryl, 3- to 8-membered heterocycloalkyl, or 3- to 8-membered heteroaryl;

[0119] R2 is -(CX2X2) n -R 2S , wherein n is 0, 1 or 2, and each X2 is independently H, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl, wherein the C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl is optionally substituted with one or more halo, -CN, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2 or oxo;

[0120] R 2S It is C1-C6 alkyl, C3-C 16 Cycloalkyl or 4 to 8 membered heterocycloalkyl, wherein the C1-C6 alkyl, C3-C 16 The cycloalkyl or 4- to 8-membered heterocycloalkyl is optionally substituted with one or more 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; and

[0121] R3 is optionally replaced by one or more R 3S substituted 5- to 12-membered heterocycloalkyl or 5- or 6-membered heteroaryl, wherein each R 3S It is independently C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halo or C3-C8 heterocycloalkyl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl or C3-C8 heterocycloalkyl is optionally substituted with -O(C1-C6 alkyl), -N(C1-C6 alkyl)2, halo or -CN.

[0122] In some aspects, the present disclosure provides, inter alia, compounds of formula (I):

[0123]

[0124] or a prodrug, solvate or pharmaceutically acceptable salt thereof, wherein:

[0125] R1 is optionally replaced by one or more R 1S substituted 5- to 12-membered heterocycloalkyl or 5- to 12-membered heteroaryl;

[0126] Each R1S are independently C1-C6 alkyl, C1-C6 haloalkyl, -O(C1-C6 alkyl), -O(C1-C6 haloalkyl), -(C1-C6 alkyl)-O(C1-C6 alkyl), cyano, halo, C3-C8 cycloalkyl, C3-C8 aryl, 3- to 8-membered heterocycloalkyl, or 3- to 8-membered heteroaryl;

[0127] R2 is -(CX2X2) n -R 2S , wherein n is 0, 1 or 2, and each X2 is independently H, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl, wherein the C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl is optionally substituted with one or more halo, -CN, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2 or oxo;

[0128] R 2S It is C1-C6 alkyl, C3-C 16 Cycloalkyl or 4 to 8 membered heterocycloalkyl, wherein the C1-C6 alkyl, C3-C 16 The cycloalkyl or 4- to 8-membered heterocycloalkyl is optionally substituted with one or more 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; and

[0129] R3 is optionally replaced by one or more R 3S substituted 7- to 12-membered heterocycloalkyl or 5- or 6-membered heteroaryl, wherein each R 3S It is independently C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halo or C3-C8 heterocycloalkyl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl or C3-C8 heterocycloalkyl is optionally substituted with -O(C1-C6 alkyl), -N(C1-C6 alkyl)2, halo or -CN.

[0130] In some aspects, the compound has Formula (I), or a prodrug, solvate, or pharmaceutically acceptable salt thereof, wherein:

[0131] R1 is a 5- to 12-membered heterocycloalkyl or a 5- to 12-membered heteroaryl, wherein at least one heteroatom in the 5- to 12-membered heterocycloalkyl or the 5- to 12-membered heteroaryl is O or S, and wherein the 5- to 12-membered heterocycloalkyl or the 5- to 12-membered heteroaryl is optionally replaced by one or more R 1S replace;

[0132] Each R1S are independently C1-C6 alkyl, C1-C6 haloalkyl, -O(C1-C6 alkyl), cyano, halo, C3-C8 cycloalkyl or C3-C8 aryl;

[0133] R2 is -(CH2) n -R 2S , where n is 0, 1, or 2;

[0134] R 2S It is C1-C6 alkyl, C3-C 16 Cycloalkyl or 4 to 8 membered heterocycloalkyl, wherein the C1-C6 alkyl, C3-C 16 Cycloalkyl or 4- to 8-membered heterocycloalkyl is optionally substituted with one or more C1-C6 alkyl, halo, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl); and

[0135] R3 is a 5- to 6-membered heterocycloalkyl or a 5- or 6-membered heteroaryl, wherein the 5- to 12-membered heterocycloalkyl or the 5- or 6-membered heteroaryl is optionally substituted with one or more C1-C6 alkyl, C3-C8 cycloalkyl or halo.

[0136] In some aspects, the compound has Formula (I), or a prodrug, solvate, or pharmaceutically acceptable salt thereof, wherein:

[0137] R1 is a 5- to 12-membered heterocycloalkyl or a 5- to 12-membered heteroaryl, wherein at least one heteroatom in the 5- to 12-membered heterocycloalkyl or the 5- to 12-membered heteroaryl is O or S, and wherein the 5- to 12-membered heterocycloalkyl or the 5- to 12-membered heteroaryl is optionally replaced by one or more R 1S replace;

[0138] Each R 1S are independently C1-C6 alkyl, C1-C6 haloalkyl, -O(C1-C6 alkyl), cyano, halo, C3-C8 cycloalkyl or C3-C8 aryl;

[0139] R2 is -(CH2) n -R 2S , where n is 0, 1, or 2;

[0140] R 2S It is C1-C6 alkyl, C3-C 16 Cycloalkyl or 4 to 8 membered heterocycloalkyl, wherein the C1-C6 alkyl, C3-C 16 Cycloalkyl or 4- to 8-membered heterocycloalkyl is optionally substituted with one or more C1-C6 alkyl, halo, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl); and

[0141] R3 is a 5- or 6-membered heteroaryl group optionally substituted with one or more C1-C6 alkyl groups, C3-C8 cycloalkyl groups or halo groups.

[0142] In some embodiments, the compound has formula (I), or a prodrug, solvate, or pharmaceutically acceptable salt thereof, wherein:

[0143] R1 is optionally replaced by one or more R 1S substituted 5- to 12-membered heteroaryl;

[0144] Each R 1S are independently C1-C6 alkyl, C1-C6 haloalkyl, -O(C1-C6 alkyl), -O(C1-C6 haloalkyl) or halo;

[0145] R2 is -(CX2X2) n -R 2S , wherein n is 0, 1 or 2, and each X2 is independently H, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl, wherein the C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl is optionally substituted with one or more halo, -CN, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2 or oxo;

[0146] R 2S It is C1-C6 alkyl, C3-C 16 Cycloalkyl or 4 to 8 membered heterocycloalkyl, wherein the C1-C6 alkyl, C3-C 16 The cycloalkyl or 4- to 8-membered heterocycloalkyl is optionally substituted with one or more 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; and

[0147] R3 is optionally replaced by one or more R 3S substituted 7- to 12-membered heterocycloalkyl or 5- or 6-membered heteroaryl, wherein each R 3S It is independently C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halo or C3-C8 heterocycloalkyl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl or C3-C8 heterocycloalkyl is optionally substituted with -O(C1-C6 alkyl), -N(C1-C6 alkyl)2, halo or -CN.

[0148] In some embodiments, the compound has formula (I), or a prodrug, solvate, or pharmaceutically acceptable salt thereof, wherein:

[0149] R1 is optionally replaced by one or more R 1S substituted 5- to 12-membered heteroaryl, wherein at least one heteroatom in the 5- to 12-membered heteroaryl is S;

[0150] Each R 1S are independently C1-C6 alkyl, C1-C6 haloalkyl, -O(C1-C6 alkyl), -O(C1-C6 haloalkyl) or halo;

[0151] R2 is -(CX2X2) n -R 2S , wherein n is 0, 1 or 2, and each X2 is independently H, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl, wherein the C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl is optionally substituted with one or more halo, -CN, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2 or oxo;

[0152] R 2S It is C1-C6 alkyl, C3-C 16 Cycloalkyl or 4 to 8 membered heterocycloalkyl, wherein the C1-C6 alkyl, C3-C 16 The cycloalkyl or 4- to 8-membered heterocycloalkyl is optionally substituted with one or more 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; and

[0153] R3 is optionally replaced by one or more R 3S substituted 7- to 12-membered heterocycloalkyl or 5- or 6-membered heteroaryl, wherein each R 3S It is independently C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halo or C3-C8 heterocycloalkyl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl or C3-C8 heterocycloalkyl is optionally substituted with -O(C1-C6 alkyl), -N(C1-C6 alkyl)2, halo or -CN.

[0154] In some embodiments, the compound has formula (I), or a prodrug, solvate, or pharmaceutically acceptable salt thereof, wherein:

[0155] R1 is optionally replaced by one or more R 1S substituted 5- to 12-membered heteroaryl;

[0156] Each R 1S are independently C1-C6 alkyl, C1-C6 haloalkyl, -O(C1-C6 alkyl), -O(C1-C6 haloalkyl) or halo;

[0157] R2 is -(CX2X2) n -R 2S , wherein n is 0, 1 or 2, and each X2 is independently H, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl, wherein the C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl is optionally substituted with one or more halo, -CN, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2 or oxo;

[0158] R 2S is a 4- to 8-membered heterocycloalkyl group optionally substituted with one or more 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; and

[0159] R3 is optionally replaced by one or more R 3S substituted 7- to 12-membered heterocycloalkyl or 5- or 6-membered heteroaryl, wherein each R 3S It is independently C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halo or C3-C8 heterocycloalkyl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl or C3-C8 heterocycloalkyl is optionally substituted with -O(C1-C6 alkyl), -N(C1-C6 alkyl)2, halo or -CN.

[0160] In some embodiments, the compound has formula (I), or a prodrug, solvate, or pharmaceutically acceptable salt thereof, wherein:

[0161] R1 is optionally replaced by one or more R 1S substituted 5- to 12-membered heteroaryl, wherein at least one heteroatom in the 5- to 12-membered heteroaryl is S;

[0162] Each R 1S are independently C1-C6 alkyl, C1-C6 haloalkyl, -O(C1-C6 alkyl), -O(C1-C6 haloalkyl) or halo;

[0163] R2 is -(CX2X2) n -R 2S, wherein n is 0, 1 or 2, and each X2 is independently H, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl, wherein the C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl is optionally substituted with one or more halo, -CN, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2 or oxo;

[0164] R 2S is a 4- to 8-membered heterocycloalkyl group optionally substituted with one or more 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; and

[0165] R3 is optionally replaced by one or more R 3S substituted 7- to 12-membered heterocycloalkyl or 5- or 6-membered heteroaryl, wherein each R 3S It is independently C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halo or C3-C8 heterocycloalkyl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl or C3-C8 heterocycloalkyl is optionally substituted with -O(C1-C6 alkyl), -N(C1-C6 alkyl)2, halo or -CN.

[0166] In some embodiments, the compound has formula (I), or a prodrug, solvate, or pharmaceutically acceptable salt thereof, wherein:

[0167] R1 is optionally replaced by one or more R 1S substituted 5- to 12-membered heteroaryl;

[0168] Each R 1S are independently C1-C6 alkyl, C1-C6 haloalkyl, -O(C1-C6 alkyl), -O(C1-C6 haloalkyl) or halo;

[0169] R2 is R 2S ;

[0170] R 2S is a 4- to 8-membered heterocycloalkyl group optionally substituted with one or more 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; and

[0171] R3 is optionally replaced by one or more R 3Ssubstituted 7- to 12-membered heterocycloalkyl or 5- or 6-membered heteroaryl, wherein each R 3S It is independently C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halo or C3-C8 heterocycloalkyl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl or C3-C8 heterocycloalkyl is optionally substituted with -O(C1-C6 alkyl), -N(C1-C6 alkyl)2, halo or -CN.

[0172] In some embodiments, the compound has formula (I), or a prodrug, solvate, or pharmaceutically acceptable salt thereof, wherein:

[0173] R1 is thienyl or benzothienyl, wherein the thienyl or benzothienyl is optionally substituted by one or more R 1S replace;

[0174] Each R 1S are independently C1-C6 alkyl, C1-C6 haloalkyl, -O(C1-C6 alkyl), -O(C1-C6 haloalkyl) or halo;

[0175] R2 is R 2S ;

[0176] R 2S is a 4- to 8-membered heterocycloalkyl group optionally substituted with one or more 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; and

[0177] R3 is optionally replaced by one or more R 3S substituted 7- to 12-membered heterocycloalkyl or 5- or 6-membered heteroaryl, wherein each R 3S It is independently C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halo or C3-C8 heterocycloalkyl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl or C3-C8 heterocycloalkyl is optionally substituted with -O(C1-C6 alkyl), -N(C1-C6 alkyl)2, halo or -CN.

[0178] In some embodiments, the compound has formula (I), or a prodrug, solvate, or pharmaceutically acceptable salt thereof, wherein:

[0179] R1 is thienyl or benzothienyl, wherein the thienyl or benzothienyl is optionally substituted by one or more R 1S replace;

[0180] Each R 1Sis a C1-C6 alkyl group or a halo group;

[0181] R2 is R 2S ;

[0182] R 2S is a 4- to 8-membered heterocycloalkyl group optionally substituted with one or more 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; and

[0183] R3 is optionally replaced by one or more R 3S substituted 7- to 12-membered heterocycloalkyl or 5- or 6-membered heteroaryl, wherein each R 3S It is independently C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halo or C3-C8 heterocycloalkyl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl or C3-C8 heterocycloalkyl is optionally substituted with -O(C1-C6 alkyl), -N(C1-C6 alkyl)2, halo or -CN.

[0184] It is to be understood that for compounds of formula (I), R1, R 1S , R2, R 2S , R3, R 3S and X2 can each be selected from the groups described herein, where applicable, and for R1, R 1S , R2, R 2S , R3, R 3S Any group described for any of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32, R3 1S , R2, R 2S , R3, R 3S and any combination of one or more of X2.

[0185] In some embodiments, the compound of Formula I is not N-(4,6-dimethoxy-1,3,5-triazin-2-yl)-N'-[[(4,6-dimethyl-2-pyrimidinyl)methylamino]sulfonyl]-urea, N-[[(4,6-dimethyl-2-pyrimidinyl)methylamino]sulfonyl]-N'-(4-methoxy-6-methyl-1,3,5-triazin-2-yl)-urea, N-(4,6-dimethoxy-2-pyrimidinyl)-N'-[(methyl-1H-pyrrol-1-ylamino)sulfonyl]-urea, or N-(4,6-dimethoxy-2-pyrimidinyl)-N'-[[(4,6-dimethyl-2-pyrimidinyl)methylamino]sulfonyl]-urea.

[0186] In some embodiments, the compound of Formula I is not N-(4,6-dimethoxy-1,3,5-triazin-2-yl)-N'-[[(4,6-dimethyl-2-pyrimidinyl)methylamino]sulfonyl]-urea, N-[[(4,6-dimethyl-2-pyrimidinyl)methylamino]sulfonyl]-N'-(4-methoxy-6-methyl-1,3,5-triazin-2-yl)-urea, N-(4,6-dimethoxy-2-pyrimidinyl)-N'-[(methyl-1H-pyrrol-1-ylamino)sulfonyl]-urea, N-(4,6-dimethoxy-2-pyrimidinyl)-N'-[[(4,6-dimethyl-2-pyrimidinyl)methylamino]sulfonyl]-urea, or a prodrug, solvate, or pharmaceutically acceptable salt thereof.

[0187] In some embodiments, R1 is a 5- to 12-membered heterocycloalkyl or a 5- to 12-membered heteroaryl, wherein at least one heteroatom in the 5- to 12-membered heterocycloalkyl or the 5- to 12-membered heteroaryl is O or S, and wherein the 5- to 12-membered heterocycloalkyl or the 5- to 12-membered heteroaryl is optionally replaced by one or more R 1S replace.

[0188] In some embodiments, R1 is a 5- to 12-membered heterocycloalkyl or a 5- to 12-membered heteroaryl, wherein the 5- to 12-membered heterocycloalkyl or the 5- to 12-membered heteroaryl is optionally replaced by one or more R 1S substituted, and wherein R1 is attached to the remainder of formula (I) via a carbon atom in R1.

[0189] In some embodiments, R1 is a 5- to 12-membered heterocycloalkyl or a 5- to 12-membered heteroaryl, wherein at least one heteroatom in the 5- to 12-membered heterocycloalkyl or the 5- to 12-membered heteroaryl is O or S; wherein the 5- to 12-membered heterocycloalkyl or the 5- to 12-membered heteroaryl is optionally replaced by one or more R 1S substituted; and wherein R1 is connected to the remainder of formula (I) via a carbon atom in R1.

[0190] In some embodiments, R1 is connected to the remainder of Formula (I) via a carbon atom in R1.

[0191] In some embodiments, R1 is optionally replaced by one or more R 1S Substituted 5- to 12-membered heterocycloalkyl.

[0192] In some embodiments, R1 is optionally replaced by one or more R 1S substituted 5- to 12-membered heterocycloalkyl, wherein R1 is C5-C 12 The carbon atom in the heterocycloalkyl group is attached to the rest of formula (I).

[0193] In some embodiments, R1 is a 5- to 12-membered heterocycloalkyl optionally substituted with one or more C1-C6 alkyl or halo.

[0194] In some embodiments, R1 is a 5- to 12-membered heterocycloalkyl group optionally substituted with one or more C1-C6 alkyl groups (eg, methyl, ethyl, or propyl).

[0195] In some embodiments, R1 is a 5- to 12-membered heterocycloalkyl optionally substituted with one or more halo (eg, Cl).

[0196] In some embodiments, R1 is 5- to 12-membered heterocycloalkyl.

[0197] In some embodiments, R1 is replaced by one or more R 1S Substituted 5- to 12-membered heterocycloalkyl.

[0198] In some embodiments, R1 is a 5- to 12-membered heterocycloalkyl substituted with one or more C1-C6 alkyl or halo groups.

[0199] In some embodiments, R1 is a 5- to 12-membered heterocycloalkyl substituted with one or more C1-C6 alkyl groups (eg, methyl, ethyl, or propyl).

[0200] In some embodiments, R1 is a 5- to 12-membered heterocycloalkyl substituted with one or more halo (eg, Cl).

[0201] In some embodiments, R1 is optionally replaced by one or more R 1S Substituted 5- to 12-membered heterocycloalkyl, wherein at least one heteroatom in the 5- to 12-membered heterocycloalkyl is N, O, or S.

[0202] In some embodiments, R1 is optionally replaced by one or more R 1S Substituted 5- to 12-membered heterocycloalkyl, wherein at least one heteroatom in the 5- to 12-membered heterocycloalkyl is S.

[0203] In some embodiments, R1 is optionally replaced by one or more R 1S Substituted 5- to 12-membered heterocycloalkyl, wherein the 5- to 12-membered heterocycloalkyl contains one heteroatom.

[0204] In some embodiments, R1 is optionally replaced by one or more R 1S Substituted 5- to 9-membered monocyclic heterocycloalkyl.

[0205] In some embodiments, R1 is optionally replaced by one or more R 1S Substituted 5- to 6-membered monocyclic heterocycloalkyl.

[0206] In some embodiments, R1 is optionally replaced by one or more R 1S Substituted 8- to 12-membered bicyclic heterocycloalkyl.

[0207] In some embodiments, R1 is optionally replaced by one or more R 1S Substituted 8- to 10-membered bicyclic heterocycloalkyl.

[0208] In some embodiments, R1 is optionally replaced by one or more R 1S Substituted 8- to 9-membered bicyclic heterocycloalkyl.

[0209] In some embodiments, R1 is optionally replaced by one or more R 1S Substituted 8- to 9-membered bicyclic heterocycloalkyl, wherein at least one heteroatom in the 8- to 9-membered bicyclic heterocycloalkyl is O or S.

[0210] In some embodiments, R1 is optionally replaced by one or more R 1S Substituted 8- to 9-membered bicyclic heterocycloalkyl, wherein at least one heteroatom in the 8- to 9-membered bicyclic heterocycloalkyl is O.

[0211] In some embodiments, R1 is optionally replaced by one or more R 1S Substituted 8- to 9-membered bicyclic heterocycloalkyl, wherein at least one heteroatom in the 8- to 9-membered bicyclic heterocycloalkyl is S.

[0212] In some embodiments, R1 is optionally replaced by one or more R 1S Substituted 8-membered bicyclic heterocycloalkyl.

[0213] In some embodiments, R1 is optionally replaced by one or more R 1S Substituted 8-membered bicyclic heterocycloalkyl, wherein at least one heteroatom in the 8-membered bicyclic heterocycloalkyl is O or S.

[0214] In some embodiments, R1 is optionally replaced by one or more R 1S A substituted 8-membered bicyclic heterocycloalkyl group, wherein at least one heteroatom in the 8-membered bicyclic heterocycloalkyl group is O.

[0215] In some embodiments, R1 is optionally replaced by one or more R 1S Substituted 8-membered bicyclic heterocycloalkyl, wherein at least one heteroatom in the 8-membered bicyclic heterocycloalkyl is S.

[0216] In some embodiments, R1 is optionally replaced by one or more R 1S Substituted 5,6-dihydro-4H-cyclopenta[b]thienyl.

[0217] In some embodiments, R1 is optionally replaced by one or more R1S Substituted 5,6-dihydro-4H-cyclopenta[b]thienyl, wherein R1 is attached to the remainder of formula (I) via a carbon atom in the 5,6-dihydro-4H-cyclopenta[b]thienyl.

[0218] In some embodiments, R1 is 5,6-dihydro-4H-cyclopenta[b]thienyl.

[0219] In some embodiments, R1 is

[0220] In some embodiments, R1 is replaced by one or more R 1S Substituted 5,6-dihydro-4H-cyclopenta[b]thienyl.

[0221] In some embodiments, R1 is

[0222] In some embodiments, R1 is

[0223] In some embodiments, R1 is 5,6-dihydro-4H-cyclopenta[b]thienyl substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, -O(C1-C6 alkyl), or halo.

[0224] In some embodiments, R1 is 5,6-dihydro-4H-cyclopenta[b]thienyl substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, or -O(C1-C6 alkyl).

[0225] In some embodiments, R1 is 5,6-dihydro-4H-cyclopenta[b]thienyl substituted with one or more C1-C6 alkyl groups (eg, methyl, ethyl, propyl, or butyl).

[0226] In some embodiments, R1 is 5,6-dihydro-4H-cyclopenta[b]thienyl substituted with one or more C1-C6 haloalkyl (eg, -CF3).

[0227] In some embodiments, R1 is 5,6-dihydro-4H-cyclopenta[b]thienyl substituted with one or more -O(C1-C6 alkyl) (eg, -OCH3).

[0228] In some embodiments, R1 is 5,6-dihydro-4H-cyclopenta[b]thienyl substituted with one or more halo groups (eg, Cl).

[0229] In some embodiments, R1 is

[0230]

[0231] In some embodiments, R1 is

[0232] In some embodiments, R1 is optionally replaced by one or more R 1S Substituted 9-membered bicyclic heterocycloalkyl.

[0233] In some embodiments, R1 is optionally replaced by one or more R 1S Substituted 9-membered bicyclic heterocycloalkyl, wherein at least one heteroatom in the 8-membered bicyclic heterocycloalkyl is O or S.

[0234] In some embodiments, R1 is optionally replaced by one or more R 1S Substituted 9-membered bicyclic heterocycloalkyl, wherein at least one heteroatom in the 8-membered bicyclic heterocycloalkyl is O.

[0235] In some embodiments, R1 is optionally replaced by one or more R 1S Substituted 4,5,6,7-tetrahydrobenzofuranyl.

[0236] In some embodiments, R1 is optionally replaced by one or more R 1S Substituted 4,5,6,7-tetrahydrobenzofuranyl, wherein R1 is attached to the remainder of formula (I) via a carbon atom in the 4,5,6,7-tetrahydrobenzofuranyl.

[0237] In some embodiments, R1 is 4,5,6,7-tetrahydrobenzofuranyl.

[0238] In some embodiments, R1 is

[0239] In some embodiments, R1 is replaced by one or more R 1S Substituted 4,5,6,7-tetrahydrobenzofuranyl.

[0240] In some embodiments, R1 is

[0241] In some embodiments, R1 is

[0242] In some embodiments, R1 is 4,4,5,6,7-tetrahydrobenzofuranyl substituted with one or more C1-C6 alkyl groups.

[0243] In some embodiments, R1 is

[0244] In some embodiments, R1 is optionally replaced by one or more R1S Substituted 9-membered bicyclic heterocycloalkyl, wherein at least one heteroatom in the 8-membered bicyclic heterocycloalkyl is S.

[0245] In some embodiments, R1 is optionally replaced by one or more R 1S Substituted 4,5,6,7-tetrahydrobenzo[b]thienyl.

[0246] In some embodiments, R1 is optionally replaced by one or more R 1S Substituted 4,5,6,7-tetrahydrobenzo[b]thienyl, wherein R1 is attached to the remainder of formula (I) via a carbon atom in the 4,5,6,7-tetrahydrobenzo[b]thienyl.

[0247] In some embodiments, R1 is 4,5,6,7-tetrahydrobenzo[b]thienyl.

[0248] In some embodiments, R1 is

[0249] In some embodiments, R1 is replaced by one or more R 1S Substituted 4,5,6,7-tetrahydrobenzo[b]thienyl.

[0250] In some embodiments, R1 is

[0251] In some embodiments, R1 is

[0252] In some embodiments, R1 is 4,5,6,7-tetrahydrobenzo[b]thienyl substituted with one or more C1-C6 alkyl groups.

[0253] In some embodiments, R1 is

[0254] In some embodiments, R1 is

[0255] In some embodiments, R1 is optionally replaced by one or more R 1S Substituted 5- to 12-membered heteroaryl.

[0256] In some embodiments, R1 is optionally replaced by one or more R 1S substituted 5- to 12-membered heteroaryl, wherein R1 is C5-C 12 The carbon atom in the heteroaryl group is attached to the remainder of formula (I).

[0257] In some embodiments, R1 is a 5- to 12-membered heteroaryl optionally substituted with one or more C1-C6 alkyl or halo.

[0258] In some embodiments, R1 is a 5- to 12-membered heteroaryl optionally substituted with one or more C1-C6 alkyl groups (eg, methyl, ethyl, or propyl).

[0259] In some embodiments, R1 is a 5- to 12-membered heteroaryl optionally substituted with one or more halo groups (eg, Cl).

[0260] In some embodiments, R1 is a 5- to 12-membered heteroaryl.

[0261] In some embodiments, R1 is replaced by one or more R 1S Substituted 5- to 12-membered heteroaryl.

[0262] In some embodiments, R1 is a 5- to 12-membered heteroaryl substituted with one or more C1-C6 alkyl or halo groups.

[0263] In some embodiments, R1 is a 5- to 12-membered heteroaryl substituted with one or more C1-C6 alkyl groups (eg, methyl, ethyl, or propyl).

[0264] In some embodiments, R1 is a 5- to 12-membered heteroaryl substituted with one or more halo groups (eg, Cl).

[0265] In some embodiments, R1 is optionally replaced by one or more R 1S Substituted 5- to 12-membered heteroaryl, wherein at least one heteroatom in the 5- to 12-membered heteroaryl is N, O, or S.

[0266] In some embodiments, R1 is optionally replaced by one or more R 1S Substituted 5- to 12-membered heteroaryl, wherein at least one heteroatom in the 5- to 12-membered heteroaryl is S.

[0267] In some embodiments, R1 is optionally replaced by one or more R 1S Substituted 5- to 12-membered heteroaryl, wherein the 5- to 12-membered heteroaryl contains one heteroatom.

[0268] In some embodiments, R1 is optionally replaced by one or more R 1S Substituted 5- to 9-membered monocyclic heteroaryl.

[0269] In some embodiments, R1 is optionally replaced by one or more R 1S Substituted 5- to 6-membered monocyclic heteroaryl.

[0270] In some embodiments, R1 is optionally replaced by one or more R1S Substituted 5-membered monocyclic heteroaryl.

[0271] In some embodiments, R1 is optionally replaced by one or more R 1S A substituted 5-membered monocyclic heteroaryl, wherein at least one heteroatom in the C5 monocyclic heteroaryl is O.

[0272] In some embodiments, R1 is optionally replaced by one or more R 1S Substituted 5-membered monocyclic heteroaryl, wherein at least one heteroatom in the C5 monocyclic heteroaryl is S.

[0273] In some embodiments, R1 is optionally replaced by one or more R 1S A substituted 5-membered monocyclic heteroaryl, wherein at least one heteroatom of the C5 monocyclic heteroaryl is S, and wherein at least one heteroatom of the C5 monocyclic heteroaryl is N.

[0274] In some embodiments, R1 is optionally replaced by one or more R 1S Substituted 5-membered monocyclic heteroaryl, wherein the C5 monocyclic heteroaryl contains one heteroatom.

[0275] In some embodiments, R1 is optionally replaced by one or more R 1S Substituted 5-membered monocyclic heteroaryl, wherein the C5 monocyclic heteroaryl contains one heteroatom which is O.

[0276] In some embodiments, R1 is optionally replaced by one or more R 1S Substituted furyl.

[0277] In some embodiments, R1 is optionally replaced by one or more R 1S Substituted furanyl, wherein R1 is attached to the remainder of formula (I) via a carbon atom in the furanyl group.

[0278] In some embodiments, R1 is furanyl.

[0279] In some embodiments, R1 is

[0280] In some embodiments, R1 is replaced by one or more R 1S Substituted furyl.

[0281] In some embodiments, R1 is

[0282] In some embodiments, R1 is

[0283] In some embodiments, R1 is

[0284] In some embodiments, R1 is furanyl substituted with one or more C1-C6 alkyl or halo.

[0285] In some embodiments, R1 is furanyl substituted with one or more C1-C6 alkyl groups (eg, methyl, ethyl, or propyl).

[0286] In some embodiments, R1 is furanyl substituted with one or more halo groups (eg, Cl).

[0287] In some embodiments, R1 is

[0288] In some embodiments, R1 is optionally replaced by one or more R 1S Substituted 5-membered monocyclic heteroaryl, wherein the C5 monocyclic heteroaryl contains one heteroatom which is S.

[0289] In some embodiments, R1 is optionally replaced by one or more R 1S Substituted thienyl.

[0290] In some embodiments, R1 is optionally replaced by one or more R 1S Substituted thienyl, wherein R1 is attached to the remainder of formula (I) via a carbon atom in the thienyl group.

[0291] In some embodiments, R1 is thienyl.

[0292] In some embodiments, R1 is

[0293] In some embodiments, R1 is replaced by one or more R 1S Substituted thienyl.

[0294] In some embodiments, R1 is

[0295] In some embodiments, R1 is

[0296] In some embodiments, R1 is

[0297] In some embodiments, R1 is thienyl substituted with one or more C1-C6 alkyl or halo groups.

[0298] In some embodiments, R1 is thienyl substituted with one or more C1-C6 alkyl groups (eg, methyl, ethyl, or propyl).

[0299] In some embodiments, R1 is thienyl substituted with one or more halo groups (eg, Cl).

[0300] In some embodiments, R1 is

[0301] In some embodiments, R1 is

[0302] In some embodiments, R1 is

[0303]

[0304] In some embodiments, R1 is optionally replaced by one or more R 1S Substituted 5-membered monocyclic heteroaryl, wherein the C5 monocyclic heteroaryl contains two heteroatoms.

[0305] In some embodiments, R1 is optionally replaced by one or more R 1S Substituted 5-membered monocyclic heteroaryl, wherein the C5 monocyclic heteroaryl contains two heteroatoms, one of which is S and the other is N.

[0306] In some embodiments, R1 is optionally replaced by one or more R 1S Substituted thiazolyl.

[0307] In some embodiments, R1 is optionally replaced by one or more R 1S Substituted thiazolyl, wherein R1 is attached to the remainder of formula (I) via a carbon atom in the thiazolyl group.

[0308] In some embodiments, R1 is thiazolyl.

[0309] In some embodiments, R1 is

[0310] In some embodiments, R1 is replaced by one or more R 1S Substituted thiazolyl.

[0311] In some embodiments, R1 is

[0312] In some embodiments, R1 is

[0313] In some embodiments, R1 is thiazolyl substituted with one or more C1-C6 alkyl or halo.

[0314] In some embodiments, R1 is thiazolyl substituted with one or more C1-C6 alkyl groups (eg, methyl, ethyl, or propyl).

[0315] In some embodiments, R1 is thiazolyl substituted with one or more halo groups (eg, Cl).

[0316] In some embodiments, R1 is

[0317] In some embodiments, R1 is optionally replaced by one or more R 1S Substituted isothiazolyl.

[0318] In some embodiments, R1 is optionally replaced by one or more R 1S Substituted isothiazolyl, wherein R1 is attached to the remainder of formula (I) via a carbon atom in the isothiazolyl group.

[0319] In some embodiments, R1 is isothiazolyl.

[0320] In some embodiments, R1 is

[0321] In some embodiments, R1 is replaced by one or more R 1S Substituted isothiazolyl.

[0322] In some embodiments, R1 is

[0323] In some embodiments, R1 is

[0324] In some embodiments, R1 is isothiazolyl substituted with one or more C1-C6 alkyl or halo.

[0325] In some embodiments, R1 is isothiazolyl substituted with one or more C1-C6 alkyl groups (eg, methyl, ethyl, or propyl).

[0326] In some embodiments, R1 is isothiazolyl substituted with one or more halo groups (eg, Cl).

[0327] In some embodiments, R1 is

[0328] In some embodiments, R1 is optionally replaced by one or more R 1S Substituted 9- to 12-membered bicyclic heteroaryl.

[0329] In some embodiments, R1 is optionally replaced by one or more R 1S Substituted 9- to 10-membered bicyclic heteroaryl.

[0330] In some embodiments, R1 is optionally replaced by one or more R 1S Substituted 9-membered bicyclic heteroaryl.

[0331] In some embodiments, R1 is optionally replaced by one or more R 1S Substituted 9-membered bicyclic heteroaryl, wherein at least one heteroatom in the 9-membered bicyclic heteroaryl is S.

[0332] In some embodiments, R1 is optionally replaced by one or more R 1S Substituted benzothienyl.

[0333] In some embodiments, R1 is optionally replaced by one or more R 1S Substituted benzothienyl, wherein R1 is attached to the remainder of formula (I) via a carbon atom in the benzothienyl.

[0334] In some embodiments, R1 is benzothienyl.

[0335] In some embodiments, R1 is

[0336] In some embodiments, R1 is replaced by one or more R 1S Substituted benzothienyl.

[0337] In some embodiments, R1 is

[0338] In some embodiments, R1 is benzothienyl substituted with one or more C1-C6 alkyl or halo groups.

[0339] In some embodiments, R1 is benzothienyl substituted with one or more C1-C6 alkyl groups (eg, methyl, ethyl, or propyl).

[0340] In some embodiments, R1 is benzothienyl substituted with one or more halo groups (eg, Cl).

[0341] In some embodiments, R1 is

[0342] In some embodiments, R1 is

[0343] In some embodiments, R1 is

[0344]

[0345] In some embodiments, at least one R 1S It is C1-C6 alkyl, C1-C6 haloalkyl, -O(C1-C6 alkyl), -O(C1-C6 haloalkyl), -(C1-C6 alkyl)-O(C1-C6 alkyl), cyano or halo.

[0346] In some embodiments, at least one R 1S It is C1-C6 alkyl, C1-C6 haloalkyl, -O(C1-C6 alkyl), -O(C1-C6 haloalkyl), -(C1-C6 alkyl)-O(C1-C6 alkyl) or halo.

[0347] In some embodiments, at least one R 1S It is C1-C6 alkyl, C1-C6 haloalkyl, -O(C1-C6 alkyl), -O(C1-C6 haloalkyl) or -(C1-C6 alkyl)-O(C1-C6 alkyl).

[0348] In some embodiments, at least one R 1S It is C1-C6 alkyl, C1-C6 haloalkyl, -O(C1-C6 alkyl), -O(C1-C6 haloalkyl) or halo.

[0349] In some embodiments, at least one R 1S It is C1-C6 alkyl, C1-C6 haloalkyl, -O(C1-C6 alkyl) or halo.

[0350] In some embodiments, at least one R 1S It is a C1-C6 alkyl group, a C1-C6 haloalkyl group or a halo group.

[0351] In some embodiments, at least one R 1S is a C1-C6 alkyl group (e.g., methyl, ethyl, or propyl) or a halo group (e.g., Cl).

[0352] In some embodiments, at least one R 1S It is methyl, ethyl, propyl or Cl.

[0353] In some embodiments, at least one R 1S It is a C1-C6 alkyl group or a C1-C6 haloalkyl group.

[0354] In some embodiments, at least one R 1S It is a C1-C6 alkyl group (eg, linear or branched).

[0355] In some embodiments, at least one R 1SIt is methyl, ethyl or propyl.

[0356] In some embodiments, at least one R 1S In some embodiments, at least one R 1S In some embodiments, at least one R 1S In some embodiments, at least one R 1S In some embodiments, at least one R 1S In some embodiments, at least one R 1S In some embodiments, at least one R 1S In some embodiments, at least one R 1S In some embodiments, at least one R 1S In some embodiments, at least one R 1S In some embodiments, at least one R 1S In some embodiments, at least one R 1S In some embodiments, at least one R 1S It is Zhong Jiji.

[0357] In some embodiments, at least one R 1S is C1-C6 haloalkyl (eg methyl, ethyl, propyl, butyl, pentyl or hexyl substituted by one or more halogens).

[0358] In some embodiments, at least one R 1S They are -CH2F, -CHF2, and -CF3.

[0359] In some embodiments, at least one R 1S is -CH2F. In some embodiments, at least one R 1S In some embodiments, at least one R 1S Yes -CF3.

[0360] In some embodiments, at least one R 1S It is -O(C1-C6 alkyl) or -O(C1-C6 haloalkyl).

[0361] In some embodiments, at least one R 1S It is -O(C1-C6 alkyl).

[0362] In some embodiments, at least one R 1S In some embodiments, at least one R 1S In some embodiments, at least one R 1SIn some embodiments, at least one R 1S In some embodiments, at least one R 1S In some embodiments, at least one R 1S It is hexyloxy.

[0363] In some embodiments, at least one R 1S It is -O(C1-C6 haloalkyl) (eg methoxy, ethoxy, propoxy, butoxy, pentyloxy or hexyloxy substituted by one or more halogens).

[0364] In some embodiments, at least one R 1S In some embodiments, at least one R 1S In some embodiments, at least one R 1S In some embodiments, at least one R 1S In some embodiments, at least one R 1S In some embodiments, at least one R 1S It is a halohexyloxy group.

[0365] In some embodiments, at least one R 1S Yes – OCF3.

[0366] In some embodiments, at least one R 1S It is –OCH2CF3.

[0367] In some embodiments, at least one R 1S It is -(C1-C6 alkyl)-O(C1-C6 alkyl).

[0368] In some embodiments, at least one R 1S It is a cyano group or a halo group.

[0369] In some embodiments, at least one R 1S It's cyano.

[0370] In some embodiments, at least one R 1S It is a halo group.

[0371] In some embodiments, at least one R 1S is F, Cl, Br or I.

[0372] In some embodiments, at least one R 1S It is F or Cl.

[0373] In some embodiments, at least one R 1S It's F.

[0374] In some embodiments, at least one R 1S It's Cl.

[0375] In some embodiments, at least one R 1S It is methyl, ethyl, isopropyl, isobutyl, sec-butyl, methoxy, ethoxy, -CF3, -OCF3, -OCH2CF3, F or Cl.

[0376] In some embodiments, at least one R 1S It is a C3-C8 cycloalkyl group, a C3-C8 aryl group, a 3- to 8-membered heterocycloalkyl group, or a 3- to 8-membered heteroaryl group.

[0377] In some embodiments, at least one R 1S It is a C3-C8 cycloalkyl group.

[0378] In some embodiments, at least one R 1S It is a C3-C8 aryl group.

[0379] In some embodiments, at least one R 1S It is a C5-C6 aryl group.

[0380] In some embodiments, at least one R 1S It is phenyl.

[0381] In some embodiments, at least one R 1S It is a 3- to 8-membered heterocycloalkyl group.

[0382] In some embodiments, at least one R 1S is a 3- to 8-membered heteroaryl group.

[0383] In some embodiments, R2 is R 2S .

[0384] In some embodiments, R2 is -(CX2X2) n -R 2S , where n is 1 or 2.

[0385] In some embodiments, R2 is -(CX2X2)-R 2S .

[0386] In some embodiments, R2 is -(CX2X2)2-R 2S .

[0387] In some embodiments, R2 is -(CH2) n -R 2S , wherein n is 1. In some embodiments, R2 is -(CH2) n -R 2S, where n is 2.

[0388] In some embodiments, at least one X2 is H.

[0389] In some embodiments, each X 2 is H.

[0390] In some embodiments, at least one X2 is C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted with one or more halo, -CN, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, or oxo.

[0391] In some embodiments, at least one X2 is C1-C6 alkyl or C2-C6 alkenyl, wherein the C1-C6 alkyl or C2-C6 alkenyl is optionally substituted with one or more halo, -CN, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, or oxo.

[0392] In some embodiments, at least one X2 is C1-C6 alkyl (e.g., methyl, ethyl, propyl, butyl, pentyl, or hexyl) optionally substituted with one or more halo, -CN, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, or oxo.

[0393] In some embodiments, at least one X2 is C1-C6 alkyl (eg, methyl, ethyl, propyl, butyl, pentyl, or hexyl).

[0394] In some embodiments, at least one X2 is C2-C6 alkenyl (e.g., ethenyl, propenyl, butenyl, pentenyl, or hexenyl) optionally substituted with one or more halo, -CN, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, or oxo.

[0395] In some embodiments, at least one X2 is C2-C6 alkenyl (eg, ethenyl, propenyl, butenyl, pentenyl, or hexenyl).

[0396] In some embodiments, at least one X2 is C2-C6 alkynyl (e.g., ethynyl, propynyl, butynyl, pentynyl, or hexynyl) optionally substituted with one or more halo, -CN, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, or oxo.

[0397] In some embodiments, at least one X2 is C2-C6 alkynyl (e.g., ethynyl, propynyl, butynyl, pentynyl, or hexynyl) optionally substituted with one or more halo, -CN, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2.

[0398] In some embodiments, at least one X2 is C2-C6 alkynyl (e.g., ethynyl, propynyl, butynyl, pentynyl, or hexynyl) optionally substituted with a halo, -CN, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, or oxo.

[0399] In some embodiments, at least one X2 is C2-C6 alkynyl (e.g., ethynyl, propynyl, butynyl, pentynyl, or hexynyl) optionally substituted with a halo, -CN, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2.

[0400] In some embodiments, at least one X2 is C2-C6 alkynyl (eg, ethynyl, propynyl, butynyl, pentynyl, or hexynyl).

[0401] In some embodiments, n is 0.

[0402] In some embodiments, n is 1 or 2.

[0403] In some embodiments, n is 1.

[0404] In some embodiments, n is 2.

[0405] In some embodiments, R 2S It is a C1-C6 alkyl group optionally substituted by one or more C1-C6 alkyl groups, C2-C6 alkenyl groups, C2-C6 alkynyl groups, C1-C6 haloalkyl groups, halo groups, -CN, -OH, -O(C1-C6 alkyl groups), -NH2, -NH(C1-C6 alkyl groups), -N(C1-C6 alkyl groups)2 or oxo groups.

[0406] In some embodiments, R 2S is a C1-C6 alkyl group optionally substituted by one or more C2-C6 alkenyl groups, C2-C6 alkynyl groups or C1-C6 haloalkyl groups.

[0407] In some embodiments, R 2S is a C1-C6 alkyl group optionally substituted by one or more C1-C6 haloalkyl groups.

[0408] In some embodiments, R 2Sis a C1-C6 alkyl group optionally substituted by one or more halo groups, -CN or -OH.

[0409] In some embodiments, R 2S is a C1-C6 alkyl group optionally substituted with one or more halo groups. 2S is C1-C6 alkyl optionally substituted with one or more F, Cl, Br or I. In some embodiments, R 2S is a C1-C6 alkyl group optionally substituted with one or more F or Cl. 2S is C1-C6 alkyl optionally substituted with one or more F. In some embodiments, R 2S is a C1-C6 alkyl group optionally substituted by one or more Cl groups.

[0410] In some embodiments, R 2S is C1-C6 alkyl optionally substituted with one or more -CN. 2S is a C1-C6 alkyl group optionally substituted with one or more -OH groups.

[0411] In some embodiments, R 2S is C1-C6 alkyl optionally substituted with one or more -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl) or -N(C1-C6 alkyl)2.

[0412] In some embodiments, R 2S is C1-C6 alkyl optionally substituted with one or more -O(C1-C6 alkyl).

[0413] In some embodiments, R 2S is C1-C6 alkyl optionally substituted with one or more -NH2, -NH(C1-C6 alkyl) or -N(C1-C6 alkyl)2.

[0414] In some embodiments, R 2S is C1-C6 alkyl optionally substituted with one or more -NH2.

[0415] In some embodiments, R 2S is C1-C6 alkyl optionally substituted with one or more -NH(C1-C6 alkyl).

[0416] In some embodiments, R 2S is C1-C6 alkyl optionally substituted with one or more -NH(methyl) groups.

[0417] In some embodiments, R 2Sis C1-C6 alkyl optionally substituted with one or more -N(C1-C6 alkyl)2.

[0418] In some embodiments, R 2S is C1-C6 alkyl optionally substituted by one or more -N(methyl)2.

[0419] In some embodiments, R 2S It is a C1-C6 alkyl group optionally substituted by one or more oxo groups.

[0420] In some embodiments, R 2S is a C1-C6 alkyl group (e.g., methyl, ethyl, propyl, butyl, pentyl or hexyl).

[0421] In some embodiments, R 2S It is C3-C 16 Cycloalkyl or 4 to 8 membered heterocycloalkyl, wherein the C3-C 16 The cycloalkyl or 4- to 8-membered heterocycloalkyl is optionally substituted with one or more 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.

[0422] In some embodiments, R 2S is a C3-C6 alkyl group optionally substituted with one or more 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. 16 Cycloalkyl.

[0423] In some embodiments, R 2S is a C3-C6 group optionally substituted with one or more C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C1-C6 haloalkyl 16 Cycloalkyl.

[0424] In some embodiments, R 2S is a C3-C6 group optionally substituted with one or more C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl groups. 16 Cycloalkyl.

[0425] In some embodiments, R 2S is a C3-C6 alkyl group optionally substituted with one or more C1-C6 alkyl groups. 16 In some embodiments, R 2Sis a C3-C6 group optionally substituted with one or more C2-C6 alkenyl groups. 16 In some embodiments, R 2S is a C3-C6 alkynyl group optionally substituted with one or more C2-C6 alkynyl groups. 16 Cycloalkyl.

[0426] In some embodiments, R 2S is a C3-C6 alkyl group optionally substituted with one or more C1-C6 haloalkyl groups 16 Cycloalkyl.

[0427] In some embodiments, R 2S is a C3-C4 optionally substituted with one or more halo, -CN or -OH 16 Cycloalkyl.

[0428] In some embodiments, R 2S is a C3-C 16 In some embodiments, R 2S is C3-C optionally substituted with one or more F, Cl, Br or I 16 In some embodiments, R 2S is C3-C optionally substituted with one or more F or Cl 16 In some embodiments, R 2S is C3-C optionally substituted with one or more F 16 In some embodiments, R 2S is C3-C optionally substituted with one or more Cl 16 Cycloalkyl.

[0429] In some embodiments, R 2S is C3-C optionally substituted with one or more –CN 16 In some embodiments, R 2S is a C3-C 16 Cycloalkyl.

[0430] In some embodiments, R 2S is a C3-C6 alkyl group optionally substituted with one or more -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl) or -N(C1-C6 alkyl)2 16 Cycloalkyl.

[0431] In some embodiments, R 2S is a C3-C6 alkyl group optionally substituted with one or more -O(C1-C6 alkyl) 16 Cycloalkyl.

[0432] In some embodiments, R 2S is a C3-C6 alkyl group optionally substituted with one or more -NH2, -NH(C1-C6 alkyl) or -N(C1-C6 alkyl)2 16 Cycloalkyl.

[0433] In some embodiments, R 2S is C3-C optionally substituted with one or more -NH2 16 Cycloalkyl.

[0434] In some embodiments, R 2S is a C3-C6 alkyl group optionally substituted with one or more -NH(C1-C6 alkyl) 16 Cycloalkyl.

[0435] In some embodiments, R 2S is C3-C optionally substituted with one or more -NH(methyl) 16 Cycloalkyl.

[0436] In some embodiments, R 2S is a C3-C6 alkyl group optionally substituted with one or more -N(C1-C6 alkyl)2 16 Cycloalkyl.

[0437] In some embodiments, R 2S is C3-C optionally substituted with one or more -N(methyl)2 16 Cycloalkyl.

[0438] In some embodiments, R 2S is a C3-C 16 Cycloalkyl.

[0439] In some embodiments, R 2S It is C3-C 16 Cycloalkyl.

[0440] In some embodiments, at least one R 2S It is a C3-C8 cycloalkyl group.

[0441] In some embodiments, at least one R 2S It is a C3-C8 cycloalkyl group optionally substituted by -O(C1-C6 alkyl), -N(C1-C6 alkyl)2, halo or -CN.

[0442] In some embodiments, at least one R 2S is a C3-C7 cycloalkyl group. In some embodiments, at least one R 2S is a C3-C6 cycloalkyl group. In some embodiments, at least one R 2Sis a C3-C5 cycloalkyl group. In some embodiments, at least one R 2S It is a C3-C4 cycloalkyl group.

[0443] In some embodiments, at least one R 2S It is cyclopropyl.

[0444] In some embodiments, at least one R 2S It is cyclobutyl.

[0445] In some embodiments, at least one R 2S It is a cyclobutyl group optionally substituted by one or more 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.

[0446] In some embodiments, at least one R 2S It is cyclopentyl.

[0447] In some embodiments, at least one R 2S It is a cyclopentyl group optionally substituted by one or more 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.

[0448] In some embodiments, at least one R 2S is cyclopentyl optionally substituted with one or more -O(C1-C6 alkyl).

[0449] In some embodiments, R 2S It is a 4- to 8-membered heterocycloalkyl group optionally substituted by one or more 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 groups.

[0450] In some embodiments, R 2S It is a 4- to 8-membered heterocycloalkyl group optionally substituted by one or more C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, halo, -CN, -OH, -NH2 or oxo groups.

[0451] In some embodiments, R 2Sis a 4- to 8-membered heterocycloalkyl group optionally substituted by one or more C1-C6 alkyl groups, C2-C6 alkenyl groups, C2-C6 alkynyl groups, C1-C6 haloalkyl groups, halo groups or oxo groups.

[0452] In some embodiments, R 2S is a 4- to 8-membered heterocycloalkyl group optionally substituted by one or more C1-C6 alkyl groups, C1-C6 haloalkyl groups or oxo groups.

[0453] In some embodiments, R 2S It is a 4- to 8-membered heterocycloalkyl group.

[0454] In some embodiments, R 2S It is a 5- to 8-membered heterocycloalkyl group.

[0455] In some embodiments, R 2S It is a 5- to 7-membered heterocycloalkyl group.

[0456] In some embodiments, R 2S It is a 5- to 6-membered heterocycloalkyl group.

[0457] In some embodiments, R 2S is a 5- or 6-membered heterocycloalkyl group having one or more heteroatoms selected from N and O.

[0458] In some embodiments, R 2S is a 5- or 6-membered heterocycloalkyl group having one heteroatom selected from N and O.

[0459] In some embodiments, R 2S is a 5- or 6-membered heterocycloalkyl group having two heteroatoms selected from N or O.

[0460] In some embodiments, R 2S It is a 6-membered heterocycloalkyl group.

[0461] In some embodiments, R 2S It is a 6-membered heterocycloalkyl group optionally substituted by one or more 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.

[0462] In some embodiments, R 2S is a 6-membered heterocycloalkyl group optionally substituted by one or more C1-C6 alkyl groups, C1-C6 haloalkyl groups or oxo groups.

[0463] In some embodiments, R 2S is a 6-membered heterocycloalkyl group optionally substituted by one or more C1-C6 alkyl groups or oxo groups.

[0464] In some embodiments, R 2S is a 6-membered heterocycloalkyl group optionally substituted by one or more C1-C6 alkyl groups or C1-C6 haloalkyl groups.

[0465] In some embodiments, R 2S is a 6-membered heterocycloalkyl group optionally substituted by one or more C1-C6 alkyl groups.

[0466] In some embodiments, R 2S is tetrahydropyranyl optionally substituted by one or more C1-C6 alkyl, C1-C6 haloalkyl or oxo groups.

[0467] In some embodiments, R 2S is tetrahydropyranyl optionally substituted by one or more C1-C6 alkyl or oxo groups.

[0468] In some embodiments, R 2S is tetrahydropyranyl optionally substituted by one or more C1-C6 alkyl or C1-C6 haloalkyl groups.

[0469] In some embodiments, R 2S is tetrahydropyranyl optionally substituted by one or more C1-C6 alkyl groups.

[0470] In some embodiments, R 2S is tetrahydropyranyl optionally substituted with one or more methyl groups. 2S is tetrahydropyranyl optionally substituted with one or more ethyl groups. 2S is tetrahydropyranyl optionally substituted with one or more propyl groups. 2S is tetrahydropyranyl optionally substituted with one or more butyl groups. 2S is tetrahydropyranyl optionally substituted with one or more pentyl groups. 2S is tetrahydropyranyl optionally substituted by one or more hexyl groups.

[0471] In some embodiments, R 2S is tetrahydropyranyl optionally substituted by one or more oxo groups.

[0472] In some embodiments, R 2S It is tetrahydropyranyl optionally substituted by one or more C1-C6 haloalkyl groups (eg methyl, ethyl, propyl, butyl, pentyl or hexyl optionally substituted by one or more halo groups).

[0473] In some embodiments, R 2S yes

[0474] In some embodiments, R 2S yes

[0475] In some embodiments, R 2S is piperidinyl optionally substituted by one or more C1-C6 alkyl, C1-C6 haloalkyl or oxo groups.

[0476] In some embodiments, R 2S is piperidinyl optionally substituted by one or more C1-C6 alkyl or oxo groups.

[0477] In some embodiments, R 2S is piperidinyl optionally substituted by one or more C1-C6 alkyl or C1-C6 haloalkyl.

[0478] In some embodiments, R 2S is piperidinyl optionally substituted by one or more C1-C6 alkyl groups.

[0479] In some embodiments, R 2S is piperidinyl optionally substituted with one or more methyl groups. 2S is piperidinyl optionally substituted with one or more ethyl groups. 2S is piperidinyl optionally substituted with one or more propyl groups. 2S is piperidinyl optionally substituted with one or more butyl groups. 2S is piperidinyl optionally substituted with one or more pentyl groups. 2S is piperidinyl optionally substituted with one or more hexyl groups.

[0480] In some embodiments, R 2S is piperidinyl optionally substituted with one or more oxo groups.

[0481] In some embodiments, R 2S is piperidinyl optionally substituted by one or more C1-C6 haloalkyl groups (eg methyl, ethyl, propyl, butyl, pentyl or hexyl optionally substituted by one or more halo groups).

[0482] In some embodiments, R 2S is piperidinyl optionally substituted with one or more -CH2F, -CHF2, -CF3, -(CH)2CH2F, -(CH)2CHF2, or -(CH)2CF3.

[0483] In some embodiments, R2S yes

[0484]

[0485] In some embodiments, R 2S yes

[0486] In some embodiments, R 2S It is a morpholinyl group.

[0487] In some embodiments, R 2S is morpholinyl optionally substituted by one or more C1-C6 alkyl, C1-C6 haloalkyl or oxo groups.

[0488] In some embodiments, R 2S Morpholinyl optionally substituted with one or more C1-C6 alkyl or oxo groups.

[0489] In some embodiments, R 2S is morpholinyl optionally substituted by one or more C1-C6 alkyl or C1-C6 haloalkyl groups.

[0490] In some embodiments, R 2S is morpholinyl optionally substituted by one or more C1-C6 alkyl groups.

[0491] In some embodiments, R 2S is morpholinyl optionally substituted with one or more methyl groups. 2S is morpholinyl optionally substituted with one or more ethyl groups. 2S is morpholinyl optionally substituted with one or more propyl groups. 2S is morpholinyl optionally substituted with one or more butyl groups. 2S is morpholinyl optionally substituted with one or more pentyl groups. 2S is morpholinyl optionally substituted by one or more hexyl groups.

[0492] In some embodiments, R 2S is morpholinyl optionally substituted by one or more oxo groups.

[0493] In some embodiments, R 2S is morpholinyl optionally substituted by one or more C1-C6 haloalkyl groups (eg methyl, ethyl, propyl, butyl, pentyl or hexyl optionally substituted by one or more halo groups).

[0494] In some embodiments, R 2S yes

[0495] In some embodiments, R2 is -(CH2) n -R 2S , where n is 0 and R 2s It is a 6-membered heterocycloalkyl group.

[0496] In some embodiments, R2 is -(CH2) n -R 2S , where n is 0 and R 2s is a 6-membered heterocycloalkyl group optionally substituted by one or more C1-C6 alkyl groups, C1-C6 haloalkyl groups or oxo groups.

[0497] In some embodiments, R2 is -(CH2) n -R 2S , where n is 0 and R 2s is tetrahydropyranyl optionally substituted by one or more C1-C6 alkyl, C1-C6 haloalkyl or oxo groups.

[0498] In some embodiments, R2 is -(CH2) n -R 2S , where n is 0 and R 2s is piperidinyl optionally substituted by one or more C1-C6 alkyl, C1-C6 haloalkyl or oxo groups.

[0499] In some embodiments, R2 is -(CH2) n -R 2S , where n is 0 and R 2s is morpholinyl optionally substituted by one or more C1-C6 alkyl, C1-C6 haloalkyl or oxo groups.

[0500] In some embodiments, R2 is -(CH2) n -R 2S , where n is 1 and R 2s It is a 6-membered heterocycloalkyl group.

[0501] In some embodiments, R2 is -(CH2) n -R 2S , where n is 1 and R 2s is a 6-membered heterocycloalkyl group optionally substituted by one or more C1-C6 alkyl groups, C1-C6 haloalkyl groups or oxo groups.

[0502] In some embodiments, R2 is -(CH2) n -R 2S , where n is 1 and R 2sis tetrahydropyranyl optionally substituted by one or more C1-C6 alkyl, C1-C6 haloalkyl or oxo groups.

[0503] In some embodiments, R2 is -(CH2) n -R 2S , where n is 1 and R 2s is piperidinyl optionally substituted by one or more C1-C6 alkyl, C1-C6 haloalkyl or oxo groups.

[0504] In some embodiments, R2 is -(CH2) n -R 2S , where n is 1 and R 2s is morpholinyl optionally substituted by one or more C1-C6 alkyl, C1-C6 haloalkyl or oxo groups.

[0505] In some embodiments, R2 is -(CH2) n -R 2S , where n is 2, and R 2s It is a 6-membered heterocycloalkyl group.

[0506] In some embodiments, R2 is -(CH2) n -R 2S , where n is 2, and R 2s is a 6-membered heterocycloalkyl group optionally substituted by one or more C1-C6 alkyl groups, C1-C6 haloalkyl groups or oxo groups.

[0507] In some embodiments, R2 is -(CH2) n -R 2S , where n is 2, and R 2s is tetrahydropyranyl optionally substituted by one or more C1-C6 alkyl, C1-C6 haloalkyl or oxo groups.

[0508] In some embodiments, R2 is -(CH2) n -R 2S , where n is 2, and R 2s is piperidinyl optionally substituted by one or more C1-C6 alkyl, C1-C6 haloalkyl or oxo groups.

[0509] In some embodiments, R2 is -(CH2) n -R 2S , where n is 2, and R 2s is morpholinyl optionally substituted by one or more C1-C6 alkyl, C1-C6 haloalkyl or oxo groups.

[0510] In some embodiments, R 2S It is a 5-membered heterocycloalkyl group.

[0511] In some embodiments, R 2S It is a 5-membered heterocycloalkyl group optionally substituted by one or more 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.

[0512] In some embodiments, R 2S is a 5-membered heterocycloalkyl group optionally substituted by one or more C1-C6 alkyl groups, C1-C6 haloalkyl groups or oxo groups.

[0513] In some embodiments, R 2S is a 5-membered heterocycloalkyl group optionally substituted by one or more C1-C6 alkyl groups or oxo groups.

[0514] In some embodiments, R 2S is a 5-membered heterocycloalkyl group optionally substituted by one or more C1-C6 alkyl groups or C1-C6 haloalkyl groups.

[0515] In some embodiments, R 2S is a 5-membered heterocycloalkyl group optionally substituted by one or more C1-C6 alkyl groups.

[0516] In some embodiments, R 2S is tetrahydrofuranyl optionally substituted by one or more C1-C6 alkyl, C1-C6 haloalkyl or oxo groups.

[0517] In some embodiments, R 2S is tetrahydrofuranyl optionally substituted by one or more C1-C6 alkyl or oxo groups.

[0518] In some embodiments, R 2S It is tetrahydrofuranyl optionally substituted by one or more C1-C6 alkyl or C1-C6 haloalkyl groups.

[0519] In some embodiments, R 2S is tetrahydrofuranyl optionally substituted by one or more C1-C6 alkyl groups.

[0520] In some embodiments, R 2S is tetrahydrofuranyl optionally substituted with one or more methyl groups. 2S is tetrahydrofuranyl optionally substituted with one or more ethyl groups. 2S is tetrahydrofuranyl optionally substituted with one or more propyl groups. 2Sis tetrahydrofuranyl optionally substituted with one or more butyl groups. 2S is tetrahydrofuranyl optionally substituted with one or more pentyl groups. 2S is tetrahydrofuranyl optionally substituted by one or more hexyl groups.

[0521] In some embodiments, R 2S is tetrahydrofuranyl optionally substituted by one or more oxo groups.

[0522] In some embodiments, R 2S It is tetrahydrofuranyl optionally substituted by one or more C1-C6 haloalkyl groups (eg methyl, ethyl, propyl, butyl, pentyl or hexyl optionally substituted by one or more halo groups).

[0523] In some embodiments, R 2S yes

[0524] In some embodiments, R 2S is pyrrolidinyl optionally substituted by one or more C1-C6 alkyl, C1-C6 haloalkyl or oxo groups.

[0525] In some embodiments, R 2S is a pyrrolidinyl group optionally substituted by one or more C1-C6 alkyl groups or oxo groups.

[0526] In some embodiments, R 2S is pyrrolidinyl optionally substituted with one or more C1-C6 alkyl or C1-C6 haloalkyl groups.

[0527] In some embodiments, R 2S is pyrrolidinyl optionally substituted with one or more C1-C6 alkyl groups.

[0528] In some embodiments, R 2S is pyrrolidinyl optionally substituted with one or more methyl groups. 2S is pyrrolidinyl optionally substituted with one or more ethyl groups. 2S is pyrrolidinyl optionally substituted with one or more propyl groups. 2S is pyrrolidinyl optionally substituted with one or more butyl groups. 2S is pyrrolidinyl optionally substituted with one or more pentyl groups. 2S is pyrrolidinyl optionally substituted with one or more hexyl groups.

[0529] In some embodiments, R 2Sis pyrrolidinyl optionally substituted with one or more oxo groups.

[0530] In some embodiments, R 2S is pyrrolidinyl optionally substituted by one or more C1-C6 haloalkyl groups (eg, methyl, ethyl, propyl, butyl, pentyl or hexyl optionally substituted by one or more halo groups).

[0531] In some embodiments, R 2S yes

[0532] In some embodiments, R2 is -(CH2) n -R 2S , where n is 0 and R 2S It is a 5-membered heterocycloalkyl group.

[0533] In some embodiments, R2 is -(CH2) n -R 2S , where n is 0 and R 2S is a 5-membered heterocycloalkyl group optionally substituted by one or more C1-C6 alkyl groups, C1-C6 haloalkyl groups or oxo groups.

[0534] In some embodiments, R2 is -(CH2) n -R 2S , where n is 0 and R 2S is tetrahydrofuranyl optionally substituted by one or more C1-C6 alkyl, C1-C6 haloalkyl or oxo groups.

[0535] In some embodiments, R2 is -(CH2) n -R 2S , where n is 0 and R 2S is pyrrolidinyl optionally substituted by one or more C1-C6 alkyl, C1-C6 haloalkyl or oxo groups.

[0536] In some embodiments, R2 is -(CH2) n -R 2S , where n is 1 and R 2S It is a 5-membered heterocycloalkyl group.

[0537] In some embodiments, R2 is -(CH2) n -R 2S , where n is 1 and R 2S is a 5-membered heterocycloalkyl group optionally substituted by one or more C1-C6 alkyl groups, C1-C6 haloalkyl groups or oxo groups.

[0538] In some embodiments, R2 is -(CH2) n-R 2S , where n is 1 and R 2S is tetrahydrofuranyl optionally substituted by one or more C1-C6 alkyl, C1-C6 haloalkyl or oxo groups.

[0539] In some embodiments, R2 is -(CH2) n -R 2S , where n is 1 and R 2S is pyrrolidinyl optionally substituted by one or more C1-C6 alkyl, C1-C6 haloalkyl or oxo groups.

[0540] In some embodiments, R2 is -(CH2) n -R 2S , where n is 2, and R 2S It is a 5-membered heterocycloalkyl group.

[0541] In some embodiments, R2 is -(CH2) n -R 2S , where n is 2, and R 2S is a 5-membered heterocycloalkyl group optionally substituted by one or more C1-C6 alkyl groups, C1-C6 haloalkyl groups or oxo groups.

[0542] In some embodiments, R2 is -(CH2) n -R 2S , where n is 2, and R 2S is tetrahydrofuranyl optionally substituted by one or more C1-C6 alkyl, C1-C6 haloalkyl or oxo groups.

[0543] In some embodiments, R2 is -(CH2) n -R 2S , where n is 2, and R 2S is pyrrolidinyl optionally substituted by one or more C1-C6 alkyl, C1-C6 haloalkyl or oxo groups.

[0544] In some embodiments, R 2S It is a 4-membered heterocycloalkyl group.

[0545] In some embodiments, R 2S It is a 4-membered heterocycloalkyl group optionally substituted by one or more 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 groups.

[0546] In some embodiments, R 2Sis a 4-membered heterocycloalkyl group optionally substituted by one or more C1-C6 alkyl groups, C1-C6 haloalkyl groups or oxo groups.

[0547] In some embodiments, R 2S is a 4-membered heterocycloalkyl group optionally substituted by one or more C1-C6 alkyl groups or oxo groups.

[0548] In some embodiments, R 2S is a 4-membered heterocycloalkyl group optionally substituted by one or more C1-C6 alkyl groups or C1-C6 haloalkyl groups.

[0549] In some embodiments, R 2S is a 4-membered heterocycloalkyl group optionally substituted by one or more C1-C6 alkyl groups.

[0550] In some embodiments, R 2S is an oxetanyl group optionally substituted by one or more C1-C6 alkyl groups, C1-C6 haloalkyl groups or oxo groups.

[0551] In some embodiments, R 2S is an oxetane group optionally substituted by one or more C1-C6 alkyl groups or oxo groups.

[0552] In some embodiments, R 2S is an oxetanyl group optionally substituted by one or more C1-C6 alkyl groups or C1-C6 haloalkyl groups.

[0553] In some embodiments, R 2S is an oxetane group optionally substituted by one or more C1-C6 alkyl groups.

[0554] In some embodiments, R 2S is an oxetane group optionally substituted with one or more methyl groups. 2S is oxetane optionally substituted with one or more ethyl groups. 2S is oxetane optionally substituted with one or more propyl groups. 2S is an oxetane group optionally substituted with one or more butyl groups. 2S is an oxetane group optionally substituted with one or more pentyl groups. 2S is oxetanyl optionally substituted with one or more hexyl groups.

[0555] In some embodiments, R 2S is oxetanyl optionally substituted by one or more oxo groups.

[0556] In some embodiments, R 2S It is an oxetanyl group optionally substituted by one or more C1-C6 haloalkyl groups (eg, methyl, ethyl, propyl, butyl, pentyl or hexyl groups optionally substituted by one or more halo groups).

[0557] In some embodiments, R 2S yes

[0558] In some embodiments, R 2S is azetidinyl optionally substituted by one or more C1-C6 alkyl, C1-C6 haloalkyl or oxo groups.

[0559] In some embodiments, R 2S is azetidinyl optionally substituted by one or more C1-C6 alkyl or oxo groups.

[0560] In some embodiments, R 2S is azetidinyl optionally substituted with one or more C1-C6 alkyl or C1-C6 haloalkyl groups.

[0561] In some embodiments, R 2S is azetidinyl optionally substituted with one or more C1-C6 alkyl groups.

[0562] In some embodiments, R 2S is azetidinyl optionally substituted with one or more methyl groups. 2S is azetidinyl optionally substituted with one or more ethyl groups. 2S is azetidinyl optionally substituted with one or more propyl groups. 2S is azetidinyl optionally substituted with one or more butyl groups. 2S is azetidinyl optionally substituted with one or more pentyl groups. 2S is azetidinyl optionally substituted with one or more hexyl groups.

[0563] In some embodiments, R 2S is azetidinyl optionally substituted with one or more oxo groups.

[0564] In some embodiments, R 2S It is azetidinyl optionally substituted by one or more C1-C6 haloalkyl groups (eg, methyl, ethyl, propyl, butyl, pentyl or hexyl groups optionally substituted by one or more halo groups).

[0565] In some embodiments, R 2S yes

[0566] In some embodiments, R2 is -(CH2) n -R 2S , where n is 0 and R 2S It is a 4-membered heterocycloalkyl group.

[0567] In some embodiments, R2 is -(CH2) n -R 2S , where n is 0 and R 2S is a 4-membered heterocycloalkyl group optionally substituted by one or more C1-C6 alkyl groups, C1-C6 haloalkyl groups or oxo groups.

[0568] In some embodiments, R2 is -(CH2) n -R 2S , where n is 0 and R 2S is an oxetanyl group optionally substituted by one or more C1-C6 alkyl groups, C1-C6 haloalkyl groups or oxo groups.

[0569] In some embodiments, R2 is -(CH2) n -R 2S , where n is 0 and R 2S is azetidinyl optionally substituted by one or more C1-C6 alkyl, C1-C6 haloalkyl or oxo groups.

[0570] In some embodiments, R2 is -(CH2) n -R 2S , where n is 1 and R 2S It is a 4-membered heterocycloalkyl group.

[0571] In some embodiments, R2 is -(CH2) n -R 2S , where n is 1 and R 2S is a 4-membered heterocycloalkyl group optionally substituted by one or more C1-C6 alkyl groups, C1-C6 haloalkyl groups or oxo groups.

[0572] In some embodiments, R2 is -(CH2) n -R 2S , where n is 1 and R 2S is an oxetanyl group optionally substituted by one or more C1-C6 alkyl groups, C1-C6 haloalkyl groups or oxo groups.

[0573] In some embodiments, R2 is -(CH2) n -R 2S , where n is 1 and R 2Sis azetidinyl optionally substituted by one or more C1-C6 alkyl, C1-C6 haloalkyl or oxo groups.

[0574] In some embodiments, R2 is -(CH2) n -R 2S , where n is 2, and R 2S It is a 4-membered heterocycloalkyl group.

[0575] In some embodiments, R2 is -(CH2) n -R 2S , where n is 2, and R 2S is a 4-membered heterocycloalkyl group optionally substituted by one or more C1-C6 alkyl groups, C1-C6 haloalkyl groups or oxo groups.

[0576] In some embodiments, R2 is -(CH2) n -R 2S , where n is 2, and R 2S is an oxetanyl group optionally substituted by one or more C1-C6 alkyl groups, C1-C6 haloalkyl groups or oxo groups.

[0577] In some embodiments, R2 is -(CH2) n -R 2S , where n is 2, and R 2S is azetidinyl optionally substituted by one or more C1-C6 alkyl, C1-C6 haloalkyl or oxo groups.

[0578] In some embodiments, R 2S It is a 7-membered heterocycloalkyl group.

[0579] In some embodiments, R 2S It is a 7-membered heterocycloalkyl group optionally substituted by one or more 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 groups.

[0580] In some embodiments, R 2S is a 7-membered heterocycloalkyl group optionally substituted by one or more C1-C6 alkyl groups, C1-C6 haloalkyl groups or oxo groups.

[0581] In some embodiments, R 2S is a 7-membered heterocycloalkyl group optionally substituted by one or more C1-C6 alkyl groups or oxo groups.

[0582] In some embodiments, R 2Sis a 7-membered heterocycloalkyl group optionally substituted by one or more C1-C6 alkyl groups or C1-C6 haloalkyl groups.

[0583] In some embodiments, R 2S is a 7-membered heterocycloalkyl group optionally substituted by one or more C1-C6 alkyl groups.

[0584] In some embodiments, R 2S is oxepanyl optionally substituted by one or more C1-C6 alkyl, C1-C6 haloalkyl or oxo groups.

[0585] In some embodiments, R 2S is an oxepanyl group optionally substituted by one or more C1-C6 alkyl groups or oxo groups.

[0586] In some embodiments, R 2S is an oxepanyl group optionally substituted by one or more C1-C6 alkyl groups or C1-C6 haloalkyl groups.

[0587] In some embodiments, R 2S is an oxepanyl group optionally substituted by one or more C1-C6 alkyl groups.

[0588] In some embodiments, R 2S is an oxepanyl group optionally substituted with one or more methyl groups. 2S is an oxepanyl group optionally substituted with one or more ethyl groups. 2S is an oxepanyl group optionally substituted with one or more propyl groups. 2S is an oxepanyl group optionally substituted with one or more butyl groups. 2S is an oxepanyl group optionally substituted with one or more pentyl groups. 2S is oxepanyl optionally substituted by one or more hexyl groups.

[0589] In some embodiments, R 2S is oxepanyl optionally substituted by one or more oxo groups.

[0590] In some embodiments, R 2S It is an oxepanyl group optionally substituted by one or more C1-C6 haloalkyl groups (eg, methyl, ethyl, propyl, butyl, pentyl or hexyl groups optionally substituted by one or more halo groups).

[0591] In some embodiments, R 2S is an azepanyl group optionally substituted by one or more C1-C6 alkyl groups, C1-C6 haloalkyl groups or oxo groups.

[0592] In some embodiments, R 2S is an azepanyl group optionally substituted by one or more C1-C6 alkyl groups or oxo groups.

[0593] In some embodiments, R 2S is an azepanyl group optionally substituted by one or more C1-C6 alkyl groups or C1-C6 haloalkyl groups.

[0594] In some embodiments, R 2S is azepanyl optionally substituted by one or more C1-C6 alkyl groups.

[0595] In some embodiments, R 2S is an azepanyl group optionally substituted with one or more methyl groups. 2S is an azepanyl group optionally substituted with one or more ethyl groups. 2S is azepanyl optionally substituted with one or more propyl groups. 2S is an azepanyl group optionally substituted with one or more butyl groups. 2S is an azepanyl group optionally substituted with one or more pentyl groups. 2S is azepanyl optionally substituted with one or more hexyl groups.

[0596] In some embodiments, R 2S is azepanyl optionally substituted with one or more oxo groups.

[0597] In some embodiments, R 2S It is azepanyl optionally substituted by one or more C1-C6 haloalkyl groups (eg, methyl, ethyl, propyl, butyl, pentyl or hexyl groups optionally substituted by one or more halo groups).

[0598] In some embodiments, R 2S yes

[0599] In some embodiments, R2 is -(CH2) n -R 2S , where n is 0 and R 2S It is a 7-membered heterocycloalkyl group.

[0600] In some embodiments, R2 is -(CH2) n -R 2S , where n is 0 and R 2Sis a 7-membered heterocycloalkyl group optionally substituted by one or more C1-C6 alkyl groups, C1-C6 haloalkyl groups or oxo groups.

[0601] In some embodiments, R2 is -(CH2) n -R 2S , where n is 0 and R 2S is oxepanyl optionally substituted by one or more C1-C6 alkyl, C1-C6 haloalkyl or oxo groups.

[0602] In some embodiments, R2 is -(CH2) n -R 2S , where n is 0 and R 2S is an azepanyl group optionally substituted by one or more C1-C6 alkyl groups, C1-C6 haloalkyl groups or oxo groups.

[0603] In some embodiments, R2 is -(CH2) n -R 2S , where n is 1 and R 2S It is a 7-membered heterocycloalkyl group.

[0604] In some embodiments, R2 is -(CH2) n -R 2S , where n is 1 and R 2S is a 7-membered heterocycloalkyl group optionally substituted by one or more C1-C6 alkyl groups, C1-C6 haloalkyl groups or oxo groups.

[0605] In some embodiments, R2 is -(CH2) n -R 2S , where n is 1 and R 2S is oxepanyl optionally substituted by one or more C1-C6 alkyl, C1-C6 haloalkyl or oxo groups.

[0606] In some embodiments, R2 is -(CH2) n -R 2S , where n is 1 and R 2S is an azepanyl group optionally substituted by one or more C1-C6 alkyl groups, C1-C6 haloalkyl groups or oxo groups.

[0607] In some embodiments, R2 is -(CH2) n -R 2S , where n is 2, and R 2S It is a 7-membered heterocycloalkyl group.

[0608] In some embodiments, R2 is -(CH2) n -R 2S , where n is 2, and R2S is a 7-membered heterocycloalkyl group optionally substituted by one or more C1-C6 alkyl groups, C1-C6 haloalkyl groups or oxo groups.

[0609] In some embodiments, R2 is -(CH2) n -R 2S , where n is 2, and R 2S is oxepanyl optionally substituted by one or more C1-C6 alkyl, C1-C6 haloalkyl or oxo groups.

[0610] In some embodiments, R2 is -(CH2) n -R 2S , where n is 2, and R 2S is an azepanyl group optionally substituted by one or more C1-C6 alkyl groups, C1-C6 haloalkyl groups or oxo groups.

[0611] In some embodiments, R 2S It is an 8-membered heterocycloalkyl group.

[0612] In some embodiments, R 2S It is an 8-membered heterocycloalkyl group optionally substituted by one or more 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 groups.

[0613] In some embodiments, R 2S is an 8-membered heterocycloalkyl group optionally substituted by one or more C1-C6 alkyl groups, C1-C6 haloalkyl groups or oxo groups.

[0614] In some embodiments, R 2S is an 8-membered heterocycloalkyl group optionally substituted by one or more C1-C6 alkyl groups or oxo groups.

[0615] In some embodiments, R 2S is an 8-membered heterocycloalkyl group optionally substituted by one or more C1-C6 alkyl groups or C1-C6 haloalkyl groups.

[0616] In some embodiments, R 2S is an 8-membered heterocycloalkyl group optionally substituted by one or more C1-C6 alkyl groups.

[0617] In some embodiments, R 2S is an oxocanyl group optionally substituted by one or more C1-C6 alkyl groups, C1-C6 haloalkyl groups or oxo groups.

[0618] In some embodiments, R 2Sis an oxocanyl group optionally substituted by one or more C1-C6 alkyl groups or oxo groups.

[0619] In some embodiments, R 2S is an oxocanyl group optionally substituted by one or more C1-C6 alkyl groups or C1-C6 haloalkyl groups.

[0620] In some embodiments, R 2S is an oxocanyl group optionally substituted by one or more C1-C6 alkyl groups.

[0621] In some embodiments, R 2S is an oxocanyl group optionally substituted with one or more methyl groups. 2S is an oxocanyl group optionally substituted with one or more ethyl groups. 2S is an oxacyclooctanyl group optionally substituted with one or more propyl groups. 2S is an oxacyclooctanyl group optionally substituted with one or more butyl groups. 2S is an oxacyclooctanyl group optionally substituted with one or more pentyl groups. 2S is oxacyclooctanyl optionally substituted by one or more hexyl groups.

[0622] In some embodiments, R 2S The oxacyclooctanyl group is optionally substituted with one or more oxo groups.

[0623] In some embodiments, R 2S It is an oxocanyl group optionally substituted by one or more C1-C6 haloalkyl groups (eg, methyl, ethyl, propyl, butyl, pentyl or hexyl groups optionally substituted by one or more halo groups).

[0624] In some embodiments, R 2S is an azocyclooctanyl group optionally substituted by one or more C1-C6 alkyl groups, C1-C6 haloalkyl groups or oxo groups.

[0625] In some embodiments, R 2S is an azocyclooctanyl group optionally substituted by one or more C1-C6 alkyl groups or oxo groups.

[0626] In some embodiments, R 2S is an azocyclooctanyl group optionally substituted by one or more C1-C6 alkyl groups or C1-C6 haloalkyl groups.

[0627] In some embodiments, R 2S is an azocyclooctanyl group optionally substituted with one or more C1-C6 alkyl groups.

[0628] In some embodiments, R 2S is an azocyclooctanyl group optionally substituted with one or more methyl groups. 2S is an azocyclooctanyl group optionally substituted with one or more ethyl groups. 2S is an azocyclooctanyl group optionally substituted with one or more propyl groups. 2S is an azocyclooctanyl group optionally substituted with one or more butyl groups. 2S is an azocyclooctanyl group optionally substituted with one or more pentyl groups. 2S is an azocanyl group optionally substituted with one or more hexyl groups.

[0629] In some embodiments, R 2S is an azocanyl group optionally substituted with one or more oxo groups.

[0630] In some embodiments, R 2S It is an azocyclooctanyl group optionally substituted by one or more C1-C6 haloalkyl groups (eg, methyl, ethyl, propyl, butyl, pentyl or hexyl groups optionally substituted by one or more halo groups).

[0631] In some embodiments, R2 is -(CH2) n -R 2S , where n is 0 and R 2S It is an 8-membered heterocycloalkyl group.

[0632] In some embodiments, R2 is -(CH2) n -R 2S , where n is 0 and R 2S is an 8-membered heterocycloalkyl group optionally substituted by one or more C1-C6 alkyl groups, C1-C6 haloalkyl groups or oxo groups.

[0633] In some embodiments, R2 is -(CH2) n -R 2S , where n is 0 and R 2S is an oxocanyl group optionally substituted by one or more C1-C6 alkyl groups, C1-C6 haloalkyl groups or oxo groups.

[0634] In some embodiments, R2 is -(CH2) n -R 2S , where n is 0 and R 2S is an azocyclooctanyl group optionally substituted by one or more C1-C6 alkyl groups, C1-C6 haloalkyl groups or oxo groups.

[0635] In some embodiments, R2 is -(CH2) n -R 2S , where n is 1 and R 2S It is an 8-membered heterocycloalkyl group.

[0636] In some embodiments, R2 is -(CH2) n -R 2S , where n is 1 and R 2S is an 8-membered heterocycloalkyl group optionally substituted by one or more C1-C6 alkyl groups, C1-C6 haloalkyl groups or oxo groups.

[0637] In some embodiments, R2 is -(CH2) n -R 2S , where n is 1 and R 2S is an oxocanyl group optionally substituted by one or more C1-C6 alkyl groups, C1-C6 haloalkyl groups or oxo groups.

[0638] In some embodiments, R2 is -(CH2) n -R 2S , where n is 1 and R 2S is an azocyclooctanyl group optionally substituted by one or more C1-C6 alkyl groups, C1-C6 haloalkyl groups or oxo groups.

[0639] In some embodiments, R2 is -(CH2) n -R 2S , where n is 2, and R 2S It is an 8-membered heterocycloalkyl group.

[0640] In some embodiments, R2 is -(CH2) n -R 2S , where n is 2, and R 2S is an 8-membered heterocycloalkyl group optionally substituted by one or more C1-C6 alkyl groups, C1-C6 haloalkyl groups or oxo groups.

[0641] In some embodiments, R2 is -(CH2) n -R 2S , where n is 2, and R 2S is an oxocanyl group optionally substituted by one or more C1-C6 alkyl groups, C1-C6 haloalkyl groups or oxo groups.

[0642] In some embodiments, R2 is -(CH2) n -R 2S , where n is 2, and R 2S is an azocyclooctanyl group optionally substituted by one or more C1-C6 alkyl groups, C1-C6 haloalkyl groups or oxo groups.

[0643] In some embodiments, R 2S It is a spiroheterocycloalkyl group optionally substituted by one or more 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 groups.

[0644] In some embodiments, R 2S is a spiroheterocycloalkyl group optionally substituted by one or more C1-C6 alkyl groups, C1-C6 haloalkyl groups or oxo groups.

[0645] In some embodiments, R2 is -(CH2) n -R 2S , where n is 0 and R 2S is a spiroheterocycloalkyl group optionally substituted by one or more C1-C6 alkyl groups, C1-C6 haloalkyl groups or oxo groups.

[0646] In some embodiments, R2 is -(CH2) n -R 2S , where n is 1 and R 2S is a spiroheterocycloalkyl group optionally substituted by one or more C1-C6 alkyl groups, C1-C6 haloalkyl groups or oxo groups.

[0647] In some embodiments, R2 is -(CH2) n -R 2S , where n is 2, and R 2S is a spiroheterocycloalkyl group optionally substituted by one or more C1-C6 alkyl groups, C1-C6 haloalkyl groups or oxo groups.

[0648] In some embodiments, R 2S is a spiro 7-membered heterocycloalkyl group optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl or oxo groups.

[0649] In some embodiments, R 2S is a spiro 7-membered heterocycloalkyl group optionally substituted with one or more C1-C6 alkyl groups.

[0650] In some embodiments, R 2S is a spiro 7-membered heterocycloalkyl group optionally substituted with one or more C1-C6 haloalkyl groups.

[0651] In some embodiments, R 2S is 2-azaspiro[3.3]heptane optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, or oxo. In some embodiments, R 2Sis 2-oxaspiro[3.3]heptane optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl or oxo groups.

[0652] In some embodiments, R 2S yes

[0653] In some embodiments, R 2S It is a bridged heterocycloalkyl group optionally substituted by one or more 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 groups.

[0654] In some embodiments, R 2S is a bridged heterocycloalkyl group optionally substituted with one or more C1-C6 alkyl groups, C1-C6 haloalkyl groups or oxo groups.

[0655] In some embodiments, R2 is -(CH2) n -R 2S , where n is 0 and R 2S is a bridged heterocycloalkyl group optionally substituted with one or more C1-C6 alkyl groups, C1-C6 haloalkyl groups or oxo groups.

[0656] In some embodiments, R2 is -(CH2) n -R 2S , where n is 1 and R 2S is a bridged heterocycloalkyl group optionally substituted with one or more C1-C6 alkyl groups, C1-C6 haloalkyl groups or oxo groups.

[0657] In some embodiments, R2 is -(CH2) n -R 2S , where n is 2, and R 2S is a bridged heterocycloalkyl group optionally substituted with one or more C1-C6 alkyl groups, C1-C6 haloalkyl groups or oxo groups.

[0658] In some embodiments, R 2S is a bridged 8-membered heterocycloalkyl group optionally substituted with one or more C1-C6 alkyl groups, C1-C6 haloalkyl groups or oxo groups.

[0659] In some embodiments, R 2S is a bridged quinuclidine group optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl or oxo groups.

[0660] In some embodiments, R 2S yes

[0661] In some embodiments, R2 is

[0662]

[0663] In some embodiments, R2 is

[0664]

[0665] In some embodiments, R2 is

[0666]

[0667] In some embodiments, R2 is

[0668] In some embodiments, R3 is optionally replaced by one or more R 3S Substituted 5- to 6-membered heterocycloalkyl.

[0669] In some embodiments, R3 is

[0670] In some embodiments, R3 is optionally replaced by one or more R 3S Substituted 7- to 12-membered heterocycloalkyl.

[0671] In some embodiments, R3 is 7-12 membered heterocycloalkyl.

[0672] In some embodiments, R3 is optionally replaced by one or more R 3S Substituted 8- to 11-membered heterocycloalkyl.

[0673] In some embodiments, R3 is 8- to 11-membered heterocycloalkyl.

[0674] In some embodiments, R3 is optionally replaced by one or more R 3S Substituted 9- or 10-membered heterocycloalkyl.

[0675] In some embodiments, R3 is a 9- or 10-membered heterocycloalkyl.

[0676] In some embodiments, R3 is optionally replaced by one or more R 3S Substituted 9-membered heterocycloalkyl.

[0677] In some embodiments, R3 is 9-membered heterocycloalkyl.

[0678] In some embodiments, R3 is

[0679] In some embodiments, R3 is

[0680] In some embodiments, R3 is optionally replaced by one or more R 3S substituted 5- or 6-membered heteroaryl, wherein each R 3S It is independently C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halo or C3-C8 heterocycloalkyl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl or C3-C8 heterocycloalkyl is optionally substituted by -O(C1-C6 alkyl), -N(C1-C6 alkyl)2 or -CN.

[0681] In some embodiments, R3 is optionally replaced by one or more R 3S substituted 5- or 6-membered heteroaryl, wherein each R 3S It is independently C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halo or C3-C8 heterocycloalkyl, wherein the C1-C6 alkyl is optionally substituted by -O(C1-C6 alkyl), -N(C1-C6 alkyl)2, halo or -CN.

[0682] In some embodiments, R3 is optionally replaced by one or more R 3S substituted 5- or 6-membered heteroaryl, wherein each R 3S It is independently C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halo or C3-C8 heterocycloalkyl, wherein the C1-C6 alkyl is optionally substituted by -O(C1-C6 alkyl) or -N(C1-C6 alkyl)2.

[0683] In some embodiments, R3 is optionally replaced by one or more R 3S substituted 5- or 6-membered heteroaryl, wherein each R 3S are independently C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halo or C3-C8 heterocycloalkyl.

[0684] In some embodiments, R3 is optionally replaced by one or more R 3S substituted 5- or 6-membered heteroaryl, wherein each R 3S are independently C1-C6 alkyl or C1-C6 haloalkyl.

[0685] In some embodiments, R3 is a 5- or 6-membered heteroaryl having one, two, or three heteroatoms.

[0686] In some embodiments, R3 is a 5- or 6-membered heteroaryl group having one, two, or three heteroatoms selected from N and O.

[0687] In some embodiments, R3 is a 5- or 6-membered heteroaryl having one heteroatom selected from N and O.

[0688] In some embodiments, R3 is a 5- or 6-membered heteroaryl having two heteroatoms selected from N and O.

[0689] In some embodiments, R3 is optionally replaced by one or more R 3S substituted 5-membered heteroaryl, wherein each R 3S It is independently C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halo or C3-C8 heterocycloalkyl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl or C3-C8 heterocycloalkyl is optionally substituted with -O(C1-C6 alkyl), -N(C1-C6 alkyl)2, halo or -CN.

[0690] In some embodiments, R3 is optionally replaced by one or more R 3S substituted 5-membered heteroaryl, wherein each R 3S It is independently C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halo or C3-C8 heterocycloalkyl, wherein the C1-C6 alkyl is optionally substituted by -O(C1-C6 alkyl), -N(C1-C6 alkyl)2, halo or -CN.

[0691] In some embodiments, R3 is optionally replaced by one or more R 3S substituted 5-membered heteroaryl, wherein each R 3S It is independently C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halo or C3-C8 heterocycloalkyl, wherein the C1-C6 alkyl is optionally substituted by -O(C1-C6 alkyl) or -N(C1-C6 alkyl)2.

[0692] In some embodiments, R3 is optionally replaced by one or more R 3S substituted 5-membered heteroaryl, wherein each R 3S are independently C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halo or C3-C8 heterocycloalkyl.

[0693] In some embodiments, R3 is optionally replaced by one or more R 3S substituted 5-membered heteroaryl, wherein each R 3S are independently C1-C6 alkyl, C1-C6 haloalkyl or C3-C8 cycloalkyl.

[0694] In some embodiments, R3 is optionally replaced by one or more R 3S substituted 5-membered heteroaryl, wherein each R 3S are independently C1-C6 alkyl or C1-C6 haloalkyl.

[0695] In some embodiments, R3 is optionally replaced by one or more R 3S substituted 5-membered heteroaryl, wherein each R 3S are independently C1-C6 alkyl.

[0696] In some embodiments, R3 is optionally replaced by one or more R 3S substituted 6-membered heteroaryl, wherein each R 3S It is independently C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halo or C3-C8 heterocycloalkyl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl or C3-C8 heterocycloalkyl is optionally substituted with -O(C1-C6 alkyl), -N(C1-C6 alkyl)2, halo or -CN.

[0697] In some embodiments, R3 is optionally replaced by one or more R 3S substituted 6-membered heteroaryl, wherein each R 3S are independently C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halo or C3-C8 heterocycloalkyl.

[0698] In some embodiments, R3 is optionally replaced by one or more R 3S substituted 6-membered heteroaryl, wherein each R 3S are independently C1-C6 alkyl.

[0699] In some embodiments, R3 is optionally replaced by one or more R 3S substituted 5- or 6-membered heteroaryl.

[0700] In some embodiments, R3 is optionally replaced by one or more R 3S Substituted 5-membered heteroaryl.

[0701] In some embodiments, R3 is optionally replaced by one or more R 3S Substituted pyrrolyl.

[0702] In some embodiments, R3 is

[0703]

[0704] In some embodiments, R3 is

[0705] In some embodiments, R3 is

[0706] In some embodiments, R3 is optionally replaced by one or more R 3S Substituted pyrazolyl.

[0707] In some embodiments, R3 is

[0708] In some embodiments, R3 is

[0709] In some embodiments, R3 is

[0710] In some embodiments, R3 is

[0711] In some embodiments, R3 is

[0712] In some embodiments, R3 is

[0713] In some embodiments, R3 is optionally replaced by one or more R 3S Substituted imidazolyl.

[0714] In some embodiments, R3 is

[0715]

[0716] In some embodiments, R3 is

[0717] In some embodiments, R3 is

[0718] In some embodiments, R3 is optionally replaced by one or more R 3S Substituted triazolyl.

[0719] In some embodiments, R3 is

[0720] In some embodiments, R3 is

[0721] In some embodiments, R3 is

[0722] In some embodiments, R3 is optionally replaced by one or more R 3S Substituted tetrazolyl.

[0723] In some embodiments, R3 is

[0724] In some embodiments, R3 is

[0725] In some embodiments, R3 is optionally replaced by one or more R 3S substituted isoxazolyl.

[0726] In some embodiments, R3 is

[0727] In some embodiments, R3 is

[0728] In some embodiments, R3 is

[0729] In some embodiments, R3 is optionally replaced by one or more R 3S Substituted furyl.

[0730] In some embodiments, R3 is

[0731] In some embodiments, R3 is

[0732] In some embodiments, R3 is

[0733] In some embodiments, R3 is optionally replaced by one or more R 3S Substituted oxazolyl.

[0734] In some embodiments, R3 is

[0735] In some embodiments, R3 is

[0736] In some embodiments, R3 is

[0737] In some embodiments, R3 is optionally replaced by one or more R 3S Substituted 4,5,6,7-tetrahydrobenzo[c]isoxazole.

[0738] In some embodiments, R3 is

[0739] In some embodiments, R3 is

[0740] In some embodiments, R3 is optionally replaced by one or more R 3S Substituted isothiazolyl.

[0741] In some embodiments, R3 is

[0742] In some embodiments, R3 is

[0743] In some embodiments, R3 is optionally replaced by one or more R 3S Substituted thiazolyl.

[0744] In some embodiments, R3 is

[0745] In some embodiments, R3 is

[0746] In some embodiments, R3 is optionally replaced by an R 3S Substituted thiadiazolyl.

[0747] In some embodiments, R3 is

[0748] In some embodiments, R3 is

[0749] In some embodiments, R3 is optionally replaced by one or more R 3S Substituted 6-membered heteroaryl.

[0750] In some embodiments, R3 is optionally replaced by one or more R 3S In some embodiments, R3 is optionally substituted with one or more R 3S In some embodiments, R3 is optionally replaced by one or more R 3S In some embodiments, R3 is optionally substituted with one or more R 3S In some embodiments, R3 is optionally replaced by one or more R 3S In some embodiments, R3 is optionally replaced by one or more R 3S In some embodiments, R3 is optionally replaced by one R 3SIn some embodiments, R3 is pentazinyl.

[0751] In some embodiments, R3 is

[0752] In some embodiments, R3 is

[0753] In some embodiments, R3 is

[0754] In some embodiments, R3 is

[0755] In some embodiments, R3 is

[0756] In some embodiments, R3 is

[0757] In some embodiments, at least one R 3S It is C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halo or C3-C8 heterocycloalkyl.

[0758] In some embodiments, at least one R 3S It is a C1-C6 alkyl group, a C1-C6 haloalkyl group or a C3-C8 cycloalkyl group.

[0759] In some embodiments, at least one R 3S It is a C1-C6 alkyl group or a C1-C6 haloalkyl group.

[0760] In some embodiments, at least one R 3S It is a C1-C6 alkyl group (eg, linear or branched).

[0761] In some embodiments, at least one R 3S In some embodiments, at least one R 3S In some embodiments, at least one R 3S In some embodiments, at least one R 3S In some embodiments, at least one R 3S In some embodiments, at least one R 3S In some embodiments, at least one R 3S In some embodiments, at least one R 3S In some embodiments, at least one R 3SIn some embodiments, at least one R 3S In some embodiments, at least one R 3S In some embodiments, at least one R 3S In some embodiments, at least one R 3S It is Zhong Jiji.

[0762] In some embodiments, at least one R 3S It is C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl or C3-C8 heterocycloalkyl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl or C3-C8 heterocycloalkyl is optionally substituted with -O(C1-C6 alkyl), -N(C1-C6 alkyl)2, halo or -CN.

[0763] In some embodiments, at least one R 3S It is a C1-C6 alkyl group optionally substituted by -O(C1-C6 alkyl), -N(C1-C6 alkyl)2, a halo group or -CN.

[0764] In some embodiments, at least one R 3S It is a C1-C6 alkyl group optionally substituted by -O(C1-C6 alkyl) or -N(C1-C6 alkyl)2.

[0765] In some embodiments, at least one R 3S It is a C1-C6 alkyl group (eg, methyl, ethyl, propyl, butyl, pentyl, hexyl) optionally substituted by -O(C1-C6 alkyl).

[0766] In some embodiments, at least one R 3S is methyl optionally substituted with -O(C1-C6 alkyl). In some embodiments, at least one R 3S is ethyl optionally substituted with -O(C1-C6 alkyl). In some embodiments, at least one R 3S is propyl optionally substituted with -O(C1-C6 alkyl). In some embodiments, at least one R 3S is butyl optionally substituted with -O(C1-C6 alkyl). In some embodiments, at least one R 3S is pentyl optionally substituted with -O(C1-C6 alkyl). In some embodiments, at least one R 3S It is a hexyl group optionally substituted with -O(C1-C6 alkyl).

[0767] In some embodiments, at least one R 3SIt is a C1-C6 alkyl group (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl) optionally substituted by -N(C1-C6 alkyl)2.

[0768] In some embodiments, at least one R 3S is methyl optionally substituted with -N(C1-C6 alkyl). 3S is ethyl optionally substituted with -N(C1-C6 alkyl)2. In some embodiments, at least one R 3S is propyl optionally substituted with -N(C1-C6 alkyl). 3S is butyl optionally substituted with -N(C1-C6 alkyl). 3S is pentyl optionally substituted with -N(C1-C6 alkyl). 3S It is a hexyl group optionally substituted by -N(C1-C6 alkyl)2.

[0769] In some embodiments, at least one R 3S It is a C1-C6 alkyl group optionally substituted with -CN.

[0770] In some embodiments, at least one R 3S is methyl optionally substituted with -CN. In some embodiments, at least one R 3S is ethyl optionally substituted with -CN. In some embodiments, at least one R 3S is propyl optionally substituted with -CN. In some embodiments, at least one R 3S is butyl optionally substituted with -CN. In some embodiments, at least one R 3S is pentyl optionally substituted with -CN. In some embodiments, at least one R 3S is hexyl optionally substituted by -CN.

[0771] In some embodiments, at least one R 3S is C1-C6 haloalkyl (eg methyl, ethyl, propyl, butyl, pentyl or hexyl substituted by one or more halogens).

[0772] In some embodiments, at least one R 3S It is a C1-C6 haloalkyl group optionally substituted by -O(C1-C6 alkyl), -N(C1-C6 alkyl)2, halo or -CN.

[0773] In some embodiments, at least one R 3S It is -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2 or -CH2CF3.

[0774] In some embodiments, at least one R 3S In some embodiments, at least one R 3S In some embodiments, at least one R 3S It is -CH2CF3.

[0775] In some embodiments, at least one R 3S It is a C3-C8 cycloalkyl group.

[0776] In some embodiments, at least one R 3S It is a C3-C8 cycloalkyl group optionally substituted by -O(C1-C6 alkyl), -N(C1-C6 alkyl)2, halo or -CN.

[0777] In some embodiments, at least one R 3S is a C3-C7 cycloalkyl group. In some embodiments, at least one R 3S is a C3-C6 cycloalkyl group. In some embodiments, at least one R 3S is a C3-C5 cycloalkyl group. In some embodiments, at least one R 3S It is a C3-C4 cycloalkyl group.

[0778] In some embodiments, at least one R 3S It is cyclopropyl.

[0779] In some embodiments, at least one R 3S It is cyclobutyl.

[0780] In some embodiments, at least one R 3S It is a C3-C8 heterocycloalkyl group.

[0781] In some embodiments, at least one R 3S It is a C3-C8 heterocycloalkyl group optionally substituted by -O(C1-C6 alkyl), -N(C1-C6 alkyl)2, halo or -CN.

[0782] In some embodiments, at least one R 3S is a C3-C7 heterocycloalkyl. In some embodiments, at least one R 3S is a C3-C6 heterocycloalkyl. In some embodiments, at least one R 3S is a C3-C5 heterocycloalkyl. In some embodiments, at least one R 3S is a C3-C4 heterocycloalkyl. In some embodiments, at least one R 3S It is a C4-C5 heterocycloalkyl group.

[0783] In some embodiments, at least one R 3S It is an oxetane group.

[0784] In some embodiments, at least one R 3S yes

[0785] In some embodiments, at least one R 3S It is methyl, ethyl, isopropyl, -CH2OCH3, -CH2CF3, -CH2CH2OCH3, -CH2CN, CH2CF2 or -CH2CH2N(CH3)2.

[0786] In some embodiments, at least one R 3S It is a halo group.

[0787] In some embodiments, at least one R 3S is F, Cl, Br or I.

[0788] In some embodiments, at least one R 3S It is F or Cl.

[0789] In some embodiments, at least one R 3S It's F.

[0790] In some embodiments, at least one R 3S It's Cl.

[0791] In some embodiments, the compound has formula (II-a) or (II-b):

[0792]

[0793]

[0794] or a prodrug, solvate, or pharmaceutically acceptable salt thereof, wherein n1 is an integer ranging from 0 to 3 (eg, 0, 1, 2, or 3).

[0795] In some embodiments, the compound has Formula (II-a), or a prodrug, solvate, or pharmaceutically acceptable salt thereof.

[0796] In some embodiments, the compound has Formula (II-b), or a prodrug, solvate, or pharmaceutically acceptable salt thereof.

[0797] In some embodiments, the compound has formula (II-c), (II-d), (II-e):

[0798]

[0799] or a prodrug, solvate or pharmaceutically acceptable salt thereof, wherein n1 is 0 or 1.

[0800] In some embodiments, the compound has Formula (II-c), or a prodrug, solvate, or pharmaceutically acceptable salt thereof.

[0801] In some embodiments, the compound has formula (II-d), or a prodrug, solvate, or pharmaceutically acceptable salt thereof.

[0802] In some embodiments, the compound has Formula (II-e), or a prodrug, solvate, or pharmaceutically acceptable salt thereof.

[0803] In some embodiments, the compound has formula (III):

[0804]

[0805] or a prodrug, solvate or pharmaceutically acceptable salt thereof.

[0806] In some embodiments, the compound has formula (III-a) or (III-b):

[0807]

[0808] or a prodrug, solvate, or pharmaceutically acceptable salt thereof, wherein n1 is an integer ranging from 0 to 3 (eg, 0, 1, 2, or 3).

[0809] In some embodiments, the compound has Formula (III-a), or a prodrug, solvate, or pharmaceutically acceptable salt thereof.

[0810] In some embodiments, the compound has Formula (III-b), or a prodrug, solvate, or pharmaceutically acceptable salt thereof.

[0811] In some embodiments, the compound has the formula (III-c), (III-d), (III-e):

[0812]

[0813] or a prodrug, solvate or pharmaceutically acceptable salt thereof, wherein n1 is 0 or 1.

[0814] In some embodiments, the compound has Formula (III-c), or a prodrug, solvate, or pharmaceutically acceptable salt thereof.

[0815] In some embodiments, the compound has Formula (III-d), or a prodrug, solvate, or pharmaceutically acceptable salt thereof.

[0816] In some embodiments, the compound has Formula (III-e), or a prodrug, solvate, or pharmaceutically acceptable salt thereof.

[0817] In some embodiments, the compound has formula (IV):

[0818]

[0819] or a prodrug, solvate, or pharmaceutically acceptable salt thereof, wherein n1 is an integer ranging from 0 to 3 (eg, 0, 1, 2, or 3).

[0820] In some embodiments, the compound has formula (IV-a):

[0821]

[0822] or a prodrug, solvate or pharmaceutically acceptable salt thereof.

[0823] It is to be understood that for compounds of any of the formulae described herein, R1, R 1S , R2, R 2S , R3, R 3S and X2 can each be selected from the groups described herein, where applicable, and for R1, R 1S , R2, R 2S , R3, R 3S Any group described for any of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32, R3 1S , R2, R 2S , R3, R 3S and any combination of one or more of X2.

[0824] In some embodiments, the compound is selected from the compounds described in Table 1 and prodrugs and pharmaceutically acceptable salts thereof.

[0825] In some embodiments, the compound is selected from the compounds described in Table 1 and pharmaceutically acceptable salts thereof.

[0826] In some embodiments, the compound is selected from prodrugs of the compounds described in Table 1 and pharmaceutically acceptable salts thereof.

[0827] In some embodiments, the compound is selected from the compounds described in Table 1.

[0828] Table 1

[0829]

[0830]

[0831]

[0832]

[0833]

[0834]

[0835]

[0836]

[0837]

[0838]

[0839]

[0840]

[0841]

[0842]

[0843]

[0844]

[0845]

[0846] In some embodiments, the compound is a pharmaceutically acceptable salt of any one of the compounds described in Table 1.

[0847] In some embodiments, the compound is a lithium salt, sodium salt, potassium salt, calcium salt, or magnesium salt of any one of the compounds described in Table 1.

[0848] In some embodiments, the compound is a sodium or potassium salt of any one of the compounds described in Table 1.

[0849] In some embodiments, the compound is a sodium salt of any one of the compounds described in Table 1. For example, the sodium salt of compound No. 131 can be

[0850]

[0851] In some embodiments, the compound is the potassium salt of any one of the compounds described in Table 1.

[0852] In some aspects, the present disclosure provides compounds that are isotopic derivatives (eg, isotopically labeled compounds) of any one of the compounds of the formulae disclosed herein.

[0853] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 1 and prodrugs and pharmaceutically acceptable salts thereof.

[0854] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 1 and pharmaceutically acceptable salts thereof.

[0855] In some embodiments, the compound is an isotopic derivative of any one of the prodrugs of the compounds described in Table 1 and pharmaceutically acceptable salts thereof.

[0856] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 1.

[0857] It should be understood that any of a variety of techniques recognized in the art can be used to prepare isotopic derivatives. For example, isotopic derivatives can generally be prepared by implementing the procedures disclosed in the schemes and / or examples described herein by replacing non-isotopically labeled reagents with isotopically labeled reagents.

[0858] In some embodiments, the isotopic derivative is a deuterium-labeled compound.

[0859] In some embodiments, the isotopic derivative is a deuterium-labeled compound of any of the compounds of the formulae disclosed herein.

[0860] As used herein, the term "isotopic derivative" refers to a derivative of a compound in which one or more atoms are isotopically enriched or labeled. For example, an isotopic derivative of a compound of Formula (I) is isotopically enriched with respect to one or more isotopes or is labeled with one or more isotopes compared to the corresponding compound of Formula (I). In some embodiments, an isotopic derivative is selected from 2 H. 13 C. 14 C. 15 N. 18 O. 29 4. 31 P and 34 One or more atoms of S are enriched or labeled with said one or more atoms. In some embodiments, the isotopic derivative is a deuterium-labeled compound (i.e., enriched with respect to one or more atoms thereof). 2 H).

[0861] In some embodiments, the compound is a deuterium-labeled compound of any one of the compounds described in Table 1 and prodrugs and pharmaceutically acceptable salts thereof.

[0862] In some embodiments, the compound is a deuterium-labeled compound of any one of the compounds described in Table 1 and pharmaceutically acceptable salts thereof.

[0863] In some embodiments, the compound is a deuterium-labeled compound of any one of the prodrugs of the compounds described in Table 1 and pharmaceutically acceptable salts thereof.

[0864] In some embodiments, the compound is a deuterium-labeled compound of any one of the compounds described in Table 1.

[0865] It will be understood that a deuterium-labeled compound comprises deuterium atoms at an abundance significantly greater than the natural deuterium abundance of 0.015%.

[0866] In some embodiments, the deuterium-labeled compound has a deuterium enrichment factor of at least 3500 (52.5% deuterium incorporation at each deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation) per deuterium atom. As used herein, the term "deuterium enrichment factor" means the ratio between the deuterium abundance and the natural deuterium abundance.

[0867] It should be understood that deuterium-labeled compounds can be prepared using any of a variety of techniques recognized in the art. For example, deuterium-labeled compounds can generally be prepared by implementing the procedures disclosed in the schemes and / or examples described herein by substituting deuterium-labeled reagents for non-deuterium-labeled reagents.

[0868] The compounds of the present invention or pharmaceutically acceptable salts or solvates thereof containing the aforementioned deuterium atoms are within the scope of the present invention. 2 H) substitutions may offer certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements.

[0869] In some embodiments, the compound is 18 F-labeled compound.

[0870] In some embodiments, the compound is 123 I-labeled compounds, 124 I-labeled compounds,125 I-labeled compounds, 129 I-labeled compounds, 131 I-labeled compounds, 135 I-labeled compound or any combination thereof.

[0871] In some embodiments, the compound is 33 S-labeled compounds, 34 S-labeled compounds, 35 S-labeled compounds, 36 S-labeled compound or any combination thereof.

[0872] It should be understood that any of a variety of techniques recognized in the art may be used to prepare 18 F. 123 I. 124 I. 125 I. 129 I. 131 I. 135 I. 32 S. 34 S. 35 S and / or 36 For example, the compound labeled with S can generally be prepared by carrying out the procedures disclosed in the schemes and / or examples described herein. 18 F. 123 I. 124 I. 125 I. 129 I. 131 I. 135 I. 3 S. 34 S. 35 S and / or 36 Deuterium-labeled compounds can be prepared by replacing non-isotopically labeled reagents with S-labeled reagents.

[0873] Contains one or more of the above 18 F. 123 I. 124 I. 125 I. 129 I. 131 I. 135 I. 3 S. 34 S. 35 S and 36 The compounds of the present invention or pharmaceutically acceptable salts or solvates thereof containing no S atom are within the scope of the present invention. 18 F. 123 I. 124 I. 125 I. 129 I.131 I. 135 I. 3 S. 34 S. 35 S and / or 36 S) substitutions may offer certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements.

[0874] For the avoidance of doubt, it is understood that where a group is limited in this specification by "described herein," that group encompasses the first occurring and broadest definition of that group as well as each and all specific definitions.

[0875] The various functional groups and substituents constituting the compound of formula (I) are typically selected so that the molecular weight of the compound does not exceed 1000 daltons. More typically, the molecular weight of the compound will be less than 900, for example less than 800 or less than 750 or less than 700 or less than 650 daltons. More conveniently, the molecular weight is less than 600 daltons, for example 550 daltons or less.

[0876] Suitable pharmaceutically acceptable salts of the compounds of the present invention are, for example, sufficiently basic acid addition salts of the compounds of the present invention, such as acid addition salts with, for example, inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, formic acid, citrate methanesulfonate or maleic acid. In addition, suitable pharmaceutically acceptable salts of the compounds of the present invention that are sufficiently acidic are alkali metal salts, such as sodium or potassium salts, alkaline earth metal salts, such as calcium or magnesium salts, ammonium salts or salts with organic bases that provide pharmaceutically acceptable cations, such as salts with methylamine, dimethylamine, diethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.

[0877] It will be understood that the compounds of any formula disclosed herein and any pharmaceutically acceptable salts thereof include stereoisomers, mixtures of stereoisomers, polymorphs of all isomeric forms of the compounds.

[0878] As used herein, the term "isomer" refers to compounds that have the same molecular formula but differ in the sequence in which their atoms are bonded or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers." Stereoisomers that are not mirror images of one another are termed "diastereomers," and stereoisomers that are non-superimposable mirror images of one another are termed "enantiomers" or sometimes optical isomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is termed a "racemic mixture."

[0879] As used herein, the term "chiral center" refers to a carbon atom bonded to four different substituents.

[0880] As used herein, the term "chiral isomer" refers to a compound having at least one chiral center. Compounds having more than one chiral center may exist as individual diastereomers or as a mixture of diastereomers (referred to as a "diastereomeric mixture"). When one chiral center is present, the stereoisomers can be characterized by the absolute configuration (R or S) of that chiral center. The absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. The substituents under consideration attached to the chiral center are ranked according to the Cahn, Ingold, and Prelog ordering 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).

[0881] As used herein, the term "geometric isomers" refers to diastereomers that exist due to hindered rotation about a double bond or a cycloalkyl linker (e.g., 1,3-cyclobutyl). The names of these configurations are distinguished by the prefixes cis and trans or Z and E according to the Cahn-Ingold-Prelog rules, which indicate whether the groups are on the same side or opposite sides of the double bond in the molecule.

[0882] It is understood that the compounds of the present disclosure may be described as different chiral isomers or geometric isomers. It is also understood that when a compound has chiral or geometric isomeric forms, all isomeric forms are intended to be included within the scope of the present disclosure, and the naming of the compound does not exclude any isomeric form. It is understood that not all isomers have the same level of activity.

[0883] It is to be understood that the structures and other compounds discussed in this disclosure include all atropisomers thereof. It is also to be understood that not all atropisomers have the same level of activity.

[0884] As used herein, the term "atropisomer" is a type of stereoisomer in which the atoms of two isomers are arranged differently in space. Atropisomers exist due to restricted rotation of bulky groups around a central bond, which is hindered. Such atropisomers typically exist as a mixture, however, due to recent advances in chromatographic techniques, it has become possible to separate mixtures of two atropisomers in select circumstances.

[0885] As used herein, the term "tautomer" refers to one of two or more structural isomers that exist in equilibrium and are easily converted from one isomeric form to another isomeric form. This conversion results in the migration of the form of hydrogen atoms, accompanied by the conversion of adjacent conjugated double bonds. Tautomers exist as a mixture of tautomeric groups in solution. In solutions where tautomerization is possible, the chemical equilibrium of tautomers will be reached. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. The concept of tautomers that can be mutually converted by tautomerization is called tautomerism. Among the various possible types of tautomerism, two are usually observed. In keto-enol tautomerism, electrons and hydrogen atoms move simultaneously. Ring-chain tautomerism is due to the reaction of the aldehyde group (-CHO) in the sugar chain molecule with one of the hydroxyl groups (-OH) in the same molecule, resulting in a cyclic (ring shape) form as shown by glucose.

[0886] It will be understood that the compounds of the present disclosure can be described as different tautomers. It will also be understood that when a compound has a tautomeric form, it is intended that all tautomeric forms are included within the scope of this disclosure, and the naming of the compound does not exclude any tautomeric form. It will be understood that certain tautomers may have a higher level of activity than other tautomers.

[0887] Compounds that have the same molecular formula but differ in the nature or order of bonding of their atoms or the arrangement of their atoms in space are referred to as "isomers". Isomers whose atoms are arranged differently in space are referred to as "stereoisomers". Stereoisomers that are not mirror images of each other are referred to as "diastereomers", and those that are non-superimposable mirror images of each other are referred to as "enantiomers". When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric center and described by the R- and S- ordering rules of Cahn and Prelog or by the way in which the molecule rotates the plane of polarized light and are designated as right- or left-handed (i.e., (+) or (-)-isomers, respectively). Chiral compounds can exist as individual enantiomers or mixtures thereof. A mixture containing equal proportions of enantiomers is referred to as a "racemic mixture".

[0888] The compounds of the present disclosure may have one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof. Unless otherwise indicated, the description or naming of a particular compound in the specification and claims is intended to include its individual enantiomers and mixtures (racemic or other). The methods for determining the stereochemistry of stereoisomers and separating stereoisomers are well known in the art (see Chapter 4 of "Advanced Organic Chemistry" 4th edition, J. March, John Wiley and Sons, New York, 2001), for example, by synthesis from optically active starting materials or by resolution of racemic forms. Some compounds of the present disclosure may have geometric isomerization centers (E- and Z-isomers). It is to be understood that the present disclosure encompasses all optical diastereomers and geometric isomers and mixtures thereof with inflammasome inhibitory activity.

[0889] The present disclosure also encompasses compounds of the present disclosure as defined herein containing one or more isotopic substitutions.

[0890] It is to be understood that the compounds of any chemical formula described herein include the compounds themselves and their salts and their solvates (if applicable). Salts can, for example, be formed between positively charged groups (e.g., amino groups) on anions and the substituted compounds disclosed herein. Suitable anions include chloride, bromide, iodide, sulfate, bisulfate, sulfamate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, glutamate, glucuronide, glutarate, malate, maleate, succinate, fumarate, tartrate, toluenesulfonate, salicylate, lactate, naphthylsulfonate, and acetate (e.g., trifluoroacetate).

[0891] As used herein, the term "pharmaceutically acceptable anion" refers to an anion suitable for forming a pharmaceutically acceptable salt. Similarly, salts can also be formed between cations and negatively charged groups (e.g., carboxylate groups) 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 ions. Substituted compounds disclosed herein also include those salts containing quaternary nitrogen atoms.

[0892] It is to be understood that the compounds of the present disclosure (e.g., salts of the compounds) can exist in hydrated or non-hydrated (anhydrous) forms or as solvates with other solvent molecules. Non-limiting examples of hydrates include monohydrates, dihydrates, etc. Non-limiting examples of solvates include ethanol solvates, acetone solvates, etc.

[0893] As used herein, the term "solvate" refers to a solvent addition form containing either stoichiometric or non-stoichiometric amounts of solvent. Some compounds tend to entrap a fixed molar ratio of solvent molecules in the crystalline solid state, thereby forming a solvate. If the solvent is water, the solvate formed is a hydrate; and if the solvent is an alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more water molecules with a molecule of a substance in which the water remains in its HO molecular form.

[0894] As used herein, the term "analog" refers to a chemical compound that is structurally similar to another compound but slightly different in composition (e.g., an atom is replaced by an atom of a different element or a specific functional group is present or replaced by another functional group). Thus, an analog is a compound that is similar or equivalent to a reference compound in function and appearance, but not similar or equivalent to the reference compound in structure or origin.

[0895] As used herein, the term "derivative" refers to compounds having a common core structure and substituted with various groups as described herein.

[0896] As used herein, the term "bioisostere" refers to a compound produced by exchanging an atom or group of atoms for another broadly similar atom or group of atoms. The purpose of bioisosteric substitution is to produce a new compound with similar biological properties to the parent compound. Bioisosteric substitution can be based on physical chemistry or topology. Examples of carboxylic acid bioisosteres include, but are not limited to, acylsulfonamides, tetrazoles, sulfonates, and phosphonates. See, for example, Patani and LaVoie, Chem. Rev. 96, 3147-3176, 1996.

[0897] It is also understood that certain compounds of any formula disclosed herein can exist in solvated as well as unsolvated forms (e.g., hydrated forms). Suitable pharmaceutically acceptable solvates are, for example, hydrates, such as hemihydrates, monohydrates, dihydrates, or trihydrates. It is understood that the present disclosure encompasses all such solvated forms having inflammasome inhibitory activity.

[0898] It is also understood that certain compounds of any formula disclosed herein may exhibit polymorphism, and the present disclosure encompasses all such forms or mixtures thereof having inflammasome inhibitory activity. It is generally known that conventional techniques can be used to analyze crystalline materials, such as using X-ray powder diffraction analysis, differential scanning calorimetry, thermogravimetric analysis, diffuse reflectance infrared Fourier transform (DRIFT) spectroscopy, near infrared (NIR) spectroscopy, solution and / or solid-state nuclear magnetic resonance spectroscopy. The water content of such crystalline materials can be determined by Karl Fischer analysis.

[0899] The compound of any formula disclosed herein can exist with a variety of different tautomeric forms, and mentions that the compound of formula (I) includes all such forms. For the avoidance of doubt, in the case where a compound can exist with one of several tautomeric forms, and only specifically describes or shows one, formula (I) still includes all other forms. The example of tautomeric form includes keto-, enol- and enolate-forms, such as in the following tautomerism pairs: keto / enol (shown below), imines / enamines, amides / imino alcohols, amidines / amidines, nitroso / oximes, thioketones / enethiol and nitro / acid nitro.

[0900]

[0901] Compounds of any formula disclosed herein containing an amine functional group may also form N-oxides. Compounds of formula (I) containing an amine functional group mentioned herein also include N-oxides. In the case where the compound contains several amine functional groups, one or more nitrogen atoms may be oxidized to form N-oxides. Specific examples of N-oxides include N-oxides of nitrogen atoms of tertiary amines or nitrogen-containing heterocycles. N-oxides can be formed by treating the corresponding amine with an oxidizing agent such as hydrogen peroxide or peracid (e.g., peroxycarboxylic acid), see, for example, Jerry March's Advanced Organic Chemistry, 4th edition, Wiley Interscience, p. 166. More particularly, N-oxides can be prepared by the procedure of LW Deady (Syn. Comm. 1977, 7, 509-514), wherein an amine compound is reacted with meta-chloroperbenzoic acid (mCPBA), for example, in an inert solvent such as dichloromethane.

[0902] The compounds of any of the formulas disclosed herein can be administered in the form of prodrugs that decompose in the human or animal body to release the compounds of the present disclosure. Prodrugs can be used to modify the physical properties and / or pharmacokinetic properties of the compounds of the present disclosure. Prodrugs can be formed when the compounds of the present disclosure contain suitable groups or substituents to which property-modifying groups can be attached. Examples of prodrugs include derivatives containing alkyl or acyl substituents that are cleavable in vivo at the ester or amide groups in any of the formulas disclosed herein.

[0903] Thus, the present disclosure includes those compounds of any of the formulae disclosed herein as defined above when obtainable by organic synthesis and when obtainable by cleavage of a prodrug in the human or animal body. Thus, the present disclosure includes those compounds of any of the formulae disclosed herein produced by organic synthesis, as well as such compounds produced in the human or animal body by metabolism of a precursor compound, i.e., a compound of any of the formulae disclosed herein may be a synthetically produced compound or a metabolically produced compound.

[0904] Suitable pharmaceutically acceptable prodrugs of the compounds of any formula disclosed herein are prodrugs that are suitable for administration to the human or animal body without undue pharmacological activity and without undue toxicity based on sound medical judgment. Various forms of prodrugs have been described, for example, in the following literature: a) Methods in Enzymology, Vol. 42, pp. 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", author H. Bundgaard, pp. 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”, ACSSymposium Series, Vol. 14; and h) E. Roche (ed.), “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987.

[0905] Suitable pharmaceutically acceptable prodrugs of compounds of any formula disclosed herein with hydroxyl groups are, for example, esters or ethers that can be cleaved in vivo. Ester or ether that can be cleaved in vivo of compounds of any formula disclosed herein containing hydroxyl groups are, for example, pharmaceutically acceptable esters or ethers that can be cleaved in the human or animal body to produce the parent hydroxyl compound. Suitable pharmaceutically acceptable ester forming groups for hydroxyl groups include inorganic esters, such as phosphates (including aminophosphoric acid cyclic esters). Further suitable pharmaceutically acceptable ester forming groups for hydroxyl groups include C1-C 10 Alkanoyl, such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl; C1-C 10Alkoxycarbonyl, such as ethoxycarbonyl, N, N- (C1-C6 alkyl) 2-carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl. Examples of ring substituents on phenylacetyl and benzoyl include aminomethyl, N-alkylaminomethyl, N, N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4- (C1-C4 alkyl) piperazin-1-ylmethyl. Suitable pharmaceutically acceptable ether-forming groups for hydroxyl groups include α-acyloxyalkyl, such as acetoxymethyl and pivaloyloxymethyl.

[0906] Suitable pharmaceutically acceptable prodrugs of compounds of any formula disclosed herein having a carboxyl group are, for example, their in vivo cleavable amides, such as amides formed with: amines, such as ammonia; C 1-4 Alkylamines such as methylamine; (C1-C4 alkyl)2 amines such as dimethylamine, N-ethyl-N-methylamine or diethylamine; C1-C4 alkoxy-C2-C4 alkylamines such as 2-methoxyethylamine; phenyl-C1-C4 alkylamines such as benzylamine; and amino acids such as glycine or its esters.

[0907] It is understood that the compounds of any of the formulae disclosed herein, wherein R3 is not H, can be used as prodrugs of the corresponding compounds wherein R3 is H. For example, the compounds of any of the formulae disclosed herein, wherein R3 is C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; wherein said C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted with one or more C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C5-C6 aryl, 5- or 6-membered heteroaryl, C3-C8 heterocycloalkyl, C1-C6 haloalkyl, -O(C1-C6 alkyl), -O(C1-C6 haloalkyl), halo, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl), oxo, or R 3S substituted) can be used as a prodrug of the corresponding compound wherein R3 is H.

[0908] Suitable pharmaceutically acceptable prodrugs of compounds of any formula disclosed herein having an amino group are, for example, amide derivatives thereof which are cleavable in vivo. Suitable pharmaceutically acceptable amides derived from an amino group include, for example, C1-C 10 Amides formed with alkanoyl groups such as acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups. Examples of ring substituents on phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl, and 4-(C1-C4 alkyl)piperazin-1-ylmethyl.

[0909] The in vivo effects of the compounds of any formula disclosed herein can be exerted in part by one or more metabolites formed in the human or animal body after administration of the compounds of any formula disclosed herein. As described above, the in vivo effects of the compounds of any formula disclosed herein can also be exerted by the metabolism of precursor compounds (prodrugs).

[0910] Suitably, the present disclosure does not encompass any individual compound that does not possess a biological activity as defined herein.

[0911] Synthesis method

[0912] In some aspects, the present disclosure provides methods of preparing the compounds of the present disclosure.

[0913] In some aspects, the present disclosure provides methods of producing compounds, comprising one or more steps as described herein.

[0914] In some aspects, the present disclosure provides compounds obtainable by, by, or directly by a method of making a compound as described herein.

[0915] In some aspects, the disclosure provides intermediates as described herein, which are useful in methods of making compounds as described herein.

[0916] The compounds of the present 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.

[0917] It is to be understood in the descriptions of the synthetic methods described herein, as well as in any reference to synthetic methods for the preparation of starting materials, that all proposed reaction conditions, including the choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment, and work-up procedures, can be selected by one skilled in the art.

[0918] It will be understood by those skilled in the art of organic synthesis that the functional groups present on the various parts of the molecule must be compatible with the reagents and reaction conditions employed.

[0919] It will be appreciated that during the synthesis of this disclosed compound by the method defined herein or during the synthesis of some starting materials, it may be necessary to protect some substituents to prevent them from undesirable reactions. A skilled chemist will understand when this protection is needed, and how this type of blocking group is arranged in an appropriate position and removed afterwards. About the example of blocking group, one of many general theme textbooks can be found, such as " Protective Groups in Organic Synthesis " (publisher: John Wiley & Sons) by Theodora Green. Any convenient method for removing the blocking group in question can be described in the literature or known to a skilled chemist, and this type of method is selected to realize the removal of the blocking group when the group interference is minimal elsewhere in the molecule. Therefore, if reactant, for example, comprises a group such as amino, carboxyl or hydroxyl, it may be necessary to protect the group in some reactions mentioned herein.

[0920] For example, suitable protecting groups for amino or alkylamino groups are, for example, acyl groups, for example, alkanoyl groups, such as acetyl groups; alkoxycarbonyl groups, such as methoxycarbonyl, ethoxycarbonyl or tert-butyloxycarbonyl groups; arylmethoxycarbonyl groups, such as benzyloxycarbonyl groups; or aroyl groups, such as benzoyl groups. The deprotection conditions for the above-mentioned protecting groups necessarily vary with the choice of protecting groups. Thus, for example, acyl groups such as alkanoyl groups or alkoxycarbonyl groups or aroyl groups can be removed by, for example, hydrolysis with a suitable base such as an alkali metal hydroxide (e.g., lithium hydroxide or sodium hydroxide). Alternatively, acyl groups such as tert-butyloxycarbonyl groups can be removed, for example, by treatment with a suitable acid such as hydrochloric acid, sulfuric acid or phosphoric acid or trifluoroacetic acid, and arylmethoxycarbonyl groups such as benzyloxycarbonyl groups can be removed, for example, by hydrogenation with a catalyst such as palladium / carbon or by treatment with a Lewis acid such as tris(trifluoroacetic acid)boron. Suitable alternative protecting groups for primary amino groups are, for example, phthaloyl groups, which can be removed by treatment with an alkylamine (e.g., dimethylaminopropylamine) or with hydrazine.

[0921] Suitable protecting groups for hydroxy groups are, for example, acyl groups, for example, alkanoyl groups, such as acetyl; aroyl groups, for example, benzoyl groups; or arylmethyl groups, for example, benzyl groups. The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, acyl groups such as alkanoyl groups or aroyl groups can be removed, for example, by hydrolysis with a suitable base, such as an alkali metal hydroxide (e.g., lithium hydroxide, sodium hydroxide) or ammonia. Alternatively, arylmethyl groups such as benzyl groups can be removed, for example, by hydrogenation over a catalyst such as palladium / carbon.

[0922] Suitable protecting groups for carboxyl groups are, for example, esterifying groups such as methyl or ethyl, which can be removed, for example, by hydrolysis with a base such as sodium hydroxide; or for example a tert-butyl group, which can be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid; or for example a benzyl group, which can be removed, for example, by hydrogenation over a catalyst such as palladium on carbon.

[0923] Once a compound of formula (I) has been synthesized by any of the methods defined herein, the method may further comprise the additional steps of: (i) removing any protecting groups present; (ii) converting the compound of formula (I) into another compound of formula (I); (iii) forming a pharmaceutically acceptable salt, hydrate or solvate thereof; and / or (iv) forming a prodrug thereof.

[0924] The resulting compound of formula (I) can be isolated and purified using techniques well known in the art.

[0925] Conveniently, the reaction of the compound is carried out in the presence of a suitable solvent, which is preferably inert under the corresponding reaction conditions. Examples of suitable solvents include, but are not limited to, 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 ethyl acetate, ethyl acetate, ethyl acetate, ethyl acetate, ethyl acetate, ethyl acetate, ethyl acetate, ethyl acetate, ethyl acetate, ethyl acetate, ethyl acetate, ethyl acetate, ethyl acetate, ethyl acetate, ethyl acetate, ethyl acetate, Glycol monomethyl ether or ethylene glycol monoethyl ether or ethylene glycol dimethyl ether (diglyme); ketones such as acetone, methyl isobutyl ketone (MIBK) or butanone; amides such as acetamide, dimethylacetamide, dimethylformamide (DMF) or N-methylpyrrolidone (NMP); nitriles such as acetonitrile; sulfoxides such as dimethyl sulfoxide (DMSO); nitro compounds such as nitromethane or nitrobenzene; esters such as ethyl acetate or methyl acetate, or mixtures of the aforementioned solvents or mixtures with water.

[0926] The reaction temperature is suitably between about -100°C and 300°C, depending on the reaction steps and conditions employed.

[0927] The reaction times is usually in the scope between a fraction of a minute and a few days, and this depends on the reactivity of the corresponding compound and corresponding reaction conditions.Can easily determine suitable reaction times by method as known in the art (for example reaction monitoring).Based on the temperature of reaction providing above, suitable reaction times is usually in the scope between 10 minutes and 48 hours.

[0928] In addition, by utilizing the procedures described herein in combination with ordinary skills in the art, additional compounds of the present disclosure can be readily prepared. Those skilled in the art will readily understand that known variations of the conditions and methods of the following preparative procedures can be used to prepare these compounds.

[0929] As will be understood by those skilled in the art of organic synthesis, the compounds of the present disclosure can be easily obtained by various synthetic routes, some of which are illustrated in the accompanying examples. It will be easy for the technician to recognize which type of reagents and reaction conditions to use and how to apply and adjust them in any particular case (whether necessary or applicable) to obtain the compounds of the present disclosure. In addition, some compounds of the present disclosure can be easily synthesized by reacting other compounds of the present disclosure under suitable conditions, such as by applying standard synthetic methods such as reduction, oxidation, addition or substitution reactions to convert a specific functional group present in the compounds of the present disclosure or its suitable precursor molecules into another functional group; These methods are well known to those skilled in the art. Similarly, the technician will apply (whether necessary or applicable) to synthesize protective (or protective) groups; suitable protective groups and methods for introducing and removing them are well known to those skilled in the art of chemical synthesis and are described in more detail in, for example, PGM Wuts, TW Greene, "Greene's Protective Groups in Organic Synthesis", 4th edition (2006) (John Wiley & Sons).

[0930] General routes for preparing compounds of the present application are described in Schemes 1-6 herein.

[0931] Solution 1

[0932]

[0933] Compound 1a (R2 substituent contains an aldehyde or ketone functionality) is reacted with compound 1b in the presence of a reducing agent (eg, sodium triacetoxyborohydride) in a solvent (eg, dichloromethane) and optionally with an acid catalyst (eg, acetic acid) to provide compound 1c.

[0934] Option 2

[0935]

[0936] Compound 2a is reacted with compound 2b (R3 substituent, wherein X is a leaving group such as bromide, iodide or methanesulfonate, etc.) in the presence of a base (e.g., sodium tert-butoxide or cesium carbonate), a precatalyst (e.g., tris(dibenzylideneacetone)dipalladium(0)) and a ligand (e.g., 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl) and elevated temperature (e.g., 100° C.) in a solvent (e.g., toluene or 1,4-dioxane) to give compound 2c.

[0937] Option 3

[0938]

[0939] Compound 3a is reacted with compound 3b in the presence of a base (eg, triethylamine) in a solvent (eg, dichloromethane) and optionally at a reduced temperature (eg, 0° C.) to provide compound 3c.

[0940] Option 4

[0941]

[0942] Compound 4a is reacted with an acid (eg, hydrochloric acid or trifluoroacetic acid) in a suitable solvent (eg, dichloromethane, 1,4-dioxane or ethyl acetate) and optionally at a reduced temperature (eg, 0 °C) to provide compound 4b.

[0943] Option 5

[0944]

[0945] Compound 5a is reacted with a suitable isocyanate-forming reagent (eg, diphosgene or triphosgene) in a solvent (eg, dichloromethane or 1,4-dioxane) and optionally in the presence of a base (eg, triethylamine) to provide compound 5b.

[0946] Option 6

[0947]

[0948] Compound 6a is reacted with compound 6b in the presence of a base (eg, sodium hydroxide or sodium hydride) in a solvent (eg, tetrahydrofuran) and optionally at a reduced temperature (eg, 0° C.) to provide compound 6c.

[0949] Biological assays

[0950] Once the compounds designed, selected and / or optimized by the above methods are generated, they can be characterized using a variety of assays known to those skilled in the art to determine whether the compounds have biological activity. For example, molecules can be characterized using conventional assays, including but not limited to those described below, to determine whether they have the predicted activity, binding activity and / or binding specificity.

[0951] In addition, high-throughput screening can be used to accelerate analysis using such assays. Thus, using techniques known in the art, it is possible to rapidly screen for activity of the molecules described herein. General methods for performing high-throughput screening are described, for example, in Devlin (1998) High Throughput Screening, Marcel Dekker; and U.S. Patent No. 5,763,263. High-throughput assays can employ one or more different assay techniques, including but not limited to those described below.

[0952] Various in vitro or in vivo biological assays may be suitable for detecting the effects of the compounds of the present disclosure. These in vitro or in vivo biological assays may include, but are not limited to, enzyme activity assays, electrophoretic mobility shift assays, reporter gene assays, in vitro cell viability assays, and assays described herein.

[0953] In some embodiments, the inhibitory activity of the compounds of the present invention can be tested in various cell lines (e.g., peripheral blood mononuclear cells). In some embodiments, the inhibitory activity of the compounds of the present invention can be tested in peripheral blood mononuclear cells. In some embodiments, the inhibitory activity of the compounds of the present invention can be tested for IL-1β release after NLRP3 activation.

[0954] In some embodiments, PBMC IC 50 Assays can be used to characterize the compounds of the present disclosure.

[0955] PBMCs can be isolated, seeded into wells of a plate, and incubated with sugar. After replacing the culture medium, a compound of the present disclosure can be added to the wells and incubated. The cells can be stimulated and the cell culture medium can be collected for analysis.

[0956] PBMCs can be isolated by density gradient centrifugation, seeded into wells of a plate, and incubated with sugar. Compounds of the present disclosure can be added to the wells and incubated. Cells can be stimulated and cell culture medium collected for analysis.

[0957] In some embodiments, the release of IL-1β can be determined by quantitative detection. In some embodiments, the release of IL-1β can be determined by quantitatively detecting IL-1β using an IL-1β enzyme-linked immunosorbent assay (ELISA). A microplate spectrophotometer can be used to detect the signal (e.g., at 450 nm).

[0958] In some embodiments, this can be accomplished by using homogeneous time-resolved fluorescence Quantitative detection of IL-1β to determine the release of IL-1β. A microplate spectrophotometer can be used to detect the signal (eg, at 655 nm and 620 nm).

[0959] In some embodiments, biological assays are described in the Examples herein.

[0960] Pharmaceutical composition

[0961] In some aspects, the present disclosure provides pharmaceutical compositions comprising a compound of the present disclosure as an active ingredient. In some embodiments, the present disclosure provides pharmaceutical compositions comprising at least one compound of each formula described herein, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable carriers or excipients. In some embodiments, the present disclosure provides pharmaceutical compositions comprising at least one compound selected from Table 1.

[0962] As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

[0963] The compounds of the present disclosure can be formulated for oral administration in the form of tablets, capsules (each of which includes sustained-release or timed-release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. The compounds of the present disclosure can also be formulated for intravenous (bolus or infusion), intraperitoneal, topical, subcutaneous, intramuscular, or transdermal (e.g., patch) administration, all of which use forms well known to those of ordinary skill in the pharmaceutical arts.

[0964] The formulations of the present disclosure may be in the form of an aqueous solution comprising an aqueous vehicle. The aqueous vehicle component may comprise water and at least one pharmaceutically acceptable excipient. Suitable acceptable excipients include those selected from the group consisting of solubility enhancers, chelating agents, preservatives, tonicity agents, viscosity / suspending agents, buffers, and pH adjusters, and mixtures thereof.

[0965] Any suitable solubility enhancer can be used. Examples of solubility enhancers include cyclodextrins, such as those selected from the group consisting of hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, random methylated-β-cyclodextrin, ethylated-β-cyclodextrin, triacetyl-β-cyclodextrin, peracetylated-β-cyclodextrin, carboxymethyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, 2-hydroxy-3-(trimethylammonium)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, random methylated-γ-cyclodextrin and trimethyl-γ-cyclodextrin, and mixtures thereof.

[0966] Any suitable chelating agent may be used. Examples of suitable chelating agents include those selected from the group consisting of ethylenediaminetetraacetic acid and its metal salts, disodium edetate, trisodium edetate and tetrasodium edetate and mixtures thereof.

[0967] Any suitable preservative can be used. Examples of preservatives include those selected from the group consisting of quaternary ammonium salts such as benzalkonium halides (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetylpyridinium chloride, benzyl bromide, phenylmercuric nitrate, phenylmercuric acetate, phenylmercuric neodecanoate, thimerosal, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethylparaben, propylaminopropyl biguanide, and butylparaben, as well as sorbic acid and mixtures thereof.

[0968] The aqueous vehicle may also include a tonicity agent to adjust the tonicity (osmotic pressure). The tonicity agent may be selected from the group consisting of glycols (such as propylene glycol, diethylene glycol, triethylene glycol), glycerol, dextrose, glycerol, mannitol, potassium chloride and sodium chloride and mixtures thereof.

[0969] The aqueous vehicle may also contain a viscosity / suspending agent. Suitable viscosity / suspending agents include those selected from the group consisting of cellulose derivatives such as methylcellulose, ethylcellulose, hydroxyethylcellulose, polyethylene glycols (e.g., polyethylene glycol 300, polyethylene glycol 400), carboxymethylcellulose, hydroxypropylmethylcellulose, and cross-linked acrylic acid polymers (carbomers), such as polymers of acrylic acid cross-linked with polyalkenyl ethers or divinyl glycol (carbopols, such as Carbopol 934, Carbopol 934P, Carbopol 971, Carbopol 974, and Carbopol 974P), and mixtures thereof.

[0970] In order to adjust the formulation to an acceptable pH (typically a pH range of about 5.0 to about 9.0, more preferably about 5.5 to about 8.5, particularly about 6.0 to about 8.5, about 7.0 to about 8.5, about 7.2 to about 7.7, about 7.1 to about 7.9, or about 7.5 to about 8.0), the formulation may contain a pH adjusting agent. The pH adjusting agent is typically an inorganic acid or a metal hydroxide base selected from potassium hydroxide, sodium hydroxide, and hydrochloric acid, and mixtures thereof, and preferably sodium hydroxide and / or hydrochloric acid. These acidic and / or alkaline pH adjusting agents are added to adjust 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, and adding one of the acid or base may be sufficient to bring the mixture to the desired pH range.

[0971] The aqueous vehicle may also contain a buffer to stabilize the pH. When a buffer is used, it is selected from the group consisting of phosphate buffers (such as sodium dihydrogen phosphate and disodium hydrogen phosphate), borate buffers (such as boric acid or salts thereof, including disodium tetraborate), citrate buffers (such as citric acid or salts thereof, including sodium citrate) and ε-aminocaproic acid and mixtures thereof.

[0972] The formulation may further comprise a wetting agent. Suitable classes of wetting agents include those selected from the group consisting of polyoxypropylene-polyoxyethylene block copolymers (poloxamers), polyethoxylated ethers of castor oil, polyoxyethylated sorbitan esters (polysorbates), polymers of oxyethylated octylphenol (tyloxapol), polyoxyl 40 stearate, fatty acid glycol esters, fatty acid glycerides, sucrose fatty acid esters, and polyoxyethylene fatty acid esters, and mixtures thereof.

[0973] Oral compositions typically include an inert diluent or an edible pharmaceutically acceptable carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be combined with excipients and used in the form of tablets, lozenges, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and gargled and expectorated or swallowed. Pharmaceutically compatible binding agents and / or adjuvant substances can 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 microcrystalline cellulose, tragacanth gum, or gelatin; excipients such as starch or lactose; disintegrants such as alginic acid, Primogel, or corn starch; lubricants such as magnesium stearate or Sterotes; glidants such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or flavorings such as peppermint, methyl salicylate, or orange flavor.

[0974] According to a further aspect of the present disclosure, there is provided a pharmaceutical composition comprising a compound of the present disclosure as defined above, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and a pharmaceutically acceptable diluent or carrier.

[0975] The compositions of the present disclosure may be in a form suitable for oral use (e.g., as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), topical use (e.g., as a cream, ointment, gel or aqueous or oily solution or suspension), administration by inhalation (e.g., as a finely divided powder or liquid aerosol), administration by insufflation (e.g., as a finely divided powder), or parenteral administration (e.g., as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular administration or as a suppository for rectal administration).

[0976] The compositions of the present disclosure can be obtained by conventional procedures using conventional pharmaceutical excipients well known in the art. Thus, compositions intended for oral use may contain, for example, one or more coloring agents, sweeteners, flavoring agents and / or preservatives.

[0977] An effective amount of a compound of the present disclosure for use in therapy is an amount sufficient to treat or prevent the inflammasome-associated conditions mentioned herein, slow the progression thereof, and / or reduce the symptoms associated with the conditions.

[0978] An effective amount of a compound of the present disclosure for use in treatment is an amount sufficient to treat the inflammasome-associated conditions mentioned herein, slow their progression, and / or reduce the symptoms associated with the conditions.

[0979] According to well-known medical principles, the size of the dose of the compound of formula (I) for therapeutic or prophylactic purposes will naturally vary depending on the nature and severity of the condition, the age and sex of the animal or patient and the route of administration.

[0980] How to use

[0981] In some aspects, the present disclosure provides methods of inhibiting inflammasome (e.g., NLRP3 inflammasome) activity (e.g., in vitro or in vivo) comprising contacting a cell with an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0982] In some aspects, the present disclosure provides methods of treating or preventing a disease or condition disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0983] In some aspects, the present disclosure provides methods of treating a disease or condition disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0984] In some embodiments, the disease or disorder is associated with implicated inflammasome activity. In some embodiments, the disease or disorder is one in which inflammasome activity is implicated.

[0985] In some embodiments, the disease or disorder is an inflammatory disorder, an autoinflammatory disorder, an autoimmune disorder, a neurodegenerative disease, or cancer.

[0986] In some embodiments, the disease or disorder is an inflammatory disorder, an autoinflammatory disorder, and / or an autoimmune disorder.

[0987] In some embodiments, the disease or disorder is selected from cold and heat protein-associated autoinflammatory syndrome (CAPS; e.g., familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurocutaneous and articular (CINCA) syndrome / neonatal onset multisystem inflammatory disease (NOMID)), familial Mediterranean fever (FMF), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), gout, rheumatoid arthritis, osteoarthritis, Crohn's disease, chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD), fibrosis, obesity, type 2 diabetes, multiple sclerosis, skin diseases (e.g., acne), and neuroinflammation occurring in protein misfolding diseases (e.g., prion diseases).

[0988] In some embodiments, the disease or disorder is a neurodegenerative disease.

[0989] In some embodiments, the disease or disorder is Parkinson's disease or Alzheimer's disease.

[0990] In some embodiments, the disease or disorder is a skin disorder.

[0991] In some embodiments, the skin disorder is acne.

[0992] In some embodiments, the disease or condition is cancer.

[0993] In some embodiments, the cancer is metastatic cancer, gastrointestinal cancer, skin cancer, non-small cell lung cancer, brain cancer (eg, glioblastoma), or colorectal adenocarcinoma.

[0994] In some aspects, the present disclosure provides methods for treating or preventing autoinflammatory disorders, autoimmune disorders, neurodegenerative diseases, or cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0995] In some aspects, the present disclosure provides methods of treating an autoinflammatory disorder, an autoimmune disorder, a neurodegenerative disease, or cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0996] In some aspects, the present disclosure provides a method for treating or preventing an inflammatory disorder, autoinflammatory disorder and / or autoimmune disorder selected from the group consisting of: cold and hot protein-associated autoinflammatory syndrome (CAPS; e.g., familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurocutaneous and articular (CINCA) syndrome / neonatal onset multisystem inflammatory disease (NOMID)), familial Mediterranean fever (FMF), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), gout, rheumatoid arthritis, osteoarthritis, Crohn's disease, chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD), fibrosis, obesity, type 2 diabetes, multiple sclerosis, skin diseases (e.g., acne), and neuroinflammation occurring in protein misfolding diseases (e.g., prion diseases) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0997] In some aspects, the present disclosure provides a method of treating an inflammatory disorder, autoinflammatory disorder and / or autoimmune disorder selected from the group consisting of: cold and hot protein-associated autoinflammatory syndrome (CAPS; e.g., familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurocutaneous and articular (CINCA) syndrome / neonatal onset multisystem inflammatory disease (NOMID)), familial Mediterranean fever (FMF), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), gout, rheumatoid arthritis, osteoarthritis, Crohn's disease, chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD), fibrosis, obesity, type 2 diabetes, multiple sclerosis, skin diseases (e.g., acne), and neuroinflammation occurring in protein misfolding diseases (e.g., prion diseases) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0998] 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 in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0999] In some aspects, the present disclosure provides a method of treating a neurodegenerative disease (e.g., Parkinson's disease or Alzheimer's disease) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[1000] In some aspects, the present disclosure provides a method of treating or preventing cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[1001] In some aspects, the present disclosure provides methods of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[1002] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in inhibiting inflammasome (eg, NLRP3 inflammasome) activity (eg, in vitro or in vivo).

[1003] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating or preventing a disease or condition disclosed herein.

[1004] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating a disease or condition disclosed herein.

[1005] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating or preventing an inflammatory disorder, an autoinflammatory disorder, an autoimmune disorder, a neurodegenerative disease, or cancer in a subject in need thereof.

[1006] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating an inflammatory disorder, an autoinflammatory disorder, an autoimmune disorder, a neurodegenerative disease, or cancer in a subject in need thereof.

[1007] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating or preventing an inflammatory disorder, autoinflammatory disorder, and / or autoimmune disorder selected from the group consisting of: cold and hot protein-associated autoinflammatory syndrome (CAPS; e.g., familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurocutaneous and articular (CINCA) syndrome / neonatal-onset multisystem inflammatory disease (NOMID)), familial Mediterranean fever (FMF), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), gout, rheumatoid arthritis, osteoarthritis, Crohn's disease, chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD), fibrosis, obesity, type 2 diabetes, multiple sclerosis, and neuroinflammation occurring in protein misfolding diseases (e.g., prion diseases) in a subject in need thereof.

[1008] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating an inflammatory disorder, autoinflammatory disorder, and / or autoimmune disorder selected from the group consisting of: cold and hot protein-associated autoinflammatory syndrome (CAPS; e.g., familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurocutaneous and articular (CINCA) syndrome / neonatal onset multisystem inflammatory disease (NOMID)), familial Mediterranean fever (FMF), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), gout, rheumatoid arthritis, osteoarthritis, Crohn's disease, chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD), fibrosis, obesity, type 2 diabetes, multiple sclerosis, and neuroinflammation occurring in protein misfolding diseases (e.g., prion diseases) in a subject in need thereof.

[1009] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating or preventing a neurodegenerative disease (eg, Parkinson's disease or Alzheimer's disease) in a subject in need thereof.

[1010] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating a neurodegenerative disease (eg, Parkinson's disease or Alzheimer's disease) in a subject in need thereof.

[1011] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating or preventing cancer in a subject in need thereof.

[1012] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating cancer in a subject in need thereof.

[1013] In some aspects, the present disclosure provides use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for inhibiting inflammasome (eg, NLRP3 inflammasome) activity (eg, in vitro or in vivo).

[1014] In some aspects, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating or preventing a disease or condition disclosed herein.

[1015] In some aspects, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating a disease or condition disclosed herein.

[1016] In some aspects, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating or preventing an inflammatory disorder, an autoinflammatory disorder, an autoimmune disorder, a neurodegenerative disease, or cancer in a subject in need thereof.

[1017] In some aspects, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating an inflammatory disorder, an autoinflammatory disorder, an autoimmune disorder, a neurodegenerative disease, or cancer in a subject in need thereof.

[1018] In some aspects, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating or preventing an inflammatory disorder, an autoinflammatory disorder, and / or an autoimmune disorder in a subject in need thereof: cold and hot protein-associated autoinflammatory syndrome (CAPS; e.g., familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurocutaneous and articular (CINCA) syndrome / neonatal onset multisystem inflammatory disease (NOMID)), familial Mediterranean fever (FMF), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), gout, rheumatoid arthritis, osteoarthritis, Crohn's disease, chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD), fibrosis, obesity, type 2 diabetes, multiple sclerosis, skin disorders (e.g., acne), and neuroinflammation occurring in protein misfolding diseases (e.g., prion diseases).

[1019] In some aspects, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating an inflammatory disorder, an autoinflammatory disorder, and / or an autoimmune disorder in a subject in need thereof: cold and hot protein-associated autoinflammatory syndrome (CAPS; e.g., familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurocutaneous and articular (CINCA) syndrome / neonatal onset multisystem inflammatory disease (NOMID)), familial Mediterranean fever (FMF), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), gout, rheumatoid arthritis, osteoarthritis, Crohn's disease, chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD), fibrosis, obesity, type 2 diabetes, multiple sclerosis, skin disorders (e.g., acne), and neuroinflammation occurring in protein misfolding diseases (e.g., prion diseases).

[1020] In some aspects, the present disclosure provides use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating or preventing a neurodegenerative disease (eg, Parkinson's disease or Alzheimer's disease) in a subject in need thereof.

[1021] In some aspects, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating a neurodegenerative disease (eg, Parkinson's disease or Alzheimer's disease) in a subject in need thereof.

[1022] In some aspects, the present disclosure provides use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating or preventing cancer in a subject in need thereof.

[1023] In some aspects, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating cancer in a subject in need thereof.

[1024] The present disclosure provides compounds that act as inhibitors of inflammasome activity.The present disclosure therefore provides a method of inhibiting inflammasome activity in vitro or in vivo, the method comprising contacting a cell with an effective amount of a compound as defined herein, or a pharmaceutically acceptable salt thereof.

[1025] The effectiveness of the compounds of the present disclosure can be determined by industry-recognized assays / disease models according to standard procedures as described in the art and within current general knowledge.

[1026] The present disclosure also provides a method of treating a disease or disorder in which inflammasome activity is implicated in a patient in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

[1027] At a general level, the compounds of the present disclosure that inhibit the maturation of cytokines of the IL-1 family are effective for all therapeutic indications mediated by or associated with elevated levels of the active form of cytokines belonging to the IL-1 family of cytokines (Sims J. et al., Nature Reviews Immunology 10, 89-102 (February 2010).

[1028] Exemplary diseases and corresponding references are given below: inflammatory, autoinflammatory and autoimmune diseases, such as CAPS (Dinarello CA. Immunity. 2004 March; 20(3):243-4; Hoffman HM. al. Reumatología 2005; 21(3)); gout, rheumatoid arthritis (Gabay C et al., Arthritis Research & Therapy 2009, 11:230; Schett G. et al., Nat Rev Rheumatol. 2016 January; 12(1):14-24.); Crohn's disease (JungMogg Kim Korean J Gastroenterol Vol. 58, No. 6, 300-310); COPD (Mortaz E. et al., Tanaffos. 2011; 10(2):9–14.); fibrosis (Gasse P. et al., Am J Respir Crit Care Med. 2009 May 15;179(10):903-13); obesity, type 2 diabetes ((Dinarello CA. et al., Curr Opin Endocrinol Diabetes Obes. 2010 Aug;17(4):314-21)); multiple sclerosis (see the EAE model in Coll RC. et al., Nat Med. 2015 Mar;21(3):248-55) and many other diseases (Martinon F. et al., Immunol. 2009.27:229-65), such as Parkinson's disease or Alzheimer's disease (Michael T. et al., Nature 493,674-678 (2013 Jan 31); Halle A. et al., Nat Immunol. 2008 Aug;9(8):857-65; Saresella M. et al., Mol. Med. 2015 Mar;21(3):248-55); Neurodegener. 2016 Mar 3;11:23) and some neoplastic conditions.

[1029] Suitably, the compound according to the present disclosure can be used to treat the disease selected from the group consisting of inflammatory diseases, autoinflammatory diseases, autoimmune diseases, neurodegenerative diseases and cancer. The inflammatory, autoinflammatory and autoimmune diseases are suitably selected from the group consisting of: cold and hot protein associated autoinflammatory syndrome (CAPS, such as familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurocutaneous and articular (CINCA) syndrome / neonatal onset multisystem inflammatory disease (NOMID)), familial Mediterranean fever (FMF), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), chronic kidney disease (CKD), gout, rheumatoid arthritis, osteoarthritis, Crohn's disease, COPD, fibrosis, obesity, type 2 diabetes, multiple sclerosis, skin diseases (e.g., acne) and the neuroinflammation such as prion disease occurring in protein misfolding diseases. The neurodegenerative diseases include but are not limited to Parkinson's disease and Alzheimer's disease.

[1030] Thus, the compounds of the present disclosure can be used to treat a disease selected from the group consisting of: cold and hot protein-associated autoinflammatory syndrome (CAPS, e.g., familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurocutaneous and articular (CINCA) syndrome / neonatal onset multisystem inflammatory disease (NOMID)), familial Mediterranean fever (FMF), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), chronic kidney disease (CKD), gout, rheumatoid arthritis, osteoarthritis, Crohn's disease, COPD, fibrosis, obesity, type 2 diabetes, multiple sclerosis, skin diseases (e.g., acne), neuroinflammation occurring in protein misfolding diseases such as prion diseases, neurodegenerative diseases (e.g., Parkinson's disease, Alzheimer's disease), and neoplastic disorders.

[1031] Cancer treatment; association with inflammasome

[1032] Chronic inflammatory responses have long been associated with various types of cancer. Inflammasomes can be activated in response to danger signals during malignant transformation or cancer treatment, and this activation can be both beneficial and detrimental in cancer.

[1033] IL-1β expression is elevated in a variety of cancers, including breast, prostate, colon, lung, head and neck cancers, and melanoma, and patients with IL-1β-producing tumors generally have a 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).

[1034] Cancers derived from epithelial cells (carcinomas) or epithelial cells in glands (adenocarcinomas) are heterogeneous; they are composed of many different cell types. This may include fibroblasts, immune cells, adipocytes, endothelial cells, and pericytes, all of which can be cytokine / chemokine secreting (Grivennikov, Sergei I., Florian R. Greten, and Michael Karin. "Immunity, inflammation, and cancer." Cell 140.6 (2010): 883-899). This can lead to cancer-related inflammation through immune cell infiltration. The presence of leukocytes in tumors is known, but it has only recently become clear that the inflammatory microenvironment is an essential component of all tumors. Most tumors (>90%) are the result of somatic mutations or environmental factors rather than germline mutations, and many environmental causes of cancer are related to chronic inflammation (20% of cancers are related to chronic infection, 30% to smoking / inhaled pollutants, and 35% to 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).

[1035] GI cancers

[1036] Cancers of the gastrointestinal (GI) tract are often associated with chronic inflammation. For example, Helicobacter pylori infection is associated with gastric cancer (Amieva, Manuel, and Richard M. Peek. "Pathobiology of Helicobacter pylori–Induced Gastric Cancer." Gastroenterology 150.1 (2016): 64-78). Colorectal cancer is associated with inflammatory bowel disease (Bernstein, Charles N. et al., "Cancer risk in patients with inflammatory bowel disease." Cancer 91.4 (2001): 854-862). Chronic inflammation in the stomach leads to upregulation of IL-1 and other cytokines (Basso D, et al. (1996) Helicobacter pylori infection enhances mucosal interleukin-1beta, interleukin-6, and the soluble receptor of interleukin-2. Int J Clin Lab Res 26:207–210), and polymorphisms in the IL-1β gene may increase the risk of gastric cancer (Wang P et al. (2007) Association of interleukin-1 gene polymorphisms with gastric cancer: a meta-analysis. Int J Cancer 120:552–562).

[1037] In 19% of gastric cancer cases, caspase-1 expression is decreased, which is associated with stage, lymph node metastasis, and survival (Jee et al., 2005). Mycoplasma hyorhinis is associated with the development of gastric cancer, and its activation of the NLRP3 inflammasome may be related to its promotion of gastric cancer metastasis (Xu et al., 2013).

[1038] Skin cancer

[1039] Ultraviolet radiation is the greatest environmental risk for skin cancer by causing DNA damage, immunosuppression, and inflammation. Melanoma, the most malignant skin cancer, is characterized by the upregulation of inflammatory cytokines, all of which can be regulated by IL-1β (Lázár-Molnár, 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 growth of melanoma cells through an IL-1-dependent mechanism in vivo. Using thymoquinone to inhibit metastasis in the B16F10 mouse melanoma model was shown to be dependent on the inhibition of the NLRP3 inflammasome (Ahmad, Israr et al., "Thymoquinone suppresses metastasis of melanoma cells by inhibition of NLRP3 inflammasome." Toxicology and applied pharmacology 270.1 (2013): 70-76).

[1040] Glioblastoma

[1041] NLRP3 contributes to radioresistance in gliomas. Ionizing radiation induces NLRP3 expression, and NLRP3 inhibition after radiotherapy reduces tumor growth and prolongs mouse survival. Therefore, NLRP3 inflammasome inhibition may provide a therapeutic strategy for radioresistant gliomas (Li, Lianling, and Yuguang Liu. "Aging-related gene signature regulated by Nlrp3 predicts glioma progression." American Journal of Cancer Research 5.1 (2015): 442).

[1042] transfer

[1043] More broadly, the applicant believes that NLRP3 is involved in the promotion of metastasis, so the regulation of NLRP3 seems to prevent this process. IL-1 is involved in tumorigenesis, tumor invasion, metastasis, tumor-host interaction (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).

[1044] The IL-1 gene is frequently expressed in metastases from patients with several types of human cancer. For example, IL-1 mRNA is highly expressed in more than half of all metastatic human tumor samples tested, including non-small cell lung cancer, colorectal adenocarcinoma, and melanoma tumor samples (Elaraj, Dina M. et al., "The role of interleukin 1ingrowth and metastasis of human cancer xenografts." Clinical Cancer Research 12.4 (2006): 1088-1096), and IL-1RA inhibits xenograft growth in IL-1-producing tumors but has no antiproliferative effects in vitro.

[1045] Furthermore, IL-1 signaling is a biomarker for predicting an increased risk of bone metastasis in breast cancer patients. In a mouse model, IL-1β and its receptor are upregulated in breast cancer cells that metastasize to the bone (compared to cells that do not metastasize). In a mouse model, the IL-1 receptor antagonist anakinra, in addition to exerting a significant effect on the tumor environment, also reduces proliferation and angiogenesis, thereby reducing bone turnover markers IL-1β and TNFα (Holen, Ingunn et al., "IL-1 drives breast cancer growth and bone metastasis in vivo." Oncotarget (2016).

[1046] IL-18 induces the production of MMP-9 in the human leukemia cell line HL-60, thereby promoting the degradation of the extracellular matrix and the migration and invasiveness of cancer cells (Zhang, Bin et al., "IL-18 increases invasiveness of HL-60 myeloid leukemia cells: up-regulation of matrix metalloproteinases-9 (MMP-9) expression." Leukemia research 28.1 (2004): 91-95). In addition, IL-18 can support the occurrence of tumor metastasis in the liver by inducing the expression of VCAM-1 on the liver 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).

[1047] CD36

[1048] The fatty acid scavenger receptor CD36 plays a dual role in initiating gene transcription of pro-IL-1β and inducing the assembly of the NLRP3 inflammasome complex. CD36 and TLR4-TLR6 heterodimers recognize oxLDL, which initiates a signaling pathway that leads to upregulation of NLRP3 and pro-IL-1β transcription (signal 1). CD36 also mediates the internalization of oxLDL into the lysosomal compartment, where it forms crystals that induce lysosomal rupture and activation of the NLRP3 inflammasome (signal 2) (Kagan, J. and Horng T., "NLRP3inflammasome activation:CD36 serves double duty." Nature immunology 14.8 (2013): 772-774).

[1049] A subpopulation of human oral cancer cells expresses high levels of the fatty acid scavenger receptor CD36 and is unique in their ability to initiate metastasis. Palmitic acid or a high-fat diet enhances the metastatic potential of CD36+ cells. Neutralizing anti-CD36 antibodies blocked metastasis in an orthotopic mouse model of human oral cancer. The presence of CD36+ metastasis-initiating cells is associated with a poor prognosis in many types of cancer. It has been suggested that dietary lipids may promote metastasis (Pasqual, G, Avgustinova, A., Mejetta, S, Martin, M, Castellanos, A, Attolini, CS-O, Berenguer, A., Prats, N, Toll, A, Hueto, JA, Bescos, C, Di Croce, L, and Benitah, SA. 2017 "Targeting metastasis-initiating cells through the fatty acid receptor CD36" Nature 541: 41-45).

[1050] In hepatocellular carcinoma, exogenous palmitic acid activates an epithelial-mesenchymal transition (EMT)-like program and induces migration, which is reduced by the CD36 inhibitor sulfo-N-succinimidyl oleate (Nath, Aritro et al., “Elevated free fatty acid uptake via CD36 promotes epithelial-mesenchymal transition in hepatocellular carcinoma.” Scientific reports 5 (2015). Body mass index did not correlate with the extent of EMT, highlighting that it is actually CD36 and free fatty acids that are important.

[1051] Cancer stem cells (CSCs) use CD36 to promote their maintenance. Oxidized phospholipids (a ligand for CD36) are present in glioblastoma, and the proliferation of CSCs, but not non-CSCs, increases with exposure to oxidized LDL. CD36 has also been associated with patient prognosis.

[1052] Chemotherapy resistance

[1053] In addition to their direct cytotoxic effects, chemotherapeutic agents also utilize the host immune system to contribute to their antitumor activity. However, gemcitabine and 5-FU have been shown to activate NLRP3 in myeloid-derived suppressor cells, leading to the production of IL-1β, which impairs antitumor efficacy. Mechanistically, these agents destabilize lysosomes, releasing cathepsin B to activate NLRP3. IL-1β drives the production of IL-17 by CD4+ T cells, which in turn attenuates the efficacy of chemotherapy. A higher antitumor effect of gemcitabine and 5-FU was observed when tumors were established in NLRP3- / - or Caps1- / - mice or in WT mice treated with IL-1RA. Therefore, myeloid-derived suppressor cell NLRP3 activation limits the anti-tumor efficacy of gemcitabine and 5-FU (Bruchard, Mélanie 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). The compounds of the present disclosure can therefore be used in chemotherapy to treat a range of cancers.

[1054] The compounds of the present disclosure, or pharmaceutically acceptable salts thereof, may be administered alone as a monotherapy or may be administered together with one or more other substances and / or treatments.Such conjoint treatment may be achieved by simultaneous, sequential or separate administration of the individual components of the treatment.

[1055] For example, the effectiveness of a treatment may be enhanced by administering an adjuvant (i.e., the adjuvant itself may have only minimal therapeutic benefit, but when combined with another therapeutic agent, the overall therapeutic benefit to the individual is enhanced.) Or, by way of example only, the benefit experienced by an individual may be increased by administering a compound of Formula (I) with another therapeutic agent (which also includes a therapeutic regimen) that also has therapeutic benefit.

[1056] In the case where the compounds of the present invention are administered in combination with other therapeutic agents, the compounds of the present invention do not need to be administered via the same route as the other therapeutic agents and can be administered by different routes because of their different physical and chemical properties. For example, the compounds of the present invention can be administered orally to produce and maintain good blood levels, while other therapeutic agents can be administered intravenously. Initial administration can be performed according to established protocols known in the art, and then, based on the observed effects, the dosage, mode of administration, and time of administration can be modified by a skilled clinician.

[1057] The specific choice of other therapeutic agents will depend on the diagnosis of the attending physician and their judgment of the individual condition and the appropriate treatment regimen. According to this aspect of the present disclosure, there is provided a combination for the treatment of a disease involving inflammasome activity, comprising a compound of the present disclosure as defined above, or a pharmaceutically acceptable salt thereof, and another suitable agent.

[1058] According to a further aspect of the present disclosure, a pharmaceutical composition is provided, comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof in combination with a suitable pharmaceutically acceptable diluent or carrier.

[1059] In addition to their use as therapeutic drugs, the compounds of formula (I) and their pharmaceutically acceptable salts can also be used as pharmacological tools in the development and standardization of in vitro and in vivo test systems for evaluating the effects of inhibitors of inflammasomes in laboratory animals such as dogs, rabbits, monkeys, rats and mice as part of the search for new therapeutic agents.

[1060] In any of the above-mentioned pharmaceutical compositions, processes, methods, uses, medicaments and manufacturing features of the present disclosure, any of the alternative embodiments of the macromolecules of the present disclosure described herein also apply.

[1061] Route of administration

[1062] The compounds of the present disclosure, or pharmaceutical compositions comprising these compounds, may be administered to a subject by any convenient route of administration, whether systemically / peripherally or topically (ie, at the desired site of action).

[1063] Routes of administration include, but are not limited to, oral (e.g., by ingestion); buccal; sublingual; transdermal (including, for example, by patches, plasters, etc.); transmucosal (including, for example, by patches, plasters, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy, e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by vaginal suppository); parenteral, e.g., by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcutaneous, intraarticular, subarachnoid, and intrasternal; by implantation of a reservoir or depot, e.g., subcutaneous or intramuscular.

[1064] Exemplary embodiments

[1065] Embodiment No. 1: A compound of formula (I):

[1066]

[1067] or a prodrug, solvate or pharmaceutically acceptable salt thereof, wherein:

[1068] R1 is optionally replaced by one or more R 1S substituted 5- to 12-membered heterocycloalkyl or 5- to 12-membered heteroaryl;

[1069] Each R 1S are independently C1-C6 alkyl, C1-C6 haloalkyl, -O(C1-C6 alkyl), -O(C1-C6 haloalkyl), -(C1-C6 alkyl)-O(C1-C6 alkyl), cyano, halo, C3-C8 cycloalkyl, C3-C8 aryl, 3- to 8-membered heterocycloalkyl, or 3- to 8-membered heteroaryl;

[1070] R2 is -(CX2X2) n -R 2S , wherein n is 0, 1 or 2, and each X2 is independently H, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl, wherein the C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl is optionally substituted with one or more halo, -CN, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2 or oxo;

[1071] R 2S It is C1-C6 alkyl, C3-C 16 Cycloalkyl or 4 to 8 membered heterocycloalkyl, wherein the C1-C6 alkyl, C3-C 16 The cycloalkyl or 4- to 8-membered heterocycloalkyl is optionally substituted with one or more 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; and

[1072] R3 is optionally replaced by one or more R 3S substituted 5- to 12-membered heterocycloalkyl or 5- or 6-membered heteroaryl, wherein each R 3S It is independently C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halo or C3-C8 heterocycloalkyl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl or C3-C8 heterocycloalkyl is optionally substituted with -O(C1-C6 alkyl), -N(C1-C6 alkyl)2, halo or -CN.

[1073] Embodiment No. 2: The compound of Embodiment 1, wherein:

[1074] R1 is optionally replaced by one or more R 1S substituted 5- to 12-membered heterocycloalkyl or 5- to 12-membered heteroaryl;

[1075] Each R 1S are independently C1-C6 alkyl, C1-C6 haloalkyl, -O(C1-C6 alkyl), -O(C1-C6 haloalkyl), -(C1-C6 alkyl)-O(C1-C6 alkyl), cyano, halo, C3-C8 cycloalkyl, C3-C8 aryl, 3- to 8-membered heterocycloalkyl, or 3- to 8-membered heteroaryl;

[1076] R2 is -(CX2X2) n -R 2S , wherein n is 0, 1 or 2, and each X2 is independently H, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl, wherein the C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl is optionally substituted with one or more halo, -CN, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2 or oxo;

[1077] R 2S It is C1-C6 alkyl, C3-C 16 Cycloalkyl or 4 to 8 membered heterocycloalkyl, wherein the C1-C6 alkyl, C3-C 16 The cycloalkyl or 4- to 8-membered heterocycloalkyl is optionally substituted with one or more 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; and

[1078] R3 is optionally replaced by one or more R 3S substituted 7- to 12-membered heterocycloalkyl or 5- or 6-membered heteroaryl, wherein each R 3S It is independently C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halo or C3-C8 heterocycloalkyl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl or C3-C8 heterocycloalkyl is optionally substituted with -O(C1-C6 alkyl), -N(C1-C6 alkyl)2, halo or -CN.

[1079] Embodiment No. 3: A compound according to any one of the preceding embodiments, wherein:

[1080] R1 is a 5- to 12-membered heterocycloalkyl or a 5- to 12-membered heteroaryl, wherein at least one heteroatom in the 5- to 12-membered heterocycloalkyl or the 5- to 12-membered heteroaryl is O or S, and wherein the 5- to 12-membered heterocycloalkyl or the 5- to 12-membered heteroaryl is optionally replaced by one or more R 1S replace;

[1081] Each R 1Sare independently C1-C6 alkyl, C1-C6 haloalkyl, -O(C1-C6 alkyl), cyano, halo, C3-C8 cycloalkyl or C3-C8 aryl;

[1082] R2 is -(CH2) n -R 2S , where n is 0, 1, or 2;

[1083] R 2S It is C1-C6 alkyl, C3-C 16 Cycloalkyl or 4 to 8 membered heterocycloalkyl, wherein the C1-C6 alkyl, C3-C 16 Cycloalkyl or 4- to 8-membered heterocycloalkyl is optionally substituted with one or more C1-C6 alkyl, halo, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl); and

[1084] R3 is a 5- to 6-membered heterocycloalkyl or a 5- or 6-membered heteroaryl, wherein the 5- to 12-membered heterocycloalkyl or the 5- or 6-membered heteroaryl is optionally substituted with one or more C1-C6 alkyl, C3-C8 cycloalkyl or halo.

[1085] Embodiment No. 4: A compound according to any one of the preceding embodiments, wherein:

[1086] R1 is a 5- to 12-membered heterocycloalkyl or a 5- to 12-membered heteroaryl, wherein at least one heteroatom in the 5- to 12-membered heterocycloalkyl or the 5- to 12-membered heteroaryl is O or S, and wherein the 5- to 12-membered heterocycloalkyl or the 5- to 12-membered heteroaryl is optionally replaced by one or more R 1S replace;

[1087] Each R 1S are independently C1-C6 alkyl, C1-C6 haloalkyl, -O(C1-C6 alkyl), cyano, halo, C3-C8 cycloalkyl or C3-C8 aryl;

[1088] R2 is -(CH2) n -R 2S , where n is 0, 1, or 2;

[1089] R 2S It is C1-C6 alkyl, C3-C 16 Cycloalkyl or 4 to 8 membered heterocycloalkyl, wherein the C1-C6 alkyl, C3-C 16 Cycloalkyl or 4- to 8-membered heterocycloalkyl is optionally substituted with one or more C1-C6 alkyl, halo, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl); and

[1090] R3 is a 5- or 6-membered heteroaryl group optionally substituted with one or more C1-C6 alkyl groups, C3-C8 cycloalkyl groups or halo groups.

[1091] Embodiment No. 5: A compound according to any one of the preceding embodiments, wherein:

[1092] R1 is optionally replaced by one or more R 1S substituted 5- to 12-membered heteroaryl, wherein at least one heteroatom in the 5- to 12-membered heteroaryl is S;

[1093] Each R 1S are independently C1-C6 alkyl, C1-C6 haloalkyl, -O(C1-C6 alkyl), -O(C1-C6 haloalkyl) or halo;

[1094] R2 is -(CX2X2) n -R 2S , wherein n is 0, 1 or 2, and each X2 is independently H, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl, wherein the C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl is optionally substituted with one or more halo, -CN, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2 or oxo;

[1095] R 2S It is C1-C6 alkyl, C3-C 16 Cycloalkyl or 4 to 8 membered heterocycloalkyl, wherein the C1-C6 alkyl, C3-C 16 The cycloalkyl or 4- to 8-membered heterocycloalkyl is optionally substituted with one or more 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; and

[1096] R3 is optionally replaced by one or more R 3S substituted 7- to 12-membered heterocycloalkyl or 5- or 6-membered heteroaryl, wherein each R 3S It is independently C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halo or C3-C8 heterocycloalkyl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl or C3-C8 heterocycloalkyl is optionally substituted with -O(C1-C6 alkyl), -N(C1-C6 alkyl)2, halo or -CN.

[1097] Embodiment No. 6: A compound according to any one of the preceding embodiments, wherein:

[1098] R1 is optionally replaced by one or more R 1S substituted 5- to 12-membered heteroaryl, wherein at least one heteroatom in the 5- to 12-membered heteroaryl is S;

[1099] Each R 1S are independently C1-C6 alkyl, C1-C6 haloalkyl, -O(C1-C6 alkyl), -O(C1-C6 haloalkyl) or halo;

[1100] R2 is -(CX2X2) n -R 2S , wherein n is 0, 1 or 2, and each X2 is independently H, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl, wherein the C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl is optionally substituted with one or more halo, -CN, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2 or oxo;

[1101] R 2S It is C1-C6 alkyl, C3-C 16 Cycloalkyl or 4 to 8 membered heterocycloalkyl, wherein the C1-C6 alkyl, C3-C 16 The cycloalkyl or 4- to 8-membered heterocycloalkyl is optionally substituted with one or more 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; and

[1102] R3 is optionally replaced by one or more R 3S substituted 7- to 12-membered heterocycloalkyl or 5- or 6-membered heteroaryl, wherein each R 3S It is independently C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halo or C3-C8 heterocycloalkyl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl or C3-C8 heterocycloalkyl is optionally substituted with -O(C1-C6 alkyl), -N(C1-C6 alkyl)2, halo or -CN.

[1103] Embodiment No. 7: A compound according to any one of the preceding embodiments, wherein:

[1104] R1 is optionally replaced by one or more R 1S substituted 5- to 12-membered heteroaryl;

[1105] Each R 1Sare independently C1-C6 alkyl, C1-C6 haloalkyl, -O(C1-C6 alkyl), -O(C1-C6 haloalkyl) or halo;

[1106] R2 is -(CX2X2) n -R 2S , wherein n is 0, 1 or 2, and each X2 is independently H, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl, wherein the C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl is optionally substituted with one or more halo, -CN, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2 or oxo;

[1107] R 2S is a 4- to 8-membered heterocycloalkyl group optionally substituted with one or more 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; and

[1108] R3 is optionally replaced by one or more R 3S substituted 7- to 12-membered heterocycloalkyl or 5- or 6-membered heteroaryl, wherein each R 3S It is independently C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halo or C3-C8 heterocycloalkyl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl or C3-C8 heterocycloalkyl is optionally substituted with -O(C1-C6 alkyl), -N(C1-C6 alkyl)2, halo or -CN.

[1109] Embodiment No. 8: A compound according to any one of the preceding embodiments, wherein:

[1110] R1 is optionally replaced by one or more R 1S substituted 5- to 12-membered heteroaryl, wherein the heteroaryl comprises at least one S;

[1111] Each R 1S are independently C1-C6 alkyl, C1-C6 haloalkyl, -O(C1-C6 alkyl), -O(C1-C6 haloalkyl) or halo;

[1112] R2 is -(CX2X2) n -R 2S, wherein n is 0, 1 or 2, and each X2 is independently H, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl, wherein the C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl is optionally substituted with one or more halo, -CN, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2 or oxo;

[1113] R 2S is a 4- to 8-membered heterocycloalkyl group optionally substituted with one or more 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; and

[1114] R3 is optionally replaced by one or more R 3S substituted 7- to 12-membered heterocycloalkyl or 5- or 6-membered heteroaryl, wherein each R 3S It is independently C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halo or C3-C8 heterocycloalkyl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl or C3-C8 heterocycloalkyl is optionally substituted with -O(C1-C6 alkyl), -N(C1-C6 alkyl)2, halo or -CN.

[1115] Embodiment No. 9: A compound according to any one of the preceding embodiments, wherein:

[1116] R1 is optionally replaced by one or more R 1S Substituted C5-C 12 heteroaryl;

[1117] Each R 1S are independently C1-C6 alkyl, C1-C6 haloalkyl, -O(C1-C6 alkyl), -O(C1-C6 haloalkyl) or halo;

[1118] R2 is R 2S ;

[1119] R 2S is a 4- to 8-membered heterocycloalkyl group optionally substituted with one or more 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; and

[1120] R3 is optionally replaced by one or more R 3Ssubstituted 7- to 12-membered heterocycloalkyl or 5- or 6-membered heteroaryl, wherein each R 3S It is independently C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halo or C3-C8 heterocycloalkyl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl or C3-C8 heterocycloalkyl is optionally substituted with -O(C1-C6 alkyl), -N(C1-C6 alkyl)2, halo or -CN.

[1121] Embodiment No. 10: A compound according to any one of the preceding embodiments, wherein:

[1122] R1 is thienyl or benzothienyl, wherein the thienyl or benzothienyl is optionally substituted by one or more R 1S replace;

[1123] Each R 1S are independently C1-C6 alkyl, C1-C6 haloalkyl, -O(C1-C6 alkyl), -O(C1-C6 haloalkyl) or halo;

[1124] R2 is R 2S ;

[1125] R 2S is a 4- to 8-membered heterocycloalkyl group optionally substituted with one or more 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; and

[1126] R3 is optionally replaced by one or more R 3S substituted 7- to 12-membered heterocycloalkyl or 5- or 6-membered heteroaryl, wherein each R 3S It is independently C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halo or C3-C8 heterocycloalkyl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl or C3-C8 heterocycloalkyl is optionally substituted with -O(C1-C6 alkyl), -N(C1-C6 alkyl)2, halo or -CN.

[1127] Embodiment No. 11: A compound according to any one of the preceding embodiments, wherein:

[1128] R1 is thienyl or benzothienyl, wherein the thienyl or benzothienyl is optionally substituted by one or more R 1S replace;

[1129] Each R 1S is a C1-C6 alkyl group or a halo group;

[1130] R2 is R 2S ;

[1131] R 2S is a 4- to 8-membered heterocycloalkyl group optionally substituted with one or more 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; and

[1132] R3 is optionally replaced by one or more R 3S substituted 7- to 12-membered heterocycloalkyl or 5- or 6-membered heteroaryl, wherein each R 3S It is independently C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halo or C3-C8 heterocycloalkyl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl or C3-C8 heterocycloalkyl is optionally substituted with -O(C1-C6 alkyl), -N(C1-C6 alkyl)2, halo or -CN.

[1133] Embodiment No. 12: A compound according to any one of the preceding embodiments, wherein R1 is optionally replaced by one or more R 1S Substituted 5- to 12-membered heterocycloalkyl.

[1134] Embodiment No. 13: A compound according to any one of the preceding embodiments, wherein R1 is optionally replaced by one or more R 1S Substituted 5,6-dihydro-4H-cyclopenta[b]thienyl.

[1135] Embodiment No. 14: A compound according to any one of the preceding embodiments, wherein R1 is

[1136] Embodiment No. 15: A compound according to any one of the preceding embodiments, wherein R1 is optionally replaced by one or more R 1S Substituted 5- to 12-membered heteroaryl.

[1137] Embodiment No. 16: A compound according to any one of the preceding embodiments, wherein R1 is optionally replaced by one or more R 1S Substituted 5- to 12-membered heteroaryl, wherein R1 is attached to the remainder of formula (I) via a carbon atom in R1.

[1138] Embodiment No. 17: A compound according to any one of the preceding embodiments, wherein R1 is a 5- to 12-membered heteroaryl group optionally substituted with one or more C1-C6 alkyl or halo groups.

[1139] Embodiment No. 18: A compound according to any one of the preceding embodiments, wherein R1 is optionally replaced by one or more R 1S substituted 5- to 12-membered heteroaryl, wherein the C5-C 12 At least one heteroatom in the heteroaryl group is S.

[1140] Embodiment No. 19: A compound according to any one of the preceding embodiments, wherein R1 is optionally replaced by one or more R 1S Substituted 5-membered monocyclic heteroaryl, wherein the C5 monocyclic heteroaryl contains one heteroatom which is O.

[1141] Embodiment No. 20: A compound according to any one of the preceding embodiments, wherein R1 is optionally replaced by one or more R 1S Substituted furyl.

[1142] Embodiment No. 21: A compound according to any one of the preceding embodiments, wherein R1 is

[1143] Embodiment No. 22: A compound according to any one of the preceding embodiments, wherein R1 is optionally replaced by one or more R 1S Substituted 5-membered monocyclic heteroaryl, wherein at least one heteroatom in the C5 monocyclic heteroaryl is S.

[1144] Embodiment No. 23: A compound according to any one of the preceding embodiments, wherein R1 is optionally replaced by one or more R 1S Substituted thienyl.

[1145] Embodiment No. 24: A compound according to any one of the preceding embodiments, wherein R1 is

[1146]

[1147] Embodiment No. 25: A compound according to any one of the preceding embodiments, wherein R1 is

[1148]

[1149] Embodiment No. 26: A compound according to any one of the preceding embodiments, wherein R1 is

[1150] Embodiment No. 27: A compound according to any one of the preceding embodiments, wherein R1 is

[1151] Embodiment No. 28: A compound according to any one of the preceding embodiments, wherein R1 is

[1152]

[1153] Embodiment No. 29: A compound according to any one of the preceding embodiments, wherein R1 is

[1154] Embodiment No. 30: A compound according to any one of the preceding embodiments, wherein R1 is

[1155] Embodiment No. 31: A compound according to any one of the preceding embodiments, wherein R1 is optionally replaced by one or more R 1S Substituted 5-membered monocyclic heteroaryl, wherein the C5 monocyclic heteroaryl contains two heteroatoms, one of which is S and the other is N.

[1156] Embodiment No. 32: A compound according to any one of the preceding embodiments, wherein R1 is optionally replaced by one or more R 1S Substituted thiazolyl.

[1157] Embodiment No. 33: A compound according to any one of the preceding embodiments, wherein R1 is

[1158] Embodiment No. 34: A compound according to any one of the preceding embodiments, wherein R1 is

[1159] Embodiment No. 35: A compound according to any one of the preceding embodiments, wherein R1 is optionally replaced by one or more R 1S Substituted isothiazolyl.

[1160] Embodiment No. 36: A compound according to any one of the preceding embodiments, wherein R1 is

[1161] Embodiment No. 37: A compound according to any one of the preceding embodiments, wherein R1 is

[1162] Embodiment No. 38: A compound according to any one of the preceding embodiments, wherein R1 is optionally replaced by one or more R 1S Substituted 9-membered bicyclic heteroaryl, wherein at least one heteroatom in the 9-membered bicyclic heteroaryl is S.

[1163] Embodiment No. 39: A compound according to any one of the preceding embodiments, wherein R1 is optionally replaced by one or more R 1S Substituted benzothienyl.

[1164] Embodiment No. 40: A compound according to any one of the preceding embodiments, wherein R1 is

[1165]

[1166] Embodiment No. 41: A compound according to any one of the preceding embodiments, wherein R1 is

[1167] Embodiment No. 42: A compound according to any one of the preceding embodiments, wherein at least one R 1S It is C1-C6 alkyl, C1-C6 haloalkyl, -O(C1-C6 alkyl), -O(C1-C6 haloalkyl) or halo.

[1168] Embodiment No. 43: A compound according to any one of the preceding embodiments, wherein at least one R 1S It is a C1-C6 alkyl group or a halo group.

[1169] Embodiment No. 44: A compound according to any one of the preceding embodiments, wherein R2 is R 2S .

[1170] Embodiment No. 45: A compound according to any one of the preceding embodiments, wherein R2 is -(CX2) n -R 2S , where n is 1 or 2.

[1171] Embodiment No. 46: A compound according to any one of the preceding embodiments, wherein R 2S It is a 6-membered heterocycloalkyl group optionally substituted by one or more 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.

[1172] Embodiment No. 47: A compound according to any one of the preceding embodiments, wherein R 2S It is a C1-C6 alkyl group optionally substituted by one or more C1-C6 alkyl groups, C2-C6 alkenyl groups, C2-C6 alkynyl groups, C1-C6 haloalkyl groups, halo groups, -CN, -OH, -O(C1-C6 alkyl groups), -NH2, -NH(C1-C6 alkyl groups), -N(C1-C6 alkyl groups)2 or oxo groups.

[1173] Embodiment No. 48: A compound according to any one of the preceding embodiments, wherein R 2S is a C3-C6 alkyl group optionally substituted with one or more 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. 16 Cycloalkyl.

[1174] Embodiment No. 49: A compound according to any one of the preceding embodiments, wherein R 2S is a 6-membered heterocycloalkyl group optionally substituted by one or more C1-C6 alkyl groups.

[1175] Embodiment No. 50: A compound according to any one of the preceding embodiments, wherein R 2S yes

[1176] Embodiment No. 51: A compound according to any one of the preceding embodiments, wherein R2 is

[1177]

[1178] Embodiment No. 52: A compound according to any one of the preceding embodiments, wherein R2 is

[1179] Embodiment No. 53: A compound according to any one of the preceding embodiments, wherein R2 is

[1180] Embodiment No. 54: A compound according to any one of the preceding embodiments, wherein R2 is

[1181] Embodiment No. 55: A compound according to any one of the preceding embodiments, wherein R2 is

[1182] Embodiment No. 56: A compound according to any one of the preceding embodiments, wherein R2 is

[1183] Embodiment No. 57: A compound according to any one of the preceding embodiments, wherein R2 is

[1184] Embodiment No. 58: A compound according to any one of the preceding embodiments, wherein R3 is a 5- to 6-membered heterocycloalkyl or a 5-membered heteroaryl, wherein said 5- to 6-membered heterocycloalkyl or 5-membered heteroaryl is optionally replaced by one or more R 3S replace.

[1185] Embodiment No. 59: A compound according to any one of the preceding embodiments, wherein R3 is optionally replaced by one or more R 3S Substituted 5- to 6-membered heterocycloalkyl.

[1186] Embodiment No. 60: A compound according to any one of the preceding embodiments, wherein R3 is

[1187] Embodiment No. 61: A compound according to any one of the preceding embodiments, wherein R3 is optionally replaced by one or more R 3S Substituted 5-membered heteroaryl.

[1188] Embodiment No. 62: A compound according to any one of the preceding embodiments, wherein R3 is optionally replaced by one or more R 3S Substituted pyrazolyl.

[1189] Embodiment No. 63: A compound according to any one of the preceding embodiments, wherein R3 is

[1190] Embodiment No. 64: A compound according to any one of the preceding embodiments, wherein R3 is

[1191] Embodiment No. 65: A compound according to any one of the preceding embodiments, wherein at least one R 3S It is C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halo or C3-C8 heterocycloalkyl.

[1192] Embodiment No. 66: A compound according to any one of the preceding embodiments, wherein at least one R 3S It is a C1-C6 alkyl group.

[1193] Embodiment No. 67: A compound according to any one of the preceding embodiments, wherein at least one R 3S It's methyl.

[1194] Embodiment No. 68: A compound of any one of the preceding embodiments, which has formula (II-a) or (II-b), or a prodrug, solvate or pharmaceutically acceptable salt thereof, wherein n1 is an integer in the range of 0 to 3 (e.g., 0, 1, 2 or 3).

[1195] Embodiment No. 69: A compound according to any one of the preceding embodiments, which has formula (II-c), (II-d), (II-e), or a prodrug, solvate or pharmaceutically acceptable salt thereof, wherein n1 is 0 or 1.

[1196] Embodiment No. 70: A compound according to any one of the preceding embodiments, which has formula (III), or a prodrug, solvate or pharmaceutically acceptable salt thereof.

[1197] Embodiment No. 71: A compound of any one of the preceding embodiments, which has formula (III-a) or (III-b), or a prodrug, solvate or pharmaceutically acceptable salt thereof, wherein n1 is an integer in the range of 0 to 3 (e.g., 0, 1, 2 or 3).

[1198] Embodiment No. 72: A compound according to any one of the preceding embodiments, which has formula (III-c), (III-d), (III-e), or a prodrug, solvate or pharmaceutically acceptable salt thereof, wherein n1 is 0 or 1.

[1199] Embodiment No. 73: A compound of any one of the preceding embodiments, which has formula (IV), or a prodrug, solvate or pharmaceutically acceptable salt thereof, wherein n1 is an integer in the range of 0 to 3 (e.g., 0, 1, 2 or 3).

[1200] Embodiment No. 74: A compound according to any one of the preceding embodiments, which has formula (IV-a), or a prodrug, solvate or pharmaceutically acceptable salt thereof.

[1201] Embodiment No. 75: A compound according to any one of the preceding embodiments, selected from Compound Nos. 1-131 and prodrugs and pharmaceutically acceptable salts thereof.

[1202] Embodiment No. 76: A compound according to any one of the preceding embodiments, selected from Compound Nos. 1-131 and pharmaceutically acceptable salts thereof.

[1203] Embodiment No. 77: A compound according to any one of the preceding embodiments, selected from Compound Nos. 1-131.

[1204] Embodiment No. 78: A compound which is an isotopic derivative of the compound according to any one of the preceding embodiments.

[1205] Embodiment No. 79: The compound of Embodiment 77, which is a deuterium-labeled compound of any one of Compound Nos. 1-131 and a prodrug and a pharmaceutically acceptable salt thereof.

[1206] Embodiment No. 80: The compound of Embodiment 77 or Embodiment 78, which is a deuterium-labeled compound of any one of Compound Nos. 1-131.

[1207] Embodiment No. 81: A compound obtainable by or by a method described herein; optionally comprising one or more steps described in Schemes 1-6.

[1208] Embodiment No. 82: A compound or intermediate obtained by the method of preparing a compound according to any one of embodiments 1-79; optionally, the intermediate is selected from the intermediates described in Examples 1-107.

[1209] Embodiment No. 83: A pharmaceutical composition comprising a compound according to any one of Embodiments 1-79 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier.

[1210] Embodiment No. 84: The pharmaceutical composition of Embodiment 82, wherein the compound is selected from Compound Nos. 1-131.

[1211] Embodiment No. 85: A method of inhibiting inflammasome activity, comprising contacting a cell with an effective amount of a compound of any one of Embodiments 1-79 or a pharmaceutically acceptable salt thereof; optionally, the inflammasome is an NLRP3 inflammasome, and the activity is in vitro or in vivo.

[1212] Embodiment No. 86: A method for treating or preventing a disease or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of Embodiments 1-79 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Embodiment 82 or Embodiment 83.

[1213] Embodiment No. 87: A compound of any one of Embodiments 1-79 or a pharmaceutical composition of Embodiment 82 or Embodiment 83 for inhibiting inflammasome activity; optionally, the inflammasome is an NLRP3 inflammasome, and the activity is in vitro or in vivo.

[1214] Embodiment No. 88: A compound according to any one of Embodiments 1-79 or a pharmaceutical composition according to Embodiment 82 or Embodiment 83 for use in treating or preventing a disease or disorder.

[1215] Embodiment No. 89: Use of a compound according to any one of Embodiments 1-79 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for inhibiting inflammasome activity; optionally, the inflammasome is NLRP3 inflammasome, and the activity is in vitro or in vivo.

[1216] Embodiment No. 90: Use of a compound according to any one of Embodiments 1 to 79 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating or preventing a disease or condition.

[1217] Embodiment No. 91: The method, compound, pharmaceutical composition or use of any one of the preceding embodiments, wherein the disease or disorder is associated with implicated inflammasome activity; optionally the disease or disorder is a disease or disorder in which inflammasome activity is implicated.

[1218] Embodiment No. 92: The method, compound, pharmaceutical composition or use of any one of the preceding embodiments, wherein the disease or disorder is an inflammatory disorder, an autoinflammatory disorder, an autoimmune disorder, a neurodegenerative disease or cancer.

[1219] Embodiment No. 93: The method, compound, pharmaceutical composition or use of any of the preceding embodiments, wherein the disease or condition is an inflammatory condition, an autoinflammatory condition or an autoimmune condition; optionally, the disease or condition is selected from the group consisting of cold and hot protein-associated autoinflammatory syndrome (CAPS; e.g., familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurocutaneous and articular (CINCA) syndrome / neonatal onset multisystem inflammatory disease (NOMID)), familial Mediterranean fever (FMF), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), gout, rheumatoid arthritis, osteoarthritis, Crohn's disease, chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD), fibrosis, obesity, type 2 diabetes, multiple sclerosis, skin diseases (e.g., acne) and neuroinflammation occurring in protein misfolding diseases (e.g., prion diseases).

[1220] Embodiment No. 94: The method, compound, pharmaceutical composition or use of any one of the preceding embodiments, wherein the disease or condition is a neurodegenerative disease; optionally the disease or condition is Parkinson's disease or Alzheimer's disease.

[1221] Embodiment No. 95: The method, compound, pharmaceutical composition or use of any of the preceding embodiments, wherein the disease or condition 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.

[1222] Example

[1223] For illustrative purposes, neutral compounds of formula (I) were synthesized and tested in the Examples. It should be understood that the neutral compounds of formula (I) can be converted to the corresponding pharmaceutically acceptable salts of the compounds using conventional techniques in the art (e.g., by saponifying the ester to a carboxylate, or by hydrolyzing the amide to form the corresponding carboxylic acid, which is then converted to a carboxylate).

[1224] Unless otherwise stated, nuclear magnetic resonance (NMR) spectra were recorded at 400 MHz or 300 MHz and 300.3 K as indicated; chemical shifts (δ) are reported in parts per million (ppm). Spectra were recorded using Bruker or Varian instruments with 8, 16, or 32 scans.

[1225] LC-MS chromatograms and spectra were recorded using an Agilent 1200 or Shimadzu LC-20 AD&MS 2020 instrument using a C-18 column such as Luna-C18 2.0x30mm or Xbridge Shield RPC18 2.1x50mm. The injection volume was 0.7-8.0 μl, and the flow rate was typically 0.8 or 1.2 ml / min. The detection method was diode array (DAD) or evaporative light scattering (ELSD) with positive ion electrospray ionization. The MS range was 100-1000 Da. The solvent was a gradient of water and acetonitrile, both containing a modifier (typically 0.01-0.04%) such as trifluoroacetic acid or ammonium carbonate.

[1226] abbreviation:

[1227]

[1228]

[1229] Synthesis of intermediates.

[1230] Intermediate 1. N-(1-methyl-1H-pyrazol-4-yl)-N-(oxan-4-yl)aminosulfonamide

[1231] Step 1: 1-Methyl-N-(oxan-4-yl)-1H-pyrazol-4-amine

[1232]

[1233] To the solution of 1-methylpyrazole-4-amine (10g, 103mmol) in DCE (205ml), AcOH (23.6ml, 412mmol) and tetrahydropyran-4-one (11.35ml, 124mmol) are added. RM is stirred for 1h under rt. Cool to 0 ℃ of reactions, then sodium triacetoxyborohydride (43.7g, 206mmol) is added to the mixture, keeping the reaction temperature between 0 ℃ and 10 ℃. Warming up to rt reaction and stir 11h. By saturated Na2CO3 aqueous solution (200ml) is added to the mixture. The gained mixture is extracted with DCM (3x50ml), and the organic phase merged is concentrated under reduced pressure to obtain residue. By flash column chromatography (silicon dioxide, 20-100% EtOAc in petroleum ether) purification of residue, obtain 1-methyl-N-(oxane-4-yl)-1H-pyrazole-4-amine, be red oily matter. Y=86%. 1H NMR(400MHz,MeOD)δ7.22(s,1H),7.15(s,1H),3.98-3.93(m,2H),3.78(s,3H) ,3.49-3.40(m,2H),3.10-3.01(m,1H),1.97-1.88(m,2H),1.47-1.36(m,2H).

[1234] Step 2: tert-Butyl N-(chlorosulfonyl)carbamate

[1235]

[1236] To a solution of N-(oxymethylene)sulfamoyl chloride (6.13 ml, 70.7 mmol) in DCM (100 ml) cooled to 0° C. was added tert-butanol (6.76 ml, 70.7 mmol). The mixture was stirred at 0° C. for 0.5 h to give a solution of tert-butyl N-(chlorosulfonyl)carbamate (100 ml, 70.7 mmol, 0.71 M in DCM). The tert-butyl N-(chlorosulfonyl)carbamate was used directly in the next step.

[1237] Step 3: tert-Butyl N-[(1-methyl-1H-pyrazol-4-yl)(oxan-4-yl)sulfamoyl]carbamate

[1238]

[1239] To a solution of 1-methyl-N-tetrahydropyran-4-yl-pyrazol-4-amine (7.0 g, 38.6 mmol) in DCM (70 ml) cooled to 0°C was added DIPEA (20.2 ml, 116 mmol). The resulting solution was treated dropwise with a solution of tert-butyl N-chlorosulfonylcarbamate in DCM (0.71 M, 54.4 ml, 38.6 mmol). The mixture was stirred at 0° C. for 2 h. The solution was concentrated under vacuum. The resulting residue was purified by preparative HPLC (column: Phenomenex Luna C18 10 μm, 250×100 mm; mobile phase: [water (0.1% TFA)-ACN]; B: 5-35% in 20 min) to give tert-butyl N-[(1-methyl-1H-pyrazol-4-yl)(oxan-4-yl)sulfamoyl]carbamate as a yellow oil. Y=26%. LCMS (ESI): m / z: [M+H] + =361.1.

[1240] Step 3: N-(1-methyl-1H-pyrazol-4-yl)-N-(oxan-4-yl)aminosulfonamide

[1241]

[1242] Tert-butyl N-[(1-methylpyrazol-4-yl)-tetrahydropyran-4-yl-sulfamoyl]carbamate (560 mg, 1.55 mmol, 1 equivalent) was dissolved in 4 M hydrochloric acid in EtOAc (10 ml). The mixture was stirred at rt for 12 h. The solution was concentrated under vacuum to give N-(1-methyl-1H-pyrazol-4-yl)-N-(oxan-4-yl)aminosulfonamide as a white solid. It was used without further purification. LCMS (ESI): m / z: [M+H] + =261.1

[1243] Intermediate 2. 1-Methyl-3-[(1-methyl-1H-pyrazol-4-yl)(sulfamoyl)amino]piperidin-1-ium trifluoroacetate

[1244] Step 1. tert-Butyl 3-[(1-methyl-1H-pyrazol-4-yl)amino]piperidine-1-carboxylate

[1245]

[1246] To a solution of 1-methylpyrazole-4-amine (2.0 g, 20.6 mmol) in DCE (41 ml) was added AcOH (4.71 ml, 82 mmol) and tert-butyl 3-oxopiperidine-1-carboxylate (4.10 g, 20.6 mmol). The mixture was stirred at rt for 1 h. The reaction was cooled to 0 ° C and sodium triacetoxyborohydride (8.73 g, 41.2 mmol) was added. The reaction was stirred between 0 ° C and 10 ° C for 12 h. The solvent was removed under reduced pressure and the resulting residue was purified by flash column chromatography (silica, 9-100% EtOAc in petroleum ether) to give tert-butyl 3-[(1-methyl-1H-pyrazol-4-yl)amino]piperidine-1-carboxylate as a red liquid. Y=78%.

[1247] Step 2. 1-Methyl-N-(1-methyl-1H-pyrazol-4-yl)piperidin-3-amine

[1248]

[1249] To a solution of tert-butyl 3-[(1-methyl-1H-pyrazol-4-yl)amino]piperidine-1-carboxylate (4.1 g, 14.6 mmol) in THF (30 ml) cooled to 0° C. was added lithium aluminum hydride (5.55 g, 146 mmol). The mixture was stirred at 0° C. for 0.5 h and then heated at 80° C. for 2 h. The RM was cooled and then H O (5.55 ml) and 10% aqueous NaOH (5.55 ml) were added. The mixture was filtered and the filtrate was concentrated under reduced pressure to give 1-methyl-N-(1-methyl-1H-pyrazol-4-yl)piperidin-3-amine as an oil. It was used without further purification. Y=95%.

[1250] Step 3. 3-[({[(tert-Butoxy)carbonyl]amino}sulfonyl)(1-methyl-1H-pyrazol-4-yl)amino]-1-methylpiperidin-1-ium trifluoroacetate

[1251]

[1252] To a solution of 1-methyl-N-(1-methylpyrazol-4-yl)piperidin-3-amine (200 mg, 1.03 mmol) in DCM (2 ml) cooled to 0° C. was added a 0.59 M solution of tert-butyl N-chlorosulfonylcarbamate in DCM (1.75 ml, 1.03 mmol) and DIPEA (538 μl, 3.09 mmol). The mixture was stirred at 0° C. for 5 h. The reaction was concentrated under vacuum, and the resulting residue was purified by preparative HPLC (column: Phenomenex Luna C18 10 μm, 250 x 50 mm; mobile phase: [water (0.1% TFA)-ACN]; B: 15-45%, 20 min) to give 3-[({[(tert-butoxy)carbonyl]amino}sulfonyl)(1-methyl-1H-pyrazol-4-yl)amino]-1-methylpiperidin-1-ium trifluoroacetate as a white solid. Y=40%. LCMS(ESI): m / z: [M+H] + =374.2

[1253] Step 4. 1-Methyl-3-[(1-methyl-1H-pyrazol-4-yl)(sulfamoyl)amino]piperidin-1-ium trifluoroacetate

[1254]

[1255] A mixture of 3-[({[(tert-butoxy)carbonyl]amino}sulfonyl)(1-methyl-1H-pyrazol-4-yl)amino]-1-methylpiperidin-1-ium trifluoroacetate (131 mg, 0.27 mmol) in DCM (2 ml) and TFA (0.4 ml) was stirred at rt for 3 h. The residue was concentrated under vacuum to 1-methyl-3-[(1-methyl-1H-pyrazol-4-yl)(sulfamoyl)amino]piperidin-1-ium trifluoroacetate as a white solid. It was used without further purification. Y=96%. LCMS (ESI): m / z: [M+H] + =274.3

[1256] Intermediate 3. 3-Isocyanato-2,4-dimethylthiophene

[1257] Step 1: 2,4-Dimethylthiophene-3-amine

[1258]

[1259] To a solution of lithium aluminum hydride (2.93 g, 77 mmol) in THF (30 ml) cooled to 0° C. was added dropwise a solution of 3-amino-4-methyl-thiophene-2-carboxylic acid methyl ester (6.00 g, 35 mmol) in THF (30 ml). The solution was stirred under nitrogen at rt for 30 minutes and then heated at 80° C. for 3 h. The reaction was cooled and quenched with water (3 ml) and a 15% aqueous solution of NaOH (3 ml). The mixture was stirred at rt for 0.5 h and then filtered. The filtrate was concentrated under reduced pressure to give 2,4-dimethylthiophene-3-amine as a yellow oil. Y=96%. 1 H NMR (400 MHz, chloroform-d) δ 6.60 (s, 1H), 3.12–3.32 (br. s, 2H), 2.24 (s, 3H), 2.07 (s, 3H)

[1260] Step 2. 3-Isocyanato-2,4-dimethylthiophene

[1261]

[1262] To a solution of 2,4-dimethylthiophene-...

Claims

1. A compound selected from the following or a pharmaceutically acceptable salt thereof:

2. The compound of claim 1, selected from compound numbers 1-4, 6-16, 18-19, 28-29, 32-67, 70-123 and 125-131.

3. A compound which is an isotopic derivative of the compound according to claim 1 or 2.

4. The compound according to claim 3, which is a deuterium-labeled compound of any one of compound Nos. 1-4, 6-16, 18-19, 28-29, 32-67, 70-123 and 125-131 as defined in claim 1 or a pharmaceutically acceptable salt thereof. 5 . The compound according to claim 4 , which is a deuterium-labeled compound of any one of compound numbers 1-4, 6-16, 18-19, 28-29, 32-67, 70-123 and 125-131.

6. A pharmaceutical composition comprising the compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier.

7. The pharmaceutical composition of claim 6, wherein the compound is selected from compound numbers 1-4, 6-16, 18-19, 28-29, 32-67, 70-123 and 125-131 defined in claim 1.

8. Use of a compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating or preventing a disease or condition selected from the group consisting of an inflammatory condition mediated by NLRP3, an autoimmune condition mediated by NLRP3, a neurodegenerative disease mediated by NLRP3, and a cancer mediated by NLRP3.

9. The use of claim 8, wherein the disease or disorder is an autoinflammatory disorder mediated by NLRP3.

10. The use of claim 8, wherein the disease or condition is selected from the group consisting of cold and hot protein associated autoinflammatory syndrome (CAPS), familial Mediterranean fever (FMF), non-alcoholic fatty liver disease (NAFLD), gout, rheumatoid arthritis, osteoarthritis, Crohn's disease, chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD), fibrosis, obesity, type 2 diabetes, multiple sclerosis, skin diseases, and neuroinflammation occurring in protein misfolding diseases.

11. The use according to claim 8, wherein the disease or disorder is non-alcoholic steatohepatitis (NASH).

12. The use according to claim 8, wherein the neurodegenerative disease mediated by NLRP3 is selected from Parkinson's disease and Alzheimer's disease.

13. The use according to claim 8, wherein the cancer mediated by NLRP3 is selected from the group consisting of brain cancer, gastrointestinal cancer, skin cancer, non-small cell lung cancer, head and neck squamous cell carcinoma, and colorectal adenocarcinoma.

14. The use of claim 8, wherein the cancer mediated by NLRP3 is a metastatic cancer.

15. The use of claim 10, wherein the cold and heat protein-associated autoinflammatory syndrome is familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurocutaneous and articular (CINCA) syndrome or neonatal onset multisystem inflammatory disease (NOMID).

16. The use according to claim 10, wherein the skin disease is acne.

17. The use according to claim 10, wherein the protein misfolding disease is a prion disease.

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