Dihydrooxazole derivative compounds

Abstract

The present invention relates to novel compounds for the treatment, alleviation or prevention of a group of diseases, disorders or disorders that respond to the modulation or inhibition of the activation of a component of the NLRP3 inflammasome pathway. In particular, the component of the inflammasome pathway is the NOD-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3) inflammasome. More specifically, the compounds of the present invention have the ability to modulate the NLRP3 inflammasome pathway. Furthermore, the compounds of the present invention are suitable for the treatment, alleviation or prevention of a group of diseases, disorders and disorders that respond to the modulation, particularly the reduction, of the levels of IL-1 beta and / or IL-18.

Description

[Technical field]

[0001] The present invention relates to novel compounds useful for the treatment, alleviation, or prevention of diseases, disorders, or disorders that respond to the inhibition of the modulation, particularly activation, of a component of the NLRP3 inflammasome pathway. In particular, a component of the inflammasome pathway is the NOD-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3) inflammasome. More specifically, the compounds of the present invention have the ability to modulate, e.g., inhibit the activation of, the NLRP3 inflammasome pathway. Furthermore, the compounds of the present invention have the ability to modulate, particularly reduce, the levels of IL-1 beta and / or IL-18. The present invention relates to novel compounds for the treatment, alleviation, or prevention of diseases, disorders, or disorders that respond to the inhibition of the activation of the NLRP3 inflammasome pathway. The present invention relates to novel compounds for the treatment, alleviation, or prevention of diseases, disorders, or disorders that respond to the modulation of the levels of IL-1 beta and / or IL-18. The present invention relates to pharmaceutical compositions comprising said compounds, methods of using said compounds in the treatment of various diseases, disorders, or disorders that respond to the modulation, medicaments containing them, and their uses. [Background technology]

[0002] Inflammasome protein complexes are key components of inflammatory signaling. These complexes assemble in response to a variety of danger signals, such as infectious pathogen-derived molecules (pathogen-associated molecular patterns, PAMPs), as well as modified host molecules, products of sterile tissue damage, and environmental factors (danger-associated molecular patterns, DAMPs). The inflammasome family consists of NALP1-14, IPAF, and NAIP1-6, with each family member providing specificity for different PAMPs / DAMPs, including nucleic acids, bacterial proteins, metabolites, protein aggregates, and toxic activities (Sharma, D. and Kanneganti, T. D., The cell biology of inflammasomes: mechanisms of inflammasome activation, and regulation, J. Cell Biol. 213, 617-629 (2016)). Inflammasomes typically consist of sensors (cytosolic pattern recognition receptors, PRRs) and adaptor proteins called apoptosis-associated speck-like proteins (ASCs) that contain a caspase recruitment domain (CARD), and effectors such as the protease caspase-1 (Broz, P.; Dixit, V. M., Inflammasomes: Mechanism of Assembly, Regulation, and Signalling. Nat. Rev. Immunol. 2016, 16, 407-420).

[0003] The NLRP3 (NOD-like receptor (NLR) family, pyrin domain-containing protein 3) inflammasome is one of the best described family members. It is a tripartite protein of the NLR family, containing an amino-terminal PYRIN (PYD) domain, a nucleotide-binding NACHT domain, and a carboxy-terminal leucine-rich repeat (LRR) domain. In response to various drugs, including aggregated proteins, crystals, and altered cellular ion homeostasis, the NLRP3 sensor molecule assembles into a multimolecular complex with the apoptosis-associated speck-like protein containing the caspase activation and recruitment domain (ASC, also known as PYCARD) adaptor protein. Polymerization of the ASC protein into a large complex (ASC speck) leads to activation of caspase-1 effector proteins and subsequent cleavage of pro-IL-1 beta (β) and pro-IL18 into their active secreted forms, mediating pyroptosis (Heneka et al., 2018, Nat Rev Neurosci). IL-1 beta (β) acts through the IL-1 beta (β) receptor to induce secondary proinflammatory signals, including IL-6 and TNF alpha secretion, and attracts and activates cells of the adaptive immune system at the site of infection. The NLRP3 / ASC complex appears to be released into the extracellular milieu where it can propagate inflammation.

[0004] A large body of genetic and pharmacological evidence highlights the importance of the NLRP3 inflammasome in human diseases. NLRP3 gain-of-function mutations result in hereditary cryopyrin-associated periodic fever syndromes (CAPS), including Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), and neonatal-onset multisystem inflammatory disease (NOMID).

[0005] Accumulation of age-related tissue damage products leads to activation of the NLRP3 inflammasome in many diseases, including metabolic disorders, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, atherosclerosis, obesity, lung disease, liver disease, and gout.

[0006] Extensive experimental evidence from animal models points to a detrimental role for excessive NLRP3 activation in a wide range of diseases. Genetic or pharmacological downregulation of the NLRP3-inflammasome has shown protection in models of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, demyelination, viral encephalitis, epilepsy, stroke, atherosclerosis, asthma, allergic inflammation, cryopyrin-associated periodic fever syndrome (CAPS), gout, inflammatory bowel disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), hypertension, myocardial infarction, oxalate-induced nephropathy, graft-versus-host disease, type 1 and type 2 diabetes, rheumatoid arthritis, and myelodysplastic syndromes, among others (Heneka et al., Nat. Rev. Neurosci. 2018 Oct;19(10):610-621; Mangan et al., Nat. Rev. Drug Discov. 2018 Aug;17(8):588-606).

[0007] For the reasons discussed above, modulation of NLRP3 inflammasome pathway activity represents a promising therapeutic approach.

[0008] Current treatments for NLRP3-related diseases include biologics that target IL-1. These are the recombinant IL-1 receptor antagonist anakinra, the neutralizing IL-1 beta (β) antibody canakinumab, and the soluble decoy IL-1 receptor rilonacept. However, their activity is restricted to downstream effectors of the inflammasome, and their bioavailability for central nervous system (CNS) applications is limited.

[0009] Several small molecules have been shown to inhibit the NLRP3 inflammasome pathway (Baldwin, A.G., Brough, D., and Freeman, S., Inhibiting the NLRP3 inflammasome pathway: a chemical perspective. J. Med. Chem. 59, 1691-1710 (2016); reviewed in Mangan et al., Nat Rev Drug Discov. 2018 Aug;17(8):588-606). These include various chemical classes such as sulfonylurea compounds (glyburide, CP-456,773 (also known as CRID3 and MCC950) and their derivatives); the fenamate class of nonsteroidal anti-inflammatory drugs; the hydroxysulfonamide analog JC-171; a novel series of boron compounds; the benzimidazole-containing structure Fc11a-2; the polyketide spirodalesol; acrylate and acrylamide derivatives; 3,4-methylenedioxy-β-nitrostyrene; the β-sulfonyl nitrile molecule OLT1177; CY-09; BOT-4-one; and Michael acceptors. Many of these compounds have full uptake modes of action and limited efficacy.

[0010] WO2016131098, WO2017 / 140778, and WO2018215818 relate to sulfonylureas and related compounds and their uses for treating or identifying diseases or conditions that respond to inhibition of NLRP3 or inhibition of the activation of NLRP3 or related components of the inflammatory process.

[0011] WO 2019008025, WO 2019008029, WO 2019034686, WO 2019034688, WO 2019034690, WO 2019034692, WO 2019034693, WO 2019034696, WO 2019034697, WO 2019068772, WO 2019092170, WO 2019092171, and WO 2019092172 relate to novel compounds (e.g. sulfonylureas, sulfonylthioureas, sulfoximine ureas, and sulfoximine thioureas) useful for the treatment and prevention of medical disorders and diseases, particularly by NLRP3 inhibition.

[0012] WO2017184604, WO2017184623, WO2017184624, WO2019023145, WO2019023147, and WO2019079119 relate to chemical entities that are useful for treating conditions, diseases, or disorders in which increased or decreased NLRP3 activity contributes to the pathology and / or symptoms and / or progression of the condition, disease, or disorder in a subject.

[0013] WO2019211463, WO2020021447, and WO2021043966, WO2021239885, WO2021219784, WO2021214284, WO2021209552, WO2021209539 disclose compounds for inhibiting NLRP3 and / or the NLRP3 inflammasome pathway.

[0014] WO2018136890 relates to sulfonylurea and sulfonylthiourea compounds and their uses for treating diseases or conditions responsive to modulation of cytokines such as IL-1 beta (β) and IL-18, modulation of NLRP3, or inhibition of activation of NLRP3 or related components of the inflammatory process.

[0015] WO2018225018 and WO2019043610 relate to the use of NLRP3 modulators, as well as novel inhibitor compounds, in the treatment of diseases or conditions, as well as disease conditions mediated by NLRP3, and in the treatment of diseases or conditions in which interleukin-1 beta (β) activity and interleukin-18 (IL-18) are affected.

[0016] WO2018015445 relates to sulfonylurea compounds that have inflammasome inhibitory activity and are therefore useful in methods of treatment of the human or animal body.

[0017] WO2020018975 discloses sulfonimidamide derivatives defined as inhibitors of interleukin-1 activity associated with inflammatory processes and as NLRP3 modulators.

[0018] WO 9832733 relates to aryl and heteroaryl substituted sulfonylureas that are inhibitors of interleukin 1 alpha (α) and interleukin 1 beta (β) processing and release.

[0019] WO2020018970 discloses sulfonylureas defined as inhibitors of interleukin-1 activity.

[0020] Crosstalk between the NLRP3 inflammasome pathway and tau pathology has recently been deciphered. Ising et al. (Nature 2019 Nov; 575(7784):669-673) investigated the critical role of microglia and NLRP3 inflammasome pathway activation in the pathogenesis of tauopathy in the Tau22 mouse model of frontotemporal dementia (FTD). Genetic ablation of components of the NLRP3 inflammasome pathway in Tau22 mice reduced tau aggregation / phosphorylation and improved cognition. Stancu et al. (Acta Neuropathol. 2019; 137(4):599-617) investigated the role of inflammasome activation in prion-like or template seeding of tau pathology. A significant inhibition of exogenously seeded tau pathology was found in ASC-deficient-PS19 tau transgenic mice. Furthermore, chronic intracerebral administration of the NLRP3 inhibitor MCC950 was demonstrated to inhibit exogenously seeded tau pathology. Finally, ASC deficiency also attenuated non-exogenously seeded tau pathology in PS19 mice. [Prior art documents] [Patent documents]

[0021] [Patent Document 1] International Publication No. 2016131098 [Patent Document 2] International Publication No. 2017 / 140778 [Patent Document 3] International Publication No. 2018215818 [Patent Document 4] International Publication No. 2019008025 [Patent Document 5] International Publication No. 2019008029 [Patent Document 6] International Publication No. 2019034686 [Patent Document 7] International Publication No. 2019034688 [Patent Document 8] International Publication No. 2019034690 [Patent Document 9] International Publication No. 2019034692 [Patent Document 10] International Publication No. 2019034693 [Patent Document 11] International Publication No. 2019034696 [Patent Document 12] International Publication No. 2019034697 [Patent Document 13] International Publication No. 2019068772 [Patent Document 14] International Publication No. 2019092170 [Patent Document 15] International Publication No. 2019092171 [Patent Document 16] International Publication No. 2019092172 [Patent Document 17] International Publication No. 2017184604 [Patent Document 18] International Publication No. 2017184623 [Patent Document 19] International Publication No. 2017184624 [Patent Document 20] International Publication No. 2019023145 [Patent Document 21] International Publication No. 2019023147 [Patent Document 22] International Publication No. 2019079119 [Patent Document 23] International Publication No. 2019211463 [Patent Document 24] International Publication No. 2020021447 [Patent Document 25] International Publication No. 2021043966 [Patent Document 26] International Publication No. 2021239885 [Patent Document 27] International Publication No. 2021219784 [Patent Document 28] International Publication No. 2021214284 [Patent Document 29] International Publication No. 2021209552

Patent document 30

Patent document 31

Patent document 32

Patent document 33

Patent document 34

Patent document 35

Patent document 36

Patent document 37

Non-licensed literature

[0022]

Non-licensed literature 1

Non-licensed Document 4

[0023] There is a need to identify and develop specific NLRP3 inflammasome pathway inhibitors and / or modulators of interleukin activity with improved pharmaceutical and / or physiological and / or physicochemical properties.

[0024] The present invention provides compounds of formula (I), which have been surprisingly found to be capable of modulating components of the NLRP3 inflammasome pathway, such as the NLRP3 inflammasome, in particular inhibiting the activation of components of the NLRP3 inflammasome pathway. Thus, such compounds are useful for treating diseases, disorders, or conditions that respond to the modulation of components of the NLRP3 inflammasome pathway and / or the modulation of the levels of IL-1 beta and / or IL-18, which generally result in pathological inflammation. [Means for solving the problem]

[0025] Thus, the present invention provides compounds that can be used to treat, alleviate, or prevent diseases, disorders, or conditions that respond to modulation, particularly inhibition, of components of the NLRP3 inflammasome pathway, or that respond to modulation, particularly reduction, of levels of IL-1beta and / or IL-18.

[0026] Various embodiments of the present invention are described herein.

[0027] Within certain embodiments, provided herein is a compound of formula (I):

[0028] [ka]

[0029] or a stereoisomer, or a racemic mixture, or a tautomer, or a polymorph, or a pharma- ceutically acceptable salt, or a prodrug, or a hydrate, or a solvate thereof. [In the formula, R 0 is H or C1-C3 alkyl; R 2 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl; R 3is independently selected from the group consisting of 5- or 6-membered heterocycloalkyl containing 1-3 heteroatoms, aryl, and heteroaryl containing 1 or 2 heteroatoms. The 5- or 6-membered heterocycloalkyl containing 1 or 2 heteroatoms and heteroaryl containing 1 or 2 heteroatoms are independently selected from N, S, and O. In the 5- or 6-membered heterocycloalkyl containing 1 or 2 heteroatoms and heteroaryl having 1 or 2 heteroatoms, at least one heteroatom is independently selected from O and S. The 5- or 6-membered heterocycloalkyl containing 1 or 2 heteroatoms, aryl, or heteroaryl containing 1 or 2 heteroatoms can be optionally substituted with -C1-C6 alkyl, -O-C1-C6 alkyl, -halogen, or -C1-C6 alkyl-OH; R 1 is as follows:

[0030] [ka]

[0031] (In the formula,

[0032] [ka]

[0033] can be optionally substituted with C1-C6 alkyl at any available position) A ring system selected from the group consisting of: Z is independently selected from the group consisting of CH2 and O; n is 0 or 1; R a is independently selected from the group consisting of C1-C3 alkyl, C1-C3 haloalkyl, and phenyl; R b is heteroaryl optionally substituted with -C1-C6 alkyl, -O-C1-C6 alkyl, or -O-C1-C6 haloalkyl; R cis independently selected from the group consisting of hydrogen and CH3; R d is independently selected from the group consisting of hydrogen and halogen; R e is independently selected from the group consisting of -C1-C6 alkyl and heteroaryl, wherein heteroaryl is optionally substituted with -C1-C6 alkyl, -C1-C6 haloalkyl, -O-C1-C6 alkyl, or -O-C1-C6 haloalkyl; R f is independently selected from the group consisting of halogen and CF3; R h is independently selected from the group consisting of -C1-C6 alkyl and heteroaryl, wherein heteroaryl is optionally substituted with -C1-C6 alkyl, -C1-C6 haloalkyl, -O-C1-C6 alkyl, or -O-C1-C6 haloalkyl.

[0034] R d In all of the embodiments, R d is preferably hydrogen or fluoro.

[0035] Within the preferred embodiments, provided herein is a compound of formula (I):

[0036] [ka]

[0037] or a stereoisomer, racemic mixture, tautomer, polymorph, pharma- ceutically acceptable salt, prodrug, hydrate, or solvate thereof. [In the formula, R 0 is H or C1-C3 alkyl; R 2 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl; R 3is independently selected from the group consisting of 5- or 6-membered heterocycloalkyl containing 1 or 2 heteroatoms, aryl, or heteroaryl containing 1 or 2 heteroatoms, the heteroatoms being independently selected from N, S, and O, and at least one heteroatom being independently selected from O and S, and the heterocycloalkyl, aryl, or heteroaryl can be optionally substituted with -C1-C6 alkyl, -O-C1-C6 alkyl, -halogen, or -C1-C6 alkyl-OH; R 1 is as follows:

[0038] [ka]

[0039] (In the formula,

[0040] [ka]

[0041] can be optionally substituted with C1-C6 alkyl at any available position) A ring system selected from the group consisting of: Z is independently selected from the group consisting of CH2 and O; n is 0 or 1; R a is independently selected from the group consisting of -C1-C3 alkyl, -C1-C3 haloalkyl, and phenyl; R b is heteroaryl optionally substituted with -C1-C6 alkyl, -O-C1-C6 alkyl, or -O-C1-C6 haloalkyl; R c is independently selected from the group consisting of hydrogen or CH3; R d is independently selected from the group consisting of hydrogen or halogen; R eis independently selected from the group consisting of -C1-C6 alkyl or heteroaryl, wherein heteroaryl is optionally substituted with -C1-C6 alkyl, -C1-C6 haloalkyl, -O-C1-C6 alkyl, or -O-C1-C6 haloalkyl; R f is independently selected from the group consisting of halogen and -CF3; R h is independently selected from the group consisting of -C1-C6 alkyl and heteroaryl, wherein heteroaryl is optionally substituted with -C1-C6 alkyl, -C1-C6 haloalkyl, -O-C1-C6 alkyl, or -O-C1-C6 haloalkyl.

[0042] Within the scope of the present invention, compounds of formula (I) have the formula

[0043] [ka]

[0044] or a stereoisomer, racemic mixture, tautomer, polymorph, pharma- ceutically acceptable salt, prodrug, hydrate, or solvate thereof. (In the formula, X is independently selected from the group consisting of O and N; Y is independently selected from the group consisting of N and O; One of X and Y is O and the other is N; R 0 , R 2 , R 3 , R 1 , Z, n, R a , R b , R c , R d , R e , R f , and R h are as defined herein)

[0045] Within the scope of the present invention, any reference to a compound of formula (I) or (II), or a preferred embodiment thereof, is also intended to refer to a stereoisomer, or a racemic mixture, or a tautomer, or a polymorph, or a pharma- ceutically acceptable salt, or a prodrug, or a hydrate, or a solvate thereof.

[0046] The compounds of formula (I), or their stereoisomers, racemic mixtures, tautomers, polymorphs, pharma- ceutically acceptable salts, prodrugs, hydrates, or solvates, are suitable for treating, alleviating, or preventing diseases, disorders, or conditions that respond to the modulation, particularly inhibition, of a component of the NLRP3 inflammasome pathway, or to the modulation, particularly reduction, of the levels of IL-1 beta and / or IL-18. In particular, the component of the inflammasome pathway is the NLRP3 inflammasome. Activation of the NLRP3 inflammasome pathway can trigger the formation of ASC specks, the cleavage and activation of caspase 1 and caspase 8, followed by the activation and release of IL-1 beta, IL-18, the cleavage and pore formation of gasdermin D, pyroptosis, and the release of IL-1 alpha, IL-33, IL-17, and high mobility group box (HMGB) proteins. The compounds of formula (I), or their stereoisomers, racemic mixtures, tautomers, polymorphs, pharma- ceutically acceptable salts, prodrugs, hydrates or solvates, have the ability to modulate, in particular reduce, levels of IL-1beta and / or IL-18.

[0047] The compounds of formula (I), or their stereoisomers, racemic mixtures, tautomers, polymorphs, pharma- ceutically acceptable salts, prodrugs, hydrates, or solvates, exhibit a high degree of ability to modulate, and in particular inhibit the activation of, the component of the NLRP3 inflammasome pathway, and in particular, the component of the inflammasome pathway is the NLRP3 inflammasome. Due to these unique design features, these compounds exhibit properties such as modulating or inhibiting the activation of the NLRP3 inflammasome pathway, which enable them to be successful pharmaceuticals for the treatment, amelioration, or prevention of diseases, disorders, and disorders that respond to the modulation or inhibition of the component of the NLRP3 inflammasome pathway, such as Alzheimer's disease, Parkinson's disease, CAPS, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and gout.

[0048] In a further embodiment, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) or a stereoisomer, racemic mixture, tautomer, polymorph, pharma- ceutically acceptable salt, prodrug, hydrate, or solvate thereof, optionally comprising at least one pharma- ceutically acceptable carrier, excipient, adjuvant, or additive.

[0049] In another embodiment, the present invention relates to a compound of formula (I) or a stereoisomer, racemic mixture, tautomer, polymorph, pharma- ceutically acceptable salt, prodrug, hydrate, or solvate thereof, for use as a medicament.

[0050] In yet another embodiment, the present invention relates to a compound of formula (I) or a stereoisomer, racemic mixture, tautomer, polymorph, pharma- ceutically acceptable salt, prodrug, hydrate or solvate thereof for use in the treatment, alleviation or prevention of a disease, disorder or condition that responds to the modulation, particularly inhibition of the activation, of a component of the NLRP3 inflammasome pathway and / or to the modulation, particularly reduction, of the levels of IL-1beta and / or IL-18.

[0051] Further embodiments relate to the use of a compound of formula (I), or a stereoisomer, racemic mixture, tautomer, polymorph, pharma- ceutically acceptable salt, prodrug, hydrate, or solvate thereof, for the manufacture of a medicament for treating, alleviating, or preventing a disease, disorder, or condition that responds to the modulation, particularly inhibition of activation, of a component of the NLRP3 inflammasome pathway and / or to the modulation, particularly reduction, of the levels of IL-1beta and / or IL-18.

[0052] In yet another embodiment, the present invention is directed to a method for treating, alleviating, or preventing a disease, disorder, or condition that responds to the inhibition of modulation, particularly activation, of a component of the NLRP3 inflammasome pathway, or to the modulation, particularly reduction, of levels of IL-1 beta and / or IL-18, comprising administering a therapeutically effective amount of a compound of formula (I), or a stereoisomer, racemic mixture, tautomer, polymorph, pharma- ceutically acceptable salt, prodrug, hydrate, or solvate thereof, to a subject (e.g., a patient) in need thereof.

[0053] Pharmaceutical compositions comprising a combination of compounds of formula (I) or a stereoisomer, racemic mixture, tautomer, polymorph, pharma- ceutically acceptable salt, prodrug, hydrate or solvate thereof with at least one further biologically active compound different from these compounds of formula (I) or a stereoisomer, racemic mixture, tautomer, polymorph, pharma- ceutically acceptable salt, prodrug, hydrate or solvate thereof, and optionally comprising at least one pharma- ceutically acceptable carrier, excipient, adjuvant or additive, are also the subject of the present invention.

[0054] In particular, the further biologically active compound may be one used for the treatment of a disease, disorder or condition associated with a different pathological mechanism, for example, a disease targeting an anti-amyloid beta antibody, an anti-tau antibody, an amyloid beta small molecule inhibitor, a tau aggregation small molecule inhibitor, an anti-alpha synuclein antibody, or an alpha synuclein aggregation small molecule inhibitor, an anti-TDP-43 antibody, or an anti-TDP-43 aggregation small molecule inhibitor, among others. When the compound of the present invention is used in combination with a further biologically active compound, the dosage of each compound may differ from the dosage when the compound is used in monotherapy.

[0055] An additional embodiment relates to the use of a compound of formula (I), or a stereoisomer, racemic mixture, tautomer, polymorph, pharma- ceutically acceptable salt, prodrug, hydrate, or solvate thereof, as an analytical reference or in vitro screening tool.

[0056] In another aspect, the present invention relates to a compound of formula (II):

[0057] [ka]

[0058] or a stereoisomer, racemic mixture, tautomer, polymorph, pharma- ceutically acceptable salt, prodrug, hydrate, or solvate thereof. (In the formula, W is S or O; R 0 , R 1 , R 2 and R 3 is as defined for formula (I).

[0059] In yet another embodiment, the present invention relates to a process for preparing a compound of formula (I), comprising the step of cyclization of a compound of formula (II).

[0060] The invention is described hereinafter. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0061] The present invention relates to compounds of formula (I) and compounds of formula (II), including their stereoisomers, racemic mixtures, tautomers, polymorphs, pharma- ceutically acceptable salts, prodrugs, hydrates, or solvates.

[0062] R given for compounds of formula (I) 0 , R 1 , R 2 and R 3 apply equally to compounds of formula (II).

[0063] The present invention relates to a compound represented by the formula (I)

[0064] [ka]

[0065] or a stereoisomer, racemic mixture, tautomer, polymorph, pharma- ceutically acceptable salt, prodrug, hydrate, or solvate thereof. [In the formula, R 0 is H or C1-C3 alkyl; R 2 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl; R 3 is independently selected from the group consisting of 5- or 6-membered heterocycloalkyl containing 1 or 2 heteroatoms, aryl, or heteroaryl containing 1 or 2 heteroatoms, the heteroatoms being independently selected from N, O, and S, and at least one heteroatom being independently selected from O and S, and the heterocycloalkyl, aryl, or heteroaryl can be optionally substituted with -C1-C6 alkyl, -O-C1-C6 alkyl, -halogen, or -C1-C6 alkyl-OH; R 1 is as follows:

[0066] [ka]

[0067] (In the formula,

[0068] [ka]

[0069] can be optionally substituted with C1-C6 alkyl at any available position) A ring system selected from the group consisting of: Z is independently selected from the group consisting of CH2 and O; n is 0 or 1; R a is independently selected from the group consisting of C1-C3 alkyl, C1-C3 haloalkyl, and phenyl; R b is heteroaryl optionally substituted with -C1-C6 alkyl, -O-C1-C6 alkyl, or -O-C1-C6 haloalkyl; R c is independently selected from the group consisting of hydrogen and CH3; R d is independently selected from the group consisting of hydrogen and halogen; R e is independently selected from the group consisting of -C1-C6 alkyl and heteroaryl, wherein heteroaryl is optionally substituted with -C1-C6 alkyl, -C1-C6 haloalkyl, -O-C1-C6 alkyl, or -O-C1-C6 haloalkyl; R f is independently selected from the group consisting of halogen and CF3; R h is independently selected from the group consisting of -C1-C6 alkyl and heteroaryl, wherein heteroaryl is optionally substituted with -C1-C6 alkyl, -C1-C6 haloalkyl, -O-C1-C6 alkyl, or -O-C1-C6 haloalkyl (e.g., CF3).

[0070] Within the scope of preferred embodiments, the present invention relates to a compound of formula (I)

[0071] [ka]

[0072] or a stereoisomer, racemic mixture, tautomer, polymorph, pharma- ceutically acceptable salt, prodrug, hydrate, or solvate thereof. [In the formula, R 0 is H or C1-C3 alkyl; R 2 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl; R 3 is independently selected from the group consisting of 5- or 6-membered heterocycloalkyl containing 1 or 2 heteroatoms, aryl, or heteroaryl containing 1 or 2 heteroatoms, the heteroatoms being independently selected from N, S, and O, and at least one heteroatom being independently selected from O and S, and the heterocycloalkyl, aryl, or heteroaryl can be optionally substituted with -C1-C6 alkyl, -O-C1-C6 alkyl, -halogen, or -C1-C6 alkyl-OH; R 1 is as follows:

[0073] [ka]

[0074] (In the formula,

[0075] [ka]

[0076] can be optionally substituted with C1-C6 alkyl at any available position; A ring system selected from the group consisting of: Z is independently selected from the group consisting of CH2 and O; n is 0 or 1; R a is independently selected from the group consisting of -C1-C3 alkyl, -C1-C3 haloalkyl, and phenyl; R b is heteroaryl optionally substituted with -C1-C6 alkyl, -O-C1-C6 alkyl, or -O-C1-C6 haloalkyl; R c is independently selected from the group consisting of hydrogen or CH3; R d is independently selected from the group consisting of hydrogen or halogen; R e is independently selected from the group consisting of -C1-C6 alkyl or heteroaryl, wherein heteroaryl is optionally substituted with -C1-C6 alkyl, -C1-C6 haloalkyl, -O-C1-C6 alkyl, or -O-C1-C6 haloalkyl; R f is independently selected from the group consisting of halogen and -CF3; R h is independently selected from the group consisting of -C1-C6 alkyl and heteroaryl, wherein heteroaryl is optionally substituted with -C1-C6 alkyl, -C1-C6 haloalkyl, -O-C1-C6 alkyl, or -O-C1-C6 haloalkyl.

[0077] In a preferred embodiment, R 0 is H or C1-C3 alkyl. Preferably, R 0 is H, methyl or ethyl. More preferably, R 0 is H. In one embodiment, R 0 is ethyl.

[0078] In one embodiment, R 1 teeth,

[0079] [ka]

[0080] and R ais independently selected from C1-C3 alkyl, C1-C3 haloalkyl, and phenyl. a is C1-C3 alkyl, preferably methyl or ethyl. More preferably, R a is methyl. In another embodiment, R a is C1-C3 haloalkyl, preferably CF3. In another embodiment, R a is phenyl.

[0081] In another embodiment, R 1 teeth,

[0082] [ka]

[0083] and Z is independently selected from the group consisting of CH2 and O. In one embodiment, Z is CH2. In another embodiment, Z is O. R b is heteroaryl optionally substituted with -C1-C6 alkyl, -O-C1-C6 alkyl, or -O-C1-C6 haloalkyl; R c is independently selected from the group consisting of hydrogen and CH3; R d are independently selected from the group consisting of hydrogen and halogen.

[0084] In another embodiment, R 1 teeth,

[0085] [ka]

[0086] and Z is independently selected from the group consisting of CH2 and O. In one embodiment, Z is CH2. In another embodiment, Z is O. R bis heteroaryl containing 1 or 2 heteroatoms independently selected from O, N and S, preferably at least one heteroatom is N. Heteroaryl is optionally substituted with -C1-C6 alkyl, -O-C1-C6 alkyl, or -O-C1-C6 haloalkyl; R c is independently selected from the group consisting of hydrogen and CH3; R d are independently selected from the group consisting of hydrogen and halogen.

[0087] In another embodiment, R 1 teeth,

[0088] [ka]

[0089] and Z is independently selected from the group consisting of CH2 and O. In one embodiment, Z is CH2. In another embodiment, Z is O. R b is heteroaryl containing one or two heteroatoms, said one or two heteroatoms being N, preferably R b is pyridyl; heteroaryl is optionally substituted with -C1-C6 alkyl, -O-C1-C6 alkyl, or -O-C1-C6 haloalkyl; R c is independently selected from the group consisting of hydrogen and CH3; R d are independently selected from the group consisting of hydrogen and halogen.

[0090] In another embodiment, R 1 teeth,

[0091] [ka]

[0092] and Z is independently selected from the group consisting of CH2 and O. In one embodiment, Z is CH2. In another embodiment, Z is O. R b is heteroaryl containing one or two heteroatoms, said one or two heteroatoms being N, preferably R b is pyridyl substituted with -C1-C6 alkyl, -O-C1-C6 alkyl, or -O-C1-C6 haloalkyl. b is pyridyl substituted with -C1-C6 alkyl, preferably -C1-C3 alkyl. In another preferred embodiment, R b is pyridyl substituted with -O-C1 to C6 alkyl, preferably -O-C1 to C3 alkyl. R c is independently selected from the group consisting of hydrogen and CH. In one preferred embodiment, R c is hydrogen. c is CH3. R d is independently selected from the group consisting of hydrogen and halogen. d is hydrogen. d is a halogen.

[0093] In another embodiment, R 1 teeth,

[0094] [ka]

[0095] and R e is independently selected from -C1-C6 alkyl, or heteroaryl, wherein heteroaryl is optionally substituted with -C1-C6 alkyl, -C1-C6 haloalkyl, -O-C1-C6 alkyl, or -O-C1-C6 haloalkyl; R fis independently selected from halogen or CF. In one preferred embodiment, R f is F.

[0096] In another embodiment, R 1 teeth,

[0097] [ka]

[0098] and R e is selected from a branched C3-C6 alkyl, preferably isopropyl or isobutyl; or heteroaryl having 1 or 2 heteroatoms independently selected from O, N and S, preferably at least one heteroatom is N, and the heteroaryl is optionally substituted with -C1-C6 alkyl, -C1-C6 haloalkyl, -O-C1-C6 alkyl, or -O-C1-C6 haloalkyl; R f is independently selected from halogen or CF. In one embodiment, R f is F.

[0099] In a preferred embodiment, R e is isopropyl.

[0100] In another embodiment, R e is heteroaryl having one or two heteroatoms independently selected from O, N, and S, preferably at least one heteroatom is N. The heteroaryl is optionally substituted with -C1-C6 alkyl, -C1-C6 haloalkyl, -O-C1-C6 alkyl, or -O-C1-C6 haloalkyl. In one embodiment, R e is heteroaryl having one or two heteroatoms, the one or two heteroatoms being N, preferably R e is pyridyl. In another embodiment, R eis heteroaryl having one or two heteroatoms, the one or two heteroatoms being N, preferably R e is pyridyl substituted with -C1-C6 alkyl, -C1-C6 haloalkyl, -O-C1-C6 alkyl, or -O-C1-C6 haloalkyl. e is pyridyl substituted with -C1-C6 alkyl, preferably -C1-C3 alkyl. In another preferred embodiment, R e is pyridyl substituted with -O-C1 to C6 alkyl, preferably -O-C1 to C3 alkyl.

[0101] R e In any of the embodiments, the heteroaryl substituent is preferably -C1-C6 alkyl, -O-C1-C6 alkyl, or -O-C1-C6 haloalkyl.

[0102] In another embodiment, R 1 is optionally substituted with C1-C6 alkyl at any available position

[0103] [ka]

[0104] and R h is independently selected from the group consisting of -C1-C6 alkyl and heteroaryl, wherein heteroaryl is optionally substituted with -C1-C6 alkyl, -C1-C6 haloalkyl, -O-C1-C6 alkyl, or -O-C1-C6 haloalkyl (e.g., CF3); n is 0 or 1.

[0105] In one embodiment, R 1 teeth,

[0106] [ka]

[0107] and R h is independently selected from the group consisting of -C1-C6 alkyl and heteroaryl, where heteroaryl is optionally substituted with -C1-C6 alkyl, -C1-C6 haloalkyl, -O-C1-C6 alkyl, or -O-C1-C6 haloalkyl (e.g., CF3), preferably R h is heteroaryl optionally substituted with -C1-C6 alkyl, -O-C1-C6 alkyl, -C1-C6 haloalkyl, or -O-C1-C6 haloalkyl. h is heteroaryl having one or two heteroatoms independently selected from O, N, and S, preferably at least one heteroatom is N, and the heteroaryl is optionally substituted with -C1-C6 alkyl, -C1-C6 haloalkyl, -O-C1-C6 alkyl, or -O-C1-C6 haloalkyl. h is heteroaryl having one or two heteroatoms, one or two heteroatoms being N, preferably R h is pyridyl. In another embodiment, R h is heteroaryl having one or two heteroatoms, one or two heteroatoms being N, preferably R h is pyridyl substituted with -C1-C6 alkyl, -C1-C6 haloalkyl, -O-C1-C6 alkyl, or -O-C1-C6 haloalkyl. h is pyridyl substituted with -C1-C6 alkyl, preferably -C1-C3 alkyl. In another preferred embodiment, R h is pyridyl substituted with -O-C1 to C6 alkyl, preferably -O-C1 to C3 alkyl.

[0108] In one embodiment, R 1 teeth,

[0109] [ka]

[0110] where n is 0 or 1, and R h is independently selected from the group consisting of -C1-C6 alkyl and heteroaryl, where heteroaryl is optionally substituted with -C1-C6 alkyl, -C1-C6 haloalkyl, -O-C1-C6 alkyl, or -O-C1-C6 haloalkyl (e.g., CF3). h is CF3. In another embodiment, R h is heteroaryl optionally substituted with -C1-C6 alkyl, -C1-C6 haloalkyl, -O-C1-C6 alkyl, or -O-C1-C6 haloalkyl. h is heteroaryl having one or two heteroatoms independently selected from O, N, and S, preferably at least one heteroatom is N, and the heteroaryl is optionally substituted with -C1-C6 alkyl, -C1-C6 haloalkyl, -O-C1-C6 alkyl, or -O-C1-C6 haloalkyl. h is heteroaryl having one or two heteroatoms, one or two heteroatoms being N, preferably R h is pyridyl. In another embodiment, R h is heteroaryl having one or two heteroatoms, one or two heteroatoms being N, preferably R h is pyridyl substituted with -C1-C6 alkyl, -C1-C6 haloalkyl, -O-C1-C6 alkyl, or -O-C1-C6 haloalkyl. h is pyridyl substituted with -C1-C6 alkyl, preferably -C1-C3 alkyl. In another preferred embodiment, R h is pyridyl substituted with -O-C1 to C6 alkyl, preferably -O-C1 to C3 alkyl.

[0111] In any of the embodiments herein, R hThe optional substituents of the heteroaryl in are preferably selected from -C1-C6 alkyl, CF3, -O-C1-C6 alkyl, or -O-C1-C6 haloalkyl.

[0112] In another embodiment, R 2 is independently selected from the group consisting of hydrogen, -C1-C6 alkyl, and C3-C6 cycloalkyl.

[0113] Preferably, R 2 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, and C5-C6 cycloalkyl. 2 is hydrogen. In another preferred embodiment, R 2 is C1-C6 alkyl, R 2 is preferably selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, or hexyl. 2 is C5-C6 cycloalkyl, preferably R 2 is cyclopentane.

[0114] More preferably, R 2 is independently selected from the group consisting of hydrogen, C1-C3 alkyl, and C5-C6 cycloalkyl. Even more preferably, R 2 is independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, or cyclopentane. Even more preferably, R 2 is independently selected from the group consisting of hydrogen, ethyl, isopropyl, or cyclopentane. 2 is ethyl or H. In one preferred embodiment, R 2 is ethyl.

[0115] R 3 In any of the embodiments, the heteroatoms in the heterocycloalkyl and heteroaryl are independently selected from N, O, and S, respectively.

[0116] In one embodiment, R 3 is independently selected from the group consisting of 5- or 6-membered heterocycloalkyl containing one or two heteroatoms, aryl, or heteroaryl containing one or two heteroatoms. The heteroatoms in the heterocycloalkyl and heteroaryl are each independently selected from N, O, and S. The at least one heteroatom in the heterocycloalkyl and heteroaryl is each independently selected from O and S. The heterocycloalkyl, aryl, or heteroaryl can be optionally substituted with -C1-C6 alkyl, -O-C1-C6 alkyl, -halogen, or -C1-C6 alkyl-OH.

[0117] In another embodiment, R 3 is independently selected from the group consisting of 5- or 6-membered heterocycloalkyl containing 1 or 2 heteroatoms, where at least one heteroatom is O, aryl, and 5- or 6-membered heteroaryl containing 1 or 2 heteroatoms, independently selected from O and S. The heteroatoms in the heterocycloalkyl and heteroaryl are each independently selected from N, O, and S. The heterocycloalkyl, aryl, or heteroaryl can be optionally substituted with -C1-C6 alkyl, -O-C1-C6 alkyl, -halogen, or -C1-C6 alkyl-OH.

[0118] In one embodiment, R 3 is aryl, optionally substituted with -C1-C6 alkyl, -O-C1-C6 alkyl, -halogen, or -C1-C6 alkyl-OH. In certain embodiments, the aryl group is optionally substituted with -O-C1-C6 alkyl or -halogen. In certain embodiments, the aryl group is optionally substituted with -O-C1 alkyl or halogen.

[0119] R 3 In this embodiment, halogen (-hal) is preferably chloro.

[0120] More preferably, R 3 is independently selected from the group consisting of 5- or 6-membered heterocycloalkyl containing 1 or 2 heteroatoms, where at least one heteroatom is O, C5-C6 aryl, or 5- or 6-membered heteroaryl containing 1 or 2 heteroatoms, and is independently selected from O and S. The heteroatoms in the heterocycloalkyl and heteroaryl are each independently selected from N, O, and S. The 5- or 6-membered heterocycloalkyl, aryl, or 5- or 6-membered heteroaryl can be optionally substituted with -C1-C6 alkyl, -O-C1-C6 alkyl, -halogen, or -C1-C6 alkyl-OH.

[0121] In a preferred embodiment, R 3 is a 5- or 6-membered heterocycloalkyl containing one heteroatom, where the heteroatom is O; the heterocycloalkyl is optionally substituted with -C1-C6 alkyl, -O-C1-C6 alkyl, -halogen, or -C1-C6 alkyl-OH.

[0122] In another preferred embodiment, R 3 is a 5- or 6-membered heteroaryl containing 1 or 2 heteroatoms independently selected from N, O, and S, where at least one heteroatom is independently selected from O and S, and the heteroaryl is optionally substituted with one substituent selected from -C1-C6 alkyl, -O-C1-C6 alkyl, -halogen, or -C1-C6 alkyl-OH.

[0123] In another preferred embodiment, R 3 is a C5-C6 heteroaryl containing two heteroatoms, at least one heteroatom being independently selected from O and S and the second heteroatom being N, and the heteroaryl is optionally substituted with one substituent selected from -C1-C6 alkyl, -O-C1-C6 alkyl, -halogen, or -C1-C6 alkyl-OH.

[0124] In another embodiment, R3 is the following:

[0125] [ka]

[0126] each of which can be optionally substituted with -C1-C6 alkyl, -O-C1-C6 alkyl, -halogen, or -C1-C6 alkyl-OH.

[0127] More preferably, R 3 is the following:

[0128] [ka]

[0129] is selected from Each of these can be optionally substituted with -C1-C6 alkyl, -O-C1-C6 alkyl, -halogen, or -C1-C6 alkyl-OH.

[0130] In another preferred embodiment, R 3 is the following:

[0131] [ka]

[0132] Selected from R 3a is selected from hydrogen, halogen, -O-C1-C6 alkyl, -C1-C6 alkyl-OH, and -C1-C6 alkyl. More preferably, R 3a is hydrogen, chloro, methoxy, methyl, isopropyl, and

[0133] [ka]

[0134] is selected from.

[0135] R 3 In the formula, C1-C6 alkyl is preferably methyl, ethyl, isopropyl, propyl, isobutyl or butyl.

[0136] [ka]

[0137] It can be optionally substituted with -OH such as:

[0138] In another embodiment, R 2 is hydrogen or C1-C6 alkyl, R 3 teeth, a)

[0139] [ka]

[0140] Preferably,

[0141] [ka]

[0142] b)

[0143] [ka]

[0144] Preferably,

[0145] [ka]

[0146] c)

[0147] [ka]

[0148] d)

[0149] [ka]

[0150] Preferably,

[0151] [ka]

[0152] e)

[0153] [ka]

[0154] Preferably,

[0155] [ka]

[0156] f)

[0157] [ka]

[0158] Preferably,

[0159] [ka]

[0160] g)

[0161] [ka]

[0162] Preferably,

[0163] [ka]

[0164] It is.

[0165] In another embodiment, R 2 is hydrogen or C1-C6 alkyl, R 3 teeth, a)

[0166] [ka]

[0167] Preferably

[0168] [ka]

[0169] b)

[0170] [ka]

[0171] Preferably

[0172] [ka]

[0173] c)

[0174] [ka]

[0175] d)

[0176] [ka]

[0177] Preferably,

[0178] [ka]

[0179] It is.

[0180] In each of the above embodiments, R 3 can be optionally substituted with halogen, -O-C1-C6 alkyl, -C1-C6 alkyl-OH, or C1-C6 alkyl. More preferably, R 3 is chloro, methoxy, methyl, or isopropyl, or

[0181] [ka]

[0182] can be arbitrarily substituted with

[0183] R 3 In the formula, C1-C6 alkyl is preferably methyl, ethyl, isopropyl, propyl, isobutyl, or butyl.

[0184] [ka]

[0185] It can be optionally substituted with -OH such as:

[0186] Preferably, R 2 is C1-C6 alkyl, R 2 is preferably selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, and hexyl. More preferably, R 2is C1 to C3 alkyl. More preferably, R 2 is independently selected from the group consisting of methyl, ethyl, propyl, and isopropyl. Even more preferably, R 2 is independently selected from the group consisting of ethyl and isopropyl, and most preferably, R 2 is ethyl.

[0187] In a further preferred embodiment, R 2 is hydrogen.

[0188] In a further embodiment, the present invention relates to a compound of formula (I)

[0189] [ka]

[0190] or a stereoisomer, racemic mixture, tautomer, polymorph, pharma- ceutically acceptable salt, prodrug, hydrate, or solvate thereof, R 1 , R 2 , and R 3 is as defined above, and R 0 is H.

[0191] In a further embodiment, the present invention relates to a compound of formula (I)

[0192] [ka]

[0193] or a stereoisomer, racemic mixture, tautomer, polymorph, pharma- ceutically acceptable salt, prodrug, hydrate, or solvate thereof, R 0 is H; R 1 is as defined above; R 2 is H or C1-C6 alkyl, for example C1-C6 alkyl; R3 teeth,

[0194] [ka]

[0195] each of which can be optionally substituted as defined above.

[0196] In a further embodiment, the present invention relates to a compound of formula (I):

[0197] [ka]

[0198] [ka]

[0199] or a stereoisomer, racemic mixture, tautomer, polymorph, pharma- ceutically acceptable salt, prodrug, hydrate, or solvate thereof.

[0200] In one embodiment, the present invention provides a method for the preparation of a compound of formula (II)

[0201] [ka]

[0202] or a stereoisomer, racemic mixture, tautomer, polymorph, pharma- ceutically acceptable salt, prodrug, hydrate, or solvate thereof, W is S or O; R 0 , R 1 , R 2 and R 3 is as defined above for formula (I).

[0203] In one embodiment of formula (II), W is S or O; R 0 is H or C1-C3 alkyl; R 2 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl; R 3 is independently selected from the group consisting of 5- or 6-membered heterocycloalkyl containing one or two heteroatoms, aryl, and heteroaryl containing one or two heteroatoms. The heteroatoms in the heterocycloalkyl and heteroaryl are each independently selected from N, O, and S, and at least one heteroatom is independently selected from O and S. The 5- or 6-membered heterocycloalkyl containing one or two heteroatoms, aryl, or heteroaryl containing one or two heteroatoms can be optionally substituted with -C1-C6 alkyl, -O-C1-C6 alkyl, -halogen, or -C1-C6 alkyl-OH; R 1 is as follows:

[0204] [ka]

[0205] (In the formula,

[0206] [ka]

[0207] can be optionally substituted with C1-C6 alkyl at any available position) A ring system selected from the group consisting of: Z is independently selected from the group consisting of CH2 and O; n is 0 or 1; R a is independently selected from the group consisting of C1-C3 alkyl, C1-C3 haloalkyl, and phenyl; R bis heteroaryl optionally substituted with -C1-C6 alkyl, -O-C1-C6 alkyl, and -O-C1-C6 haloalkyl; R c is independently selected from the group consisting of hydrogen and CH3; R d is independently selected from the group consisting of hydrogen and halogen; R e is independently selected from the group consisting of -C1-C6 alkyl and heteroaryl, wherein heteroaryl is optionally substituted with -C1-C6 alkyl, -C1-C6 haloalkyl, -O-C1-C6 alkyl, or -O-C1-C6 haloalkyl; R f is independently selected from the group consisting of halogen and CF3; R h is independently selected from the group consisting of -C1-C6 alkyl and heteroaryl, wherein heteroaryl is optionally substituted with -C1-C6 alkyl, -C1-C6 haloalkyl, -O-C1-C6 alkyl, or -O-C1-C6 haloalkyl.

[0208] In one embodiment, the present invention relates to compounds of formula (II), wherein W is O. In another embodiment, the present invention relates to compounds of formula (II), wherein W is S. In a preferred embodiment, W is S.

[0209] In one embodiment, R 0 is H or C1-C3 alkyl. Preferably, R 0 is H, methyl or ethyl. More preferably, R 0 is H. In one embodiment, R 0 is ethyl.

[0210] In one embodiment, R 1 teeth,

[0211] [ka]

[0212] and R a is independently selected from the group consisting of C1-C3 alkyl, C1-C3 haloalkyl, and phenyl. a is C1-C3 alkyl, preferably methyl or ethyl. More preferably, R a is methyl. In another embodiment, R a is C1-C3 haloalkyl, preferably CF3. In another embodiment, R a is phenyl.

[0213] In another embodiment, R 1 teeth,

[0214] [ka]

[0215] and Z is independently selected from the group consisting of CH2 and O. In one embodiment, Z is CH2. In another embodiment, Z is O. R b is heteroaryl optionally substituted with -C1-C6 alkyl, -O-C1-C6 alkyl, or -O-C1-C6 haloalkyl; R c is independently selected from the group consisting of hydrogen and CH3; R d are independently selected from the group consisting of hydrogen and halogen.

[0216] In another embodiment, R 1 teeth,

[0217] [ka]

[0218] and Z is independently selected from the group consisting of CH2 and O. In one embodiment, Z is CH2. In another embodiment, Z is O. R bis heteroaryl having 1 or 2 heteroatoms independently selected from O, N and S, preferably at least one heteroatom is N, and the heteroaryl can be optionally substituted with -C1-C6 alkyl, -O-C1-C6 alkyl, or -O-C1-C6 haloalkyl; R c is independently selected from the group consisting of hydrogen and CH3; R d are independently selected from the group consisting of hydrogen and halogen.

[0219] In another embodiment, R 1 teeth,

[0220] [ka]

[0221] and Z is independently selected from the group consisting of CH2 and O. In one embodiment, Z is CH2. In another embodiment, Z is O. R b is heteroaryl containing one or two heteroatoms, said one or two heteroatoms being N, preferably R b is pyridyl; heteroaryl can be optionally substituted with -C1-C6 alkyl, -O-C1-C6 alkyl, or -O-C1-C6 haloalkyl; R c is independently selected from the group consisting of hydrogen and CH3; R d is independently selected from the group consisting of hydrogen and halogen; in another embodiment, R 1 teeth,

[0222] [ka]

[0223] and Z is independently selected from the group consisting of CH2 and O. In one embodiment, Z is CH2. In another embodiment, Z is O. R b is heteroaryl having one or two heteroatoms, the one or two heteroatoms being N, preferably R b is pyridyl substituted with -C1-C6 alkyl, -O-C1-C6 alkyl, or -O-C1-C6 haloalkyl. b is pyridyl substituted with -C1-C6 alkyl, preferably -C1-C3 alkyl. In another preferred embodiment, R b is pyridyl substituted with -O-C1 to C6 alkyl, preferably -O-C1 to C3 alkyl. R c is independently selected from the group consisting of hydrogen and CH. In one preferred embodiment, R c is hydrogen. c is CH3. R d is independently selected from the group consisting of hydrogen and halogen. d is hydrogen. d is a halogen.

[0224] In another embodiment, R 1 teeth,

[0225] [ka]

[0226] and R e is independently selected from the group consisting of -C1-C6 alkyl and heteroaryl, wherein heteroaryl is optionally substituted with -C1-C6 alkyl, -C1-C6 haloalkyl, -O-C1-C6 alkyl, or -O-C1-C6 haloalkyl; R fis independently selected from the group consisting of halogen and CF. In one preferred embodiment, R f is F.

[0227] In another embodiment, R 1 teeth,

[0228] [ka]

[0229] and R e is independently selected from the group consisting of branched C3-C6 alkyl, preferably isopropyl or isobutyl; or heteroaryl having 1 or 2 heteroatoms independently selected from O, N and S, preferably at least one heteroatom is N, and the heteroaryl is optionally substituted with -C1-C6 alkyl, -C1-C6 haloalkyl, -O-C1-C6 alkyl, or -O-C1-C6 haloalkyl; R f is independently selected from the group consisting of halogen or CF. f is F.

[0230] In a preferred embodiment, R e is isopropyl.

[0231] In another embodiment, R e is heteroaryl having one or two heteroatoms independently selected from O, N, and S, preferably at least one heteroatom is N, and the heteroaryl is optionally substituted with -C1-C6 alkyl, -C1-C6 haloalkyl, -O-C1-C6 alkyl, or -O-C1-C6 haloalkyl. e is heteroaryl having one or two heteroatoms, the one or two heteroatoms being N, preferably R e is pyridyl. In another embodiment, R eis heteroaryl having one or two heteroatoms, the one or two heteroatoms being N, preferably R e is pyridyl, and the heteroaryl is substituted with -C1-C6 alkyl, -C1-C6 haloalkyl, -O-C1-C6 alkyl, or -O-C1-C6 haloalkyl. e is pyridyl substituted with -C1-C6 alkyl, preferably -C1-C3 alkyl. In another preferred embodiment, R e is pyridyl substituted with -O-C1 to C6 alkyl, preferably -O-C1 to C3 alkyl.

[0232] In another embodiment, R 1 is optionally substituted with C1-C6 alkyl at any available position

[0233] [ka]

[0234] and R h is independently selected from the group consisting of -C1-C6 alkyl and heteroaryl, wherein heteroaryl is optionally substituted with -C1-C6 alkyl, -C1-C6 haloalkyl, -O-C1-C6 alkyl, or -O-C1-C6 haloalkyl, e.g., CF3; n is 0 or 1.

[0235] In one embodiment, R 1 teeth,

[0236] [ka]

[0237] and R his independently selected from the group consisting of -C1-C6 alkyl and heteroaryl, where heteroaryl is optionally substituted with -C1-C6 alkyl, -C1-C6 haloalkyl, -O-C1-C6 alkyl, or -O-C1-C6 haloalkyl (e.g., CF3), preferably R h is heteroaryl optionally substituted with -C1-C6 alkyl, -C1-C6 haloalkyl, -O-C1-C6 alkyl, or -O-C1-C6 haloalkyl. h is heteroaryl having one or two heteroatoms independently selected from O, N, and S, preferably at least one heteroatom is N, and the heteroaryl can be optionally substituted with -C1-C6 alkyl, -C1-C6 haloalkyl, -O-C1-C6 alkyl, or -O-C1-C6 haloalkyl. h is heteroaryl having one or two heteroatoms, the one or two heteroatoms being N, preferably R h is pyridyl. In another embodiment, R h is heteroaryl having one or two heteroatoms, the one or two heteroatoms being N, preferably R h is pyridyl substituted with -C1-C6 alkyl, -C1-C6 haloalkyl, -O-C1-C6 alkyl, or -O-C1-C6 haloalkyl. h is pyridyl substituted with -C1-C6 alkyl, preferably -C1-C3 alkyl. In another preferred embodiment, R h is pyridyl substituted with -O-C1 to C6 alkyl, preferably -O-C1 to C3 alkyl.

[0238] In one embodiment, R 1 teeth,

[0239] [ka]

[0240] where n is 0 or 1; R h is independently selected from the group consisting of -C1-C6 alkyl and heteroaryl, where heteroaryl is optionally substituted with -C1-C6 alkyl, -C1-C6 haloalkyl, -O-C1-C6 alkyl, or -O-C1-C6 haloalkyl (e.g., CF3). h is CF3. In another embodiment, R h is heteroaryl optionally substituted with -C1-C6 alkyl, -C1-C6 haloalkyl, -O-C1-C6 alkyl, or -O-C1-C6 haloalkyl. h is heteroaryl having one or two heteroatoms independently selected from O, N, and S, preferably at least one heteroatom is N, and the heteroaryl is optionally substituted with -C1-C6 alkyl, -C1-C6 haloalkyl, -O-C1-C6 alkyl, or -O-C1-C6 haloalkyl. h is heteroaryl having one or two heteroatoms, the one or two heteroatoms being N, preferably R h is pyridyl. In another embodiment, R h is heteroaryl having one or two heteroatoms, the one or two heteroatoms being N, preferably R h is pyridyl substituted with -C1-C6 alkyl, -C1-C6 haloalkyl, -O-C1-C6 alkyl, or -O-C1-C6 haloalkyl. h is pyridyl substituted with -C1-C6 alkyl, preferably -C1-C3 alkyl. In another preferred embodiment, R h is pyridyl substituted with -O-C1 to C6 alkyl, preferably -O-C1 to C3 alkyl.

[0241] In another embodiment, R 2 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl.

[0242] Preferably, R 2 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, and C5-C6 cycloalkyl. 2 is hydrogen. In another preferred embodiment, R 2 is C1-C6 alkyl, R 2 is preferably selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, and hexyl. 2 is C5-C6 cycloalkyl, preferably R 2 is cyclopentane.

[0243] More preferably, R 2 is independently selected from the group consisting of hydrogen, C1-C3 alkyl, and C5-C6 cycloalkyl. Even more preferably, R 2 is independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, and cyclopentane. Even more preferably, R 2 is independently selected from the group consisting of hydrogen, ethyl, isopropyl, and cyclopentane. 2 is ethyl or hydrogen. In a preferred embodiment, R 2 is ethyl.

[0244] In one embodiment, R 3 is independently selected from the group consisting of 5- or 6-membered heterocycloalkyl containing one or two heteroatoms, aryl, and heteroaryl containing one or two heteroatoms. The heteroatoms in the heterocycloalkyl and heteroaryl are each independently selected from N, O, and S. The at least one heteroatom is independently selected from O and S. The heterocycloalkyl, aryl, or heteroaryl can be optionally substituted with -C1-C6 alkyl, -O-C1-C6 alkyl, -halogen, or -C1-C6 alkyl-OH.

[0245] In another embodiment, R 3 is independently selected from the group consisting of 5- or 6-membered heterocycloalkyl containing 1 or 2 heteroatoms, where at least one heteroatom is O, aryl, and 5- or 6-membered heteroaryl containing 1 or 2 heteroatoms, independently selected from O and S. The heteroatoms in the heterocycloalkyl and heteroaryl are each independently selected from N, O, and S. The heterocycloalkyl, aryl, or heteroaryl can be optionally substituted with -C1-C6 alkyl, -O-C1-C6 alkyl, -halogen, or -C1-C6 alkyl-OH.

[0246] In one embodiment, R 3 is aryl optionally substituted with -C1-C6 alkyl, -O-C1-C6 alkyl, -halogen, or -C1-C6 alkyl-OH. In certain embodiments, the aryl group is optionally substituted with -O-C1-C6 alkyl, or -halogen. In certain embodiments, the aryl group is optionally substituted with -O-CH3, or -halogen, where halogen (-hal) is preferably chloro.

[0247] More preferably, R 3 is independently selected from the group consisting of 5- or 6-membered heterocycloalkyl containing one or two heteroatoms, where at least one heteroatom is O, C5-C6 aryl, and 5- or 6-membered heteroaryl containing one or two heteroatoms. The heteroatoms in the heterocycloalkyl and heteroaryl are each independently selected from N, O, and S. The at least one heteroatom is independently selected from O and S. The heterocycloalkyl, aryl, or heteroaryl can be optionally substituted with -C1-C6 alkyl, -O-C1-C6 alkyl, -halogen, or -C1-C6 alkyl-OH.

[0248] In a preferred embodiment, R 3is a 5- or 6-membered heterocycloalkyl containing one heteroatom, where the heteroatom is O. The heterocycloalkyl is optionally substituted with -C1-C6 alkyl, -O-C1-C6 alkyl, -halogen, or -C1-C6 alkyl-OH.

[0249] In another preferred embodiment, R 3 is a 5- or 6-membered heteroaryl containing 1 or 2 heteroatoms independently selected from N, O, and S, where at least one heteroatom is independently selected from O and S. The heteroaryl is optionally substituted with one substituent selected from -C1-C6 alkyl, -O-C1-C6 alkyl, -halogen, or -C1-C6 alkyl-OH.

[0250] In another preferred embodiment, R 3 is a 5- or 6-membered heteroaryl containing two heteroatoms, where one heteroatom is independently selected from O and S, and the second heteroatom is N. The heteroaryl is optionally substituted with one substituent selected from -C1-C6 alkyl, -O-C1-C6 alkyl, -halogen, or -C1-C6 alkyl-OH.

[0251] In another embodiment, R 3 is the following:

[0252] [ka]

[0253] each of which can be optionally substituted with -C1-C6 alkyl, -O-C1-C6 alkyl, -halogen, or -C1-C6 alkyl-OH.

[0254] More preferably, R 3 is the following:

[0255] [ka]

[0256] each of which can be optionally substituted with -C1-C6 alkyl, -O-C1-C6 alkyl, -halogen, or -C1-C6 alkyl-OH.

[0257] In another embodiment, R 3 is the following:

[0258] [ka]

[0259] Selected from R 3a is selected from hydrogen, halogen, -O-C1-C6 alkyl, -C1-C6 alkyl-OH, or -C1-C6 alkyl.

[0260] Preferably, R 3a is hydrogen, chloro, methoxy, methyl, isopropyl, or

[0261] [ka]

[0262] is selected from.

[0263] R 3 In the formula, C1-C6 alkyl is preferably methyl, ethyl, isopropyl, propyl, isobutyl or butyl.

[0264] [ka]

[0265] It can be optionally substituted with -OH such as:

[0266] In another embodiment, R 2 is hydrogen or C1-C6 alkyl, R 3 teeth, a)

[0267] [ka]

[0268] Preferably,

[0269] [ka]

[0270] b)

[0271] [ka]

[0272] Preferably,

[0273] [ka]

[0274] c)

[0275] [ka]

[0276] d)

[0277] [ka]

[0278] Preferably,

[0279] [ka]

[0280] e)

[0281] [ka]

[0282] Preferably,

[0283] [ka]

[0284] f)

[0285] [ka]

[0286] Preferably,

[0287] [ka]

[0288] g)

[0289] [ka]

[0290] Preferably,

[0291] [ka]

[0292] It is.

[0293] In another embodiment, R 2 is hydrogen or C1-C6 alkyl, R 3 teeth, a)

[0294] [ka]

[0295] Preferably

[0296] [ka]

[0297] b)

[0298] [ka]

[0299] Preferably

[0300] [ka]

[0301] c)

[0302] [ka]

[0303] d)

[0304] [ka]

[0305] Preferably,

[0306] [ka]

[0307] or

[0308] In each of the above embodiments, R 3 can be optionally substituted with halogen, -O-C1-C6 alkyl, -C1-C6 alkyl-OH, or C1-C6 alkyl. More preferably, R3 is chloro, methoxy, methyl, or isopropyl, or

[0309] [ka]

[0310] can be arbitrarily substituted with

[0311] R 3 In the formula, C1-C6 alkyl is preferably methyl, ethyl, isopropyl, propyl, isobutyl, or butyl.

[0312] [ka]

[0313] It can be optionally substituted with -OH such as:

[0314] Preferably, R 2 is C1-C6 alkyl, R 2 is preferably selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, and hexyl. More preferably, R 2 is C1 to C3 alkyl. More preferably, R 2 is independently selected from the group consisting of methyl, ethyl, propyl and isopropyl. Even more preferably, R 2 is independently selected from the group consisting of ethyl and isopropyl, and is most preferably ethyl.

[0315] In another preferred embodiment, R 2 is hydrogen.

[0316] In a further embodiment, the present invention relates to a compound of formula (IIa) or (IIb)

[0317] [ka]

[0318] or a stereoisomer, racemic mixture, tautomer, polymorph, pharma- ceutically acceptable salt, prodrug, hydrate, or solvate thereof, 0 , R 1 , R 2 and R 3 is as defined above. The embodiments defined for compounds of formula (II) apply herein.

[0319] In a further embodiment, the present invention relates to a compound of formula (II):

[0320] [ka]

[0321] or a stereoisomer, or a racemic mixture, or a tautomer, or a polymorph, or a pharma- ceutically acceptable salt, or a prodrug, or a hydrate, or a solvate thereof.

[0322] The present invention further relates to a pharmaceutical composition comprising a compound of formula (I) as defined in the present invention, or a stereoisomer, racemic mixture, tautomer, polymorph, pharma- ceutically acceptable salt, prodrug, hydrate or solvate thereof, optionally comprising at least one pharma- ceutically acceptable carrier, excipient, adjuvant or additive.

[0323] In one embodiment, the pharmaceutical composition comprises a compound of formula (I') as defined in the present invention, or a stereoisomer, racemic mixture, tautomer, polymorph, pharma- ceutically acceptable salt, prodrug, hydrate, or solvate thereof, and optionally at least one pharma- ceutically acceptable carrier, excipient, adjuvant, or additive.

[0324] Various embodiments of the invention are described herein, and it will be appreciated that features specified in each embodiment may be combined with other specified features to provide further embodiments of the invention.

[0325] The present invention relates to a compound of formula (I) as defined in the present invention or a stereoisomer, racemic mixture, tautomer, polymorph, pharma- ceutically acceptable salt, prodrug, hydrate or solvate thereof, for use as a medicament.

[0326] The present invention relates to a compound of formula (I) as defined in the present invention, or a stereoisomer, racemic mixture, tautomer, polymorph, pharma- ceutically acceptable salt, prodrug, hydrate, or solvate thereof, for use in the treatment, alleviation, or prevention of diseases, disorders, or conditions that respond to the modulation, particularly inhibition of activation, of a component of the NLRP3 inflammasome pathway, and / or to the modulation, particularly reduction, of the levels of IL-1 beta and / or IL-18. In one embodiment, the modulation is the reduction and / or inhibition of IL-1 beta and / or IL-1 beta levels. In particular, the modulation is the reduction and / or inhibition of IL-1 beta.

[0327] In another embodiment, the present invention relates to a compound of formula (I) as defined in the present invention or a stereoisomer, racemic mixture, tautomer, polymorph, pharma- ceutically acceptable salt, prodrug, hydrate or solvate thereof, for use in a method for reducing and / or inhibiting IL-1 beta, in particular inhibiting IL-1 beta.

[0328] The present invention relates to a compound of formula (I) as defined in the present invention, or a stereoisomer, racemic mixture, tautomer, polymorph, pharma- ceutically acceptable salt, prodrug, hydrate or solvate thereof, for use in the treatment, alleviation or prevention of a disease, disorder or condition responsive to the inhibition of modulation, in particular the activation, of a component of the NLRP3 inflammasome pathway.

[0329] The present invention relates to a compound of formula (I) as defined in the present invention, or a stereoisomer, racemic mixture, tautomer, polymorph, pharma- ceutically acceptable salt, prodrug, hydrate or solvate thereof, for use in the treatment, alleviation or prevention of a disease, disorder or abnormality responsive to the inhibition of modulation, in particular activation, of the NLRP3 inflammasome pathway.

[0330] The present invention relates to a compound of formula (I) as defined in the present invention, or a stereoisomer, racemic mixture, tautomer, polymorph, pharma- ceutically acceptable salt, prodrug, hydrate or solvate thereof, for use in the treatment, alleviation or prevention of diseases, disorders or conditions responsive to the modulation, in particular the reduction, of the levels of IL-1 beta and / or IL-18.

[0331] In other words, the present invention relates to a method for treating, alleviating or preventing a disease, disorder or condition that responds to the inhibition of modulation, in particular activation, of a component of the NLRP3 inflammasome pathway and / or to the modulation, in particular reduction, of the levels of IL-1beta and / or IL-18, comprising administering to a subject (e.g., a patient) in need thereof a therapeutically effective amount of a compound of formula (I) as defined in the present invention, or a stereoisomer, racemic mixture, tautomer, polymorph, pharma- ceutically acceptable salt, prodrug, hydrate or solvate thereof.

[0332] In one embodiment, the present invention relates to a method for treating, preventing or alleviating a disease, disorder or condition responsive to the inhibition of modulation, in particular activation, of a component of the NLRP3 inflammasome pathway, comprising administering a therapeutically effective amount of a compound of formula (I) as defined in the present invention, or a stereoisomer, racemic mixture, tautomer, polymorph, pharma- ceutically acceptable salt, prodrug, hydrate or solvate thereof, to a subject (e.g., a patient) in need thereof.

[0333] The present invention further relates to a method for treating, preventing or alleviating a disease, disorder or abnormality responsive to the inhibition of modulation, in particular activation, of the NLRP3 inflammasome pathway, comprising administering a therapeutically effective amount of a compound of formula (I) as defined in the present invention, or a stereoisomer, racemic mixture, tautomer, polymorph, pharma- ceutically acceptable salt, prodrug, hydrate or solvate thereof, to a subject (e.g., a patient) in need thereof.

[0334] In one embodiment, the present invention relates to a method for treating, preventing or alleviating a disease, disorder or condition responsive to modulation, in particular reduction, of the levels of IL-1beta and / or IL-18, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) as defined in the present invention, or a stereoisomer, racemic mixture, tautomer, polymorph, pharma-ceutically acceptable salt, prodrug, hydrate or solvate thereof.

[0335] The present invention relates to the use of a compound of formula (I) as defined in the present invention, or a stereoisomer, racemic mixture, tautomer, polymorph, pharma- ceutically acceptable salt, prodrug, hydrate, or solvate thereof, for the manufacture of a medicament.In a further embodiment, the present invention relates to the use of a compound of formula (I) as defined in the present invention, or a stereoisomer, racemic mixture, tautomer, polymorph, pharma- ceutically acceptable salt, prodrug, hydrate, or solvate thereof, for the manufacture of a medicament for the treatment, alleviation, or prevention of a disease, disorder, or condition that responds to the inhibition of modulation, in particular activation, of a component of the NLRP3 inflammasome pathway, and / or to the modulation, in particular reduction, of the levels of IL-1 beta and / or IL-18.In one embodiment, the disease, disorder, or condition is selected from the list disclosed herein.

[0336] The present invention relates to the use of a compound of formula (I) as defined in the present invention, or a stereoisomer, racemic mixture, tautomer, polymorph, pharma- ceutically acceptable salt, prodrug, hydrate or solvate thereof, for the manufacture of a medicament for the treatment, alleviation or prevention of a disease, disorder or condition responsive to the modulation, in particular the inhibition of the activation, of a component of the NLRP3 inflammasome pathway.

[0337] The present invention relates to the use of a compound of formula (I) as defined in the present invention, or a stereoisomer, racemic mixture, tautomer, polymorph, pharma- ceutically acceptable salt, prodrug, hydrate or solvate thereof, for the manufacture of a medicament for the treatment, alleviation or prevention of a disease, disorder or abnormality responsive to the modulation, in particular the inhibition of the activation, of the NLRP3 inflammasome pathway.

[0338] The present invention relates to the use of a compound of formula (I) as defined in the present invention, or a stereoisomer, racemic mixture, tautomer, polymorph, pharma- ceutically acceptable salt, prodrug, hydrate or solvate thereof, for the manufacture of a medicament for the treatment, alleviation or prevention of a disease, disorder or condition responsive to the modulation, in particular the reduction, of the levels of IL-1beta and / or IL-18.

[0339] The present invention relates to the use of a compound of formula (I) as defined herein, or a stereoisomer, racemic mixture, tautomer, polymorph, pharma- ceutically acceptable salt, prodrug, hydrate, or solvate thereof, for the manufacture of a medicament for reducing and / or inhibiting IL-1 beta and / or IL-1 beta levels. In one embodiment, the present invention relates to the use of a compound of the present invention, as defined herein, for the manufacture of a medicament for reducing and / or inhibiting IL-1 beta. In another embodiment, the present invention relates to the use of a compound of the present invention, as defined herein, for the manufacture of a medicament for reducing IL-1 beta.

[0340] In one embodiment, the present invention relates to a compound of formula (I) as defined in the present invention, or a stereoisomer, racemic mixture, tautomer, polymorph, pharma- ceutically acceptable salt, prodrug, hydrate or solvate thereof, for use in the treatment, alleviation or prevention of tauopathy by modulating a component of the inflammasome pathway, in particular by modulating the NLRP3 inflammasome pathway.

[0341] In another embodiment, the disease, disorder, or condition is responsive to modulation of one or more of IL-1β, IL-17, IL-18, IL-1a, IL-37, IL-33, and Th17 cells, preferably IL-1β and IL-18.

[0342] In yet another embodiment, the disease, disorder, or condition is a disease, disorder, or condition selected from Alzheimer's disease, Parkinson's disease, cryopyrin-associated periodic fever syndrome (CAPS), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and gout.

[0343] In another embodiment, the disease, disorder, or condition is a disease, disorder, or condition selected from multiple sclerosis, hidradenitis suppurativa (HS), and chronic kidney disease.

[0344] In a further embodiment, the disease, disorder, or condition is a disease, disorder, or condition of the immune system. In one embodiment, the disease, disorder, or condition is an inflammatory disease, disorder, or condition. In yet another embodiment, the disease, disorder, or condition is an autoimmune disease, disorder, or condition. In yet another embodiment, the disease, disorder, or condition is a disease, disorder, or condition of the central nervous system (CNS). In yet another embodiment, the disease, disorder, or condition can be a disease, disorder, or condition of the skin. The disease, disorder, or condition can be a disease, disorder, or condition of the cardiovascular system. The disease, disorder, or condition can be a cancer, tumor, or other malignancy. The disease, disorder, or condition can be a disease, disorder, or condition of the renal system. The disease, disorder, or condition can be a disease, disorder, or condition of the gastrointestinal tract. The disease, disorder, or condition can be a disease, disorder, or condition of the respiratory system. The disease, disorder or condition may be a disease, disorder or condition of the endocrine system.The disease, disorder or condition may be a liver-related disease, disorder or condition.

[0345] In one embodiment, the disease, disorder, or condition responsive to modulation, particularly inhibition of activation, of a component of the NLRP3 inflammasome pathway is Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, demyelination, viral encephalitis, epilepsy, stroke, atherosclerosis, asthma, allergic inflammation, cryopyrin-associated periodic fever syndrome (CAPS), Muckle-Wells syndrome (MWS), familial common cold autoinflammatory syndrome (FCAS), neonatal-onset multisystem inflammatory disease (NOMID), gout, pseudogout, inflammatory bowel disease, nonalcoholic fatty liver disease, nonalcoholic fatty liver disease, and the like. Hepatitis, hypertension, myocardial infarction, oxalate-induced nephropathy, graft-versus-host disease, type 1 diabetes, type 2 diabetes, rheumatoid arthritis, myelodysplastic syndromes, familial Mediterranean fever (FMF), tumor necrosis factor receptor-associated periodic syndromes (TRAPS), mevalonate kinase deficiency (MKD), hyperimmunoglobulinemia D, periodic fever syndromes (HIDS), interleukin-1 receptor antagonist deficiency (DIRA), Majeed syndrome, suppurative arthritis, pyoderma gangrenosum, and acne (PAPA), haploinsufficiency of A20 (HA20), PLCG2-associated antibody deficiency and immune dysregulation (PLAID), pediatric granulomatous Arthritis (PGA), PLCG2-associated autoinflammatory disease, antibody deficiency, and immune dysregulation (APLAID), sideroblastic anemia, periodic fever, and developmental delay with B-cell immunodeficiency (SIFD), chronic nonbacterial osteomyelitis (CNO), Sweet's syndrome, chronic relapsing multifocal osteomyelitis (CRMO), synovitis, pustulosis, acne, eczema, alopecia, actinic keratosis, hyperostosis, and osteitis syndrome (SAPHO), multiple sclerosis (MS), psoriasis, Behçet's disease, Sjögren's syndrome, Schnitzler's syndrome, chronic obstructive pulmonary disease (COPD), steroid-resistant asthma, asbestosis, silicosis, cystic fibrosis, motor neuro encephalopathy, Huntington's disease, cerebral malaria, brain damage from pneumococcal meningitis, obesity, age-related macular degeneration (AMD), corneal infection, uveitis, dry eye, chronic kidney disease, diabetic nephropathy, alcoholic liver disease, skin contact hypersensitivity, sunburn, osteoarthritis, systemic juvenile idiopathic arthritis, adult-onset Still's disease, relapsing polychondritis, chikungunya virus, Ross River virus, influenza, HIV, coronavirus, dengue fever, Zika virus, hidradenitis suppurativa (HS), lung cancer metastasis, pancreatic cancer, gastric cancer, myelodysplastic syndrome, leukemia, polymyositis, colitis, helminth infection, bacterial infection,The condition may be selected from abdominal aortic aneurysm, wound healing, depression, psychological stress, pericarditis including Dressler's syndrome, ischemia-reperfusion injury, frontotemporal dementia, HIV-associated neurocognitive disorder, coronavirus-associated inflammatory pathology, and traumatic brain injury.

[0346] In another embodiment, the disease, disorder, or abnormality responsive to modulation, particularly reduced activation, of a component of the NLRP3 inflammasome pathway can be selected from diabetic edema (DME), geographic atrophy (GA), and coronavirus associated respiratory distress syndrome (CARDS).

[0347] Preferably, the disease, disorder, or condition is selected from Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, demyelination, viral encephalitis, epilepsy, stroke, atherosclerosis, asthma and allergic inflammation, cryopyrin-associated periodic fever syndrome (CAPS), gout, inflammatory bowel disease, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), hypertension, myocardial infarction, oxalate-induced nephropathy, graft-versus-host disease, type 1 diabetes, type 2 diabetes, rheumatoid arthritis, myelodysplastic syndrome, antineutrophil cytoplasmic antibody-associated vasculitis (AAV), lupus nephritis, anti-glomerular basement membrane (GMB) disease, IgA nephropathy, glomerulonephritis (GN), systemic lupus erythematosus (SLE), focal segmental glomerulosclerosis, minimal change disease (MCD), psoriatic arthritis, and hereditary relapsing fever (HRF).

[0348] In another preferred embodiment, the disease, disorder, or condition is selected from multiple sclerosis, traumatic brain injury, spinal cord injury, acute kidney disease, chronic kidney disease, acne, atopic dermatitis, and hidradenitis suppurativa (HS).

[0349] More preferably, the disease, disorder, or condition is selected from Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, demyelination, viral encephalitis, epilepsy, stroke, atherosclerosis, asthma and allergic inflammation, cryopyrin-associated periodic fever syndromes (CAPS), gout, inflammatory bowel disease, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), hypertension, myocardial infarction, oxalate-induced nephropathy, graft-versus-host disease, type 1 and type 2 diabetes, rheumatoid arthritis, and myelodysplastic syndromes.

[0350] Even more preferably, the disease, disorder, or condition is selected from Alzheimer's disease, Parkinson's disease, cryopyrin-associated periodic fever syndrome (CAPS), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), rheumatoid arthritis, and gout.Even more preferably, the disease, disorder, or condition is selected from Alzheimer's disease, Parkinson's disease, cryopyrin-associated periodic fever syndrome (CAPS), rheumatoid arthritis, and gout.

[0351] In one embodiment, the present invention relates to a compound of formula (I) as defined in the present invention, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof, for use in the treatment, alleviation, or prevention of IL-18 and / or IL-1 beta related diseases by modulating a component of the NLRP3 inflammasome pathway, in particular by modulating the NLRP3 inflammasome pathway. The level of IL-18 and / or IL-1 beta in a subject is reduced as a result of administration of a compound of formula (I) as defined in the present invention, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof.

[0352] The IL-18 and / or IL-1 beta associated disease, disorder, or abnormality may be any of the following: chronic obstructive pulmonary disease (COPD), transfusion-associated lung injury, bronchopulmonary dysplasia (BPD), acute respiratory distress syndrome (ARDS), pediatric autoinflammatory diseases or conditions, Still's disease, particularly adult Still's disease or juvenile Still's disease, juvenile rheumatoid arthritis (JRA), juvenile idiopathic arthritis (JIA), systemic juvenile idiopathic arthritis (SoJIA), systemic juvenile idiopathic arthritis (sJIA), interstitial lung disease (ILD), macrophage activation syndrome (MAS), including primary, secondary, and recurrent MAS, hemophagocytic lymphohistiocytosis (HLH), perforin, munc 13-4 and 18-2, familial (hereditary) hemophagocytic lymphohistiocytosis (FHLH) associated with genetic defects in syntaxin 11, immune deficiencies such as Chediak-Higashi syndrome (CHS), Griscelli syndrome (GS), X-linked lymphoproliferative syndrome (XLP2), X-linked inhibitor of apoptosis protein deficiency (XIAP), infectious conditions, especially acquired hemophagocytic lymphohistiocytosis associated with herpes viruses such as EBV and other pathogens, autoinflammatory syndromes associated with NLRC4 mutations, giant cell arteritis (GCA), acne, pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA), pulmonary sarcoidosis, heart failure, ischemic heart disease, dry eye syndrome (D ED), keratitis, corneal ulcers and abrasions, iritis, glaucoma, Sjogren's syndrome, autoimmune uveitis, Behcet's disease, conjunctivitis, allergic conjunctivitis, type 2 diabetes mellitus, solid organ and hematological stem cell transplantation, ischemia-reperfusion injury, Familial Mediterranean Fever (FMF), Tumor Necrosis Factor Receptor 1-Associated Periodic Syndrome (TRAPS), Hyper IgD syndrome (mevalonate kinase gene mutation), gout, Schnitzler's syndrome, Wegener's granulomatosis also known as granulomatosis with polyangiitis (GPA), Hashimoto's disease, Crohn's disease, early onset inflammatory bowel disease (EOIBD), extremely EOIBD (VEOIBD), infantile IBD, neonatal IBD, ulcerative colitis, and Blau syndrome (NOD-2 mutation).

[0353] Modulation of the NLRP3 inflammasome pathway appears to be beneficial in diseases or disorders or conditions involving altered IL-18 levels and / or IL-1beta, resulting in pathological inflammation.

[0354] The present invention relates to compounds of formula (I) as defined in the present invention which are modulators of NLRP3 inflammasome activity and / or modulators of IL-18 and / or IL-1b levels in a subject.

[0355] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I) as defined herein, or a stereoisomer, racemic mixture, tautomer, polymorph, pharma- ceutically acceptable salt, prodrug, hydrate, or solvate thereof, and at least one further biologically active compound. Optionally, the pharmaceutical combination may comprise a pharma- ceutically acceptable carrier, excipient, adjuvant, or additive as described herein.

[0356] In another embodiment, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) as defined herein, or a stereoisomer, racemic mixture, tautomer, polymorph, pharma- ceutically acceptable salt, prodrug, hydrate or solvate thereof, in combination with at least one further biologically active compound different from the compound of formula (I), optionally comprising at least one pharma- ceutically acceptable carrier, excipient, adjuvant or additive.

[0357] In another embodiment, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) as defined herein, or a stereoisomer, racemic mixture, tautomer, polymorph, pharma- ceutically acceptable salt, prodrug, hydrate or solvate thereof, in combination with at least one further biologically active compound different from the compound of formula (I), optionally comprising at least one pharma- ceutically acceptable carrier, excipient, adjuvant or additive.

[0358] In particular, the further biologically active compound may be one that is used to treat a disease, disorder, or condition that targets a different pathological mechanism, such as, inter alia, anti-amyloid beta antibodies, anti-tau antibodies, amyloid beta small molecule inhibitors, tau aggregation small molecule inhibitors, anti-alpha synuclein antibodies, or alpha synuclein aggregation small molecule inhibitors, anti-TDP-43 antibodies, or anti-TDP-43 aggregation small molecule inhibitors. When the compound of the present invention is used in combination with a further biologically active compound, the dosage of each compound may be different from the dosage when the compound is used in monotherapy. Such biologically active compounds are well known from the literature. Such biologically active compounds are, for example, chemical compounds, peptides, antibodies, antibody fragments, or nucleic acids, which are therapeutically active or improve therapeutic activity when administered in combination with the compound of the present invention to a subject (e.g., a patient).

[0359] In another embodiment, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) as described in the present invention, or a stereoisomer, racemic mixture, tautomer, polymorph, pharma- ceutically acceptable salt, prodrug, hydrate or solvate thereof, and a combination comprising at least one further biologically active compound different from the compound of formula (I), for use as a medicament, optionally comprising at least one pharma- ceutically acceptable carrier, excipient, adjuvant or additive.

[0360] The term "combination" refers to either a fixed combination in one unit dosage form, or a combined administration in which a compound of the invention and a combination partner (e.g., another drug as described above, also referred to as a "therapeutic agent" or "additional biologically active compound") can be administered independently at the same time or separately within a time interval.

[0361] In another embodiment, the present invention relates to a combination, in particular a pharmaceutical combination, comprising a therapeutically effective amount of a compound of formula (I) as described in the present invention, or a stereoisomer, racemic mixture, tautomer, polymorph, pharma- ceutically acceptable salt, prodrug, hydrate or solvate thereof, and at least one further biologically active compound, and optionally at least one pharma- ceutically acceptable carrier, excipient, adjuvant or additive. In particular, the at least one further biologically active compound is a compound different from the compound of formula (I).

[0362] In another embodiment, the present invention relates to a combination comprising a therapeutically effective amount of a compound of formula (I) as described in the present invention, or a stereoisomer, racemic mixture, tautomer, polymorph, pharma- ceutically acceptable salt, prodrug, hydrate, or solvate thereof, and at least one further biologically active compound different from the compound of formula (I), optionally including at least one pharma- ceutically acceptable carrier, excipient, adjuvant, or additive, for use as a medicament.

[0363] The present invention relates to the use of the compounds of formula (I) defined in the present invention, or their stereoisomers, racemic mixtures, tautomers, polymorphs, pharmaceutically acceptable salts, prodrugs, hydrates, or solvates, as analytical references or in vitro screening tools. The compounds of the present invention, or their stereoisomers, racemic mixtures, tautomers, polymorphs, pharmaceutically acceptable salts, prodrugs, hydrates, or solvates, can be used as analytical references or in vitro screening tools for characterizing cells with activated NLRP3 inflammasome pathway and for testing compounds that target the NLRP3 inflammasome pathway.

[0364] Thus, the present invention provides the use of a compound of formula (I) as defined in the present invention, or a stereoisomer, racemic mixture, tautomer, polymorph, pharma- ceutically acceptable salt, prodrug, hydrate, or solvate thereof, for treating, alleviating, or preventing disorders or disorders that respond to the modulation of a component of the NLRP3 inflammasome pathway or to the modulation, particularly the reduction, of the levels of IL-1 beta and / or IL-18, the medicament being prepared for administration with a further biologically active agent.The present invention also provides the use of a further biologically active agent for treating, alleviating, or preventing disorders or disorders that respond to the modulation of a component of the NLRP3 inflammasome pathway or to the modulation, particularly the reduction, of the levels of IL-1 beta and / or IL-18, the further biologically active agent being administered together with a compound of the present invention, or a stereoisomer, racemic mixture, tautomer, polymorph, pharma- ceutically acceptable salt, prodrug, hydrate, or solvate thereof.

[0365] In another embodiment, the present invention provides the use of a compound of formula (I) as defined in the present invention, or a stereoisomer, racemic mixture, tautomer, polymorph, pharma- ceutically acceptable salt, prodrug, hydrate, or solvate thereof, for treating, alleviating, or preventing a disorder or abnormality that responds to modulation of a component of the NLRP3 inflammasome pathway or to modulation, in particular reduction, of the levels of IL-1 beta and / or IL-18, wherein the modulation is reduction and / or inhibition of IL-1 beta and / or IL-1 beta levels. Preferably, the modulation is reduction and / or inhibition of IL-1 beta. Preferably, the modulation is inhibition of IL-1 beta. In another embodiment, the present invention provides a compound of formula (I) as defined in the present invention, or a stereoisomer, racemic mixture, tautomer, polymorph, pharma- ceutically acceptable salt, prodrug, hydrate, or solvate thereof, for use as a medicament, in particular for inhibiting IL-1 beta.

[0366] In another embodiment, the present invention also provides a compound of formula (I) as defined in the present invention, or a stereoisomer, racemic mixture, tautomer, polymorph, pharma- ceutically acceptable salt, prodrug, hydrate or solvate thereof, for use in a method for treating, alleviating or preventing a disease, disorder or condition that responds to modulation of a component of the NLRP3 inflammasome pathway or to modulation, in particular reduction, of the levels of IL-1beta and / or IL-18, wherein said compound of formula (I) is formulated for administration with a further biological compound (as defined herein).

[0367] In another embodiment, the present invention also relates to a method for treating Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, demyelination, viral encephalitis, epilepsy, stroke, atherosclerosis, asthma, allergic inflammation, cryopyrin-associated periodic fever syndrome (CAPS), Muckle-Wells syndrome (MWS), familial common cold autoinflammatory syndrome (FCAS), neonatal-onset multisystem inflammatory disease (NOMID), gout, pseudogout, inflammatory bowel disease, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, hypertension, myocardial infarction, oxalate-induced nephropathy, graft-versus-host disease, type 1 diabetes, type 2 diabetes, Diabetes mellitus, Rheumatoid arthritis, Myelodysplastic syndromes, Familial Mediterranean fever (FMF), TNF receptor-associated periodic syndromes (TRAPS), Mevalonate kinase deficiency (MKD), Hyperimmunoglobulinemia D, Periodic fever syndrome (HIDS), Interleukin-1 receptor antagonist deficiency (DIRA), Majeed syndrome, Acne, Suppurative arthritis, pyoderma gangrenosum, and acne (PAPA), Haploinsufficiency of A20 (HA20), PLCG2-associated antibody deficiency and immune dysregulation (PLAID), Pediatric granulomatous arthritis (PGA), PLCG2-associated autoinflammatory disease, antibody deficiency, and immune dysregulation (A PLAID), sideroblastic anemia, periodic fevers and developmental delay with B-cell immunodeficiency (SIFD), chronic nonbacterial osteomyelitis (CNO), Sweet's syndrome, chronic relapsing multifocal osteomyelitis (CRMO), synovitis, pustulosis, acne, eczema, alopecia, actinic keratosis, hyperostosis, osteitis syndrome (SAPHO), multiple sclerosis (MS), psoriasis, Behçet's disease, Sjögren's syndrome, Schnitzler's syndrome, chronic obstructive pulmonary disease (COPD), steroid-resistant asthma, asbestosis, silicosis, cystic fibrosis, motor neuron disease, Huntington's disease, cerebral malaria, brain damage from pneumococcal meningitis, obesity, age-related jaundice AMD, corneal infection, uveitis, dry eye, chronic kidney disease, diabetic nephropathy, alcoholic liver disease, skin contact sensitivity, sunburn, osteoarthritis, systemic juvenile idiopathic arthritis, adult onset Still's disease, relapsing polychondritis, chikungunya virus, Ross River virus, influenza, HIV, coronavirus, dengue fever, Zika virus, hidradenitis suppurativa (HS), lung cancer metastases, pancreatic cancer, gastric cancer, myelodysplastic syndrome, leukemia, polymyositis, colitis, helminth infection, bacterial infection, abdominal aortic aneurysm, wound healing, depression, psychological stress, pericarditis including Dressler's syndrome,A method for treating, alleviating or preventing a disease, disorder or condition that responds to modulation of a component of the NLRP3 inflammasome pathway or responds to modulation, in particular reduction, of levels of IL-1 beta and / or IL-18, selected from ischemia-reperfusion injury, frontotemporal dementia, HIV-associated neurocognitive disorders, coronavirus-associated inflammatory pathology, and traumatic brain injury, preferably wherein the disorder is selected from Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, demyelination, viral encephalitis, epilepsy, stroke, atherosclerosis, asthma, allergic inflammation, cryopyrin-associated periodic fever syndrome (CAPS), gout, inflammatory bowel disease, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NALD), and / or IL-18. The present invention provides a method for treating a subject suffering from a disease selected from ASH, hypertension, myocardial infarction, oxalate-induced nephropathy, graft-versus-host disease, type 1 diabetes, type 2 diabetes, rheumatoid arthritis, myelodysplastic syndrome, antineutrophil cytoplasmic antibody-associated vasculitis (AAV), lupus nephritis, antiglomerular basement membrane (GMB) disease, IgA nephropathy, glomerulonephritis (GN), systemic lupus erythematosus (SLE), focal segmental glomerulosclerosis, minimal change disease (MCD), psoriatic arthritis, and hereditary relapsing fever (HRF), comprising administering to the subject a therapeutically effective amount of a compound of formula (I) as defined in the present invention, or a stereoisomer, or a racemic mixture, or a tautomer, or a polymorph, or a pharma- ceutically acceptable salt, or a hydrate, or a solvate thereof.

[0368] In another embodiment, the disease, disorder, or abnormality can be selected from chronic edema (DME), geographic atrophy (GA), coronavirus associated respiratory distress syndrome (CARDS), multiple sclerosis, traumatic brain injury, spinal cord injury, acute kidney disease, chronic kidney disease, acne, atopic dermatitis, and hidradenitis suppurativa (HS).

[0369] In another embodiment, the present invention also provides a method of inhibiting IL-1 beta in a subject in need thereof, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), or a stereoisomer, racemic mixture, tautomer, polymorph, pharma- ceutically acceptable salt, prodrug, hydrate, or solvate thereof.

[0370] In particular, the disease, disorder, or disorder is responsive to inhibition of activation of NLRP3 inflammasome pathway. More specifically, the disease, disorder, or disorder is responsive to one or more of the modulation of, for example, but not limited to, IL-1β or IL-18. For example, the disease, disorder, or disorder is responsive to one or more of the modulation of IL-1β, IL-17, IL-18, IL-1a, IL-37, IL-33, and Th17 cells, and preferably, the disease, disorder, or disorder is responsive to the modulation of IL-1β and / or IL-18.

[0371] Methods of Synthesizing the Compounds of the Invention The compounds of the present invention can be prepared according to the definition of the compound of formula (I) disclosed herein by the synthetic routes described in the following schemes or examples. All methods described herein can be carried out in any suitable order, unless otherwise indicated herein or otherwise clearly contradicted by the context. The use of any or all examples or exemplary language (e.g., such as, preferably) provided herein is intended only to better illustrate the invention, and does not claim any limitation on the scope of the invention specifically claimed.

[0372] In the following general way, R 0 , R 1 , R 2 , R 3 X, Y, and W are as previously defined in the above examples or limited as indicated in the schemes. Unless otherwise stated, starting materials are either commercially available or prepared via known methods.

[0373] The present invention relates to methods for preparing the compounds of formula (I) disclosed herein.

[0374] In one embodiment, the method comprises the step of cyclization of a compound of formula (II) in the presence of a condensing agent to prepare a compound of formula (I):

[0375] [ka]

[0376] Includes W, X, Y, R 1 , R 2 , R 3 , and R 0 is as defined above.

[0377] Preferably, the process comprises the step of cyclization of a compound of formula (II) in the presence of a condensing agent to prepare a compound of formula (I).

[0378] A condensation agent is used for the cyclization of the compound of formula (II) to prepare the compound of formula (I) in the presence of a base. The base is preferably trimethylamine (Et3N). The condensation agent is preferably N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDC), Mukaiyama's reagent, iodomethane, or TsCl. The cyclization is preferably carried out at room temperature (rt).

[0379] Any combination of the embodiments, preferred embodiments, and more preferred embodiments disclosed herein is contemplated in the present invention.

[0380] Pharmaceutical Compositions While it is possible for the compounds of the invention, or their stereoisomers, racemic mixtures, tautomers, polymorphs, pharma- ceutically acceptable salts, prodrugs, hydrates, or solvates, to be administered alone, it is preferable to formulate them into pharmaceutical compositions in accordance with standard pharmaceutical practice.Thus, the present invention also provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula (I), or its stereoisomers, racemic mixtures, tautomers, polymorphs, pharma- ceutically acceptable salts, prodrugs, hydrates, or solvates, optionally in admixture with a pharma- ceutically acceptable carrier, excipient, adjuvant, or additive.

[0381] The term "therapeutically effective amount" for a compound of the present invention refers to an amount of a compound of the present invention (i.e., a compound of formula (I)), or a stereoisomer, racemic mixture, tautomer, polymorph, pharma- ceutically acceptable salt, prodrug, hydrate, or solvate thereof) that induces a biological or medical response in a subject, such as a reduction or inhibition of an enzyme or protein activity, or improves symptoms, alleviates a condition, slows or delays the progression of a disease, or prevents a disease, disorder, or disorder, etc. In one embodiment, the term "therapeutically effective amount" refers to an amount of a compound of the present invention that, when administered to a subject (e.g., a patient) in need thereof, is effective to at least partially alleviate, prevent, and / or ameliorate a disease, disorder, or disorder that responds to the modulation of a component of the NLRP3 inflammasome pathway or responds to the modulation, particularly the reduction, of IL-1 beta and / or IL-18.

[0382] Pharmaceutically acceptable carriers, excipients, adjuvants, and additives are well known in the pharmaceutical arts and can be found in, for example, Remington, Pharmaceutical Sciences, 18th Edition (Alfonso R. Gennaro, ed.; Mack Publishing Company, Easton, PA, 1990), Remington: the Science, and Practice of Pharmacy, 19th Edition (Lippincott, Williams & Wilkins, 1995), Handbook of Pharmaceutical Excipients, 3rd Edition (Arthur H. Kibbe, ed.; Amer. Pharmaceutical Assoc, 1999), Pharmaceutical Codex: Principles, and Practice of Pharmaceutics, 12th Edition (Walter Lund, ed.; Pharmaceutical Press, London, 1994), The United States Pharmacopeia: The National Formulary (United States Pharmacopeial Convention), Fiedler "Lexikon der Hilfsstoffe" 5th Edition, Editio Cantor Verlag, Aulendorf, 2002, The Handbook of Pharmaceutical Excipients, 4th ed., American Pharmaceuticals Association, 2003, and Goodman and Gilman: the Pharmacological Basis of Therapeutics (Louis S. Goodman and Lee E. Limbird, eds.; McGraw Hill, 1992), the disclosures of which are incorporated herein by reference.

[0383] Carriers, excipients, adjuvants, and pharmaceutical additives can be selected with regard to the intended route of administration and standard pharmaceutical practice. The compounds must be acceptable in the sense of not being harmful to the recipient thereof.

[0384] Pharmaceutically useful additives that may be used in formulating the pharmaceutical compositions of the present invention include, for example, vehicles, solvents (e.g., monohydric alcohols such as ethanol, isopropanol, and polyhydric alcohols such as glycols), edible oils (e.g., soybean oil, coconut oil, olive oil, safflower oil, and cottonseed oil), oily esters (e.g., ethyl oleate and isopropyl myristate), binders (e.g., hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), pregelatinized starch, and combinations thereof), solubilizers, thickeners, stabilizers, disintegrants (e.g., carboxymethylcellulose calcium (CMC-Ca), carboxymethylcellulose sodium (CMC-Na), crosslinked PVP (e.g., crospovidone, Polyplasdone (registered trademark)), and combinations thereof. ), or Kollidon® XL), alginic acid, sodium alginate, guar gum, cross-linked CMC (croscarmellose sodium, e.g. Ac-Di-Sol®), carboxymethyl starch-Na (sodium starch glycolate) (e.g. Primogel® or Explotab®), preferably cross-linked PVP and / or croscarmellose sodium), glidants (e.g. colloidal SiO2 (e.g. Aerosil® 200), magnesium trisilicate, powdered cellulose, talc, and combinations thereof), lubricants (e.g. magnesium stearate, aluminum or calcium silicate, stearic acid, hydrogenated castor oil, talc, glyceryl behenate, sodium stearate fumarate (sodium fumarate), In some embodiments, the surfactants may include, but are not limited to, calcium phosphate, stearate, fumarate, and combinations thereof), buffering agents, emulsifying agents, wetting agents, suspending agents, sweetening agents, coloring agents, flavoring agents, coating agents, preservatives, antioxidants, processing agents, drug delivery modifiers and enhancers (e.g., calcium phosphate), magnesium stearate, talc, monosaccharides, disaccharides, starch, gelatin, cellulose, methylcellulose, sodium carboxymethylcellulose, dextrose, hydroxypropyl-β-cyclodextrin, polyvinylpyrrolidone, low melting point waxes, and ion exchange resins.

[0385] The carrier is not particularly limited, and depends on the route of administration and the form of the pharmaceutical composition (i.e., solid, liquid, etc.). Suitable carriers include, but are not limited to, polyols, such as mannitol, sorbitol, xylitol; disaccharides, such as lactose, sucrose, dextrose, and maltose; polysaccharides, such as maltodextrin and dextran; starches, such as corn starch; celluloses, such as microcrystalline cellulose, sodium carboxymethylcellulose, low-substituted hydroxypropylcellulose, hydroxylethylcellulose, hydroxypropylcellulose, or mixtures thereof; cyclodextrin, and inorganic agents, such as dicalcium phosphate, calcium hydrogen phosphate, hydroxyapatite, tricalcium phosphate, talcum, and silica. Microcrystalline cellulose, sucrose, and / or lactose are preferred as carriers. Combinations thereof can also be utilized. Carriers can also include proteins and cell-penetrating peptides, which must be selected according to the route of administration and target.

[0386] The excipient is not particularly limited and will depend on the route of administration and the form of the pharmaceutical composition (i.e., solid, liquid, etc.) Excipients include, for example, water, ethanol, propylene glycol, and glycerin, and combinations thereof.

[0387] An adjuvant is an additive substance that has little or no pharmacological effect by itself, but which enhances the efficacy or potency of a compound of the invention when administered together.

[0388] Routes of administration (delivery) of the compounds of the invention include, but are not limited to, one or more of the following routes of administration: oral (e.g., tablets, capsules, or ingestible solutions), topical, mucosal (e.g., nasal sprays or aerosols for inhalation), nasal, parenteral (e.g., via injectable form), gastrointestinal, intrathecal, intraperitoneal, intramuscular, intravenous, intraarterial, intrathecal, intrauterine, intraocular, intradermal, intracranial, intratracheal, intravaginal, intraventricular, intracerebral, subcutaneous, ocular (intravitreous or intracameral), transdermal, rectal, buccal, epidural, and sublingual.

[0389] For example, the compounds can be administered orally in the form of tablets, capsules, ovules, elixirs, solutions, or suspensions and can contain flavoring or coloring agents for immediate, delayed, modified, sustained, pulsed, or controlled release applications.

[0390] Tablets may contain additives such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, calcium hydrogen phosphate, and glycine, disintegrants such as starch (preferably corn, potato, or tapioca starch), sodium starch glycolate, croscarmellose sodium, and certain complex silicates, and granulation binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin, and acacia. In addition, lubricants such as magnesium stearate, stearic acid, glyceryl behenate, and talc may be included. Similar types of solid compositions may also be utilized as fillers in gelatin capsules. Preferred additives in this regard include starch, cellulose, milk sugars such as lactose, or high molecular weight polyethylene glycols. For aqueous suspensions and / or elixirs, the drug may be combined with various sweetening or flavoring agents, coloring agents or dyes, emulsifying and / or suspending agents, and excipients such as water, ethanol, propylene glycol, and glycerin, and combinations thereof.

[0391] When the compounds of the present invention are administered parenterally as disclosed herein, examples of such administration include one or more of administering the compounds intravenously, intraarterially, intraperitoneally, intrathecally, intraventricularly, intraurethrally, intrasternally, intracranially, intramuscularly, or subcutaneously, and / or using injection techniques. For parenteral administration, the compounds can be used in the form of a sterile aqueous solution which may contain other substances, for example, sufficient salts or glucose to make the solution isotonic with blood. The aqueous solution should be suitably buffered, if necessary (preferably to have a pH of from 3 to 9). The preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.

[0392] As indicated, the compounds of the present invention can be administered intranasally or by inhalation, and are conveniently delivered in the form of a dry powder inhaler or aerosol spray presentation from a pressurized container, pump, spray, or nebulizer, with the use of a suitable propellant, for example, hydrofluoroalkanes such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, 1,1,1,2-tetrafluoroethane (HFA134AT) or 1,1,1,2,3,3,3-heptafluoropropane (HFA227EA), carbon dioxide, or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve that delivers a metered amount. The pressurized container, pump, spray, or nebulizer can contain a solution or suspension of the active compound, for example, using a mixture of a propellant such as ethanol and a solvent, and can further contain a lubricant, for example, sorbitan trioleate. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator can be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.

[0393] Alternatively, the compounds of the invention can be administered in the form of a suppository or pessary, as defined herein, or may be applied topically in the form of a gel, hydrogel, lotion, solution, cream, ointment or dusting powder.The compounds of the invention may also be administered dermally or transdermally, for example, by the use of a skin patch, as defined herein.

[0394] They can also be administered by pulmonary or rectal routes. They can also be administered by ocular routes. For ocular use, the compounds can be formulated as a micronized suspension in isotonic, pH-adjusted sterile saline, or preferably as a solution in isotonic, pH-adjusted sterile saline, optionally combined with a preservative, such as benzylalkonium chloride. Alternatively, they can be formulated in an ointment, such as petrolatum.

[0395] For topical application to the skin, the compounds of the invention can be formulated in a suitable ointment containing the active compound suspended or dissolved in a mixture of one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, emulsifying wax, and water. Alternatively, they can be formulated in a suitable lotion or cream containing the active compound suspended or dissolved in a mixture of one or more of the following: mineral oil, sorbitan monostearate, polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0396] Typically, a physician will determine the actual dosage that will be most suitable for an individual subject. The specific dose level and frequency of dosing for any particular individual may vary and will depend on a variety of factors, including the activity of the specific compound employed, the metabolic stability and length of action of that compound, age, body weight, general health, sex, diet, mode and time of administration, excretion rate, drug combination, the severity of the particular condition, and therapies the individual is undergoing.

[0397] The claimed compounds, as defined herein, can be used alone or in combination with one or more other biologically active compounds, as defined herein, for the treatment, alleviation, or prevention of the cited conditions. In particular, the other biologically active compounds can be those that are used for the treatment, alleviation, or prevention of the cited diseases.

[0398] The combinations mentioned above can be conveniently presented for use in the form of pharmaceutical preparations.The individual components of such combinations can be administered separately or together in pharmaceutical preparations by any convenient route, either sequentially or simultaneously.When administered sequentially, either the compound of the present invention or other biologically active compound can be administered first.When administered simultaneously, the combinations can be administered either in the same pharmaceutical composition or in different pharmaceutical compositions.When combined in the same preparation, it is understood that the two compounds must be stable and compatible with each other and with the other components of the preparation.When formulated separately, they can be provided in any convenient preparation, conveniently in the manner known in the art for such compounds.

[0399] The pharmaceutical compositions of the invention can be prepared in a manner known per se to those skilled in the art, for example as described in Remington, Pharmaceutical Sciences, 15th ed., Mack Publishing Co., New Jersey (1975).

[0400] The compounds according to the invention can also be provided in the form of a mixture with at least one further biologically active compound and / or a pharma- ceutically acceptable carrier, excipient, adjuvant, or additive, as disclosed herein, The compounds and / or further biologically active compounds are preferably present in a therapeutically effective amount.

[0401] The nature of the further biologically active compound depends on the intended use of the mixture. The further biologically active substance or compound may exert its biological effect by the same or a similar mechanism as the compound according to the invention, or by an unrelated mechanism of action, or by a variety of related and / or unrelated mechanisms of action.

[0402] The present invention also includes all suitable isotopic variations of the compounds of the present invention. An isotopic variation of a compound of the present invention is defined as one in which at least one atom is replaced with an atom having the same atomic number but an atomic mass different from the atomic mass normally found in nature. Examples of isotopes that can be incorporated into the compounds of the present invention are: 2 H, 3 H, 13 C. 14 C. 15 N, 17 O. 18 O. 35 S, 18 F, and 36 Certain isotopic variations of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, and chlorine, such as Cl. 3 H or 14 Those incorporating a radioisotope such as C are useful for drug and / or substrate tissue distribution studies. Tritiated, i.e. 3 H and carbon 14, i.e. 14 The C isotope is particularly preferred for its ease of preparation and pleasant taste. 18 F labeled compounds are particularly suitable for imaging applications such as PET. 2 Substitution with an isotope such as H may be preferred in some circumstances since it may provide certain therapeutic advantages due to better metabolic stability, for example increased half-life in vivo, or reduced dosage requirements. Isotopic variations of the compounds of the invention can generally be prepared by conventional procedures such as those described in the examples and preparations below using appropriate isotopic variations of suitable reagents.

[0403] Methods of Use of the Invention Evidence exists for a role for NLRP3-induced IL-1 and IL-18 in inflammatory responses associated with or resulting from many different diseases, disorders, or conditions that respond to modulation of components of the NLRP3 inflammasome pathway and / or to modulation of levels of IL-1beta and / or IL-18 (Menu et al., Clinical, and Experimental Immunology, 2011, 166, 1-15; Strowig et al., Nature, 2012, 481, 278-286). The present invention provides compounds of formula (I) as defined herein, or stereoisomers, racemic mixtures, tautomers, polymorphs, pharma- ceutically acceptable salts, prodrugs, hydrates, or solvates thereof, that exhibit valuable pharmaceutical properties, such as NLRP3 inhibitory properties in the NLRP3 inflammasome pathway. The compounds of the invention may be useful for the treatment, amelioration, or prevention of diseases or disorders or conditions that respond to modulation of components of the NLRP3 inflammasome pathway and / or to modulation of levels of IL-1beta and / or IL-18. Several diseases, disorders, or conditions have been shown to involve NLRP3, including, for example, one of the following: A. A central nervous system (CNS) disease, disorder, or abnormality, such as Alzheimer's disease, Parkinson's disease, dementia, frontotemporal dementia, Huntington's disease, cerebral malaria, brain injury from pneumococcal meningitis, motor neuron disease, traumatic brain injury, spinal cord injury, neuropathic pain, amyotrophic lateral sclerosis, migraine, or multiple sclerosis (MS); B. An immune disease, disorder, or abnormality (e.g., an autoimmune disease, disorder, or abnormality, and a disease, disorder, or abnormality involving the immune system), such as type 1 diabetes, hidradenitis suppurativa (HS), Schnitzler's syndrome, primary progressive multiple sclerosis (PPMS), Sjogren's syndrome, secondary progressive multiple sclerosis (SPMS), TNF receptor-associated periodic syndrome (TRAPS), graft-versus-host disease, antiphospholipid syndrome, refractory celiac disease, autoimmune pancreatitis, or multiple sclerosis (MS), including relapsing-remitting multiple sclerosis (RRMS); C. Inflammatory diseases, including autoinflammation and inflammation resulting from an inflammatory disease, disorder, or abnormality, such as mevalonate kinase deficiency (MKD), hyperimmunoglobulinemia D, cryopyrin-associated periodic fever syndrome (CAPS), Muckle-Wells syndrome (MWS), familial common cold autoinflammatory syndrome (FCAS), neonatal-onset multisystem inflammatory disease (NOMID), familial Mediterranean fever (FMF), acne, septic arthritis, pyoderma gangrenosum, and acne (PAPA), adult-onset Still's disease (AOSD), Majeed syndrome, PLCG2-associated antibody deficiency and immunoregulation disorder (PLAID), PLCG2-associated autoinflammatory disease, antibody deficiency, and immunoregulation disorder (APLAID), septic arthritis, haploinsufficiency of A20 (HA20), granulomatous arthritis of childhood (PGA), or sideroblastic anemia, periodic fevers, and developmental delay with B-cell immunodeficiency (SIFD); D. A disease, disorder, or abnormality of the skin, including an inflammatory condition of the skin, such as hidradenitis suppurativa (HS), dermatitis, psoriasis, cutaneous contact sensitivity, acne, periodic fever syndrome (HIDS), Sweet's syndrome, eczema, skin lesions, burns, wounds, wound healing, trauma, sunburn, actinic keratosis, interleukin-1 receptor antagonist deficiency (DIRA), epidermolysis bullosa, vitiligo vulgaris, atopic dermatitis, cutaneous lupus, or alopecia areata; E. An ophthalmic disease, disorder, or condition, such as age-related macular degeneration (AMD), corneal infection, uveitis, glaucoma, dry eye, geographic atrophy (GA), or demyelination; F. a cardiovascular disease, disorder, or condition (e.g., a disease, disorder, or condition of the cardiovascular system), e.g., myocardial infarction, hypertension, ischemia-reperfusion injury, pericarditis including Dressler's syndrome, aneurysm including abdominal aortic aneurysm, heart failure, coronary artery disease, or stroke; G. A metabolic disease, disorder, or abnormality, such as type 2 diabetes, diabetic edema (DME), obesity, atherosclerosis, diabetes, gout, or pseudogout; H. A respiratory disease, disorder, or condition (e.g., a disease, disorder, or condition of the respiratory system), such as asbestosis, silicosis, cystic fibrosis, allergic inflammation, chronic obstructive pulmonary disease (COPD), coronavirus associated respiratory distress syndrome (CARDS), steroid-resistant asthma, or asthma; I. A liver disease, disorder, or abnormality (e.g., a hepatic disease, disorder, or abnormality), such as hepatitis, primary biliary cholangitis, alcoholic liver disease, alcoholic fatty liver disease (AFLD), alcoholic fatty liver (ASH), non-alcoholic fatty liver disease (NAFLD), cytokine release syndrome, or non-alcoholic steatohepatitis (NASH), including advanced fibrosis stages F3 and F4; J. A kidney disease, disorder, or condition (e.g., a disease, disorder, or condition of the renal system), e.g., oxalate-induced nephropathy, diabetic nephropathy, chronic kidney disease, lupus nephritis, or kidney disease; K. A cancer disease, disorder, or condition (e.g., a cancer, tumor, or malignancy), such as lung cancer (e.g., lung cancer metastasis), pancreatic cancer, gastric cancer, leukemia, myelodysplastic syndrome (MOS), skin cancer, a tumor of the endocrine system, or thyroid cancer; L. infectious diseases, including viral infections, such as helminth infections (e.g., from schistosomes, nematodes, cestodes, or flukes), viral encephalitis, bacterial infections, periodontitis, human immunodeficiency virus (HIV), HIV-associated neurocognitive disorders, chronic nonbacterial osteomyelitis (CNO), chronic bacterial osteomyelitis, interleukin-1 receptor antagonist deficiency (DIRA), or epilepsy; alphaviruses (e.g., chikungunya virus and Ross River virus), flaviviruses (e.g., dengue and Zika viruses), coronavirus-associated inflammatory pathologies, coronaviruses, or influenza viruses; M. Psychological diseases, disorders, or disorders, such as depression and psychological stress; N. Inflammation, including inflammation that occurs as a result of an inflammatory disease, disorder, or condition, e.g., an autoinflammatory disease, inflammation that occurs as a symptom of a non-inflammatory disorder, inflammation that occurs as a result of infection, or inflammation that is secondary to trauma, injury, or autoimmunity. Examples of inflammation include inflammatory responses associated with or as a result of: i. a joint disease, disorder, or condition, such as periodic fever syndrome (HIDS), rheumatoid arthritis, pustulosis, synovitis, osteoarthritis, chronic relapsing multiple myelitis (CRMO), systemic juvenile idiopathic arthritis, osteoarthritis syndrome (SAPHO), hyperostosis, relapsing polychondritis, ankylosing spondylitis, or adult-onset Still's disease; ii. a gastrointestinal disease, disorder, or condition (e.g., a disease, disorder, or condition of the gastrointestinal tract), such as colitis, ulcerative colitis, Crohn's disease, or inflammatory bowel disease; iii. a muscle disease, disorder, or condition, such as polymyositis or myasthenia gravis; iv. a disease, disorder, or abnormality of the endocrine system, such as diabetes, parathyroid disease (e.g., hypothyroidism), endocrine tumors, thyroid cancer, or hypoglycemia; and / or v. Vascular diseases, disorders, or disorders, such as Behcet's disease or mucocutaneous lymph node syndrome.

[0404] In one embodiment, the disease, disorder, or condition is selected from Alzheimer's disease, Parkinson's disease, cryopyrin-associated periodic fever syndrome (CAPS), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and gout.

[0405] In particular, the disease, disorder, or abnormality may be Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, demyelination, viral encephalitis, epilepsy, stroke, atherosclerosis, asthma, allergic inflammation, cryopyrin-associated periodic fever syndrome (CAPS), Muckle-Wells syndrome (MWS), familial common cold autoinflammatory syndrome (FCAS), neonatal-onset multisystem inflammatory disease (NOMID), gout, pseudogout, inflammatory bowel disease, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, hypertension, myocardial infarction, oxalate-induced nephropathy, graft-versus-host disease, type 1 diabetes, type 2 diabetes Disease, rheumatoid arthritis, myelodysplastic syndromes, familial Mediterranean fever (FMF), tumor necrosis factor receptor-associated periodic syndromes (TRAPS), mevalonate kinase deficiency (MKD), hyperimmunoglobulinemia D, periodic fever syndrome (HIDS), interleukin-1 receptor antagonist deficiency (DIRA), Majeed syndrome, acne, suppurative arthritis, pyoderma gangrenosum, and acne vulgaris (PAPA), haploinsufficiency of A20 (HA20), PLCG2-associated antibody deficiency and immunoregulation disorder (PLAID), childhood granulomatous arthritis (PGA), PLCG2-associated autoinflammatory disease, antibody deficiency, and immunoregulation disorder (APL AID), sideroblastic anemia, periodic fevers and developmental delay with B-cell immunodeficiency (SIFD), chronic nonbacterial osteomyelitis (CNO), Sweet's syndrome, chronic relapsing multifocal osteomyelitis (CRMO), synovitis, pustulosis, acne, eczema, alopecia, actinic keratosis, hyperostosis, osteitis syndrome (SAPHO), multiple sclerosis (MS), psoriasis, Behçet's disease, Sjögren's syndrome, Schnitzler's syndrome, chronic obstructive pulmonary disease (COPD), steroid-resistant asthma, asbestosis, silicosis, cystic fibrosis, motor neuron disease, Huntington's disease, cerebral malaria, brain damage from pneumococcal meningitis, obesity, age-related macula Degeneration (AMD), corneal infection, uveitis, dry eye, chronic kidney disease, diabetic nephropathy, alcoholic liver disease, skin contact sensitivity, sunburn, osteoarthritis, systemic juvenile idiopathic arthritis, adult onset Still's disease, relapsing polychondritis, chikungunya virus, Ross River virus, influenza, HIV, coronavirus, dengue fever, Zika virus, hidradenitis suppurativa (HS), lung cancer metastases, pancreatic cancer, gastric cancer, myelodysplastic syndrome, leukemia, polymyositis, colitis, helminth infection, bacterial infection, abdominal aortic aneurysm, wound healing, depression, psychological stress, pericarditis including Dressler's syndrome,The disorder is selected from ischemia-reperfusion injury, frontotemporal dementia, HIV-associated neurocognitive disorders, coronavirus-associated inflammatory pathology, and traumatic brain injury, and preferably the disorder is selected from Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, demyelination, viral encephalitis, epilepsy, stroke, atherosclerosis, asthma, allergic inflammation, cryopyrin-associated periodic fever syndrome (CAPS), gout, inflammatory bowel disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic fatty liver disease (NAFLD), and nonalcoholic fatty liver disease (NF-. The present invention is directed to a method for treating or preventing atopic dermatitis, comprising administering to a patient a therapeutically effective amount of nivolumab or nasal steatohepatitis (NASH), hypertension, myocardial infarction, oxalate-induced nephropathy, graft-versus-host disease, type 1 diabetes mellitus, type 2 diabetes mellitus, rheumatoid arthritis, myelodysplastic syndrome, antineutrophil cytoplasmic antibody-associated vasculitis (AAV), lupus nephritis, antiglomerular basement membrane (GMB) disease, IgA nephropathy, glomerulonephritis (GN), systemic lupus erythematosus (SLE), focal segmental glomerulosclerosis, minimal change disease (MCD), psoriatic arthritis, and hereditary relapsing fever (HRF).

[0406] In yet another embodiment, the disease, disorder or condition is preferably an inflammatory disease, disorder or condition; or an autoimmune disease, disorder or condition; or a skin disease, disorder or condition (such as, but not limited to, psoriasis, acne, eczema, alopecia, or actinic keratosis); or a disease, disorder or condition of the cardiovascular system; or a disease, disorder or condition such as a cancer, tumor, or malignancy; or a disease, disorder, or condition of the renal system; a disease, disorder, or condition of the gastrointestinal tract; a disease, disorder, or condition of the respiratory system; or a disease, disorder, or condition of the endocrine system; or a disease, disorder, or condition of the central nervous system (CNS); or a disease, disorder, or condition of the liver.

[0407] In one embodiment, the disease, disorder, or condition is selected from chronic edema (DME), geographic atrophy (GA), coronavirus associated respiratory distress syndrome (CARDS), multiple sclerosis, traumatic brain injury, spinal cord injury, acute kidney disease, chronic kidney disease, acne, atopic dermatitis, and hidradenitis suppurativa (HS).

[0408] In one embodiment, the disease, disorder, or condition is selected from Alzheimer's disease, Parkinson's disease, multiple sclerosis, cryopyrin-associated periodic fever syndromes (CAPS), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), hidradenitis suppurativa (HS), chronic kidney disease, and gout.

[0409] In one embodiment, the disease, disorder, or condition is selected from Alzheimer's disease, Parkinson's disease, cryopyrin-associated periodic fever syndrome (CAPS), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and gout.

[0410] In another embodiment, the disease, disorder, or condition is selected from Alzheimer's disease, Parkinson's disease, cryopyrin-associated periodic fever syndromes (CAPS), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and hidradenitis suppurativa (HS).

[0411] In particular, the disease, disorder, or abnormality may be Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, demyelination, viral encephalitis, epilepsy, stroke, atherosclerosis, allergic inflammation, cryopyrin-associated periodic fever syndrome (CAPS), Muckle-Wells syndrome (MWS), familial common cold autoinflammatory syndrome (FCAS), neonatal-onset multisystem inflammatory disease (NOMID), gout, pseudogout, inflammatory bowel disease (IBD) (Crohn's disease, ulcerative colitis), hepatitis, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, hypertension, myocardial infarction, heart failure, coronary artery disease, osteoporosis ... xanthate-induced nephropathy, graft-versus-host disease, type 1 diabetes mellitus, type 2 diabetes mellitus, degenerative melanoma (DME), geographic atrophy (GA), rheumatoid arthritis, myelodysplastic syndromes, familial mediterranean fever (FMF), tumor necrosis factor receptor-associated periodic syndromes (TRAPS), mevalonate kinase deficiency (MKD), hyperimmunoglobulinemia D, periodic fever syndromes (HIDS), interleukin-1 receptor antagonist deficiency (DIRA), Majeed syndrome, suppurative arthritis, pyoderma gangrenosum, and acne (PAPA), haploinsufficiency of A20 (HA20), PLCG2-associated antibody deficiency and immune dysregulation (PLAID), Pediatric granulomatous arthritis (PGA), PLCG2-associated autoinflammatory disease, antibody deficiency, and immune dysregulation (APLAID), sideroblastic anemia, periodic fever, and developmental delay with B-cell immunodeficiency (SIFD), chronic nonbacterial osteomyelitis (CNO), Sweet's syndrome, chronic relapsing multifocal osteomyelitis (CRMO), synovitis, pustular disease, skin contact hypersensitivity, sunburn, psoriasis, hidradenitis suppurativa (HS), epidermolysis bullosa, acne, eczema, alopecia areata, actinic keratosis, hyperostosis, osteitis syndrome (SAPHO), vitiligo, atopic dermatitis, cutaneous lupus, multiple sclerosis (MS), Behçet's disease, Sjögren's syndrome, Schnitzler syndrome, chronic obstructive pulmonary disease (COPD), asthma, steroid-resistant asthma, coronavirus-associated inflammatory pathologies including coronavirus-associated respiratory distress syndrome (CARDS), asbestosis, silicosis, cystic fibrosis, motor neuron disease, Huntington's disease, cerebral malaria, brain damage from pneumococcal meningitis, obesity, age-related macular degeneration (AMD), corneal infections, uveitis, dry eye, acute kidney injury, chronic kidney disease, lupus nephritis, diabetic nephropathy, alcoholic liver disease, osteoarthritis, systemic juvenile idiopathic arthritis, adult-onset Still's disease, relapsing polychondritis, chikungunya virus,Selected from Ross River Virus, influenza, HIV, coronavirus, dengue fever, Zika virus, primary biliary cholangitis, antiphospholipid syndrome, refractory celiac disease, pancreatitis, autoimmune pancreatitis, mucocutaneous lymph node syndrome, lung cancer metastasis, pancreatic cancer, gastric cancer, myelodisplastic syndrome, leukemia; polymyositis, colitis, helminth infection, bacterial infection, abdominal aortic aneurysm, wound healing, migraine, depression, psychological stress, pain, neuropathic pain, periodontitis, pericarditis including Dressler's syndrome, ischemia-reperfusion injury, frontotemporal dementia, HIV-associated neurocognitive disorder, traumatic brain injury, traumatic spinal cord injury, ankylosing spondylitis, cytokine release syndrome. Preferably, the disease, disorder, or abnormality is Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, demyelination, multiple sclerosis, encephalomyelitis, leukoencephalopathy, viral encephalitis, epilepsy, stroke, traumatic brain and spinal cord injury, atherosclerosis, asthma and allergic inflammation, cryopyrin-associated periodic fever syndrome (CAPS), gout, inflammatory bowel disease (IBD), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), hypertension, myocardial infarction ... Selected from infarction, oxalate-induced nephropathy, graft-versus-host disease, type 1 diabetes, type 2 diabetes, hidradenitis suppurativa (HS), rheumatoid arthritis, acute kidney disease, chronic kidney disease, myelodysplastic syndrome, antineutrophil cytoplasmic antibody-associated vasculitis (AAV), lupus nephritis, antiglomerular basement membrane (GMB) disease, IgA nephropathy, glomerulonephritis (GN), systemic lupus erythematosus (SLE), focal segmental glomerulosclerosis, minimal change disease (MCD), psoriatic arthritis, and hereditary relapsing fever (HRF).

[0412] In yet another embodiment, the disease, disorder, or condition is Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, demyelination, viral encephalitis, epilepsy, stroke, atherosclerosis, asthma, allergic inflammation, cryopyrin-associated periodic fever syndrome (CAPS), Muckle-Wells syndrome (MWS), familial common cold autoinflammatory syndrome (FCAS), neonatal-onset multisystem inflammatory disease (NOMID), gout, pseudogout, inflammatory bowel disease, nonalcoholic fatty liver disease, nonalcoholic fatty liver, hypertension, myocardial infarction, oxalate-induced nephropathy. , Graft-versus-host disease, Type 1 diabetes mellitus, Type 2 diabetes mellitus, Rheumatoid arthritis, Myelodysplastic syndromes, Familial Mediterranean fever (FMF), TNF receptor-associated periodic syndromes (TRAPS), Mevalonate kinase deficiency (MKD), Hyperimmunoglobulinemia D, Periodic fever syndrome (HIDS), Interleukin-1 receptor antagonist deficiency (DIRA), Majeed syndrome, Acne, Septic arthritis, pyoderma gangrenosum, and acne (PAPA), Haploinsufficiency of A20 (HA20), PLCG2-associated antibody deficiency and immune dysregulation (PLAID), Pediatric granulomatous arthritis (PGA ), PLCG2-associated autoinflammatory disease, antibody deficiency, and immune dysregulation (APLAID), sideroblastic anemia, periodic fevers, and developmental delay with B-cell immunodeficiency (SIFD), chronic nonbacterial osteomyelitis (CNO), Sweet's syndrome, chronic relapsing multifocal osteomyelitis (CRMO), synovitis, pustular disease, acne, eczema, alopecia areata, actinic keratosis, hyperostosis, and osteitis syndrome (SAPHO), multiple sclerosis (MS), psoriasis, Behçet's disease, Sjögren's syndrome, Schnitzler's syndrome, chronic obstructive pulmonary disease (COPD), steroid-resistant asthma, asbestosis, silicosis, and cystic fibrosis , motor neuron disease, Huntington's disease, cerebral malaria, brain damage from pneumococcal meningitis, obesity, age-related macular degeneration (AMD), corneal infection, uveitis, dry eye, chronic kidney disease, diabetic nephropathy, alcoholic liver disease, skin contact hypersensitivity, sunburn, osteoarthritis, systemic juvenile idiopathic arthritis, adult-onset Still's disease, relapsing polychondritis, chikungunya virus, Ross River virus, influenza, HIV, coronavirus, dengue fever, Zika virus, hidradenitis suppurativa (HS), lung cancer metastasis, pancreatic cancer, gastric cancer, myelodysplastic syndrome, leukemia;and / or polymyositis, colitis, helminth infection, bacterial infection, abdominal aortic aneurysm, wound healing, depression, psychological stress, pericarditis including Dressler's syndrome, ischemia-reperfusion injury, frontotemporal dementia, HIV-associated neurocognitive disorders, coronavirus-associated inflammatory pathology, and traumatic brain injury; preferably, the disorder is selected from Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, demyelination, viral encephalitis, epilepsy, stroke, atherosclerosis, asthma, allergic inflammation, cryopyrin-associated periodic fever syndrome (CAPS), gout, inflammation. the disease is selected from chronic enteropathy, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), hypertension, myocardial infarction, oxalate-induced nephropathy, graft-versus-host disease, type 1 diabetes, type 2 diabetes, rheumatoid arthritis, myelodysplastic syndrome, antineutrophil cytoplasmic antibody-associated vasculitis (AAV), lupus nephritis, antiglomerular basement membrane (GMB) disease, IgA nephropathy, glomerulonephritis (GN), systemic lupus erythematosus (SLE), focal segmental glomerulosclerosis, minimal change disease (MCD), psoriatic arthritis, and hereditary relapsing fever (HRF);

[0413] In yet another embodiment, the disease, disorder or condition is preferably an inflammatory disease, disorder or condition; or an autoimmune disease, disorder or condition; or a skin disease, disorder or condition (such as, but not limited to, psoriasis, acne, eczema, alopecia areata, or actinic keratosis); or a disease, disorder or condition of the cardiovascular system; or a disease, disorder or condition such as cancer, tumor or malignancy; or a disease, disorder or condition of the renal system; a disease, disorder or condition of the gastrointestinal tract; a disease, disorder or condition of the respiratory system; or a disease, disorder or condition of the endocrine system; or a disease, disorder or condition of the central nervous system (CNS); or a liver disease, disorder or condition.

[0414] definition Within the meaning of this application, the following definitions apply unless otherwise specified, and where appropriate, terms used in the singular also include the plural and vice versa.

[0415] "Alkyl" refers to a saturated, straight or branched, organic moiety consisting of carbon and hydrogen atoms. Examples of suitable alkyl groups have from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms, more preferably from 1 to 3 carbon atoms, and include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, and isobutyl (as appropriate). The term "C1-C6 alkyl" refers to an alkyl group having from 1 to 6 carbon atoms. The terms "C1-C4 alkyl", "C1-C3 alkyl", or "C1 alkyl" should be construed accordingly.

[0416] "Hal", "halo" or "halogen" refers to F, Cl, Br, and I. Preferably, the halogen is F or Cl. More preferably, the halogen is Cl. Even more preferably, the halogen is F.

[0417] "-O-C1-C6 alkyl" means that "C1-C6 alkyl" is as defined above in its entirety. Examples of "-O-C1-C6 alkyl" include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, pentoxy, and hexoxy.

[0418] "C1-C6 alkyl-OH" refers to a C1-C6 alkyl group as defined above, in which one of the hydrogen atoms of the C1-C6 alkyl group is replaced with "OH". Examples of "C1-C6 alkyl-OH" include, but are not limited to, hydroxy-methyl, 2-hydroxy-ethyl, 2-hydroxy-propyl, 3-hydroxy-ethyl, and 5-hydroxy-pentyl.

[0419] The term "C3-C6 cycloalkyl" refers to a saturated monocyclic hydrocarbyl group having 3 to 6 carbon atoms. The term "C5-C6 cycloalkyl" should be construed accordingly. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0420] "5- or 6-membered heterocycloalkyl" refers to a stable 5- or 6-membered non-aromatic monocyclic group containing one or two heteroatoms independently selected from nitrogen, oxygen, and sulfur. Preferably, the 5- or 6-membered heterocycloalkyl contains one or two heteroatoms. More preferably, the heteroatom is oxygen or nitrogen. Examples include tetrahydrofuran and oxane.

[0421] "Aryl" refers to an aromatic hydrocarbon group having 4 to 8 carbon atoms in a ring portion "3-8 membered", i.e., 4, 5, 6, 7, or 8 membered ring. Preferably, the term "aryl" refers to an aromatic hydrocarbon group having 6 carbon atoms. Preferably, "aryl" is phenyl.

[0422] "Heteroaryl" refers to an aromatic "3- to 8-membered ring", i.e., a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, in which one or two of the carbon atoms of the ring are replaced with a heteroatom selected from O, N, and S. Preferably, "heteroaryl" refers to an aromatic 5- to 8-membered ring. More preferably, "heteroaryl" refers to an aromatic 5- to 6-membered heteroaromatic monocyclic group. The heteroaryl group may be bonded via a carbon atom or a heteroatom. Examples of heteroaryl include, but are not limited to, thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole.

[0423] "Optionally substituted" with reference to a particular group refers to said group which may be optionally substituted with one or more substituents (ie, the substituents may or may not be present).

[0424] Unless otherwise specified, the term "compound of the invention" refers to a compound of formula (I) or (II) disclosed herein, or a subformula thereof disclosed herein, or a stereoisomer thereof, or a racemic mixture thereof, or a tautomer thereof, or a polymorph thereof, or a pharma- ceutically acceptable salt thereof, or a prodrug thereof, or a hydrate thereof, or a solvate thereof. Compounds of the invention having one or more optically active carbons may exist as racemates and racemic mixtures (including mixtures in all ratios), stereoisomers (including diastereomeric mixtures and individual diastereomers, enantiomeric mixtures and single enantiomers, mixtures of conformers and single conformers), tautomers, atropisomers, and rotamers. All isomeric forms are included in the present invention. Compounds described in the present invention that contain olefinic double bonds include E and Z geometric isomers. Also included in the present invention are all pharma- ceutically acceptable salts, prodrugs, hydrates, and solvates of the compounds of Formula (I) or (II).

[0425] Tautomers are isomers of a compound that differ only in the position of protons and electrons. The skeleton of the compound remains the same. A common tautomer pair is the ketone-enol (

[0426] [ka]

[0427] ), enamine-imine (

[0428] [ka]

[0429] ).

[0430] Solvates, hydrates, and anhydrous forms of salts are also included in the present invention. The solvent contained in the solvate is not particularly limited and can be any pharma- ceutically acceptable solvent. Examples include water and C 1~4 Includes alcohol (e.g., methanol or ethanol).

[0431] "Pharmaceutically acceptable salts" are defined as derivatives of the disclosed compounds, where the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. Pharmaceutically acceptable salts include the conventional non-toxic salts or quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids, such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like, and salts prepared from organic acids, such as, but not limited to, acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, and the like. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or in a mixture of the two. Organic solvents include, but are not limited to, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile. Lists of suitable salts can be found in Remington, Pharmaceutical Sciences, 18th Edition, Mack Publishing Company, Easton, PA, 1990, p. 1445, the disclosure of which is incorporated herein by reference.

[0432] The compounds of the present invention may also be provided in the form of prodrugs, i.e. compounds that are metabolized in vivo to active metabolites, as defined herein. As used hereafter in the present description and claims, the term "prodrug" refers to any covalently bonded compound that releases an active parent drug through in vivo biotransformation. The reference by Goodman and Gilman (The Pharmacological Basis of Therapeutics, 8th Edition, McGraw-Hill, Int., ed., 1992, Biotransformation of Drugs, pp. 13-15) describing prodrugs is incorporated herein by reference in its entirety.

[0433] "Pharmaceutically acceptable" is defined as those compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in association with human and animal tissues without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit / risk ratio.

[0434] As used herein, the term "patient" or "subject" according to the present invention typically refers to animals, particularly mammals (e.g., rabbits, rats, dogs, mice, guinea pigs, pigs), more specifically primates (e.g., humans, male or female). In certain embodiments, the subject is a human.

[0435] "NLRP3" as used herein refers to the pyrin domain-containing protein triad of the NOD-like receptor (NLR) family, the inflammasome. The inflammasome is an intracellular supramolecular complex that includes a sensor molecule, the CARD-containing adaptor apoptosis-associated speck-like protein (ASC), and the effector protease caspase-1. Upon activation of the inflammasome sensor molecule, ASC self-associates into a helical fibrillar assembly that results in the formation of the so-called ASC speck or pyroptosome, which acts as a molecular platform for the activation of procaspase-1 via proximity-induced autocatalytic activation. Active caspase-1 triggers the activation and release of interleukin-1 (IL-1) family proteins, allowing the unconventional secretion of many cytosolic proteins. Among the proinflammatory mediators released upon NLRP3 activation are IL-1 beta (β), IL-18, high mobility group protein B1 (HMGB1), leukotrienes, and prostaglandins.

[0436] Activation of the NLRP3 inflammasome pathway is a key driver of inflammation that interacts with different cytokine pathways to shape the immune response to infection and injury. The formation of several proinflammatory cytokines is triggered by activation of the NLRP3 inflammasome pathway.

[0437] The terms "inhibit," "inhibition," or "inhibiting" refer to the alleviation or suppression of a given condition, symptom, or disorder, or disease, or abnormality, or a significant reduction in the baseline activity of a biological activity or process, responsive to modulation of a component of the NLRP3 inflammasome pathway.

[0438] The terms "treat," "treating," or "treatment" with respect to any disease, disorder, or condition refers to alleviating, improving, or modulating the disease, disorder, or condition (i.e., slowing or halting the development of the disease, disorder, or condition, or at least one of its clinical symptoms), or alleviating, improving, or modulating at least one physical parameter or biomarker associated with the disease, disorder, or condition, including those that are unrecognized by the subject (e.g., patient).

[0439] The terms "prevent," "preventing," or "prevention," with respect to any disease or disorder or abnormality responsive to modulation of a component of the NLRP3 inflammasome pathway, refer to prophylactic treatment of the disease or disorder or abnormality, or delaying the onset or progression of the disease or disorder.

[0440] The term "in need of" a treatment in the case of such a subject would benefit biologically, medically, or quality of life from such treatment.

[0441] As used herein, "modulation" refers to an alteration, such as upregulation, downregulation, increase or decrease, preferably a reduction.

[0442] [Table 1]

[0443] The definitions and preferred definitions given in the "Definitions" section apply to all of the embodiments described herein unless otherwise stated.

[0444] The compounds of the present invention can be synthesized by one of ordinary skill in the art by using commonly known preparative procedures, such as the general methods depicted in the following schemes, which are given for illustrative purposes only and should not be construed as limiting.

[0445] Overall synthetic scheme for the preparation of compounds of the present invention:

[0446] [ka]

[0447] From commercially available aryl ketoesters, the nitro derivatives were synthesized using nitroalkanes such as nitromethane with a suitable base and solvent. Reduction of the nitro was then achieved either by hydrogen with a suitable catalyst or by using metals under acidic conditions such as iron or zinc in acetic acid. The thiourea or urea derivatives were subsequently obtained by treating the amine intermediate with an isothiocyanate or isocyanate, optionally in the presence of a base. Finally, cyclization was carried out as known in the art, for example using N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDC) with base, Mukaiyama's reagent with base, iodomethane with base, or TsCl with base. Alternatively, R 2 Functionality could also be introduced at the end of the synthesis by a two-step strategy via a saponification / esterification procedure. Finally, the enantiomers could be separated by chiral supercritical fluid chromatography (SFC) to give the desired single enantiomers. EXAMPLES

[0448] The present disclosure is further illustrated by the following examples and synthetic schemes, which should not be construed as limiting the scope of the specific procedures described herein. It is understood that the examples are provided to illustrate certain embodiments and are not intended herein to limit the scope of the disclosure.

[0449] [Table 2A]

[0450] [Table 2B]

[0451] All reagents and solvents were obtained from commercial sources and used without further purification. 1 H-NMR spectra were recorded in deuterated solvents on a Bruker 400MHz-AVANCE III HD NMR, a Bruker 500MHz-AVANCE III HD NMR spectrometer, or a Spinsolve 80Mhz. Chemical shifts (δ) are recorded in parts per million and coupling constants (J values) are recorded in Hertz. Spin multiplicities are indicated by the following symbols: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), bs (broad singlet). Mass spectra were obtained on a Waters ACQUITY SQD2 UPLC / MS system. GC-MS data were collected using an Agilent 7890B gas chromatograph and a 5977A mass spectrometer. Chromatography was performed using silica gel (Acme: Silica gel 60, 0.063-0.2 mm) and appropriate solvents as indicated in the examples. Flash purification was performed on Biotage's Isolera one or Reveleris X2 with KP-NH SNAP cartridges (Biotage) or Reveleris silica cartridges (Grace) with solvent gradients as indicated. Thin-layer chromatography (TLC) was performed on silica gel plates (Merck) with UV detection.

[0452] Intermediate 1: 4-(5-fluoro-3-isopropyl-2-isothiocyanatophenyl)-2-methoxypyridine

[0453] [ka]

[0454] Process A To a stirred solution of 2-bromo-4-fluoroaniline (9.0 g, 47.365 mmol) and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (8.35 g, 49.73 mmol) in 1,4-dioxane (45 ml) and water (9 ml) was added K2CO3 (13.09 g, 94.73 mmol) in a sealed tube at room temperature and the resulting mixture was purged with N2 for 10 min. After adding Pd(dppf)Cl2×CH2Cl2 (1.932 g, 2.368 mmol), the reaction mixture was heated to 80° C. After stirring for 16 h, the reaction mixture was diluted with water (100 ml) and extracted with ethyl acetate (2×100 ml). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude residue was purified by flash chromatography (SiO2 column, 0-10% ethyl acetate in hexanes) to give 4-fluoro-2-(prop-1-en-2-yl)aniline as a yellow oil (5.0 g, 70%). MS: 152.00 [M+H] + .

[0455] Process B To a solution of the compound from step A (5.0 g, 33.112 mmol) in MeOH (100 ml) was added 10% Pd / C (2.0 g) and the resulting mixture was hydrogenated at 50 psi for 12 h. The reaction mixture was filtered through Celite and the filtrate was evaporated under reduced pressure to give 4-fluoro-2-isopropylaniline as a black oil (5.0 g, 98%). MS: 154.04 [M+H] + .

[0456] Process C To a stirred solution of the compound obtained from step B (7.0 g, 45.751 mmol) in toluene (105 ml) was added N-bromosuccinimide (8.142 g, 45.751 mmol) in portions at 0° C., and the resulting mixture was stirred at 0° C. for 30 min under N2 atmosphere. After complete consumption of the starting material, the reaction mixture was quenched with ice water (100 ml) and extracted with ethyl acetate (2×100 ml). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The resulting crude residue was purified by flash chromatography (SiO2 column, 100% hexanes) to give 2-bromo-4-fluoro-6-isopropylaniline as a brown oil (8.0 g, 75%). MS: 232.03 [M+H] + .

[0457] Process D To a stirred solution of compound from step C (8.0 g, 34.482 mmol) and (2-methoxypyridin-4-yl)boronic acid (8.35 g, 49.73 mmol) in 1,4-dioxane (80 ml) and water (16 ml) was added Na2CO3 (9.13 g, 86.205 mmol) followed by Pd(dppf)Cl2×CHCl2 (2.81 g, 3.448 mmol) at room temperature and the resulting mixture was heated to 80° C. After stirring for 12 hours, the reaction mixture was filtered through Celite and the filtrate was diluted with water (100 ml) and extracted with ethyl acetate (2×100 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting crude residue was purified by flash chromatography (SiO2 column, 0-10% ethyl acetate in hexanes) to afford 4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)aniline as an off-white solid (5.7 g, 63.5%). 1H-NMR (500MHz DMSO-d6): δ = 8.27-8.21 (dd, 1H), 7.03-7.02 (dd, 1H), 6.94-6.92 (dd, 1H), 6.82-6.82 (s,1H), 6.74-6.72 (dd, 1H), 4.47 (s, 2H), 3.89 (s, 3H), 3.08-3.03 (m, 1H), 1.18-1.16 (d, 6H). MS: 261.44 [M+H] + .

[0458] Process E A solution of compound from step D (500 mg, 1.92 mmol) in CS2 (1.16 mL, 19.20 mmol) and NEt3 (0.53 mL, 3.84 mmol) was stirred at 0° C. for 30 min, then a solution of Boc2O (0.88 mL, 3.84 mmol) in EtOH (3 mL) was added dropwise at 0° C., followed by a catalytic amount of DMAP (10 mg). The resulting mixture was allowed to warm to room temperature and stirred for 72 h. After complete consumption of the starting material, the reaction mixture was concentrated under reduced pressure. The crude residue was purified by flash chromatography (SiO2 column, 0-10% ethyl acetate in hexanes) to give 4-(5-fluoro-3-isopropyl-2-isothiocyanatophenyl)-2-methoxypyridine (0.380 g, 65.3%). 1 H-NMR (400MHz CDCl3): δ = 8.28-8.26 (d, 1H), 7.05-7.02 (d, 1H), 6.95-6.89 (m, 2H), 6.79 (bs, 1H), 4.15-4.09 (m, 1H), 4.00 (s, 3H), 3.32-3.28 (m, 1H), 1.30-1.25 (m, 6H). MS: 303.20 [M+H] + .

[0459] Intermediate 2: 4-(4-isothiocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine

[0460] [ka]

[0461] Process A To a stirred solution of 2,3-dihydro-1H-inden-4-amine (25.0 g, 187.70 mmol) and trimethylamine (32.5 mL, 244.01 mmol) in DCM (400 mL) was added acetic anhydride (20 mL, 225.24 mmol) in one portion at 0° C. and the reaction mixture was allowed to warm slowly to room temperature. After stirring for 2 h, the reaction mixture was diluted with water (500 mL), extracted with DCM (2×500 mL), and the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give N-(2,3-dihydro-1H-inden-4-yl)acetamide as an off-white solid (32.5 g, 99%). 1 H-NMR (400MHz CDCl3): δ = 7.74-7.72 (d, 1H), 7.17-7.13 (t, 1H), 7.03-7.01 (d,1H), 6.95 (brs,1H), 2.97-2.93 (t, 2H), 2.83-2.79 (t, 2H), 2.19 (s, 3H), 2.15-2.07 (m, 2H). MS:176.22 [M+H] + .

[0462] Process B To a stirred solution of the compound from step A (30.0 g, 0.171 mol) in toluene (400 ml) was added p-toluenesulfonic acid (17.93 g, 0.094 mol) followed by Pd(OAc)2 (1.91 g, 0.008 mol) at room temperature. After stirring for 30 min, N-bromosuccinimide (33.569 g, 0.188 mol) was added and the reaction mixture was stirred for an additional 2 h. The reaction mixture was diluted with ice water (500 ml) and extracted with ethyl acetate (2 x 500 ml). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude residue was triturated with diethyl ether (200 ml), filtered and dried to give N-(5-bromo-2,3-dihydro-1H-inden-4-yl)acetamide as an off-white solid (33.0 g, 76%). 1H-NMR (400MHz CDCl3): δ = 7.36-7.34 (d, 1H), 7.01-6.98 (d, 1H), 2.92-2.85 (m, 4H), 2.22 (s, 3H), 2.10-2.03(m, 2H). MS: 254.19 [M+H] + .

[0463] Process C To a stirred solution of compound from step B (33.0 g, 129.92 mmol) in EtOH (200 ml) was added concentrated HCl (230 ml) at 0° C., then the mixture was heated at 80° C. After stirring for 48 h, the reaction mixture was cooled to 0° C. The solid that formed was filtered through a Buchner funnel, washed with ice-cold water (200 ml) and dried to give 5-bromo-2,3-dihydro-1H-inden-4-amine as an off-white solid (22.0 g, 80%). 1 H-NMR (500MHz DMSO-d6): δ = 7.12-7.10 (d, 1H), 6.42-6.41 (d, 1H), 2.77-2.75 (t, 2H), 2.72-2.69 (t, 2H), 2.01-1.98 (m, 2H). MS: 212.22 [M+H] + .

[0464] Process D To a stirred solution of compound from step C (5.0 g, 0.0235 mol) and (2-methoxypyridin-4-yl)boronic acid (5.4 g, 0.035 mol) in 1,4-dioxane (120 ml) and water (30 ml) was added K2CO3 (6.5 g, 0.0471 mol) in one portion at room temperature and the resulting mixture was degassed by bubbling N2 for 10 min. Then Pd(dppf)Cl2×CH2Cl2 (0.96 g, 0.0013 mol) was added at room temperature and the mixture was heated to 80° C. After stirring for 3 h, the reaction mixture was filtered through Celite and the filtrate was diluted with water (400 ml) and extracted with ethyl acetate (2×300 ml). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The resulting crude residue was purified by flash chromatography (SiO2 column, 0-40% ethyl acetate in hexanes) to afford 5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (4.0 g, 71.4%) as an off-white solid. 1 H-NMR (500MHz CDCl3): δ = 8.21-8.20 (d, 1H), 7.01-6.99 (d, 1H), 6.98-6.96 (d, 1H), 6.85 (s,1H), 6.76-6.75 (d, 1H), 3.98 (s,3H), 3.74 (brs, 2H), 2.97-2.94 (t, 2H), 2.77-2.74 (t, 2H), 2.19-2.14 (m, 2H). MS: 241.36 [M+H] + .

[0465] Process E A solution of the compound from step D (500 mg, 2.08 mmol) in CS2 (1.5 mL, 20.82 mmol) and NEt3 (0.58 mL, 4.16 mmol) was stirred at 0° C. for 30 min, then a solution of Boc2O (0.95 mL, 4.16 mmol) in EtOH (3 mL) was added dropwise at 0° C., followed by a catalytic amount of DMAP (10 mg). The resulting mixture was allowed to warm to room temperature and stirred. After stirring for 72 h, the reaction mixture was concentrated under reduced pressure. The crude residue was purified by flash chromatography (SiO2 column, 0-10% ethyl acetate in hexanes) to give 4-(4-isothiocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine (0.3 g, 50.84%). 1 H-NMR (400MHz CDCl3): δ = 8.24-8.23 (d, 1H), 7.21-7. (d, 1H), 7.16-7.14 (d, 1H), 6.99-6.97 (d, 1H), 6.82 (bs, 1H), 3.98 (s, 3H), 3.11-3.07 (m, 2H), 2.98-3.02 (m, 2H), 2.22-2.14 (m, 2H). MS: 283.17 [M+H] + .

[0466] Intermediate 3: 4-isothiocyanato-8-methyl-1,2,3,5,6,7-hexahydro-s-indacene

[0467] [ka]

[0468] Process A: To a stirred solution of 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (3.0 g, 17.31 mmol), ACN (45 ml), NBS (3.389 g, 19.04 mmol) and NEt3 (0.53 ml, 3.84 mmol) were added and the resulting mixture was stirred at room temperature. After stirring for 2 h, the reaction mixture was concentrated under reduced pressure. The crude residue was diluted with ethyl acetate (200 ml) and washed with brine (100 ml). The organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure. The resulting crude material was purified by romatography (SiO2 column, 2-10% ethyl acetate in hexane) to give 8-bromo-1,2,3,5,6,7-hexahydro-s-indacen-4-amine (2.9 g, 89.55%). 1 H-NMR (400MHz CDCl3): δ = 3.44 (s, 2H), 2.92-2.88 (t, 4H), 2.81-2.77 (t, 4H), 2.17-2.09 (m, 4H). MS: 252.11 [M+H] + .

[0469] Process B: A sealed tube was charged with compound from step A (1.5 g, 5.948 mmol), NBS (3.389 g, 19.04 mmol), methylboronic acid (0.534 g, 8.922 mmol), NEt3 (0.53 ml, 3.84 mmol), K2CO3 (2.46 g, 17.84 mmol) in 1,4-dioxane (25 ml) and H2O (6 ml) and the mixture was purged with N2 for 10 min followed by the addition of Pd(PPh3)4 (0.343 g, 0.297 mmol). The resulting mixture was heated at 100° C. After stirring for 8 h, the mixture was diluted with water (30 ml) and extracted with ethyl acetate (100 ml). The organic layer was washed with brine (100 ml), dried over Na2SO4, filtered and evaporated under reduced pressure. The resulting crude residue was purified by flash chromatography (SiO2 column, 0-10% ethyl acetate in hexanes) to give 8-methyl-1,2,3,5,6,7-hexahydro-s-indacen-4-amine (0.9 g, 88.27%). MS: 187.29 [M+H]+ .

[0470] Process C: A solution of the compound from step B (0.100 g, 0.534 mmol) in CS2 (0.32 ml, 5.347 mmol) and NEt3 (0.074 ml, 0.534 mmol) was stirred at 0° C. for 30 min, then a solution of Boc2O (1.0 ml, 0.534 mmol) in EtOH (2 ml) was added dropwise at 0° C., followed by a catalytic amount of DMAP (2 mg, 0.016 mmol) and the resulting mixture was allowed to warm to room temperature. After stirring for 5 h, the mixture was concentrated under reduced pressure to give 4-isothiocyanato-8-methyl-1,2,3,5,6,7-hexahydro-s-indacene (0.120 g, 91%). MS: 229.34 [M+H] + .

[0471] Intermediate 4: 4-(7-Fluoro-4-isothiocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine

[0472] [ka]

[0473] Process A: To a mixture of 7-fluoro-2,3-dihydro-1H-inden-1-one (10 g, 0.0666 mol) in concentrated sulfuric acid (80 ml) at -15°C, a solution of nitric acid (30 ml) in concentrated sulfuric acid (20 ml) was added dropwise and the reaction mixture was stirred at -15°C for 10 min. The mixture was quenched with water (1000 ml) at 0°C and extracted with EtOAc (3 x 500 ml). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting crude residue was purified by flash chromatography (SiO2 column 230-400 mesh, 0-50% ethyl acetate in petroleum ether) to give 7-fluoro-4-nitro-2,3-dihydro-1H-inden-1-one (6.2 g, 47%) as a yellow solid. MS: 196.02 [M+H] + .

[0474] Process B: To a solution of compound from step A (6 g, 13.95 mmol) in MeOH (60 ml) was added NaBH4 (2.27 g, 61.53 mmol) in portions and the resulting mixture was stirred at 15° C. After stirring at 15° C. for 1 h, the mixture was poured into water (500 ml) and extracted with EtOAc (2×500 ml). The combined organics were washed with brine (200 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give 7-fluoro-4-nitro-2,3-dihydro-1H-inden-1-ol (7 g, crude) as a brown oil. MS: 197.82 [M+H] + .

[0475] Process C: To a solution of compound from step B (6 g, 0.03045 mol) in TFA (60 ml) was added triethylsilane (24.5 ml, 0.1522 mol) in one portion. The resulting reaction mixture was heated at 50° C. After stirring at 50° C. for 4 h, the mixture was concentrated under reduced pressure and quenched with 1M aqueous NaOH (100 ml). The resulting mixture was extracted with EtOAc (3×100 ml). The combined organics were washed with brine (50 ml), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give fluoro-7-nitro-2,3-dihydro-1H-indene (8 g, crude) as a brown oil.

[0476] Process D: To a solution of compound from step C (5.5 g, 0.03038 mol) in MeOH (60 ml) under nitrogen atmosphere was added 10% Pd / C (9.6 g, 50% wet) in one portion and the reaction mixture was stirred under H2 atmosphere at 25°C. After stirring for 12 h, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2 column 230-400 mesh, 0-60% ethyl acetate in petroleum ether) to give 7-fluoro-2,3-dihydro-1H-inden-4-amine (4.5 g, 97%) as a brown solid. MS: 152.02 [M+H] + .

[0477] Process E: To a stirred solution of compound from step D (4.5 g, 0.02980 mol) in toluene (45 ml) was added NBS (10.5 g, 0.02980 mol) in one portion at 25° C. The resulting dark brown mixture was stirred at 25° C. After 30 min, the reaction mixture was quenched with saturated aqueous Na2SO3 (150 ml) and extracted with EtOAc (2×150 ml). The combined organic phases were washed with brine (100 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2 column 230-400 mesh, 0-20% ethyl acetate in petroleum ether) to give 5-bromo-7-fluoro-2,3-dihydro-1H-inden-4-amine (4 g, 58%) as a brown solid. MS: 230.06 [M+H] + .

[0478] Process F: To a stirred solution of compound from step E (4 g, 0.01754 mol) in dioxane (40 ml) and water (10 ml) was added K2CO3 (4.84 g, 0.03508 mol) and the resulting mixture was degassed with nitrogen for 10 h. To this mixture was added Pd(dppf)Cl2×CH2Cl2 complex (816 mg, 0.00877 mol) in one portion under N2 atmosphere. The reaction mixture was then heated to 80° C. After stirring at 80° C. for 16 h, the mixture was quenched with water (50 ml) and extracted with EtOAc (3×50 ml). The combined organics were washed with brine (30 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2 column 230-400 mesh, 0-30% ethyl acetate in petroleum ether) to give 7-fluoro-5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (4 g, 91%) as a brown solid. MS: 259.24 [M+H] + .

[0479] Process G: To a solution of compound from step F (4 g, 0.01550 mol) in EtOH (40 ml), CS2 (2.3 ml, 0.04651 mmol) and Et3N (6.4 ml, 0.04651 mol) were added and the reaction mixture was stirred at room temperature. After stirring for 16 h, the reaction mixture was concentrated in vacuo. The crude compound was purified by silica gel column chromatography (SiO2 column 230-400 mesh, 0-30% ethyl acetate in petroleum ether) to give 4-(7-fluoro-4-isothiocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine (1.1 g, 24%) as a light brown solid. MS: 301.29 [M+H] + .

[0480] Intermediate 5: 4-Isothiocyanato-8-(trifluoromethyl)-1,2,3,5,6,7-hexahydro-s-indacene

[0481] [ka]

[0482] Process A: 1,2,3,5,6,7-Hexahydro-s-indacen-4-amine (2.0 g, 11.54 mmol) was added to a cooled solution of H2SO4 (10 ml) at -15°C, followed by portionwise addition of NaNO3 (0.981 g, 11.543 mmol) at -15°C, and the resulting mixture was stirred. After stirring at -15°C for 30 min, the reaction mixture was quenched with ice water (20 ml) and stirred for an additional 15 min, resulting in the precipitation of a brown solid. The solid was filtered off, washed with ice water (20 ml), and thoroughly dried under vacuum to give 8-nitro-1,2,3,5,6,7-hexahydro-s-indacen-4-amine (1.6 g, 63.54%) as a brown solid. 1 H-NMR (400MHz CDCl3): δ =7.26 (s, 2H), 4.05 (brs, 4H), 2.86-2.84 (m, 2H), 2.11-2.09 (m, 2H), 1.56 (brs, 4H) MS: 219.12 [M+H]+ .

[0483] Process B: To a stirred solution of silver(I) fluoride (4.359 g, 34.362 mmol) in ACN (30 ml) was added trifluoromethyltrimethylsilane (5.08 ml, 34.36 mmol) dropwise at -78°C and the resulting mixture was stirred for 15 minutes. The reaction mixture was allowed to warm to room temperature and stirred for 30 minutes until a dark grey suspension was observed. To a solution of the compound from step A (1.5 g, 6.87 mmol) in ACN (30 ml) was added 11.6 N HCl (1.184 ml, 13.745 mmol) at -15°C, followed by dropwise addition of t-BuNO2 (0.906 ml, 7.559 mmol) at -15°C and stirred for 15 minutes. To this was added the previously prepared AgCF3 suspension at -78°C. The resulting reaction mixture was allowed to stand and slowly warm to room temperature. After stirring for 6 h, the resulting residue was diluted with ethyl acetate (30 ml), filtered through a pad of Celite and washed with EtOAc (60 ml). The filtrate was washed with brine (50 ml). The organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure. The crude compound was purified by flash chromatography (SiO2 column, 0-30% ethyl acetate in petroleum ether) to give 4-nitro-8-(trifluoromethyl)-1,2,3,5,6,7-hexahydro-s-indacene (0.25 g, 13%) as a colorless liquid. MS: 271.1 [M] + .

[0484] Process C: To a stirred solution of the compound from step B (0.25 g, 0.921 mmol) in EtOH (10 ml) and H2O (3 ml) was added NH4Cl (0.295 g, 5.530 mmol) followed by iron powder (0.257 g, 4.608 mmol) in one portion at room temperature and the resulting mixture was refluxed for 2 h. The reaction mixture was diluted with ethyl acetate (20 ml), filtered through a pad of Celite and washed with EtOAc (30 ml). The filtrate was washed with brine (30 ml). The organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure to give crude 8-(trifluoromethyl)-1,2,3,5,6,7-hexahydro-s-indacen-4-amine (0.20 g, crude) as a colorless liquid. MS: 242.09 [M+H] + .

[0485] Process D: To the compound obtained from step C (0.180 g, 0.746 mmol), 1,1'-thiocarbonyldiimidazole (0.199 g, 1.119 mmol) was added in one portion at room temperature and the resulting mixture was heated to 80°C. After stirring at 80°C for 30 minutes, the reaction mixture was diluted with 10% diethyl ether in n-pentane (20 ml) and stirred for 5 minutes. The resulting mixture was filtered through a silica bed, washed with 10% diethyl ether in n-pentane (40 ml) and the filtrate was evaporated under reduced pressure to give 4-isothiocyanato-8-(trifluoromethyl)-1,2,3,5,6,7-hexahydro-s-indacene (0.22 g, crude) as a colorless gum. MS: 283.1 [M] + .

[0486] Intermediate 6: 4-Fluoro-7-isothiocyanato-2,3-dihydro-1H-indene

[0487] [ka]

[0488] Process A A solution of 2,3-dihydro-1H-inden-4-amine (15 g, 112.60 mmol) in acetic anhydride (50 ml) was stirred at room temperature. After stirring for 1 h, the reaction mixture was concentrated under reduced pressure to give N-(2,3-dihydro-1H-inden-4-yl)acetamide (17 g, 86.2%) as an off-white solid. 1 H-NMR (400 MHz CDCl3): δ = 7.73-7.71 (d, 1H), 7.16-7.12 (t, 1H), 7.03-7.01 (d, 2H), 2.96-2.92 (t, 2H), 2.82-2.78 (t, 2H), 2.18 (s, 3H), 2.14-2.06 (m, 2H). MS: 176.06 [M+H] + .

[0489] Process B To a stirred solution of compound from step A (16 g, 91.31 mmol) in THF (160 ml) and water (160 ml) was added Selectfluor (64.6 g, 182.62 mmol) at room temperature and the resulting mixture was heated to 60° C. After stirring at 60° C. for 16 h, the reaction mixture was diluted with water (500 ml) and extracted with EtOAc (2×500 ml). The combined organic layers were washed with brine (100 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a crude mixture of N-(5-fluoro-2,3-dihydro-1H-inden-4-yl)acetamide and N-(7-fluoro-2,3-dihydro-1H-inden-4-yl)acetamide (20 g, crude) as a brown gummy solid. MS: 194.07 [M+H] + .

[0490] Process C A solution of the mixture of compounds from step B (20 g, 103.51 mmol) in 6N HCl (100 ml) was stirred at 100° C. After stirring at 100° C. for 6 h, the reaction mixture was basified with aqueous NaHCO3 at 0° C. The resulting mixture was stirred for 10 min and then extracted with EtOAc (2×500 ml) and water (100 ml). The combined organic layers were washed with brine solution (100 ml), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude mixture was purified by flash chromatography (SiO2 column, 0-10% ethyl acetate in petroleum ether) to give 5-fluoro-2,3-dihydro-1H-inden-4-amine (1.2 g, 9.2%) as the first eluting isomer. 1 H-NMR (400 MHz DMSO-d6): δ = 6.77-6.72 (m, 1H), 6.39-6.32 (m, 1H), 4.69 (s, 2H), 2.79-2.72 (t, 2H), 2.69-2.65 (t, 2H), 2.02-1.95 (m, 2H). MS: 151.98 [M+H] +. 7-Fluoro-2,3-dihydro-1H-inden-4-amine (1 g, 7.7%) was obtained as the second eluting isomer. 1 HNMR (400 MHz DMSO- d6): δ = 6.65-6.60 (t, 1H), 6.36-6.33 (m, 1H), 4.837 (s, 2H), 2.82- 2.78 (t, 2H), 2.66-2.63 (t, 2H), 2.04-1.97 (m, 2H). MS: 151.98 [(M+H)]+.

[0491] Process D A stirred solution of 7-fluoro-2,3-dihydro-1H-inden-4-amine (1.0 g, 6.614 mmol) from step C and 1,1'-thiocarbonyldiimidazole (1.76 g, 9.922 mmol) was heated to 80° C. in a sealed tube. After stirring at 80° C. for 10 min, the reaction mixture was diluted with DCM (10 ml) and concentrated under reduced pressure. The crude product was purified by flash chromatography (SiO column, 100% petroleum ether) to give 4-fluoro-7-isothiocyanato-2,3-dihydro-1H-indene (1.0 g, 78.7%) as a yellow liquid. 1 H-NMR (400 MHz CDCl3) : δ = 6.97-6.94 (t, 1H), 6.82-6.78 (t, 1H), 2.05-2.01 (t, 2H), 2.99-2.95 (t, 2H), 2.20-2.12 (m, 2H). MS: 193.1 [M] + .

[0492] Example 1 Ethyl 2-{[4-fluoro-2-(2-methoxypyridin-4-yl)-6-(propan-2-yl)phenyl]amino}-5-(1,2-oxazol-3-yl)-4,5-dihydro-1,3-oxazole-5-carboxylate

[0493] [ka]

[0494] Process A To a stirred solution of isoxazole-3-carboxylic acid (25.0 g, 221.21 mmol) and N,O-dimethylhydroxylamine hydrochloride (25.89 g, 265.46 mmol) in DCM (250 ml) cooled to 0° C., DMAP (27.02 g, 221.21 mmol), EDC.HCl (50.96 g, 265.46 mmol), and Et3N (46.2 ml, 331.6 mmol) were added, and the resulting mixture was allowed to warm to room temperature and stirred under N2 atmosphere for 6 h. After complete consumption of the starting material, the reaction mixture was diluted with H2O (200 ml) and extracted with DCM (2×500 ml). The organic layer was evaporated under reduced pressure. The resulting crude residue was purified by flash chromatography (SiO2 column, 0-20% ethyl acetate in hexanes) to give N-methoxy-N-methylisoxazole-3-carboxamide as a pale yellow liquid (28 g, 82.3%). 1 H-NMR (400MHz CDCl3): δ = 8.48-8.47 (d, 1H), 6.72 (s, 1H), 3.98 (s, 3H), 3.40 (s,3H). MS: 156.90 [M+H] + .

[0495] Process B To a stirred solution of compound from step A (6.0 g, 38.42 mmol) in dry THF (60 ml) cooled to 0° C. under N2 atmosphere was added methylmagnesium bromide (3 M solution in diethyl ether, 19.2 ml, 57.64 mmol) dropwise over 10 min. After complete consumption of the starting material, the reaction mixture was quenched with ice water, extracted with diethyl ether (2×200 ml), dried over Na2SO4, filtered and evaporated under reduced pressure (water bath maintained at room temperature) to give 1-(isoxazol-3-yl)ethan-1-one as a pale yellow liquid (4.5 g, crude). MS: 112.01 [M+H] + .

[0496] Process C: To a stirred solution of compound from step B (4.5 g, 40.50 mmol) in THF (45 ml) was added phenyltrimethylammonium tribromide (16.74 g, 44.55 mmol) and the mixture was stirred at room temperature under N2 atmosphere for 16 h. After complete consumption of the starting material as monitored by TLC, the reaction mixture was diluted with diethyl ether (30 ml), filtered through Celite and washed with diethyl ether (30 ml). The filtrate was evaporated under reduced pressure to give 2-bromo-1-(isoxazol-3-yl)ethan-1-one as a brown liquid (9 g, crude). MS: 192 [M+2] + .

[0497] Process D: To a stirred solution of compound from step C (9 g, 47.36 mmol) in ethanol (90 ml) was added SeO2 (10.5 g, 94.73 mmol). The reaction mixture was heated to 80° C. After stirring for 16 h, the reaction mixture was filtered through Celite and the filtrate was evaporated under reduced pressure. The resulting crude residue was diluted with brine (100 ml) and extracted with ethyl acetate (200 ml). The organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure to give ethyl 2-(isoxazol-3-yl)-2-oxoacetate as a brown liquid (6 g, crude). MS: 170.28 [M+H] + .

[0498] Process E: To a stirred solution of compound from step D (6 g, 35.47 mmol) in nitromethane (50 ml, 0.92 mol) was added NEt3 (0.98 ml, 7.09 mmol) at room temperature and the resulting mixture was stirred at room temperature for 2 h. After complete consumption of the starting material as monitored by TLC, the reaction mixture was concentrated under reduced pressure. The resulting crude residue was purified by flash chromatography (silica gel, 120 g column; 0-20% ethyl acetate hexane) to give ethyl 2-hydroxy-2-(isoxazol-3-yl)-3-nitropropanoate as a light brown liquid (2.9 g, 35.62% for 4 steps). 1H-NMR (400MHz CDCl3): δ = 8.44-8.44 (d, 1H), 6.49-6.48 (d, 1H), 5.46 (d, 1H), 5.01-4.97 (d, 1H), 4.47-4.39 (m, 2H), 4.28-4.36 (m, 1H), 1.33-1.26 (t, 3H). MS: 231.10 [M+H] + .

[0499] Process F: To a stirred solution of compound from step E (1.2 g, 5.21 mmol) in acetic acid (12 ml) cooled to 10° C. was added zinc dust (6.81 g, 104.26 mmol). The resulting mixture was allowed to warm slowly to room temperature. After stirring for 1 h, the mixture was filtered through Celite. The Celite pad was rinsed with ethyl acetate (15 ml) and the filtrate was evaporated under reduced pressure to give ethyl 3-amino-2-hydroxy-2-(isoxazol-3-yl)propanoate as a yellow gummy compound (1.9 g, crude). MS: 201.27 [M+H] + .

[0500] Process G: To a stirred solution of compound from step F (1000 mg, 4.99 mmol) in DCM (15 ml) was added 4-(5-fluoro-3-isopropyl-2-isothiocyanatophenyl)-2-methoxypyridine intermediate 1 (377.60 mg, 1.24 mmol) and NEt3 (2.09 ml, 14.98 mmol) and the resulting reaction mixture was stirred at room temperature. After stirring for 16 h, the reaction mixture was concentrated under reduced pressure. The resulting crude residue was purified by flash chromatography (SiO2 column, 0-50% ethyl acetate in hexanes) to give ethyl 3-(3-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)thioureido)-2-hydroxy-2-(isoxazol-3-yl)propanoate as a gummy solid (0.530 g, 21.09% for two steps). MS: 503.34 [M+H] + .

[0501] Process H: To a stirred solution of compound from step G (530 mg, 1.05 mmol) in acetonitrile (3 ml) was added N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (404.33 mg, 2.10 mmol) followed by EtN (0.44 ml, 3.16 mmol). After stirring at room temperature for 16 h, the reaction mixture was quenched with ice (15 ml) and extracted with DCM (2 x 30 ml), the organic layer was separated, dried over NaSO, filtered and concentrated under reduced pressure. The resulting crude residue was purified by flash chromatography (SiO column, 0-50% ethyl acetate in hexanes) to afford ethyl 2-((4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)amino)-5-(isoxazol-3-yl)-4,5-dihydrooxazole-5-carboxylate as an off-white solid (0.130 g, 26.80%). 1 H-NMR (400 MHz DMSO-d6): δ = 8.88 (bs, 1H), 8.02-8.01 (d, 1H), 7.05-7.03 (d, 1H), 6.94-6.93 (d, 1H), 6.88-6.87 (d, 1H), 6.73 (s, MS: 469.50 [M+H] + .

[0502] Example 2 Optically pure ethyl 2-{[4-fluoro-2-(2-methoxypyridin-4-yl)-6-(propan-2-yl)phenyl]amino}-5-(1,2-oxazol-3-yl)-4,5-dihydro-1,3-oxazole-5-carboxylate

[0503] [ka]

[0504] The optically pure compound was obtained as an off-white solid by chiral SFC separation starting from the racemic mixture of Example 1. (Chiral Pak IG (30×250) mm, 5μ; co-solvent: 10% (100% ethanol), outlet pressure: 100 bar; temperature: 30° C.); first eluting peak. 1 H-NMR (400MHz DMSO-d6): δ = 8.87 (bs, 1H), 8.02-8.01 (d, 1H), 7.04-7.02 (d, 1H), 6.94-6.93 (d, 1H), 6.88-6.86 (d, 1H), 6.73 (s, MS: 469.40 [M+H] + .

[0505] Example 3 Optically pure ethyl 2-{[4-fluoro-2-(2-methoxypyridin-4-yl)-6-(propan-2-yl)phenyl]amino}-5-(1,2-oxazol-3-yl)-4,5-dihydro-1,3-oxazole-5-carboxylate The other optically pure compound was obtained as an off-white solid as the second eluting peak. 1 H-NMR (400MHz DMSO-d6): δ = 8.87 (bs, 1H), 8.02-8.01 (d, 1H), 7.05-7.02 (d, 1H), 6.94-6.93 (d, 1H), 6.88-6.86 (m, 1H), 6.74 (s, MS: 469.41 [M+H] + .

[0506] Following the above procedure, the following preparation examples were prepared.

[0507] [Table 3A]

[0508] [Table 3B]

[0509] [Table 3C]

[0510] [Table 3D]

[0511] Example 10 2-{[4-fluoro-2-(2-methoxypyridin-4-yl)-6-(propan-2-yl)phenyl]amino}-5-(1,2-oxazol-3-yl)-4,5-dihydro-1,3-oxazole-5-carboxylic acid

[0512] [ka]

[0513] To a stirred solution of the ester of Example 1 (30 mg, 0.064 mmol) in THF (0.1 ml) was added sodium trimethylsilanolate (8.6 mg, 0.076 mmol) at room temperature, and the reaction mixture was stirred at room temperature for 1 h. After complete consumption of the starting material as monitored by TLC, the reaction mixture was concentrated under reduced pressure and purified by preparative HPLC to give 2-((4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)amino)-5-(isoxazol-3-yl)-4,5-dihydrooxazole-5-carboxylic acid as an off-white solid (0.010 g, 37.31%). 1H-NMR (400MHz DMSO-d6): δ = 8.71 (bs, 1H), 7.97-7.96 (d, 1H), 7.01-6.99 (bs, 2H), 6.85-6.83 (d, 1H), 6.73 (s, 1H), 6.31 (s, 1H), 3.81 (bs, 5H), 3.12-3.11 (bs, 1H), 1.11-1.08 (t, 6H). MS: 441.35 [M+H] + .

[0514] Following the saponification procedure described in Example 10, the following preparations were synthesized.

[0515] [Table 4A]

[0516] [Table 4B]

[0517] [Table 4C]

[0518] (Example 28) Optically pure lithium 5-(isoxazol-4-yl)-2-((8-phenyl-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)amino)-4,5-dihydrooxazole-5-carboxylate

[0519] [ka]

[0520] To a stirred solution of Example 16 (30 mg, 0.065 mmol) in THF (1 ml) and water (0.2 ml) was added LiOH.HO (3.02 mg, 0.072 mmol) and the resulting mixture was stirred with nitrogen. After stirring for 1 h, the reaction mixture was concentrated under reduced pressure. The resulting residue was triturated with diethyl ether (5 ml) followed by n-pentane (2 ml) and dried under reduced pressure to give optically pure lithium 5-(isoxazol-4-yl)-2-((8-phenyl-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)amino)-4,5-dihydrooxazole-5-carboxylate (27 mg, 92%) as an off-white solid. 1 H-NMR (400 MHz DMSO-d6): δ = 8.74 (s, 1H), 7.39-7.24 (m, 5H), 6.39 (s, 1H), 3.93 (br s, 1H), 3.81 (br s, 1H), 2.66-2.62 (t, 8H), 1.86-1.83 (m, 4H).MS: [(M-Li)+2H] + .

[0521] Biological assay description NLRP3 inhibition assay The following assay was used to determine the inhibitory activity of test compounds on the NLRP3 inflammasome pathway using the common stimuli nigericin (Invivogen) or monosodium urate crystals (MSU) (Invivogen).

[0522] cell culture Human monocyte-like cells were cultured in RPMI-1640 Glutamax medium supplemented with 10% heat-inactivated FCS and 50 U / ml penicillin-streptomycin (Life Technologies).

[0523] NLRP3 inflammasome pathway activation assay Human monocyte-like cells were seeded at 75,000 cells per well in 96-well plates and differentiated overnight into macrophages with 10 ng / ml PMA (phorbol myristate acetate). The following day, medium containing 10 ng / ml LPS (lipopolysaccharide) was added. After 3 h of LPS priming, test compounds at concentrations ranging from 100 μM to 6 nM were added 30 min prior to stimulation of the NLRP3 inflammasome pathway with nigericin 3.75 μM or MSU 200 μg / ml for 3 h.

[0524] Measurement of IL-1β For IL-1β quantification, the supernatants were analyzed using a HTRF kit according to the manufacturer's instructions (Cisbio 62HIL1BPEH). Briefly, 8 μl of sample was mixed with 4 μl of anti-IL1β cryptate antibody (40x) and anti-IL1β XL antibody (40x) in a 384-well ProxiPlate™ microplate, then incubated overnight at room temperature. Reading was performed using an EnVision reader (PerkinElmer).

[0525] I C 50 (concentration corresponding to 50% inhibition) was determined using GraphPad Prism 8.

[0526] The compounds of the following examples were measured:

[0527] [Table 5]

[0528] Test compounds demonstrated inhibition of IL-1beta release in human monocyte-like cells: (A) using MSU or nigericin as activators; (B) in a human whole blood assay using ATP as an activator, see Table 1.

Claims

1. Compounds of formula (I) 【Chemistry 1】 or a stereoisomer, racemic mixture, tautomer, polymorph, pharma- ceutically acceptable salt, prodrug, hydrate, or solvate thereof. [In the formula, R 0 is H or C 1 ~C 3 is alkyl; R 2 is hydrogen, C 1 ~C 6 Alkyl, and C 3 ~C 6 independently selected from the group consisting of cycloalkyl; R 3 is independently selected from the group consisting of a 5- or 6-membered heterocycloalkyl containing 1 or 2 heteroatoms, an aryl, or a heteroaryl containing 1 or 2 heteroatoms, the heteroatoms being independently selected from N, S, and O, and at least one heteroatom being independently selected from O and S; and the heterocycloalkyl, aryl, or heteroaryl is selected from the group consisting of -C 1 ~C 6 Alkyl, -OC 1 ~C 6 Alkyl, -halogen, or -C 1 ~C 6 Optionally substituted with alkyl-OH; R 1 is as follows: 【Chemistry 2】 (In the formula, 【Chemistry 3】 C in any possible position 1 ~C 6 may be optionally substituted with alkyl; A ring system selected from the group consisting of: Z is CH 2 and O; n is 0 or 1; R a is C 1 ~C 3 Alkyl, C 1 ~C 3 independently selected from the group consisting of haloalkyl and phenyl; R b -C 1 ~C 6 Alkyl, -OC 1 ~C 6 Alkyl or -OC 1 ~C 6 heteroaryl optionally substituted with haloalkyl; R c is hydrogen or CH 3 independently selected from the group consisting of: R d is independently selected from the group consisting of hydrogen or halogen; R e -C 1 ~C 6 Independently selected from the group consisting of alkyl, heteroaryl, and -C 1 ~C 6 Alkyl, -C 1 ~C 6 Haloalkyl, -OC 1 ~C 6 Alkyl or -OC 1 ~C 6 optionally substituted with haloalkyl; R f is halogen and -CF 3 independently selected from the group consisting of: R h -C 1 ~C 6 Independently selected from the group consisting of alkyl and heteroaryl, heteroaryl being -C 1 ~C 6 Alkyl, -C 1 ~C 6 Haloalkyl, -OC 1 ~C 6 Alkyl or -OC 1 ~C 6 optionally substituted with haloalkyl

2. Formula (I) 【Chemistry 4】 or a stereoisomer, racemic mixture, tautomer, polymorph, pharma- ceutically acceptable salt, prodrug, hydrate, or solvate thereof; R 1 , R 2 , and R 3 is as defined in claim 1, and R 0 But H.

2. The compound of claim 1.

3. R 1 is as defined in claim 1; R 2 But H or C 1 ~C 3 is alkyl; R 3 but, 【Chemistry 5】 independently selected from the group consisting of: Each of these is -C 1 ~C 6 Alkyl, -OC 1 ~C 6 Alkyl, -halogen, or -C 1 ~C 6 may be optionally substituted with alkyl-OH; 3. The compound of claim 2.

4. R 1 But, 【Chemistry 6】 (In the formula, R a is CH 3 , C.F. 3 and phenyl). 【Chemistry 7】 (In the formula, R b -C 1 ~C 6 Alkyl, -OC 1 ~C 6 Alkyl or -OC 1 ~C 6 pyridyl optionally substituted with haloalkyl; Z, R c and R d is as defined in claim 1) 【Chemistry 8】 (In the formula, R f is F;R e is branch C 3 ~C 6 Alkyl, and -C 1 ~C 6 Alkyl, -C 1 ~C 6 Haloalkyl, -OC 1 ~C 6 Alkyl or -OC 1 ~C 6 pyridyl optionally substituted with haloalkyl 【Chemistry 9】 (In the formula, R h and n are as defined in claim 1) 4. The compound according to claim 1, wherein the ring system is independently selected from the ring systems:

5. R 1 But, 【Chemistry 10】 (In the formula, R a is CH 3 , C.F. 3 or phenyl) 【Chemistry 11】 (In the formula, R b -C 1 ~C 6 Alkyl, -OC 1 ~C 6 Alkyl or -OC 1 ~C 6 pyridyl optionally substituted with haloalkyl; Z is CH 2 Or O and R c and R d is as defined in claim 1), or 【Chemistry 12】 (In the formula, R f is F;R e is independently selected from isopropyl and pyridyl, pyridyl being -C 1 ~C 6 Alkyl, -C 1 ~C 6 Haloalkyl, -OC 1 ~C 6 Alkyl or -OC 1 ~C 6 (Optionally substituted with haloalkyl) Independently selected from the ring systems 5. A compound according to any one of claims 1 to 4. 【Request 6】 【Chemical 13】 or a stereoisomer, racemic mixture, tautomer, polymorph, pharma- ceutically acceptable salt, prodrug, hydrate, or solvate thereof, selected from 6. A compound according to any one of claims 1 to 5.

7. 7. A pharmaceutical composition comprising a compound according to any one of claims 1 to 6, or a stereoisomer, racemic mixture, tautomer, polymorph, pharma- ceutically acceptable salt, prodrug, hydrate, or solvate thereof, and optionally at least one pharma- ceutically acceptable carrier, excipient, adjuvant, or additive.

8. 7. A compound according to any one of claims 1 to 6, or a stereoisomer, racemic mixture, tautomer, polymorph, pharma- ceutically acceptable salt, prodrug, hydrate, or solvate thereof, for use as a pharmaceutical.

9. A compound according to any one of claims 1 to 6, or a stereoisomer, racemic mixture, tautomer, polymorph, pharma- ceutically acceptable salt, prodrug, hydrate or solvate thereof, for use in the treatment, alleviation or prevention of a disease or disorder or abnormality responsive to modulation of a component of the NLRP3 inflammasome pathway and / or responsive to modulation of levels of IL-1 beta and / or IL-18.

10. 10. The compound for use according to claim 9, wherein the modulation is a reduction and / or inhibition of IL-1 beta.

11. 10. The compound for use according to claim 9, wherein the component of the inflammasome pathway is the NLRP3 inflammasome.

12. 12. A compound for use according to claim 9 or 11, wherein activation of the NLRP3 inflammasome pathway is inhibited.

13. The disease, disorder, or abnormality is Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, demyelination, viral encephalitis, epilepsy, stroke, atherosclerosis, asthma, allergic inflammation, cryopyrin-associated periodic fever syndrome (CAPS), Muckle-Wells syndrome (MWS), familial common cold autoinflammatory syndrome (FCAS), neonatal-onset multisystem inflammatory disease (NOMID), gout, pseudogout, inflammatory bowel disease, nonalcoholic fatty liver disease, nonalcoholic fatty liver disease, hypertension, myocardial infarction, oxalate-induced nephropathy, graft-versus-host disease, type 1 diabetes mellitus Disease, type 2 diabetes mellitus, edema (DME), geographic atrophy (GA), rheumatoid arthritis, myelodysplastic syndrome, familial Mediterranean fever (FMF), tumor necrosis factor receptor-associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD), hyperimmunoglobulinemia D, periodic fever syndrome (HIDS), interleukin-1 receptor antagonist deficiency (DIRA), Majeed syndrome, acne, suppurative arthritis, pyoderma gangrenosum, and acne vulgaris (PAPA), haploinsufficiency of A20 (HA20), PLCG2-associated antibody deficiency and immunoregulatory dysregulation (PLAID), childhood granulomatous arthritis ( PGA), PLCG2-associated autoinflammatory disease, antibody deficiency, and immune dysregulation (APLAID), sideroblastic anemia, periodic fever, and developmental delay with B-cell immunodeficiency (SIFD), chronic nonbacterial osteomyelitis (CNO), Sweet's syndrome, chronic relapsing multifocal osteomyelitis (CRMO), synovitis, pustular disease, acne, eczema, alopecia areata, actinic keratosis, hyperostosis, and osteitis syndrome (SAPHO), multiple sclerosis (MS), psoriasis, Behçet's disease, Sjögren's syndrome, Schnitzler's syndrome, chronic obstructive pulmonary disease (COPD), steroid-resistant asthma, asbestosis, silicosis, cystic adenocarcinoma Fibrosis, motor neuron disease, Huntington's disease, cerebral malaria, brain damage from pneumococcal meningitis, obesity, age-related macular degeneration (AMD), corneal infection, uveitis, dry eye, chronic kidney disease, diabetic nephropathy, alcoholic liver disease, skin contact hypersensitivity, sunburn, osteoarthritis, systemic juvenile idiopathic arthritis, adult-onset Still's disease, relapsing polychondritis, chikungunya virus, Ross River virus, influenza, HIV, coronavirus, dengue fever, Zika virus, hidradenitis suppurativa (HS), lung cancer metastasis, pancreatic cancer, gastric cancer, myelodysplastic syndrome, leukemia;and / or polymyositis, colitis, helminth infection, bacterial infection, abdominal aortic aneurysm, wound healing, depression, psychological stress, pericarditis including Dressler's syndrome, ischemia-reperfusion injury, frontotemporal dementia, HIV-associated neurocognitive disorder, coronavirus-associated inflammatory pathology including coronavirus associated respiratory distress syndrome (CARDS), and traumatic brain injury; preferably, the disorder is selected from Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, demyelination, multiple sclerosis, viral encephalitis, epilepsy, stroke, traumatic brain injury, spinal cord injury, atherosclerosis, asthma, allergic inflammation, cryopyrin-associated periodic fever syndrome (CAPS), gout, inflammatory bowel disease, non-alcoholic 13. The compound for use according to any one of claims 9 to 12, selected from chronic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), hypertension, myocardial infarction, oxalate-induced nephropathy, graft-versus-host disease, type 1 diabetes, type 2 diabetes, rheumatoid arthritis, myelodysplastic syndrome, antineutrophil cytoplasmic antibody-associated vasculitis (AAV), acute kidney disease, chronic kidney disease, lupus nephritis, anti-glomerular basement membrane (GMB) disease, IgA nephropathy, glomerulonephritis (GN), systemic lupus erythematosus (SLE), focal segmental glomerulosclerosis, minimal change disease (MCD), psoriatic arthritis, and hereditary relapsing fever (HRF), acne, atopic dermatitis, and hidradenitis suppurativa (HS);

14. 14. The compound for use according to claim 13, wherein the disease, disorder or abnormality is selected from Alzheimer's disease, Parkinson's disease, multiple sclerosis, cryopyrin-associated periodic fever syndrome (CAPS), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), hidradenitis suppurativa (HS), chronic kidney disease, and gout.

15. 13. Use of a compound according to any one of claims 1 to 6, or a stereoisomer, racemic mixture, tautomer, polymorph, pharma- ceutically acceptable salt, prodrug, hydrate or solvate thereof, as an analytical reference or in vitro screening tool.

16. Formula (II) 【Chemistry 14】 or a stereoisomer, racemic mixture, tautomer, polymorph, pharma- ceutically acceptable salt, prodrug, hydrate, or solvate thereof. (In the formula, W is S or O; R 0 , R 1 , R 2 and R 3 is as defined in any one of claims 1 to 6)

17. A method for preparing a compound of formula (I) according to any one of claims 1 to 6, comprising reacting a compound of formula (II) in the presence of a condensing agent 【Chemistry 15】 or a stereoisomer, racemic mixture, tautomer, polymorph, pharma- ceutically acceptable salt, prodrug, hydrate, or solvate thereof. (In the formula, W is S or O; R 0 , R 1 , R 2 and R 3 is as defined in any one of claims 1 to 6)

Images