Dihydrooxazoles and thiourea or urea derivatives that regulate the NLRP3 inflammasome pathway

Abstract

The present invention relates to novel compounds for treating, alleviating or preventing diseases, disorders and abnormalities that respond to modulation of NLRP3 inflammasome pathway components or inhibition of their activation. In particular, the inflammasome pathway component is the NOD-like receptor (NLR) family pyrin domain-containing protein 3 (NLRP3) inflammasome. More particularly, the compounds of the present invention have the ability to modulate the NLRP3 inflammasome pathway. In addition, the compounds of the present invention are suitable for treating, alleviating or preventing diseases, disorders and abnormalities that respond to modulation, particularly reduction, of IL-1β and / or IL-18 levels. #imgabs0#

Description

Field of the Invention

[0001] The present invention relates to novel compounds that can be used to treat, alleviate or prevent diseases, disorders and abnormalities that respond to modulation of NLRP3 inflammasome pathway components, particularly inhibition of their activation. In particular, the inflammasome pathway component is the NOD-like receptor (NLR) family pyrin domain-containing protein 3 (NLRP3) inflammasome. More particularly, the compounds of the present invention have the ability to modulate the NLRP3 inflammasome pathway, for example, to inhibit its activation. Moreover, the compounds of the present invention have the ability to modulate, particularly to reduce, IL-1β and / or IL-18 levels. The present invention relates to novel compounds for treating, alleviating or preventing diseases, disorders and abnormalities that respond to inhibition of NLRP3 inflammasome pathway activation. The present invention relates to novel compounds for treating, alleviating or preventing diseases, disorders and abnormalities that respond to modulation of IL-1β and / or IL-18 levels. The present invention relates to pharmaceutical compositions comprising the compounds, methods for using the compounds to treat various diseases, disorders or abnormalities that respond to the above-mentioned modulation, drugs containing them, and their uses. Background of the Invention

[0003] Inflammasome protein complex is a key component of inflammatory signal transduction. These complexes are assembled in response to a variety of danger signals, such as molecules from infectious agents (pathogen-associated molecular patterns, PAMPs) and altered host molecules, sterile tissue damage products and environmental factors (danger associated molecular patterns, DAMPs). The inflammasome family is composed of NALP1-14, IPAF and NAIP 1-6, wherein each family member provides specificity to different PAMPs / DAMPs (including nucleic acids, bacterial proteins, metabolites, protein aggregates and toxin activity) (Sharma, D. & Kanneganti, TD The cell biology of inflammasomes: mechanisms of inflammasome activation and regulation. J. Cell Biol. 213, 617–629 (2016)). Inflammasomes are typically composed of sensors (cytosolic pattern recognition receptors, PRRs) and adaptor proteins called apoptosis-associated speck-like proteins containing a caspase recruitment domain (CARD) (ASC) and effectors such as the protease caspase-1 (Broz, P.; Dixit, VM Inflammasomes: Mechanism of Assembly, Regulation and Signalling. Nat. Rev. Immunol. 2016, 16, 407–420).

[0004] The NLRP3 (NOD-like receptor (NLR) family pyrin domain-containing protein 3) inflammasome is one of the best-described members of the family. 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 a variety of substances, 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. ASC protein aggregation into large complexes (ASC specks) leads to the activation of caspase-1 effector proteins, which subsequently cleave pro-IL1β and pro-IL18 into their active secreted forms and mediate pyroptosis (Heneka et al., 2018 Nat Rev Neurosci). IL-1β acts through the IL-1β receptor, inducing secondary proinflammatory signals, including the secretion of IL-6 and TNFα, and attracting and activating cells of the adaptive immune system at the site of infection. NLRP3 / ASC complexes have been shown to be released into the extracellular environment, where they can propagate inflammation.

[0005] Multiple lines of genetic and pharmacological evidence highlight the importance of the NLRP3 inflammasome in human disease. NLRP3 gain-of-function mutations cause inherited cryptopyrin-associated periodic syndromes (CAPS), including Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), and neonatal-onset multisystem inflammatory disease (NOMID).

[0006] The accumulation of tissue damage products associated with aging leads to NLRP3 inflammasome activation in a variety of diseases, including metabolic disorders, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, atherosclerosis, obesity, lung disease, liver disease, and gout.

[0007] A large body of experimental evidence from animal models points to the adverse effects of excessive NLRP3 activation in a wide range of diseases. Genetic or pharmacological downregulation of the NLRP3-inflammasome has shown protective effects in models of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, demyelination, viral encephalitis, epilepsy, stroke, atherosclerosis, asthma, allergic inflammation, cryptopyrin-associated periodic 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 and type 2 diabetes, rheumatoid arthritis, myelodysplastic syndrome, etc. (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).

[0008] For the reasons mentioned above, modulation of NLRP3 inflammasome pathway activity represents a promising therapeutic avenue.

[0009] Current treatments for NLRP3-related diseases include biologics that target IL-1. These include the recombinant IL-1 receptor antagonist anakinra, the IL-1β-neutralizing antibody canakinumab, and the soluble decoy IL-1 receptor rilonacept. However, their activity is limited to downstream effectors of the inflammasome, and their bioavailability for central nervous system (CNS) applications is limited.

[0010] Several small molecules have been shown to inhibit the NLRP3 inflammasome pathway (Baldwin, AG, Brough, D. & 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 a variety of chemical classes, such as sulfonylurea-based compounds (glyburide, CP 456,773 (also known as CRID3 and MCC950) and their derivatives); the fenamates class of nonsteroidal anti-inflammatory drugs; the hydroxysulfonamide analog JC-171; a new 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-ketone; and Michael acceptors. Most of these compounds have promiscuous modes of action and limited efficacy.

[0011] WO2016131098, WO2017 / 140778 and WO2018215818 relate to sulfonylureas and related compounds and their use in treating or identifying diseases or conditions responsive to NLRP3 inhibition or inhibition of activation of NLRP3 or components associated with inflammatory processes.

[0012] WO2019008025, WO2019008029, WO2019034686, WO2019034688, WO2019034690, WO2019034692, WO2019034693, WO2019034696, WO2019034697, WO2019068772, WO2019092170, WO2019092171 and WO2019092172 relate to new compounds (e.g., sulfonylureas, sulfonylthioureas, sulfoximine ureas and sulfoximine thioureas) that are useful for treating and preventing medical disorders and diseases, most particularly through NLRP3 inhibition.

[0013] WO2017184604, WO2017184623, WO2017184624, WO2019023145, WO2019023147 and WO2019079119 relate to chemical entities for treating conditions, diseases or disorders in which a decrease or increase in NLRP3 activity contributes to the pathology and / or symptoms and / or progression of the condition, disease or disorder in a subject.

[0014] WO2019211463, WO2020021447 and WO2021043966 disclose compounds for inhibiting NLRP3 and / or NLRP3 inflammasome pathways.

[0015] WO2018136890 relates to sulfonylurea and sulfonylthiourea compounds and their use in treating diseases or conditions that respond to modulation of cytokines such as IL-1β and IL-18, modulation of NLRP3, or inhibition of activation of NLRP3 or components associated with inflammatory processes.

[0016] WO2018225018 and WO2019043610 relate to the use of NLRP3 modulators and novel inhibitor compounds in treating diseases or disorders and treating disease states mediated by NLRP3 and treating diseases or disorders in which interleukin 1β activity and interleukin-18 (IL-18) are involved.

[0017] WO2018015445 relates to sulfonylurea compounds which have inflammasome inhibitory activity and are therefore useful in methods of treating the human or animal body.

[0018] WO2020018975 discloses sulfonimidamide derivatives defined as inhibitors of interleukin-1 activity and NLRP3 modulators associated with inflammatory processes.

[0019] WO9832733 relates to aryl and heteroaryl substituted sulfonylureas which are inhibitors of interleukin-1 alpha and interleukin-1 beta processing and release.

[0020] WO2020018970 discloses sulfonylureas defined as inhibitors of interleukin-1 activity.

[0021] The crosstalk between the NLRP3 inflammasome and Tau pathology has recently been deciphered. Ising et al. (Nature 2019 Nov;575(7784):669-673) investigated the important 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 NLRP3 inflammasome pathway components 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 templated seeding of Tau pathology. Significant inhibition of exogenously seeded Tau pathology was found in ASC-deficient-PS19 Tau transgenic mice. Furthermore, long-term intracerebral administration of the NLRP3 inhibitor MCC950 has been shown to inhibit exogenously seeded Tau pathology. Finally, ASC deficiency also reduced non-exogenously seeded Tau pathology in PS19 mice.

[0022] There is a need to identify and develop specific NLRP3 inflammasome pathway inhibitors and / or interleukin activity modulators with improved pharmacological and / or physiological and / or physicochemical properties.

[0023] The present invention provides compounds of formula (I'), formula (I), formula (II'), or formula (II), which have surprisingly been found to modulate NLRP3 inflammasome pathway components, in particular to inhibit activation of NLRP3 inflammasome pathway components, such as NLRP3 inflammasome. Therefore, such compounds are useful for treating diseases, disorders, or abnormalities that respond to modulation of NLRP3 inflammasome pathway components and / or to modulation of IL-1β and / or IL-18 levels that typically lead to pathological inflammation.

[0024] Summary of the Invention

[0025] Therefore, the present invention provides a compound of formula (I'), a compound of formula (I), a compound of formula (II') or a compound of formula (II) or a stereoisomer, or a racemic mixture, or a tautomer, or a polymorph, or a pharmaceutically acceptable salt, or a prodrug, or a hydrate, or a solvate thereof. In the present invention, any reference to a compound of formula (I'), (I), (II') 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 pharmaceutically acceptable salt, or a prodrug, or a hydrate, or a solvate thereof.

[0026] The compounds of formula (I'), (I), (II') or (II) or their stereoisomers, racemic mixtures, tautomers, polymorphs, pharmaceutically acceptable salts, prodrugs, hydrates or solvates are suitable for treating, alleviating or preventing diseases, disorders or abnormalities that are responsive to the regulation, particularly inhibition, of NLRP3 inflammasome pathway components or to the regulation, particularly reduction, of IL-1β and / or IL-18 levels. In particular, the inflammasome pathway component is the NLRP3 inflammasome. Activation of the NLRP3 inflammasome pathway can trigger the formation of ASC spots, the cleavage and activation of caspase-1 and caspase-8, and the subsequent activation and release of IL-1β, IL-18, gasdermin D cleavage and pore formation, pyroptosis, and the release of IL-1α, IL-33, IL-17 and high-mobility group box (HMGB) proteins. Compounds of formula (I'), (I), (II') or (II) or stereoisomers, racemic mixtures, tautomers, polymorphs, pharmaceutically acceptable salts, prodrugs, hydrates or solvates thereof have the ability to modulate, in particular reduce, IL-1β and / or IL-18 levels.

[0027] The compounds of formula (I'), (I), (II') and (II) or their stereoisomers, racemic mixtures, tautomers, polymorphs, pharmaceutically acceptable salts, prodrugs, hydrates or solvates exhibit a high ability to modulate NLRP3 inflammasome pathway components and, in particular, inhibit their activation, particularly wherein the inflammasome pathway component is the NLRP3 inflammasome. Due to their unique design features, these compounds exhibit properties such as modulating or inhibiting activation of the NLRP3 inflammasome pathway, thereby allowing them to become successful drugs for treating, alleviating or preventing diseases, disorders and abnormalities that are responsive to modulation or inhibition of NLRP3 inflammasome pathway components, such as Alzheimer's disease, Parkinson's disease, CAPS, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH) and gout.

[0028] In a further embodiment, the present invention relates to a pharmaceutical composition comprising a compound of formula (I'), (I), (II') or (II) or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, and optionally comprising at least one pharmaceutically acceptable carrier, diluent, adjuvant or excipient.

[0029] In another embodiment, the present invention relates to a compound of formula (I'), (I), (II') or (II), or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, for use as a medicament.

[0030] In yet another embodiment, the present invention relates to a compound of formula (I'), (I), (II') or (II) or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof for use in treating, alleviating or preventing a disease, disorder or abnormality that responds to modulation of NLRP3 inflammasome pathway components, particularly inhibition of their activation and / or modulation of IL-1β and / or IL-18 levels, particularly reduction.

[0031] Another embodiment relates to the use of a compound of formula (I'), (I), (II') or (II), or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, in the preparation of a medicament for treating, alleviating or preventing a disease, disorder or abnormality that responds to modulation of NLRP3 inflammasome pathway components, particularly inhibition of their activation, and / or modulation of IL-1β and / or IL-18 levels, particularly reduction.

[0032] In yet another embodiment, the present invention relates to a method for treating, alleviating or preventing a disease, disorder or abnormality that responds to the modulation of NLRP3 inflammasome pathway components, particularly the inhibition of its activation and / or to the modulation of IL-1β and / or IL-18 levels, particularly the reduction thereof, comprising administering to an individual (e.g., a patient) in need thereof a therapeutically effective amount of a compound of formula (I'), (I), (II') or (II) or its stereoisomers, racemic mixtures, tautomers, polymorphs, pharmaceutically acceptable salts, prodrugs, hydrates, or solvates.

[0033] Also subject of the present invention are pharmaceutical compositions comprising a compound of formula (I'), (I), (II') or (II) or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof in combination with at least one further biologically active compound different from a compound of formula (I'), (I), (II') or (II) or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, and optionally comprising at least one pharmaceutically acceptable carrier, diluent, adjuvant or excipient.

[0034] In particular, the additional biologically active compound can be a compound used to treat a disease, disorder or abnormality associated with a disease that targets a different pathological mechanism, such as an anti-amyloid beta antibody, an anti-Tau antibody, an amyloid beta small molecule inhibitor, a Tau aggregation small molecule inhibitor, an anti-α-synuclein antibody or an α-synuclein aggregation small molecule inhibitor, an anti-TDP-43 antibody or an anti-TDP-43 aggregation small molecule inhibitor, etc. When a compound of the present invention is used in combination with an additional biologically active compound, the dosage of each compound may be different from the dosage when the compound is used as a monotherapy.

[0035] Another embodiment relates to the use of a compound of formula (I'), (I), (II') or (II), or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, as an analytical reference or in vitro screening tool.

[0036] The following items are also part of this invention:

[0037] A1. Compounds of formula (I)

[0038]

[0039] or a stereoisomer, racemic mixture, tautomer, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof;

[0040] in

[0041] X is independently selected from O, N and S;

[0042] Y is independently selected from N and O;

[0043] When valence permits, It is a combination of single and double bonds or two single bonds;

[0044] n is 1 or 2;

[0045] R 1 yes

[0046]

[0047] in

[0048] Z is independently selected from CH2 and O, provided that no more than two Z are O;

[0049] R 5 independently selected from hydrogen and halogen;

[0050] R 2 Independently selected from C1-C6 alkyl and C3-C6 cycloalkyl;

[0051] R3 Independently selected from

[0052]

[0053] In addition to R 4 Outside of the location, R 3 may be optionally substituted with halogen, C1-C6 alkyl or -OMe; R 4 independently selected from hydrogen, C1-C6 alkyl and C3-C6 cycloalkyl;

[0054] in

[0055] Any of the mentioned C1-C6 alkyl groups may be optionally substituted with -OH; and

[0056] The C3-C6 cycloalkyl group may be optionally substituted with -OH.

[0057] A2. The compound of formula (I) according to item A1, which is a compound of formula (Ic) or a compound of formula (Id)

[0058]

[0059] or a stereoisomer, racemic mixture, tautomer, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof,

[0060] in, X, Y, R 1 、R 2 and R 3 As defined in item 1.

[0061] A3. The compound of formula (I) according to item A2, which is a compound of formula (Ic)

[0062]

[0063] in, X, Y, R 1 、R 2 and R 3 As defined in item 1.

[0064] A4. A compound of formula (I) according to item A3, wherein

[0065] R 1 yes

[0066] in

[0067] Z is CH2;

[0068] R 5 It is hydrogen;

[0069] X is O;

[0070] Y is N;

[0071] When valence permits, It is a combination of single and double bonds;

[0072] R 2 It is ethyl;

[0073] R 3 Independently selected from

[0074]

[0075] in

[0076] In addition to R 4 Outside of the location, R 3 may be optionally substituted with Cl, isopropyl or -OMe, wherein the isopropyl may be optionally substituted with -OH; and

[0077] R 4 It is a methyl or ethyl group.

[0078] A5. The compound according to items A1 to A4, selected from

[0079]

[0080]

[0081] A6. Compound of formula (II)

[0082]

[0083] or a stereoisomer, racemic mixture, tautomer, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof;

[0084] in

[0085] W is independently selected from O and S;

[0086] m is 1 or 2;

[0087] R 6 yes

[0088]

[0089] in

[0090] Z 1 are independently selected from CH2 and O, provided that no more than two Z 1 It is O;

[0091] R 9 independently selected from hydrogen and halogen;

[0092] R 8 Independently selected from C1-C6 alkyl and C3-C6 cycloalkyl;

[0093] R 7 Independently selected from

[0094]

[0095] in

[0096] In addition to R 4 Outside of the location, R 7 may be optionally substituted with halogen, C1-C6 alkyl or -OMe;

[0097] R 4 is selected from hydrogen, C1-C6 alkyl and C3-C6 cycloalkyl;

[0098] in

[0099] Any of the mentioned C1-C6 alkyl groups may be optionally substituted with -OH; and

[0100] The C3-C6 cycloalkyl group may be optionally substituted with -OH.

[0101] A7. The compound according to item A6, which is

[0102]

[0103] A8. A pharmaceutical composition comprising a compound of formula (I) or formula (II) as defined in any one of the preceding items, and optionally comprising at least one pharmaceutically acceptable carrier, diluent, adjuvant or excipient.

[0104] A9. A compound of formula (I) or formula (II) according to any one of items A1 to A7 for use as a medicament.

[0105] A10. A compound of formula (I) or formula (II) according to any one of items A1 to A7 for treating, alleviating or preventing conditions or abnormalities associated with the regulation of inflammasome pathway components and / or the regulation of IL-1β and / or IL-18 levels.

[0106] A11. The compound of formula (I) or formula (II) for use according to item A10, wherein the inflammasome pathway component is NLRP3 inflammasome.

[0107] A12. The compound of formula (I) or formula (II) for use according to item A10 or A11, wherein the inflammasome pathway component is inhibited.

[0108] A13. A compound of formula (I) or formula (II) for use according to any one of items A10 to A12, wherein the disorder or abnormality is selected from Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, demyelination, viral encephalitis, epilepsy, stroke, atherosclerosis, asthma, allergic inflammation, cryptopyrin-associated periodic syndrome (CAPS), Muckle-Wells syndrome (MWS), familial 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 mellitus, disease, type 2 diabetes, rheumatoid arthritis, myelodysplastic syndrome, familial Mediterranean fever (FMF), TNF 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 (PAPA), A20 haploinsufficiency (HA20), PLCG2-related antibody deficiency and immune dysregulation (PLAID), pediatric granulomatous arthritis (PGA), PLCG2-related autoinflammatory, antibody deficiency and immune dysregulation (APLAID), with B-cell immunodeficiency Stomach ulcer, periodic fever, sideroblastic anemia with delayed development (SIFD), chronic nonbacterial osteomyelitis (CNO), Sweet's syndrome, chronic relapsing multifocal osteomyelitis (CRMO), synovitis, impetigo, acne, hyperostosis, osteoarthritis syndrome (SAPHO), multiple sclerosis (MS), psoriasis, Behçet's disease, Sjögren's syndrome, Schnitzler syndrome, chronic obstructive pulmonary disease (COPD), steroid-resistant asthma, asbestosis, silicosis, cystic fibrosis, motor neuron disease, Huntington's disease, cerebral malaria, brain damage due to pneumococcal meningitis, obesity, age-related macular degeneration (AMD), corneal infection, uveitis, dry eye, chronic kidney disease, diabetic nephropathy , alcoholic liver disease, contact allergies, 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, helminthic infections, bacterial infections, 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 pathologies, and traumatic brain injury;Preferably, the disorder is selected from the group consisting of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, demyelination, viral encephalitis, epilepsy, stroke, atherosclerosis, asthma, allergic inflammation, cryptopyrin-associated periodic syndrome (CAPS), gout, inflammatory bowel disease, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis, 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, glomerular basement membrane (GMB) disease, IgA nephropathy, glomerulonephritis (GN), systemic lupus erythematosus (SLE), focal segmental glomerulosclerosis, minimal change disease (MCD), psoriatic arthritis, and hereditary recurrent fever (HRF).

[0109] A14. A compound of formula (I) or formula (II) for the use according to item A13, wherein the disorder or abnormality is selected from Alzheimer's disease, Parkinson's disease, cryopyrin-associated periodic syndrome (CAPS), non-alcoholic fatty liver disease, NASH and gout.

[0110] A15. A pharmaceutical composition comprising a combination of a compound of formula (I) or (II) according to any one of items A1 to A7 and at least one additional biologically active compound different from a compound of formula (I) or (II), and optionally comprising at least one pharmaceutically acceptable carrier, diluent, adjuvant or excipient.

[0111] A16. A pharmaceutical mixture comprising a combination of compounds of formula (I) or formula (II) according to any one of items A1 to A7.

[0112] A17. Use of a compound of formula (I) or formula (II) according to any one of items A1 to A7 as an analytical reference or in vitro screening tool.

[0113] A18. A method for preparing a compound of formula (Ic) according to items A1 to A5, comprising the step of cyclizing a compound of formula (II) in the presence of a condensing agent

[0114]

[0115] where R 6 , W, R 7 、R 8 , X, Y, R 1 、R 2 and R 3 As defined in any of items A1 to A4 and A6.

[0116] A19. A method for preparing a compound of formula (II) according to item A6 or A7, comprising the step of coupling a compound of formula (III) with a urea or thiourea derivative of formula (IV) in the presence of a solvent and a base

[0117]

[0118] where R 6 , W, R 7 and R 8 As defined in any of items A1 to A4 and A6.

[0119] In another aspect, the following items are also part of the present invention:

[0120] B1. Compounds of formula (I)

[0121]

[0122] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof;

[0123] in

[0124] X is independently selected from O, N and S;

[0125] Y is independently selected from N and O;

[0126] When valence permits, It is a combination of single and double bonds or two single bonds;

[0127] n is 1 or 2;

[0128] R 1 yes

[0129]

[0130] in

[0131] Z is independently selected from CH2 and O, provided that no more than two Z are O;

[0132] R 5 independently selected from hydrogen and halogen;

[0133] R 2 Independently selected from hydrogen, C1-C6 alkyl, C 3-6 cycloalkyl; and

[0134] R 3 independently selected from heteroC3-C6 cycloalkyl, aryl or heteroaryl, each of which may be optionally substituted by -C 1-6 Alkyl, -OC 1-6 Alkyl, -Hal or -C1-6 Alkyl-OH substitution.

[0135] B2. The compound according to item B1, which is a compound of formula (Ic) or a compound of formula (Id),

[0136]

[0137] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof;

[0138] in, X, Y, R 1 、R 2 and R 3 As defined in Item B1.

[0139] B3. The compound according to item B2, which is a compound of formula (Ic)

[0140]

[0141] in, X, Y, R 1 、R 2 and R 3 As defined in item B1.

[0142] B4. A compound according to any one of the preceding items, wherein R 2 is hydrogen or ethyl.

[0143] B5. A compound according to any one of the preceding items, wherein

[0144] R 1 yes

[0145] in

[0146] Z is CH2;

[0147] R 5 It is hydrogen;

[0148] X is O;

[0149] Y is N;

[0150] When valence permits, is a combination of single and double bonds; and

[0151] R 3 yes

[0152] Each of them may be optionally substituted, and R 4 Independently selected from hydrogen, C1-C6 alkyl and C3-C6 cycloalkyl.

[0153] B6. A compound according to any one of the preceding items, selected from

[0154]

[0155]

[0156] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof.

[0157] B7. Compound of formula (II)

[0158]

[0159] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof,

[0160] in

[0161] W is independently selected from O and S;

[0162] m is 1 or 2;

[0163] R 6 yes

[0164]

[0165] in

[0166] Z 1 are independently selected from CH2 and O, provided that no more than two Z 1 It is O;

[0167] R 9 independently selected from hydrogen and halogen;

[0168] R 8 Independently selected from hydrogen, C1-C6 alkyl, C 3-6 cycloalkyl; and

[0169] R 7 independently selected from heteroC3-C6 cycloalkyl, aryl or heteroaryl, each of which may be optionally substituted.

[0170] B8. The compound according to item B7, wherein R 8 It is hydrogen or ethyl.

[0171] B9. The compound according to item B8, wherein R 7 yes

[0172]

[0173] Each of them may be optionally substituted, and R 4 Independently selected from hydrogen, C1-C6 alkyl and C3-C6 cycloalkyl.

[0174] B10. The compound according to items B7 to B9, which is

[0175]

[0176]

[0177] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof.

[0178] B11. A pharmaceutical composition comprising a compound of formula (I) or a compound of formula (II) as defined in any one of items B1 to B10, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, and optionally comprising at least one pharmaceutically acceptable carrier, diluent, adjuvant or excipient.

[0179] B12. A compound according to any one of items B1 to B10, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, for use as a medicament.

[0180] B13. A compound according to any one of items B1 to B10, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, for treating, alleviating or preventing a disease or disorder or abnormality that is responsive to modulation of NLRP3 inflammasome pathway components and / or responsive to modulation of IL-1β and / or IL-18 levels.

[0181] B14. The compound for use according to claim 13, wherein the inflammasome pathway component is NLRP3 inflammasome.

[0182] B15. The compound for use according to item B13 or item B14, wherein activation of the NLRP3 inflammasome pathway is inhibited.

[0183] B16. A compound for use according to any one of items B13 to B15, wherein the disorder or abnormality is selected from Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, demyelination, viral encephalitis, epilepsy, stroke, atherosclerosis, asthma, allergic inflammation, cryptopyrin-associated periodic syndrome (CAPS), Muckle-Wells syndrome (MWS), familial 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, Rheumatoid arthritis, myelodysplastic syndrome, familial Mediterranean fever (FMF), TNF 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 (PAPA), A20 haploinsufficiency (HA20), PLCG2-related antibody deficiency and immune dysregulation (PLAID), pediatric granulomatous arthritis (PGA), PLCG2-related autoinflammatory, antibody deficiency and immune dysregulation (APLAID), with B-cell immunodeficiency, periodic fever , sideroblastic anemia with delayed development (SIFD), chronic nonbacterial osteomyelitis (CNO), Sweet's syndrome, chronic relapsing multifocal osteomyelitis (CRMO), synovitis, impetigo, acne, eczema, alopecia areata, actinic keratosis, hyperostosis, osteitis syndrome (SAPHO), multiple sclerosis (MS), psoriasis, Behçet's disease, Sjögren's syndrome, Schnitzler syndrome, chronic obstructive pulmonary disease (COPD), steroid-resistant asthma, asbestosis, silicosis, cystic fibrosis, motor neuron disease, Huntington's disease, cerebral malaria, brain damage due to pneumococcal meningitis, obesity, age-related macular degeneration (AMD), corneal infection, uveitis, dry eye, Chronic kidney disease, diabetic nephropathy, alcoholic liver disease, contact allergy, 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, helminthic 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 pathologies, and traumatic brain injury;Preferably, the disorder is selected from the group consisting of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, demyelination, viral encephalitis, epilepsy, stroke, atherosclerosis, asthma, allergic inflammation, cryptopyrin-associated periodic syndrome (CAPS), gout, inflammatory bowel disease, non-alcoholic fatty liver disease, 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, glomerular basement membrane (GMB) disease, IgA nephropathy, glomerulonephritis (GN), systemic lupus erythematosus (SLE), focal segmental glomerulosclerosis, minimal change disease (MCD), psoriatic arthritis, and hereditary recurrent fevers (HRFs).

[0184] B17. The compound for use according to item B16, wherein the disease, disorder or abnormality is selected from Alzheimer's disease, Parkinson's disease, cryopyrin-associated periodic syndrome (CAPS), non-alcoholic fatty liver disease, NASH and gout.

[0185] B18. The compound for use according to any one of items B13 to B15, wherein the disease, disorder or abnormality is a disease, disorder or abnormality of the immune system.

[0186] B19. The compound for use according to any one of items B13 to B15, wherein the disease, disorder or abnormality is an inflammatory disease, disorder or abnormality.

[0187] B20. The compound for use according to any one of items B13 to B15, wherein the disease, disorder or abnormality is an autoimmune disease, disorder or abnormality.

[0188] B21. The compound for use according to any one of items B13 to B15, wherein the disease, disorder or abnormality is a disease, disorder or abnormality of the skin.

[0189] B22. The compound for use according to item B21, wherein the disease, disorder or abnormality of the skin is selected from psoriasis, acne, eczema, alopecia areata or actinic keratosis.

[0190] B23. The compound for use according to any one of items B13 to B15, wherein the disease, disorder or abnormality is a disease, disorder or abnormality of the cardiovascular system.

[0191] B24. The compound for use according to any one of items B13 to B15, wherein the disease, disorder or abnormality is cancer, tumor or malignancy.

[0192] B25. The compound for use according to any one of items B13 to B15, wherein the disease, disorder or abnormality is a disease, disorder or abnormality of the renal system.

[0193] B26. The compound for use according to any one of items B13 to B15, wherein the disease, disorder or abnormality is a disease, disorder or abnormality of the gastrointestinal tract.

[0194] B27. The compound for use according to any one of items B13 to B15, wherein the disease, disorder or abnormality is a disease, disorder or abnormality of the respiratory system.

[0195] B28. The compound for use according to any one of items B13 to B15, wherein the disease, disorder or abnormality is a disease, disorder or abnormality of the endocrine system.

[0196] B29. The compound for use according to any one of items B13 to B15, wherein the disease, disorder or abnormality is a disease, disorder or abnormality of the central nervous system (CNS).

[0197] B30. The compound for use according to any one of items B13 to B15, wherein the disease, disorder or abnormality is a disease, disorder or abnormality of the liver.

[0198] B31. A pharmaceutical composition comprising a compound according to any one of items B1 to B10 or a combination of a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof and at least one additional biologically active compound different from the compound of formula (I), and optionally comprising at least one pharmaceutically acceptable carrier, diluent, adjuvant or excipient.

[0199] B32. A combination comprising a therapeutically effective amount of a compound according to any one of items B1 to B10 or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, and at least one additional biologically active compound different from the compound of formula (I) or the compound of formula (II), and optionally at least one pharmaceutically acceptable carrier, diluent, adjuvant or excipient.

[0200] B33. The pharmaceutical composition according to item B31 or the combination according to item B32 for use as a medicament.

[0201] B34. Use of a compound of formula (I) according to any one of items B1 to B10 or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof as an analytical reference or in vitro screening tool.

[0202] The present invention is described below. BRIEF DESCRIPTION OF THE DRAWINGS

[0204] Figure 1 Shown is the IL-1β release in peritoneal lavage samples of mice administered (1 mg / kg or 3 mg / kg) of Examples 16 and 23 by intraperitoneal injection in an LPS-ATP-induced peritonitis model. Detailed Description of the Invention

[0206] The present invention relates to compounds of formula (I'), compounds of formula (I), including sub-embodiments (Ia), (Ib), (Ic), (Ic'), (Id), (Id'), (Id"), (Id'"), (Ie) and (If), and compounds of formula (II'), compounds of formula (II), including sub-embodiments (IIa'), (IIa), (IIb') and (IIb), including stereoisomers, racemic mixtures, tautomers, polymorphs, pharmaceutically acceptable salts, prodrugs, hydrates or solvates thereof.

[0207] The present invention relates to compounds of formula (I') as defined below:

[0208]

[0209] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof;

[0210] in

[0211] X is independently selected from O, N and S;

[0212] Y is independently selected from N and O;

[0213] When valence permits, It is a combination of single and double bonds or two single bonds;

[0214] n is 1 or 2;

[0215] R 0 is H or C1-C3 alkyl;

[0216] R 1 yes

[0217]

[0218] in

[0219] Z is independently selected from CH2 and O, provided that no more than two Z are O;

[0220] R 5 independently selected from hydrogen and halogen;

[0221] R 2 Independently selected from hydrogen, C1-C6 alkyl, C 3-6 cycloalkyl; and

[0222] R 3 independently selected from heteroC3-C6 cycloalkyl, aryl or heteroaryl, each of which may be optionally substituted by -C 1-6 Alkyl, -OC 1-6 Alkyl, -Hal or -C 1-6 Alkyl-OH substitution.

[0223] Furthermore, in one embodiment, the present invention relates to a 0 The compound of formula (I') is H, having the following definition of formula (I):

[0224]

[0225] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof;

[0226] in

[0227] X is independently selected from O, N and S;

[0228] Y is independently selected from N and O;

[0229] When valence permits, It is a combination of single and double bonds or two single bonds;

[0230] n is 1 or 2;

[0231] R 1 yes

[0232]

[0233] in

[0234] Z is independently selected from CH2 and O, provided that no more than two Z are O;

[0235] R 5 independently selected from hydrogen and halogen;

[0236] R 2 independently selected from hydrogen, C1-C6 alkyl and C3-C6 cycloalkyl;

[0237] R 3 Independently selected from heteroC3-C6 cycloalkyl, aryl or heteroaryl, each of which may be optionally substituted with -C1-C6 alkyl, -O-C1-C6 alkyl, -Hal or -C1-C6 alkyl-OH.

[0238] In another embodiment, the present invention relates to a compound of formula (I'), in particular to a compound of formula (I), or a stereoisomer, or racemic mixture, or tautomer, or polymorph, or pharmaceutically acceptable salt, or hydrate, or solvate thereof.

[0239] In another embodiment, the present invention relates to compounds of formula (I'), in particular to compounds of formula (I), wherein X is independently selected from O and N; and Y is independently selected from N and O.

[0240] More preferably, X is independently selected from O and N; and Y is independently selected from N and O; wherein X and Y are never the same.

[0241] More preferably, X is O; and Y is N.

[0242] In another embodiment, the present invention relates to compounds of formula (I'), in particular to compounds of formula (I), wherein, when valency permits, is a combination of single bonds and double bonds. More preferably, As the following Present.

[0243] In another embodiment, the present invention relates to compounds of formula (I'), in particular to compounds of formula (I), wherein n is 1.

[0244] In one embodiment, the present invention relates to compounds of formula (I'), in particular to compounds of formula (I), wherein R 0 is H or C1-C3 alkyl. Preferably, R 0 is H, methyl or ethyl. More preferably, R 0 It’s H.

[0245] In another embodiment, the present invention relates to compounds of formula (I'), in particular to compounds of formula (I), wherein R 1 yes

[0246]

[0247] in

[0248] Z is selected from CH2; and

[0249] R 5 is selected from halogen or hydrogen. 5 is halogen, wherein the halogen is preferably fluorine. More preferably, R 5 It's hydrogen.

[0250] In another embodiment, the present invention relates to compounds of formula (I'), in particular to compounds of formula (I), wherein R 2 Independently selected from hydrogen, C1-C6 alkyl and C3-C6 cycloalkyl.

[0251] Preferably, R 2 In a preferred embodiment, R 2 In another preferred embodiment, R 2 is a C1-C6 alkyl group, wherein R 2 Preferably, R is selected from methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl or hexyl. 2 is a C5-C6 cycloalkyl group, more preferably, R 2 It's cyclopentane.

[0252] More preferably, R 2 is independently selected from hydrogen, C1-C3 alkyl and C5-C6 cycloalkyl. Even more preferably, R 2 is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl or cyclopentane. Even more preferably, R 2 R is independently selected from hydrogen, ethyl, isopropyl or cyclopentane. 2 may be optionally substituted with OH, for example in middle.

[0253] In one embodiment, the present invention relates to compounds of formula (I'), in particular to compounds of formula (I), wherein R 3 Independently selected from heteroC3-C6 cycloalkyl, aryl or heteroaryl, each of which may be optionally substituted with -C1-C6 alkyl, -O-C1-C6 alkyl, -Hal or -C1-C6 alkyl-OH.

[0254] In another embodiment, the present invention relates to compounds of formula (I'), in particular to compounds of formula (I), wherein R 3 independently selected from heteroC3-C6 cycloalkyl containing one or two heteroatoms selected from N or O, aryl or C5-C6 heteroaryl containing one, two or three heteroatoms independently selected from S, N and O; wherein each of them may be optionally substituted by -C1-C6 alkyl, -O-C1-C6 alkyl, -Hal or -C1-C6 alkyl-OH.

[0255] In one embodiment, the present invention relates to compounds of formula (I'), in particular to compounds of formula (I), wherein R 3 Is aryl, optionally substituted by-C1-C6 alkyl,-O-C1-C6 alkyl,-Hal or-C1-C6 alkyl-OH. In a particular embodiment, aryl groups are optionally substituted by-O-C1-C6 alkyl or-Hal. In a particular embodiment, aryl groups are optionally substituted by-O-C1-C6 alkyl or-Hal, wherein halogen (-Hal) is preferably chlorine.

[0256] More preferably, R 3 independently selected from heteroC3-C6 cycloalkyl containing one or two heteroatoms selected from N or O, C5-C6 aryl or C5-C6 heteroaryl containing one, two or three heteroatoms independently selected from S, N and O; wherein each of them may be optionally substituted by -C1-C6 alkyl, -O-C1-C6 alkyl, -Hal or -C1-C6 alkyl-OH.

[0257] Even more preferably, R 3 is a heteroC3-C6 cycloalkyl group containing one heteroatom, wherein the heteroatom is O; and R 3 Optionally substituted with -C1-C6 alkyl, -O-C1-C6 alkyl, -Hal or -C1-C6 alkyl-OH.

[0258] Even more preferably, R 3 is a C5-C6 heteroaryl group containing one, two or three heteroatoms independently selected from S, N and O; wherein each of them may be optionally substituted by a substituent selected from -C1-C6 alkyl, -O-C1-C6 alkyl, -Hal or -C1-C6 alkyl-OH.

[0259] In another embodiment, the present invention provides compounds of formula (I'), in particular compounds of formula (I), wherein R 3 Selected from the following groups:

[0260] in

[0261] R 4 independently selected from hydrogen, C1-C6 alkyl and C3-C6 cycloalkyl, and wherein each of them may be optionally substituted with -C1-C6 alkyl, -O-C1-C6 alkyl, -Hal or -C1-C6 alkyl-OH.

[0262] More preferably, R 3 Selected from the following groups:

[0263] in

[0264] R 4 independently selected from hydrogen, C1-C6 alkyl and C3-C6 cycloalkyl, and wherein each of them may be optionally substituted with -C1-C6 alkyl, -O-C1-C6 alkyl, -Hal or -C1-C6 alkyl-OH.

[0265] Even more preferably, R 3 Selected from the following groups:

[0266] in

[0267] R 4 independently selected from hydrogen, C1-C6 alkyl and C3-C6 cycloalkyl, and wherein each of them may be optionally substituted with -C1-C6 alkyl, -O-C1-C6 alkyl, -Hal or -C1-C6 alkyl-OH.

[0268] Even more preferably, R 3 yes

[0269] in

[0270] R 4 Independently selected from hydrogen, C1-C6 alkyl and C3-C6 cycloalkyl.

[0271] In another preferred embodiment, the present invention provides compounds of formula (I'), in particular compounds of formula (I), wherein R 3 Selected from the following groups:

[0272] where R 3 Optional R 3a substituted, and wherein R 3a is selected from hydrogen, halogen, -O-C1-C6 alkyl, -C1-C6 alkyl-OH or C1-C6 alkyl. More preferably, R 3a Selected from hydrogen, chlorine, methoxy, methyl, isopropyl or

[0273] In R 3 In the C1-C6 alkyl group, preferably methyl, ethyl, isopropyl, propyl, isobutyl or butyl, and may be optionally substituted with -OH, for example

[0274] In another embodiment, the present invention relates to compounds of formula (I'), in particular to compounds of formula (I), wherein R 4 are independently selected from hydrogen, methyl, ethyl, isopropyl and propyl. 4 is methyl or isopropyl. More preferably, R 4 It's methyl.

[0275] In another embodiment, the present invention relates to compounds of formula (I'), in particular to compounds of formula (I), wherein R 2 is hydrogen, and R 3 yes

[0276] a) Preferred

[0277] b) Preferred

[0278] c) Preferred

[0279] d)

[0280] e) Preferred or

[0281] f) Preferred where R 4 Independently selected from hydrogen, C1-C6 alkyl and C3-C6 cycloalkyl.

[0282] In another embodiment, the present invention relates to compounds of formula (I'), in particular to compounds of formula (I), wherein R 2 is hydrogen, and R 3 yes

[0283] a) Preferred

[0284] b) Preferred or

[0285] c) Preferred And R 3 Each may be optionally substituted with -C1-C6 alkyl, -O-C1-C6 alkyl, -Hal or -C1-C6 alkyl-OH.

[0286] R 4 are independently selected from hydrogen, methyl, ethyl, isopropyl and propyl. More preferably, R 4 It's methyl.

[0287] In each of the above embodiments, R 3 Can be optionally substituted by halogen, -O-C1-C6 alkyl, -C1-C6 alkyl-OH or C1-C6 alkyl. More preferably, R 3 may be optionally substituted with chloro, methoxy, methyl, isopropyl or replace.

[0288] In R 3 In the C1-C6 alkyl group, preferably methyl, ethyl, isopropyl, propyl, isobutyl or butyl, and may be optionally substituted by -OH, for example in middle.

[0289] In another embodiment, the present invention relates to compounds of formula (I'), in particular to compounds of formula (I), wherein R 2 is a C1-C6 alkyl group, and R3 yes

[0290] a) Preferred

[0291] b) Preferred

[0292] c) Preferred

[0293] d)

[0294] e) Preferred

[0295] f) Preferred where R 4 independently selected from hydrogen, C1-C6 alkyl and C3-C6 cycloalkyl;

[0296] g) Preferred

[0297] h) Preferred

[0298] i) Preferred

[0299] j) Preferred or

[0300] k) Preferred

[0301] In another embodiment, the present invention relates to compounds of formula (I'), in particular to compounds of formula (I), wherein R 2 is a C1-C6 alkyl group, and R 3 yes

[0302] a) Preferred

[0303] b) Preferred

[0304] c) Preferred

[0305] d)

[0306] e) Preferred or

[0307] f) Preferred where R 4 Independently selected from hydrogen, C1-C6 alkyl and C3-C6 cycloalkyl.

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

[0309] In R 3 In the C1-C6 alkyl group, preferably methyl, ethyl, isopropyl, propyl, isobutyl or butyl, and may be optionally substituted by -OH, for example in middle.

[0310] Preferably, R 2 is a C1-C6 alkyl group, wherein R 2 Preferably, R is selected from methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl or hexyl. More preferably, R 2 is a C1-C3 alkyl group. More preferably, R 2 is independently selected from methyl, ethyl, propyl or isopropyl. Even more preferably, R 2 R is independently selected from ethyl or isopropyl. 2 May be optionally substituted with OH.

[0311] In another embodiment, the present invention relates to compounds of formula (I'), in particular to compounds of formula (I), wherein R 2 is a C3-C6 cycloalkyl group, and R 3 yes

[0312] a) Preferred

[0313] b) Preferred

[0314] c) Preferred

[0315] d)

[0316] e) Preferred or

[0317] f) Preferred where R 4 Independently selected from hydrogen, C1-C6 alkyl and C3-C6 cycloalkyl.

[0318] In each of the above embodiments, R 3 Can be optionally substituted by halogen, -O-C1-C6 alkyl, -C1-C6 alkyl-OH or C1-C6 alkyl. More preferably, R 3 may be optionally substituted with chloro, methoxy, methyl or isopropyl, or replace.

[0319] In R 3 In the C1-C6 alkyl group, preferably methyl, ethyl, isopropyl, propyl, isobutyl or butyl, and may be optionally substituted by -OH, for example in middle.

[0320] Preferably, R 2 is a C5-C6 cycloalkyl group. More preferably, R 2 is cyclopentane. 2 May be optionally substituted with -OH.

[0321] Preferably, R 4 are independently selected from hydrogen, methyl, ethyl, isopropyl and propyl. More preferably, R 4 It's methyl.

[0322] Furthermore, in one embodiment, the present invention relates to compounds of formula (I) as defined below

[0323]

[0324] or a stereoisomer, racemic mixture, tautomer, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof;

[0325] in

[0326] X is independently selected from O, N and S;

[0327] Y is independently selected from N and O;

[0328] When valence permits, It is a combination of single and double bonds or two single bonds;

[0329] n is 1 or 2;

[0330] R 1 yes

[0331]

[0332] in

[0333] Z is independently selected from CH2 and O, provided that no more than two Z are O;

[0334] R 5 independently selected from hydrogen and halogen;

[0335] R 2 Independently selected from C1-C6 alkyl and C3-C6 cycloalkyl;

[0336] R 3 Independently selected from

[0337]

[0338] in

[0339] In addition to R 4 Outside of the location, R 3 may be optionally substituted with halogen, C1-C6 alkyl or -OMe;

[0340] R 4 independently selected from hydrogen, C1-C6 alkyl and C3-C6 cycloalkyl;

[0341] in

[0342] Any of the mentioned C1-C6 alkyl groups may be optionally substituted with -OH; and

[0343] The C3-C6 cycloalkyl group may be optionally substituted with -OH.

[0344] In one embodiment, the present invention relates to a compound of formula (I) or a stereoisomer, or a racemic mixture, or a tautomer, or a polymorph, or a pharmaceutically acceptable salt, or a hydrate, or a solvate thereof.

[0345] Preferably, R 1 yes

[0346] Where Z is CH2 and R 5 is hydrogen or a halogen.

[0347] More preferably, R 1 yes

[0348] Where Z is CH2 and R 5 It is hydrogen or F (fluorine).

[0349] Preferably, R 5 is hydrogen or a halogen selected from F and Cl. More preferably, R 5 is F or Cl, even more preferably, R 5 It is F (fluorine).

[0350] Preferably, X is O.

[0351] Preferably, Y is preferably N.

[0352] n is preferably 1.

[0353] R 2 are independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl. 2 In a preferred embodiment, R 2 is hydrogen. Preferably, R 2 is a C1-C6 alkyl group, wherein R 2 Preferably, R is selected from methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl or hexyl. 2 is a C5-C6 cycloalkyl group, more preferably, R 2 is cyclopentane. Preferably, R 2 is methyl, ethyl, propyl or cyclopropyl. More preferably, R 2 It's ethyl.

[0354] In a preferred embodiment, the present invention provides compounds of formula (I), wherein R 3 Selected from the following groups, R 3 Selected from the following groups:

[0355] in

[0356] R 4 independently selected from hydrogen, C1-C6 alkyl and C3-C6 cycloalkyl, and wherein each of them may be optionally substituted with -C1-C6 alkyl, -O-C1-C6 alkyl, -Hal or -C1-C6 alkyl-OH.

[0357] Preferably, R 3 Selected from the following groups:

[0358] where R 4 independently selected from hydrogen, C1-C6 alkyl and C3-C6 cycloalkyl, and wherein each of them may be optionally substituted with -C1-C6 alkyl, -O-C1-C6 alkyl, -Hal or -C1-C6 alkyl-OH.

[0359] Preferably, R 3 yes

[0360]

[0361] More preferably, R 3 Selected from the following groups:

[0362]

[0363] Preferably, in addition to R 4 Outside of the location, R 3 It may be optionally substituted by one or two groups selected from halogen, C1-C6 alkyl or -OMe. 3 May be optionally substituted by one or two C1-C6 alkyl groups, which may be further optionally substituted by -OH. More preferably, R 3 May be optionally substituted by one or two groups selected from -Cl, C1-C4 alkyl or -OMe, wherein C1-C4 alkyl may be optionally substituted by -OH. Even more preferably, R 3 Can be optionally selected from one or two of -C l , isopropyl and -OMe, wherein the isopropyl group may be optionally substituted by -OH.

[0364] More preferably, R 3 Selected from the following groups:

[0365] where R 3 Optional R 3a substituted, and wherein R 3a is selected from hydrogen, halogen, -O-C1-C6 alkyl, -C1-C6 alkyl-OH or C1-C6 alkyl. More preferably, R 3a Selected from hydrogen, chlorine, methoxy, methyl, isopropyl or

[0366] Preferably, R 4 is selected from hydrogen and C1-C6 alkyl. More preferably, R 4 is methyl, isopropyl or ethyl; in particular methyl or isopropyl. More preferably, R 4 is methyl or ethyl. Even more preferably, R 4 It's methyl.

[0367] Preferably, in any case of C1-C6 alkyl, the C1-C6 alkyl may be optionally substituted with -OH.

[0368] Preferably, in any case of C3-C6 cycloalkyl, the C3-C6 cycloalkyl may be optionally substituted with -OH.

[0369] In a further embodiment, the present invention relates to compounds of formula (I'), wherein when the compound permits, is a combination of single bonds and double bonds, as described in formula (Ia') or (Ib'),

[0370]

[0371] or a stereoisomer, or a racemic mixture, or a tautomer, or a polymorph, or a pharmaceutically acceptable salt, or a hydrate, or a solvate thereof,

[0372] Where X, Y, n, R 0 、R 1 、R 2 and R 3 As defined above. The embodiments as defined for the compounds of formula (I') apply hereto.

[0373] In a further embodiment, the present invention relates to compounds of formula (I'), in particular to compounds of formula (I), wherein, when valency permits, is a combination of single bonds and double bonds, as described in formula (Ia) or (Ib),

[0374]

[0375] or a stereoisomer, or a racemic mixture, or a tautomer, or a polymorph, or a pharmaceutically acceptable salt, or a hydrate, or a solvate thereof.

[0376] Where X, Y, n, R 1 、R 2 and R 3 As defined above. 0 The embodiments defined for compounds of formula (I') or compounds of formula (I) where H is H apply hereto.

[0377] Preferably, the combination of single bonds and double bonds is as described in the compound of formula (Ib') or (Ib),

[0378]

[0379] or its stereoisomers, or racemic mixtures, or tautomers, or polymorphs, or pharmaceutically acceptable salts, or hydrates, or solvates, wherein X, Y, n, R 0 、R 1 、R 2 and R 3 As defined above.

[0380] In yet another embodiment, the present invention is directed to a compound of formula (I'), which is defined as a compound of formula (Ic'), (Id'), (Id"), or (Id'"),

[0381]

[0382] or its stereoisomers, or racemic mixtures, or tautomers, or polymorphs, or pharmaceutically acceptable salts, or hydrates, or solvates, wherein X, Y, n, R 0 、R 1、R 2 and R 3 As defined above.

[0383] In a preferred embodiment, the present invention relates to compounds of formula (I'), which are defined as compounds of formula (Ic), (Ic'), (Id) or (Id')

[0384]

[0385] or its stereoisomers, or racemic mixtures, or tautomers, or polymorphs, or pharmaceutically acceptable salts, or hydrates, or solvates, wherein X, Y, R 1 、R 2 and R 3 As defined above; and wherein R 0 It is a C1-C3 alkyl group.

[0386] In a more preferred embodiment, the present invention relates to compounds of formula (I'), in particular to compounds of formula (I), which are defined as compounds of formula (Ic) or (Id),

[0387]

[0388] or its stereoisomers, or racemic mixtures, or tautomers, or polymorphs, or pharmaceutically acceptable salts, or hydrates, or solvates, wherein X, Y, R 1 、R 2 and R 3 As defined above. The embodiments as defined for the compounds of formula (I') or (I) apply hereto.

[0389] The compound of formula (Ic) or (Ic') corresponds to the compound of formula (I') when n is 1. The compound of formula (Id), (Id'), (Id") or (Id'") corresponds to the compound of formula (I') when n is 2.

[0390] Preferably, the compound of formula (I') is a compound of formula (Ic) or (Ic')

[0391]

[0392] or its stereoisomers, or racemic mixtures, or tautomers, or polymorphs, or pharmaceutically acceptable salts, or hydrates, or solvates, wherein R 0 It is a methyl or ethyl group.

[0393] More preferably, the compound of formula (I') is a compound of formula (Ic)

[0394]

[0395] or a stereoisomer, or a racemic mixture, or a tautomer, or a polymorph, or a pharmaceutically acceptable salt, or a hydrate, or a solvate thereof.

[0396] In yet a further embodiment, the present invention relates to stereoisomers of compounds of formula (I'), defined as compounds of formula (Ie') or (If'),

[0397]

[0398] or its stereoisomers, or racemic mixtures, or tautomers, or polymorphs, or pharmaceutically acceptable salts, or hydrates, or solvates, wherein X, Y, n, R 0 、R 1 、R 2 and R 3 As defined above. The embodiments defined for compounds of formula (I') apply here.

[0399] In a preferred embodiment, the present invention relates to stereoisomers of compounds of formula (I), which are defined as compounds of formula (Ie) or (If)

[0400]

[0401] or its stereoisomers, or racemic mixtures, or tautomers, or polymorphs, or pharmaceutically acceptable salts, or hydrates, or solvates, wherein X, Y, n, R 1 、R 2 and R 3 As defined above. The embodiments defined for the compounds of formula (I) apply here.

[0402] In a further embodiment, the present invention relates to a compound of formula (Ic)

[0403]

[0404] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof;

[0405] in

[0406] R 1 yes

[0407] in

[0408] Z is CH2;

[0409] R 5 independently selected from hydrogen or halogen;

[0410] X is O;

[0411] Y is N;

[0412] When valence permits, It is a combination of single and double bonds;

[0413] R 2 In a preferred embodiment, R 2 As defined above. In another embodiment, R 2 It's ethyl.

[0414] In one embodiment, the present invention relates to compounds of formula (I'), wherein R 3 In a preferred embodiment, R 3 As defined above.

[0415] In another embodiment, the present invention provides compounds of formula (I'), wherein R 3 Selected from:

[0416] in

[0417] R 4 independently selected from hydrogen, C1-C6 alkyl and C3-C6 cycloalkyl, and wherein each of them may be optionally substituted with -C1-C6 alkyl, -O-C1-C6 alkyl, -Hal or -C1-C6 alkyl-OH.

[0418] More preferably, R 3 Selected from:

[0419] in

[0420] R 4 independently selected from hydrogen, C1-C6 alkyl and C3-C6 cycloalkyl, and wherein each of them may be optionally substituted with -C1-C6 alkyl, -O-C1-C6 alkyl, -Hal or -C1-C6 alkyl-OH.

[0421] Even more preferably, R 3 Selected from:

[0422] in

[0423] R 4 are independently selected from hydrogen, C1-C6 alkyl and C3-C6 cycloalkyl, and each of which may be optionally substituted by -C1-C6 alkyl, -O-C1-C6 alkyl, -Hal or -C1-C6 alkyl-OH. Preferably, R4 is methyl, isopropyl or ethyl. More preferably, R 4 is methyl or isopropyl. Even more preferably, R 4 It's methyl.

[0424] In a further embodiment, the present invention relates to a compound of formula (Ic)

[0425]

[0426] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof;

[0427] in

[0428] R 1 yes

[0429] in

[0430] Z is CH2;

[0431] R 5 It is hydrogen;

[0432] X is O;

[0433] Y is N;

[0434] When valence permits, It is a combination of single and double bonds;

[0435] R 2 It is ethyl;

[0436] R 3 Independently selected from

[0437]

[0438] in

[0439] In addition to R 4 Outside of the location, R 3 may be optionally substituted with -Cl, isopropyl or -OMe, wherein the isopropyl group may be optionally substituted with -OH; and

[0440] R 4 It is a methyl or ethyl group.

[0441] Preferably, the compound of formula (Ic) is:

[0442]

[0443] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof; wherein

[0444] R 1 yes

[0445] in

[0446] Z is CH2;

[0447] R 5 It is hydrogen;

[0448] X is O;

[0449] Y is N;

[0450] When valence permits, It is a combination of single and double bonds;

[0451] R 2 is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl or cyclopentane. Even more preferably, R 2 R is independently selected from hydrogen, ethyl, isopropyl or cyclopentane. 2 may be optionally substituted with OH, for example in middle;

[0452] R 3 Independently selected from:

[0453] In addition to R 4 Outside of the location, R 3 may be optionally substituted with Cl, isopropyl or -OMe, wherein isopropyl may be optionally substituted with -OH; and R 4 is methyl, isopropyl or ethyl. More preferably, R 4 is methyl or isopropyl. Even more preferably, R 4 It's methyl.

[0454] Preferably, the compound of formula (Ic) is:

[0455]

[0456] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof;

[0457] in

[0458] R 1 yes

[0459] in

[0460] Z is CH2;

[0461] R 5 It is hydrogen;

[0462] X is O;

[0463] Y is N;

[0464] When valence permits, It is a combination of single and double bonds;

[0465] R 2 It is ethyl;

[0466] R 3 Independently selected from

[0467]

[0468] in

[0469] In addition to R 4 Outside of the location, R 3 may be optionally substituted with Cl, isopropyl or -OMe, wherein isopropyl may be optionally substituted with -OH; and

[0470] R 4 It is a methyl or ethyl group.

[0471] In a further embodiment, the present invention relates to a compound of formula (I')

[0472]

[0473]

[0474]

[0475] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof.

[0476] In another embodiment, the present invention relates to a compound of formula (I')

[0477]

[0478]

[0479] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof.

[0480] In another embodiment, the present invention relates to a compound of formula (I')

[0481]

[0482] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof.

[0483] In a further embodiment, the present invention relates to a compound of formula (I')

[0484]

[0485] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof.

[0486] In a further embodiment, the present invention relates to a compound of formula (I')

[0487]

[0488]

[0489] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof.

[0490] In a further embodiment, the present invention relates to a compound of formula (I')

[0491]

[0492] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof.

[0493] In one embodiment, the present invention further relates to compounds of formula (II') as defined below

[0494]

[0495] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof;

[0496] in

[0497] W is independently selected from O and S;

[0498] m is 1 or 2;

[0499] R 0 is H or C1-C3 alkyl;

[0500] R 6 yes

[0501]

[0502] in

[0503] Z 1 are independently selected from CH2 and O, provided that no more than two Z1 It is O;

[0504] R 9 independently selected from hydrogen and halogen;

[0505] R 8 independently selected from hydrogen, C1-C6 alkyl and C3-C6 cycloalkyl; and

[0506] R 7 independently selected from heteroC3-C6 cycloalkyl, aryl or heteroaryl, each of which may be optionally substituted.

[0507] Further, in one embodiment, the present invention relates to wherein R 0 The compound of formula (II') is H, having the following definition of formula (II),

[0508]

[0509] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof;

[0510] in

[0511] W is independently selected from O and S;

[0512] m is 1 or 2;

[0513] R 6 yes

[0514]

[0515] in

[0516] Z 1 are independently selected from CH2 and O, provided that no more than two Z 1 It is O;

[0517] R 9 independently selected from hydrogen and halogen;

[0518] R 8 independently selected from hydrogen, C1-C6 alkyl and C3-C6 cycloalkyl; and

[0519] R 7 independently selected from heteroC3-C6 cycloalkyl, aryl or heteroaryl, each of which may be optionally substituted.

[0520] In another embodiment, the present invention relates to compounds of formula (II'), in particular to compounds of formula (II), wherein W is independently selected from O and S. Preferably, W is O. More preferably, W is S.

[0521] In another embodiment, the present invention relates to compounds of formula (II'), in particular to compounds of formula (II), wherein m is 1.

[0522] In one embodiment, the present invention relates to a 0 is a compound of formula (II') wherein R 0 is H, methyl or ethyl. More preferably, R 0 It’s H.

[0523] In another embodiment, the present invention relates to compounds of formula (II'), in particular to compounds of formula (II), wherein R 6 yes

[0524] where Z 1 is CH2; and R 9 It's hydrogen.

[0525] In another embodiment, the present invention relates to compounds of formula (II'), in particular to compounds of formula (II), wherein R 8 is independently selected from hydrogen, C1-C6 alkyl and C3-C6 cycloalkyl. More preferably, R 8 is independently selected from hydrogen, C1-C6 alkyl and C5-C6 cycloalkyl. Even more preferably, R 8 are independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl or cyclopentane, preferably, R 8 is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl or cyclopentane. Even more preferably, R 8 R is independently selected from ethyl, isopropyl or cyclopentane. 8 May be optionally substituted with OH. More preferably, R 8 It's ethyl.

[0526] R 7 Independently selected from heteroC3-C6 cycloalkyl, aryl or heteroaryl, each of which may be optionally substituted with -C1-C6 alkyl, -O-C1-C6 alkyl, -Hal or -C1-C6 alkyl-OH.

[0527] In another embodiment, the present invention relates to compounds of formula (II'), in particular to compounds of formula (II), wherein R 7 is independently selected from heteroC3-C6 cycloalkyl containing one or two heteroatoms selected from N or O, aryl, or C5-C6 heteroaryl containing one, two or three heteroatoms independently selected from S, N and O; wherein each of them may be optionally substituted by -C1-C6 alkyl, -O-C1-C6 alkyl, -Hal, or -C1-C6 alkyl-OH. More preferably, R 7is independently selected from heteroC3-C6 cycloalkyl containing one or two heteroatoms selected from N or O, C5-C6 aryl or C5-C6 heteroaryl containing one, two or three heteroatoms independently selected from S, N and O; wherein each of them may be optionally substituted by -C1-C6 alkyl, -O-C1-C6 alkyl, -Hal or -C1-C6 alkyl-OH. Even more preferably, R 7 is a heteroC3-C6 cycloalkyl group containing one heteroatom, wherein the heteroatom is O; and R 7 Optionally substituted with -C1-C6 alkyl, -O-C1-C6 alkyl, -Hal or -C1-C6 alkyl-OH.

[0528] In one embodiment, the present invention relates to compounds of formula (II'), in particular to compounds of formula (II), wherein R 7 Is aryl, optionally substituted by-C1-C6 alkyl,-O-C1-C6 alkyl,-Hal or-C1-C6 alkyl-OH. In a specific embodiment, the aryl group is optionally substituted by-O-C1-C6 alkyl or-Hal. In a specific embodiment, the aryl group is optionally substituted by-O-C1-C6 alkyl or-Hal, wherein the halogen (-Hal) is preferably chlorine.

[0529] In one embodiment, the present invention relates to compounds of formula (II'), in particular to compounds of formula (II), wherein R 7 is a C5-C6 heteroaryl group containing one, two or three heteroatoms independently selected from S, N and O; wherein each of them may be optionally substituted by a substituent selected from -C1-C6 alkyl, -O-C1-C6 alkyl, -Hal or -C1-C6 alkyl-OH.

[0530] Even more preferably, R 7 Independently selected from

[0531] in

[0532] R 4 independently selected from hydrogen, C1-C6 alkyl and C3-C6 cycloalkyl, and wherein each of them may be optionally substituted with -C1-C6 alkyl, -O-C1-C6 alkyl, -Hal or -C1-C6 alkyl-OH, wherein any of the mentioned C1-C6 alkyl may be optionally substituted with -OH; and

[0533] The C3-C6 cycloalkyl group may be optionally substituted with -OH.

[0534] Preferably, R 7 Independently selected from:

[0535] in

[0536] R 4 independently selected from hydrogen, C1-C6 alkyl and C3-C6 cycloalkyl, and wherein each of them may be optionally substituted with -C1-C6 alkyl, -O-C1-C6 alkyl, -Hal or -C1-C6 alkyl-OH.

[0537] More preferably, R 7 Selected from:

[0538] in

[0539] R 4 independently selected from hydrogen, C1-C6 alkyl and C3-C6 cycloalkyl, and wherein each of them may be optionally substituted with -C1-C6 alkyl, -O-C1-C6 alkyl, -Hal or -C1-C6 alkyl-OH.

[0540] In each of the above embodiments, R 7 Can be optionally substituted by halogen, -O-C1-C6 alkyl, -C1-C6 alkyl-OH or C1-C6 alkyl. More preferably, R 7 may optionally be substituted with chloro, methoxy, methyl or isopropyl or replace.

[0541] In R 7 In the C1-C6 alkyl group, preferably methyl, ethyl, isopropyl, propyl, isobutyl or butyl, and may be optionally substituted by -OH, for example in middle.

[0542] In another embodiment, the present invention relates to compounds of formula (II'), in particular to compounds of formula (II), wherein R 4 are independently selected from hydrogen, methyl, ethyl, isopropyl and propyl. More preferably, R 4 It's methyl.

[0543] In one embodiment, the present invention relates to compounds of formula (II'), in particular to compounds of formula (II), wherein R 8 is hydrogen, and R 7 yes

[0544] a) Preferred

[0545] b) Preferred

[0546] c) Preferred

[0547] d)

[0548] e) Preferred or

[0549] f) Preferred where R 4 Independently selected from hydrogen, C1-C6 alkyl and C3-C6 cycloalkyl.

[0550] In another embodiment, the present invention relates to compounds of formula (II'), in particular to compounds of formula (II), wherein R 8 is hydrogen, and R 7 yes

[0551] a) Preferred

[0552] b) Preferred or

[0553] c) Preferred and among them

[0554] R 7 Each may be optionally substituted with -C1-C6 alkyl, -O-C1-C6 alkyl, -Hal or -C1-C6 alkyl-OH.

[0555] In each of the above embodiments, R 7 Can be optionally substituted by halogen, -O-C1-C6 alkyl, -C1-C6 alkyl-OH or C1-C6 alkyl. More preferably, R 7 may optionally be substituted with chloro, methoxy, methyl or isopropyl or replace.

[0556] In R 7 In the C1-C6 alkyl group, preferably methyl, ethyl, isopropyl, propyl, isobutyl or butyl, and may be optionally substituted by -OH, for example in middle.

[0557] Preferably, R 4 are independently selected from hydrogen, methyl, ethyl, isopropyl and propyl. More preferably, R 4 It's methyl.

[0558] In one embodiment, the present invention relates to compounds of formula (II'), in particular to compounds of formula (II), wherein R 8 is a C1-C6 alkyl group, and R 7 yes

[0559] a) Preferred

[0560] b) Preferred

[0561] c) Preferred

[0562] d)

[0563] e) Preferred or

[0564] f) Preferred where R 4 independently selected from hydrogen, C1-C6 alkyl and C3-C6 cycloalkyl;

[0565] g) Preferred

[0566] h) Preferred

[0567] i) Preferred

[0568] j) Preferred or

[0569] k) Preferred

[0570] In one embodiment, the present invention relates to compounds of formula (II'), in particular to compounds of formula (II), wherein R 8 is a C1-C6 alkyl group, and R 7 yes

[0571] a) Preferred

[0572] b) Preferred

[0573] c) Preferred

[0574] d)

[0575] e) Preferred or

[0576] f) Preferred where R 4 Independently selected from hydrogen, C1-C6 alkyl and C3-C6 cycloalkyl.

[0577] In each of the above embodiments, R 7 Can be optionally substituted by halogen, -O-C1-C6 alkyl, -C1-C6 alkyl-OH or C1-C6 alkyl. More preferably, R 7 may optionally be substituted with chloro, methoxy, methyl or isopropyl or replace.

[0578] In R 7 In the C1-C6 alkyl group, preferably methyl, ethyl, isopropyl, propyl, isobutyl or butyl, and may be optionally substituted by -OH, for example in middle.

[0579] Preferably, R 8 is a C1-C6 alkyl group, wherein R 8 Preferably, R is selected from methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl or hexyl. More preferably, R 8 is a C1-C3 alkyl group. More preferably, R 8 is independently selected from methyl, ethyl, propyl or isopropyl. Even more preferably, R 8 R is independently selected from ethyl or isopropyl. 8 May be optionally substituted with OH.

[0580] In one embodiment, the present invention relates to compounds of formula (II'), in particular to compounds of formula (II), wherein R 8 is a C3-C6 cycloalkyl group, and R 7 yes

[0581] a) Preferred

[0582] b) Preferred

[0583] c) Preferred

[0584] d)

[0585] e) Preferred or

[0586] f) Preferred where R 4Independently selected from hydrogen, C1-C6 alkyl and C3-C6 cycloalkyl.

[0587] In each of the above embodiments, R 7 Can be optionally substituted by halogen, -O-C1-C6 alkyl, -C1-C6 alkyl-OH or C1-C6 alkyl. More preferably, R 7 may optionally be substituted with chloro, methoxy, methyl or isopropyl or replace.

[0588] In R 7 In the C1-C6 alkyl group, preferably methyl, ethyl, isopropyl, propyl, isobutyl or butyl, and may be optionally substituted by -OH, for example in middle.

[0589] Preferably, R 8 is a C1-C6 alkyl group or a C5-C6 cycloalkyl group. More preferably, R 8 is ethyl or cyclopentane. Even more preferably, R 8 Preferably, R 8 is a C5-C6 cycloalkyl group. More preferably, R 8 is cyclopentane. 8 May be optionally substituted with OH.

[0590] Preferably, R 4 are independently selected from hydrogen, methyl, ethyl, isopropyl and propyl. More preferably, R 4 It's methyl.

[0591] In a further embodiment, the present invention relates to compounds of formula (II) as defined below,

[0592]

[0593] or its stereoisomers, racemic mixtures, tautomers, polymorphs, pharmaceutically acceptable salts, prodrugs, hydrates, or solvates; wherein W, m, R 6 , Z 1 、R 9 、R 8 and R 7 As defined above for the compound of formula (II').

[0594] In one embodiment, the present invention relates to a compound of formula (II) or a stereoisomer, or a racemic mixture, or a tautomer, or a polymorph, or a pharmaceutically acceptable salt, or a hydrate, or a solvate thereof.

[0595] In a further embodiment, the present invention relates to compounds of formula (II) as defined below

[0596]

[0597] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof;

[0598] in

[0599] W is independently selected from O and S;

[0600] m is 1 or 2;

[0601] R 6 yes

[0602]

[0603] in

[0604] Z 1 are independently selected from CH2 and O, provided that no more than two Z 1 It is O;

[0605] R 9 independently selected from hydrogen and halogen;

[0606] R 8 Independently selected from C1-C6 alkyl and C3-C6 cycloalkyl;

[0607] R 7 Independently selected from

[0608]

[0609] in

[0610] In addition to R 4 Outside of the location, R 7 may be optionally substituted with halogen, C1-C6 alkyl or -OMe;

[0611] R 4 is selected from hydrogen, C1-C6 alkyl and C3-C6 cycloalkyl;

[0612] in

[0613] Any of the mentioned C1-C6 alkyl groups may be optionally substituted with -OH; and

[0614] The C3-C6 cycloalkyl group may be optionally substituted with -OH.

[0615] Preferably, R 6 yes

[0616] where Z 1 is CH2, and R 9 is hydrogen or a halogen.

[0617] More preferably, R6 yes

[0618] where Z 1 is CH2, and R 9 It is hydrogen or F (fluorine).

[0619] In another embodiment, the present invention relates to compounds of formula (II), wherein R 9 is hydrogen or a halogen selected from F and Cl. More preferably, R 9 It's hydrogen.

[0620] In one embodiment, the invention relates to compounds of formula (II), wherein W is O. In one embodiment, W is preferably S.

[0621] In one embodiment, the present invention relates to compounds of formula (II), wherein m is 1.

[0622] In one embodiment, the present invention relates to compounds of formula (II), wherein R 8 is methyl, ethyl, propyl or cyclopropyl. More preferably, R 8 It's ethyl.

[0623] In one embodiment, the present invention relates to compounds of formula (II), wherein R 7 Independently selected from the following groups:

[0624] in

[0625] R 4 independently selected from hydrogen, C1-C6 alkyl and C3-C6 cycloalkyl, and wherein each of them may be optionally substituted with -C1-C6 alkyl, -O-C1-C6 alkyl, -Hal or -C1-C6 alkyl-OH.

[0626] Preferably, R 7 Selected from the following groups:

[0627] where R 4 independently selected from hydrogen, C1-C6 alkyl and C3-C6 cycloalkyl, and wherein each of them may be optionally substituted with -C1-C6 alkyl, -O-C1-C6 alkyl, -Hal or -C1-C6 alkyl-OH.

[0628] In one embodiment, the present invention relates to compounds of formula (II), wherein R 7 yes

[0629]

[0630] More preferably, R 7 yes

[0631]

[0632] Preferably, in addition to R 4 Outside of the location, R 7 It may be optionally substituted by one or two groups selected from halogen, C1-C6 alkyl or -OMe. 7 May be optionally substituted by one or two C1-C6 alkyl groups, which may be further optionally substituted by -OH. More preferably, R 7 May be optionally substituted by one or two groups selected from -Cl, C1-C4 alkyl or -OMe, wherein C1-C4 alkyl may be optionally substituted by -OH. Even more preferably, R 7 It may be optionally substituted with one or two groups selected from -Cl, isopropyl and -OMe, wherein the isopropyl group may be optionally substituted with -OH.

[0633] Preferably, R 4 is selected from hydrogen and C1-C6 alkyl. More preferably, R 4 is methyl or ethyl. Even more preferably, R 4 It's methyl.

[0634] Preferably, in any case of C1-C6 alkyl, the C1-C6 alkyl may be optionally substituted with -OH.

[0635] Preferably, in any case of C3-C6 cycloalkyl, the C3-C6 cycloalkyl may be optionally substituted with -OH.

[0636] In a further embodiment, the present invention relates to stereoisomers of compounds of formula (II'), which are defined as compounds of formula (IIa') or (IIb')

[0637]

[0638] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof, wherein W, m, R 6 、R 7 、R 0 and R 8 As defined above. The embodiments defined for compounds of formula (II') apply here.

[0639] In a preferred embodiment, the present invention relates to stereoisomers of compounds of formula (II), which are defined as compounds of formula (IIa) or (IIb)

[0640]

[0641] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof, wherein W, m, R 6 、R 7 and R 8 As defined above. The embodiments defined for the compounds of formula (II) apply here.

[0642] In a further embodiment, the present invention relates to a compound of formula (II'):

[0643]

[0644]

[0645] or a stereoisomer, or a racemic mixture, or a tautomer, or a polymorph, or a pharmaceutically acceptable salt, or a hydrate, or a solvate thereof.

[0646] In a further embodiment, the present invention relates to a compound of formula (II'):

[0647]

[0648] or a stereoisomer, or a racemic mixture, or a tautomer, or a polymorph, or a pharmaceutically acceptable salt, or a hydrate, or a solvate thereof.

[0649] In a further embodiment, the present invention relates to a compound of formula (II'):

[0650]

[0651] or a stereoisomer, or a racemic mixture, or a tautomer, or a polymorph, or a pharmaceutically acceptable salt, or a hydrate, or a solvate thereof.

[0652] In a further embodiment, the present invention relates to compounds of formula (II):

[0653]

[0654] The present invention further relates to a pharmaceutical composition comprising a compound of formula (I'), (I), (II') or (II) as defined herein, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, and optionally at least one pharmaceutically acceptable carrier, diluent, adjuvant or excipient.

[0655] In one embodiment, the pharmaceutical composition comprises a compound of formula (I') as defined herein or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof and optionally at least one pharmaceutically acceptable carrier, diluent, adjuvant or excipient.

[0656] In one embodiment, the pharmaceutical composition comprises a compound of formula (I) as defined herein or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof and optionally at least one pharmaceutically acceptable carrier, diluent, adjuvant or excipient.

[0657] In a further embodiment, the pharmaceutical composition comprises a compound of formula (Ia'), (Ia), (Ib'), (Ib), (Ic'), (Ic), (Id'), (Id"), (Id"), (Id"), (Ie'), (Ie), (If') or (If) as an embodiment of formula (I') as defined in the present invention, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, and optionally at least one pharmaceutically acceptable carrier, diluent, adjuvant or excipient.

[0658] In one embodiment, the pharmaceutical composition comprises a compound of formula (II') or (II) as defined in the present invention, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, and optionally at least one pharmaceutically acceptable carrier, diluent, adjuvant or excipient.

[0659] In a further embodiment, the pharmaceutical composition comprises a compound of formula (IIa'), (IIa), (IIb') or (IIb) as an embodiment of formula (II') as defined in the present invention, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, and optionally at least one pharmaceutically acceptable carrier, diluent, adjuvant or excipient.

[0660] The embodiments as defined above for the compounds of formula (I'), (I), (Ia'), (Ia), (Ib'), (Ib), (Ic'), (Ic), (Id'), (Id"), (Id'"), (Id"), (Ie'), (Ie), (If') or (If) and (II'), (II), (IIa'), (IIa), (IIb') or (IIb) also apply here and can be combined with one another.

[0661] Having described various embodiments of the invention, it should be recognized that specified features within each embodiment may be combined with other specified features to provide further embodiments of the invention.

[0662] In other words, the present invention relates to a compound of formula (I'), (I), (II') or (II) as defined in the present invention, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, for use as a medicament.

[0663] The present invention relates to compounds of formula (I'), (I), (II') or (II) as defined herein, or stereoisomers, racemic mixtures, tautomers, polymorphs, pharmaceutically acceptable salts, prodrugs, hydrates or solvates thereof, for use in treating, alleviating or preventing diseases, disorders or abnormalities that respond to modulation of NLRP3 inflammasome pathway components, particularly inhibition of their activation and / or modulation of IL-1β and / or IL-18 levels, particularly reduction. In one embodiment, modulation is reduction and / or inhibition of IL-1β and / or IL-1β levels. In particular, modulation is reduction and / or inhibition of IL-1β.

[0664] In another embodiment, the present invention relates to a compound of formula (I'), (I), (II') or (II) as defined herein, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, for use in a method of reducing and / or inhibiting IL-1β. In particular, inhibiting IL-1β.

[0665] The present invention relates to compounds of formula (I'), (I), (II') or (II) as defined in the present invention, or stereoisomers, racemic mixtures, tautomers, polymorphs, pharmaceutically acceptable salts, prodrugs, hydrates or solvates thereof, for use in treating, alleviating or preventing diseases, disorders or abnormalities that respond to modulation of NLRP3 inflammasome pathway components, particularly inhibition of their activation.

[0666] The present invention relates to compounds of formula (I'), (I), (II') or (II) as defined in the present invention, or stereoisomers, racemic mixtures, tautomers, polymorphs, pharmaceutically acceptable salts, prodrugs, hydrates or solvates thereof, for use in treating, alleviating or preventing diseases, disorders or abnormalities that respond to modulation of the NLRP3 inflammasome pathway, particularly inhibition of its activation.

[0667] The present invention relates to compounds of formula (I'), (I), (II') or (II) as defined in the present invention, or stereoisomers, racemic mixtures, tautomers, polymorphs, pharmaceutically acceptable salts, prodrugs, hydrates or solvates thereof, for use in treating, alleviating or preventing diseases, disorders or abnormalities that respond to the regulation, in particular the reduction, of IL-1β and / or IL-18 levels.

[0668] In other words, the present invention relates to a method for treating, alleviating or preventing a disease, disorder or abnormality that responds to the modulation of NLRP3 inflammasome pathway components, in particular the inhibition of its activation and / or to the modulation of IL-1β and / or IL-18 levels, in particular the reduction thereof, wherein the method comprises administering to an individual in need thereof (e.g., a patient) a therapeutically effective amount of a compound of formula (I'), (I), (II') or (II) as defined in the present invention, or its stereoisomers, racemic mixtures, tautomers, polymorphs, pharmaceutically acceptable salts, prodrugs, hydrates or solvates.

[0669] In one embodiment, the present invention relates to a method for treating, preventing or alleviating a disease, disorder or abnormality that responds to modulation of a component of the NLRP3 inflammasome pathway, in particular inhibition of its activation, wherein the method comprises administering to an individual in need thereof (e.g., a patient) a therapeutically effective amount of a compound of formula (I'), (I), (II') or (II) as defined herein, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof.

[0670] The present invention further relates to a method for treating, preventing or alleviating a disease, disorder or abnormality that responds to modulation of NLRP3 inflammasome pathway components, in particular inhibition of its activation, wherein the method comprises administering to an individual (e.g., a patient) in need thereof a therapeutically effective amount of a compound of formula (I'), (I), (II') or (II) as defined in the present invention, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof.

[0671] In one embodiment, the present invention relates to a method for treating, preventing or alleviating a disease, disorder or abnormality that is responsive to the modulation, in particular reduction, of IL-1β and / or IL-18 levels, wherein the method comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I'), (I), (II') or (II) as defined herein, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof.

[0672] The present invention relates to the use of a compound of formula (I'), (I), (II') or (II) as defined herein, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof in the preparation of a medicament. In a further embodiment, the present invention relates to the use of a compound of formula (I'), (I), (II') or (II) as defined herein, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof in the preparation of a medicament for treating, alleviating or preventing a disease, disorder or abnormality that responds to modulation of a component of the NLRP3 inflammasome pathway, in particular inhibition of its activation, and / or modulation of IL-1β and / or IL-18 levels, in particular reduction. In one embodiment, the disease, disorder or abnormality is selected from the list disclosed herein.

[0673] The present invention relates to the use of a compound of formula (I'), (I), (II') or (II) as defined in the present invention, or its stereoisomers, racemic mixtures, tautomers, polymorphs, pharmaceutically acceptable salts, prodrugs, hydrates or solvates, in the preparation of a medicament for treating, alleviating or preventing a disease, disorder or abnormality that responds to the modulation of NLRP3 inflammasome pathway components, in particular the inhibition of their activation.

[0674] The present invention relates to the use of a compound of formula (I'), (I), (II') or (II) as defined in the present invention, or its stereoisomers, racemic mixtures, tautomers, polymorphs, pharmaceutically acceptable salts, prodrugs, hydrates or solvates, in the preparation of a medicament for treating, alleviating or preventing a disease, disorder or abnormality that responds to the modulation of NLRP3 inflammasome pathway components, in particular the inhibition of their activation.

[0675] The present invention relates to the use of a compound of formula (I'), (I), (II') or (II) as defined in the present invention or its stereoisomers, racemic mixtures, tautomers, polymorphs, pharmaceutically acceptable salts, prodrugs, hydrates or solvates in the preparation of a medicament for treating, alleviating or preventing diseases, disorders or abnormalities that respond to the regulation, in particular the reduction, of IL-1β and / or IL-18 levels.

[0676] The present invention relates to the use of a compound of formula (I'), (I), (II') or (II) as defined herein, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, in the preparation of a medicament for reducing and / or inhibiting IL-1β and / or IL-1β levels. In one embodiment, the present invention relates to the use of a compound of the present invention as defined herein in the preparation of a medicament for reducing and / or inhibiting IL-1β. In another embodiment, the present invention relates to the use of a compound of the present invention as defined herein in the preparation of a medicament for reducing IL-1β.

[0677] In one embodiment, the present invention relates to a compound of formula (I'), (I), (II') or (II) as defined in the present invention, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, for use in treating, alleviating or preventing tauopathy by modulating components of the inflammasome pathway, in particular by modulating the NLRP3 inflammasome pathway.

[0678] In another embodiment, the disease, disorder or abnormality 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.

[0679] In yet another embodiment, the disease, disorder or abnormality is a disease, disorder or abnormality selected from the group consisting of Alzheimer's disease, Parkinson's disease, cryopyrin-associated periodic syndromes (CAPS), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH) and gout.

[0680] In a further embodiment, the disease, disorder or abnormality is a disease, disorder or abnormality of the immune system. In one embodiment, the disease, disorder or abnormality is an inflammatory disease, disorder or abnormality. In yet another embodiment, the disease, disorder or abnormality is an autoimmune disease, disorder or abnormality. In yet another embodiment, the disease, disorder or abnormality is a disease, disorder or abnormality of the central nervous system (CNS). In yet another embodiment, the disease, disorder or abnormality may be a disease, disorder or abnormality or condition of the skin. The disease, disorder or abnormality may be a disease, disorder or abnormality or condition of the cardiovascular system. The disease, disorder or abnormality or condition may be cancer, a tumor or other malignancy. The disease, disorder or abnormality or condition may be a disease, disorder or abnormality of the renal system. The disease, disorder or abnormality or condition may be a disease, disorder or abnormality of the gastrointestinal tract. The disease, disorder or abnormality or condition may be a disease, disorder or abnormality of the respiratory system. The disease, disorder or abnormality or condition may be a disease, disorder or abnormality of the endocrine system. The disease, disorder or abnormality or condition may be a liver-related disease, disorder or abnormality.

[0681] In one embodiment, the disease, disorder or abnormality responsive to modulation of NLRP3 inflammasome pathway components, in particular inhibition of its activation, can be selected from Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, demyelination, viral encephalitis, epilepsy, stroke, atherosclerosis, asthma, allergic inflammation, cryptopyrin-associated periodic syndrome (CAPS), Muckle-Wells syndrome (MWS), familial 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 mellitus, disease, type 2 diabetes, rheumatoid arthritis, myelodysplastic syndrome, familial Mediterranean fever (FMF), TNF 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 (PAPA), A20 haploinsufficiency (HA20), PLCG2-related antibody deficiency and immune dysregulation (PLAID), pediatric granulomatous arthritis (PGA), PLCG2-related autoinflammatory, antibody deficiency and immune dysregulation (APLAID), with B-cell immunodeficiency Stomach ulcer, periodic fever, sideroblastic anemia with delayed development (SIFD), chronic nonbacterial osteomyelitis (CNO), Sweet's syndrome, chronic relapsing multifocal osteomyelitis (CRMO), synovitis, impetigo, acne, eczema, alopecia areata, actinic keratosis, hyperostosis, osteoarthritis 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 due to pneumococcal meningitis, obesity, age-related macular degeneration (AMD), corneal infection, uveitis, dry eye Eye, chronic kidney disease, diabetic nephropathy, alcoholic liver disease, contact allergy, 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, helminthic 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.

[0682] Preferably, the disease, disorder or abnormality is selected from Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, demyelination, viral encephalitis, epilepsy, stroke, atherosclerosis, asthma, allergic inflammation, cryptopyrin-associated periodic 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, anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV), lupus nephritis, 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 fevers (HRFs).

[0683] More preferably, the disease, disorder or abnormality 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 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 and myelodysplastic syndrome.

[0684] Even more preferably, the disease, disorder or abnormality is selected from Alzheimer's disease, Parkinson's disease, cryptopyrin-associated periodic syndrome (CAPS), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), rheumatoid arthritis and gout. Even more preferably, the disease, disorder or abnormality is selected from Alzheimer's disease, Parkinson's disease, cryptopyrin-associated periodic syndrome (CAPS), rheumatoid arthritis and gout.

[0685] In one embodiment, the present invention relates to a compound of formula (I'), (I), (II') or (II) as defined herein, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, for treating, alleviating or preventing IL-18 and / or IL-1β-related diseases by modulating NLRP3 inflammasome pathway components, in particular by modulating NLRP3 inflammasome pathways. As a result of administering a compound of formula (I'), (I), (II') or (II) as defined herein, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, the level of IL-18 and / or IL-1β in the individual is reduced.

[0686] The disease, disorder or abnormality associated with IL-18 and / or IL-1β is selected from chronic obstructive pulmonary disease (COPD), transfusion-related lung injury, bronchopulmonary dysplasia (BPD), acute respiratory distress syndrome (ARDS), pediatric autoinflammatory diseases or conditions, Still's disease and in particular adult-onset Still's disease or juvenile Still's disease, juvenile rheumatoid arthritis (JRA), juvenile idiopathic arthritis (JIA), systemic juvenile-onset idiopathic arthritis (SoJIA), systemic juvenile idiopathic arthritis (sJIA), interstitial lung disease (ILD), macrophage activation syndrome (MAS) and including primary, secondary and recurrent MAS, hemophagocytic lymphohistiocytosis (HLH), and perforin, munc 13-4 and 18-2, synthaxin Familial (hereditary) hemophagocytic lymphohistiocytosis (FHLH) associated with gene defects in 11, immunodeficiencies such as Chediak-Higashi syndrome (CHS), Griscelli syndrome (GS), X-linked lymphoproliferative syndrome (XLP2), X-linked inhibitor of apoptosis protein deficiency (XIAP), acquired hemophagocytic lymphohistiocytosis associated with infectious conditions, particularly herpes viruses such as EBV and other pathogens, autoinflammatory syndromes associated with NLRC4 mutations, giant cell arteritis (GCA), acne, septic arthritis, pyoderma gangrenosum and acne vulgaris (PAPA), pulmonary sarcoidosis, heart failure, ischemic heart disease, dry eye disease (DED), keratitis, corneal ulcers and abrasions, iritis, glaucoma, Sjögren's syndrome, autoimmune uveitis, Behçet's disease, conjunctivitis, allergic conjunctivitis, type 2 diabetes mellitus, solid organ and blood stem cell transplantation, ischemia-reperfusion injury, familial Mediterranean fever (FMF), tumor necrosis factor receptor 1-associated periodic syndromes (TRAPS), hyper-IgD syndrome (mevalonate kinase gene mutation), gout, Schnitzler syndrome, Wegener's granulomatosis (also known as granulomatosis with polyangiitis (GPA)), Hashimoto's thyroiditis, Crohn's disease, early-onset inflammatory bowel disease (EOIBD), very early-onset EOIBD (VEOIBD), infantile IBD, neonatal IBD, ulcerative colitis, and Blau syndrome (NOD-2 mutation).

[0687] Modulation of the NLRP3 inflammasome pathway has been shown to be beneficial in diseases, disorders, and abnormalities with altered IL-18 levels and / or IL-1β that lead to pathological inflammation.

[0688] The embodiments as defined above for compounds of formula (I'), such as (Ia'), (Ia), (Ib'), (Ib), (Ic'), (Ic), (Id'), (Id"), (Id"), (Id"), (Ie'), (Ie), (If') or (If) and for compounds of formula (II'), such as (IIa'), (IIa), (IIb') and (IIb), apply here and can be combined with one another.

[0689] The present invention relates to compounds of formula (I'), (I), (II') or (II) as defined herein, which are modulators of NLRP3 inflammasome activity and / or modulators of IL-18 and / or IL-1b levels in an individual.

[0690] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I'), (I), (II') or (II) as defined herein, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof and at least one additional biologically active compound. Optionally, the pharmaceutical composition may comprise a pharmaceutically acceptable carrier, diluent, adjuvant or excipient as described herein.

[0691] In another embodiment, the present invention relates to a pharmaceutical composition comprising a compound of formula (I'), (I), (II') or (II) as defined herein, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, in combination with at least one additional biologically active compound different from the compound of formula (I'), (I), (II') or (II), and optionally comprising at least one pharmaceutically acceptable carrier, diluent, adjuvant or excipient.

[0692] In particular, the additional bioactive compounds can be those for treating diseases, disorders or abnormalities targeting different pathological mechanisms, such as 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, etc. When the compound of the present invention is used in combination with additional bioactive compounds, the dosage of each compound may be different from the dosage when the compound is used as a monotherapy. Such bioactive compounds are well known in the literature. Such bioactive compounds are, for example, chemical compounds, peptides, antibodies, antibody fragments or nucleic acids, which, when administered to an individual (e.g., a patient) in combination with the compound of the present invention, have therapeutic activity or enhance therapeutic activity.

[0693] In another embodiment, the present invention relates to a pharmaceutical composition comprising a combination of a compound of formula (I'), (I), (II') or (II) or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof as defined herein and at least one additional biologically active compound different from a compound of formula (I'), (I), (II') or (II), and optionally comprising at least one pharmaceutically acceptable carrier, diluent, adjuvant or excipient, for use as a medicament.

[0694] The term "combination" refers to a fixed combination in the form of a dosage unit or a combined administration wherein a compound of the invention and a combination partner (e.g. another drug, also referred to as a "therapeutic agent" or "additional biologically active compound") as described above can be administered independently at the same time or separately within time intervals.

[0695] 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'), (I), (II') or (II) as defined herein, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof and at least one additional biologically active compound, and optionally at least one pharmaceutically acceptable carrier, diluent, adjuvant or vehicle. In particular, the at least one additional biologically active compound is a compound different from the compound of formula (I'), (I), (II') or (II).

[0696] In another embodiment, the present invention relates to a combination comprising a therapeutically effective amount of a compound of formula (I'), (I), (II') or (II) as defined herein, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof and at least one additional biologically active compound different from the compound of formula (I'), (I), (II') or (II), and optionally at least one pharmaceutically acceptable carrier, diluent, adjuvant or excipient, for use as a medicament.

[0697] The present invention relates to the use of compounds of formula (I'), (I), (II') or (II) as defined herein, 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 pathways and for testing compounds targeting the NLRP3 inflammasome pathway.

[0698] Thus, the present invention provides a compound of formula (I'), (I), (II') or (II) as defined herein, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, for use in treating, alleviating or preventing a condition or abnormality that responds to modulation of a component of the NLRP3 inflammasome pathway or to modulation of IL-1β and / or IL-18 levels, particularly a decrease in response, wherein the medicament is prepared for administration with another bioactive agent. The present invention also provides the use of another bioactive agent for treating, alleviating or preventing a condition or abnormality that responds to modulation of a component of the NLRP3 inflammasome pathway or to modulation of IL-1β and / or IL-18 levels, particularly a decrease in response, wherein the other bioactive agent is administered with a compound of the present invention, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof.

[0699] In another embodiment, the present invention also provides a compound of formula (I'), (I), (II') or (II) as defined in the present invention, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, for use in treating, alleviating or preventing disorders or abnormalities that respond to modulation of NLRP3 inflammasome pathway components or modulation of IL-1β and / or IL-18 levels, particularly reduction, wherein the modulation is a reduction and / or inhibition of IL-1β and / or IL-1β levels. Preferably, the modulation is a reduction and / or inhibition of IL-1β. Preferably, the modulation is the inhibition of IL-1β. In another embodiment, the present invention provides a compound of formula (I'), (I), (II') or (II) as defined in the present invention, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, for use as a medicament, particularly for inhibiting IL-1β.

[0700] In another embodiment, the present invention also provides a compound of formula (I'), (I), (II') or (II) as defined herein, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, for use in a method for treating, alleviating or preventing a disease, disorder or abnormality that responds to modulation of NLRP3 inflammasome pathway components or to modulation, in particular reduction, of IL-1β and / or IL-18 levels, wherein the compound of formula (I'), (I), (II') or (II) is prepared for administration with an additional biologically active compound (as defined herein).

[0701] In another embodiment, the present invention also provides a method for treating, alleviating or preventing a disease, disorder or abnormality that responds to modulation of NLRP3 inflammasome pathway components or to modulation of IL-1β and / or IL-18 levels, particularly to reduction, selected from Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, demyelination, viral encephalitis, epilepsy, stroke, atherosclerosis, asthma, allergic inflammation, cryptopyrin-associated periodic syndrome (CAPS), Muckle-Wells syndrome (MWS), familial 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 mellitus, type 2 diabetes mellitus, rheumatoid arthritis, myelodysplastic syndrome, familial Mediterranean fever (FMF), TNF receptor-associated periodic syndrome (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 vulgaris (PAPA), A20 haploinsufficiency (HA20), PL CG2-related antibody deficiency and immune dysregulation (PLAID), pediatric granulomatous arthritis (PGA), PLCG2-related autoinflammatory, antibody deficiency and immune dysregulation (APLAID), sideroblastic anemia with B-cell immunodeficiency, periodic fever, developmental delay (SIFD), chronic nonbacterial osteomyelitis (CNO), Sweet's syndrome, chronic relapsing multifocal osteomyelitis (CRMO), synovitis, impetigo, acne, eczema, alopecia areata, actinic keratosis, hyperostosis, osteitis syndrome (SAPHO), multiple sclerosis (MS), psoriasis, Behçet's disease, Sjögren's syndrome, Schnitzler syndrome, chronic obstructive pulmonary disease Lung disease (COPD), steroid-resistant asthma, asbestosis, silicosis, cystic fibrosis, motor neuron disease, Huntington's disease, cerebral malaria, brain damage due to pneumococcal meningitis, obesity, age-related macular degeneration (AMD), corneal infection, uveitis, dry eye, chronic kidney disease, diabetic nephropathy, alcoholic liver disease, skin contact allergies, 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, helminthic infection, bacterial infection, abdominal aortic aneurysm, wound healing, depression, psychological stress, pericarditis and including Dressler's syndrome, ischemia-reperfusion injury, frontotemporal dementia, HIV-related neurocognitive disorders, coronavirus-related inflammatory pathological diseases 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, cryptopyrin-associated periodic syndrome (CAPS), gout, inflammatory bowel disease, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis (NASH), hypertension, myocardial infarction, oxalate-induced nephropathy, transplantation drug-versus-host disease, type 1 diabetes, type 2 diabetes, rheumatoid arthritis, myelodysplastic syndrome, antineutrophil cytoplasmic antibody-associated vasculitis (AAV), lupus nephritis, glomerular basement membrane (GMB) disease, IgA nephropathy, glomerulonephritis (GN), systemic lupus erythematosus (SLE), focal segmental glomerulosclerosis, minimal change disease (MCD), psoriatic arthritis and hereditary recurrent fevers (HRFs), the method comprising administering to the individual a therapeutically effective amount of a compound of formula (I'), (I), (II') or (II) as defined herein, or a stereoisomer, or racemic mixture, or tautomer, or polymorph, or pharmaceutically acceptable salt, or hydrate, or solvate thereof.

[0702] In another embodiment, the present invention also provides a method of inhibiting IL-1β in an individual in need thereof, comprising administering to the individual in need thereof a therapeutically effective amount of a compound of Formula (I'), (I), (II') or (II) or its stereoisomers, racemic mixtures, tautomers, polymorphs, pharmaceutically acceptable salts, prodrugs, hydrates or solvates.

[0703] In particular, the disease, disorder or abnormality is one that responds to inhibition of NLRP3 inflammasome pathway activation. More particularly, the disease, disorder or abnormality responds to modulation of one or more of: for example, but not limited to, IL-1β or IL-18. For example, the disease, disorder or abnormality responds to modulation of one or more of IL-1β, IL-17, IL-18, IL-1a, IL-37, IL-33, and TH17 cells, preferably, the disease, disorder or abnormality responds to modulation of IL-1β and / or IL-18.

[0704] Synthesis method of the compound of the present invention

[0705] The compounds of the present invention can be prepared according to the definitions of compounds of formula (I'), (I), (II') or (II) as disclosed herein, by the synthetic routes described in the following schemes or examples. Unless otherwise indicated herein or clearly contradicted by the context, all methods described herein can be carried out in any suitable order. The use of any and all examples or exemplary terms (e.g., for example, preferably) provided herein is intended only to better illustrate the present invention and does not limit the scope of the claimed invention.

[0706] In the following general method, R 0 、R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 , X, Y, W and n are as previously defined in the above embodiments or as specified in the schemes. Unless otherwise stated, starting materials are either commercially available or prepared by known methods.

[0707] The present invention relates to a process for preparing a compound of formula (I'), (I), (II') or (II) as disclosed herein. Preferably, the process is used to prepare a compound of formula (I') or any subembodiment as disclosed above, more preferably a compound of formula (I), even more preferably a compound of formula (Ic). In a further embodiment, the process is preferably used to prepare a compound of formula (II'), a compound of formula (II) or any subembodiment as disclosed above.

[0708] In one embodiment, the method comprises the step of cyclizing a compound of formula (II') in the presence of a condensing agent to prepare a compound of formula (I'):

[0709]

[0710] where R 6 ,W,m,n,R 7 、R 8 , X, Y, R 1 、R 2 、R 0 and R 3 As defined above.

[0711] In one embodiment, the method comprises the step of cyclizing a compound of formula (II) in the presence of a condensing agent to prepare a compound of formula (I):

[0712]

[0713] where R 6,W,m,n,R 7 、R 8 , X, Y, R 1 、R 2 and R 3 As defined above.

[0714] Preferably, the present method comprises the step of cyclizing the compound of formula (II) in the presence of a condensing agent to prepare the compound of formula (I).

[0715] A condensing agent is used to cyclize the compound of formula (II) in the presence of a base to prepare the compound of formula (I). The base is preferably trimethylamine (Et3N). The condensing agent is preferably N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDC), Mukaiyama reagent, iodomethane or TsCl. Preferably, the cyclization is carried out at room temperature (RT).

[0716] In a further embodiment, the method comprises the step of cyclizing a compound of formula (II) in the presence of a condensing agent to prepare a compound of formula (Ic):

[0717]

[0718] where R 6 , W, R 7 、R 8 , X, Y, R 1 、R 2 and R 3 As defined above.

[0719] Preferably, the method comprises the step of cyclizing the compound of formula (II') in the presence of a condensing agent to prepare the compound of formula (I'). More preferably, the method comprises the step of cyclizing the compound of formula (II) in the presence of a condensing agent to prepare the compound of formula (I).

[0720] A condensing agent is used to cyclize the compound of formula (II') in the presence of a base to prepare the compound of formula (I'). The base is preferably trimethylamine (Et3N). The condensing agent is preferably N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDC), Mukaiyama reagent, iodomethane or TsCl. Preferably, the cyclization is carried out at room temperature (rt).

[0721] In one embodiment, the process for preparing the compound of formula (II') comprises the step of coupling the compound of formula (III') with a urea or thiourea derivative of formula (IV) in the presence of a solvent and a base,

[0722]

[0723] where R 6 , W, R 7 、R0 and R 8 As defined above.

[0724] In one embodiment, the process for preparing the compound of formula (II) comprises the step of coupling the compound of formula (III) with a urea or thiourea derivative of formula (IV) in the presence of a solvent and a base.

[0725]

[0726] where R 6 , W, R 7 and R 8 As defined above.

[0727] The solvent is preferably dichloromethane (DCM). The base is preferably trimethylamine (Et3N). Preferably, the coupling reaction is carried out at room temperature (rt).

[0728] In one embodiment, the method comprises the step of cyclizing a compound of formula (II') in the presence of a condensing agent to prepare a compound of formula (I'):

[0729]

[0730] where R 6 ,W,m,n,R 7 、R 8 , X, Y, R 1 、R 2 、R 0 and R 3 As defined above; followed by a step of saponifying in the presence of a saponifying agent to prepare a compound of formula (I'), wherein X, Y, R 0 、R 1 and R 3 As defined above, and R 2 It's hydrogen.

[0731] In a preferred embodiment, the method comprises the step of cyclizing a compound of formula (II) in the presence of a condensing agent to prepare a compound of formula (I):

[0732]

[0733] where R 6 ,W,m,n,R 7 、R 8 , X, Y, R 1 、R 2 and R 3 As defined above; then, a saponification step is carried out in the presence of a saponifying agent to prepare a compound of formula (I), wherein X, Y, R 1 and R 3 As defined above, and R2 It's hydrogen.

[0734] Any combination of the embodiments, preferred embodiments and more preferred embodiments disclosed herein is also included in the present invention.

[0735] Pharmaceutical composition

[0736] Although the compounds of the present invention or their stereoisomers, racemic mixtures, tautomers, polymorphs, pharmaceutically acceptable salts, prodrugs, hydrates or solvates can be administered alone, it is preferred that they be formulated into pharmaceutical compositions according to standard pharmaceutical practice. Accordingly, the present invention also provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula (I'), (I), (II') or (II) or its stereoisomers, racemic mixtures, tautomers, polymorphs, pharmaceutically acceptable salts, prodrugs, hydrates or solvates, optionally mixed with a pharmaceutically acceptable carrier, diluent, adjuvant or excipient.

[0737] The term "therapeutically effective amount" of a compound of the present invention refers to an amount of a compound of the present invention (e.g., a compound of Formula (I'), (I), (II'), or (II), or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof) that elicits a biological or medical response in a subject, such as reduction or inhibition of enzyme or protein activity, improvement of symptoms, alleviation of symptoms, slowing or delaying of disease progression, or prevention of a disease, disorder, or abnormality. 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 in at least partially alleviating, preventing, and / or ameliorating a disease, disorder, or abnormality that is responsive to modulation of NLRP3 inflammasome pathway components or modulation of IL-1β and / or IL-18, particularly a reduction in responsiveness.

[0738] Pharmaceutically acceptable carriers, diluents, adjuvants, and excipients are well known in the pharmaceutical art and are described, for example, in Remington's Pharmaceutical Sciences, 18th ed. (Alfonso R. Gennaro, ed.; Mack Publishing Company, Easton, PA, 1990); Remington: the Science and Practice of Pharmacy, 19th ed. (Lippincott, Williams & Wilkins, 1995); Handbook of Pharmaceutical Excipients, 3rd ed. (Arthur H. Kibbe, ed.; Amer. Pharmaceutical Assoc., 1999); Pharmaceutical Codex: Principles and Practice of Pharmaceutics, 12th ed. (Walter Lund, ed.; Pharmaceutical Press, London, 1994); U.S. Pharmacopoeia: The National Formulary (United States Pharmacopeial Convention); Fiedler's "Lexikon der Hilfsstoffe," 5th ed., Edition Cantor Verlag Aulendorf 2002; “The Handbook of Pharmaceutical Excipients,” 4th ed., American Pharmaceutical Association, 2003; and Goodman and Gilman's: 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.

[0739] The choice of carrier, diluent, adjuvant and pharmaceutical excipient can be selected with regard to the intended route of administration and standard pharmaceutical practice. The compound must be acceptable in the sense of not being deleterious to the recipient thereof.

[0740] Pharmaceutically useful excipients that can be used to formulate the pharmaceutical compositions of the present invention may include, for example, vehicles, solvents (e.g., monohydric alcohols such as ethanol, isopropyl alcohol and polyhydric alcohols such as ethylene glycol), 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), cross-linked PVP (e.g., crospovidone, or XL), alginic acid, sodium alginate, guar gum, cross-linked CMC (cross-linked sodium carboxymethylcellulose, e.g. ), carboxymethyl starch-Na (sodium starch glycolate) (e.g. or ) and preferably cross-linked PVP and / or cross-linked sodium carboxymethylcellulose), glidants (e.g. colloidal SiO2 (e.g. 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 stearyl fumarate, and combinations thereof), buffers, emulsifiers, wetting agents, suspending agents, sweeteners, colorants, flavorings, coating agents, preservatives, antioxidants, processing aids, 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, a low melting point wax, and ion exchange resins.

[0741] There is no particular limitation on the carrier, and it will depend 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; cellulose such as microcrystalline cellulose, sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, or mixtures thereof; cyclodextrins and inorganic substances such as dicalcium phosphate, calcium hydrogen phosphate; hydroxyapatite, tricalcium phosphate, talc, and silicon dioxide. Microcrystalline cellulose, sucrose, and / or lactose are preferably used as carriers. Combinations thereof may also be used. The carrier may also include proteins and cell penetrating peptides, which should be selected depending on the route of administration and target.

[0742] There are no particular limitations on the diluent and it will depend on the route of administration and the form of the pharmaceutical composition (ie, solid, liquid, etc.) Diluents include, for example, water, ethanol, propylene glycol, and glycerol, and combinations thereof.

[0743] Adjuvants are additives which have no or little pharmacological effect on their own, but which, if administered together with the compounds of the invention, increase the efficacy or effectiveness of the compounds of the invention.

[0744] 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., as a tablet, capsule, or as an ingestible solution), topical, mucosal (e.g., as a nasal spray or aerosol for inhalation), nasal, parenteral (e.g., by injectable form), gastrointestinal, intraspinal, intraperitoneal, intramuscular, intravenous, intraarterial, intrathecal, intrauterine, intraocular, intradermal, intracranial, intratracheal, intravaginal, intracerebroventricular, intracerebral, subcutaneous, ophthalmic (including intravitreal or intracameral), transdermal, rectal, buccal, epidural, and sublingual.

[0745] For example, the compounds can be administered orally in the form of tablets, capsules, ovules, elixirs, solutions or suspensions, which may contain flavorings or colorings for immediate, delayed, modified, sustained, pulsed or controlled-release applications.

[0746] Tablets can include excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, calcium hydrogen phosphate, and glycine, disintegrants such as starch (preferably corn starch, potato starch, or tapioca starch), sodium starch glycolate, cross-linked sodium carboxymethyl cellulose, and some complex silicates, and granulation binders such as polyvinyl pyrrolidone, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), sucrose, gelatin, and gum arabic. In addition, lubricants such as magnesium stearate, stearic acid, glyceryl behenate, and talc can be included. Similar types of solid compositions can also be used as fillers in gelatin capsules. Preferred excipients in this regard include starch, cellulose, milk sugars such as lactose, or high molecular weight polyethylene glycols. For aqueous suspensions and / or elixirs, the substance can be combined with various sweeteners or flavorings, coloring matter, or dyes, with emulsifiers and / or suspending agents, and with diluents such as water, ethanol, propylene glycol, and glycerol, and combinations thereof.

[0747] If the compounds of the present invention as disclosed herein are administered parenterally, examples of such administration include one or more of the following: intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​intrasternal, intracranial, intramuscular or subcutaneous administration of the compound; and / or using infusion techniques. For parenteral administration, the compound can be used in the form of a sterile aqueous solution, which may contain other substances, such as sufficient salts or glucose to make the solution isotonic with the blood. If necessary, the aqueous solution should be appropriately buffered (preferably at a pH of 3-9). The preparation of suitable parenteral formulations under sterile conditions can be easily accomplished by standard pharmaceutical techniques well known to those skilled in the art.

[0748] As indicated, the compounds of the invention can be administered intranasally or by inhalation and are conveniently delivered in the form of a dry powder inhaler or aerosol spray from a pressurized container, pump, sprayer or nebulizer using a suitable propellant, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, a hydrofluoroalkane such as 1,1,1,2-tetrafluoroethane (HFA134AT) or 1,1,1,2,3,3,3-heptafluoropropane (HFA 227EA), carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount. The pressurized container, pump, sprayer or nebulizer may contain a solution or suspension of the active compound, for example, using a mixture of ethanol and the propellant as a solvent, which may additionally contain a lubricant, for example, sorbitan trioleate. Capsules and cartridges (e.g., made of gelatin) for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound and a suitable powder base (e.g., lactose or starch).

[0749] Alternatively, the compounds of the invention as defined herein may be administered in the form of a suppository or pessary, or they may be applied topically in the form of a gel, hydrogel, lotion, solution, cream, ointment or powder. The compounds of the invention as defined herein may also be administered dermally or transdermally, for example, by use of a skin patch.

[0750] They can also be administered via the pulmonary or rectal routes. They can also be administered via the ophthalmic route. For ophthalmic use, the compounds can be formulated as micronized suspensions in isotonic, pH-adjusted sterile saline, or preferably as solutions in isotonic, pH-adjusted sterile saline, optionally in combination with a preservative such as benzalkonium chloride. Alternatively, they can be formulated in an ointment, such as petrolatum.

[0751] For topical application to the skin, the compounds of the invention may be formulated into a suitable ointment containing the active compound suspended or dissolved in a mixture, for example, of one or more of mineral oil, liquid petrolatum, white petrolatum, propylene glycol, emulsifying wax, and water. Alternatively, they may be formulated into a suitable lotion or cream suspended or dissolved in a mixture, for example, of one or more of mineral oil, sorbitan monostearate, polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0752] Typically, the clinician will determine the actual dosage that is most appropriate for an individual subject. The specific dosage level and dosage frequency for any particular individual may vary and will depend on a variety of factors, including the activity of the specific compound used, the metabolic stability and duration of action of the compound, age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, severity of the particular condition, and the individual being treated.

[0753] The claimed compounds as defined herein may be used alone or in combination with one or more other biologically active compounds for treating, alleviating or preventing the conditions, as defined herein. In particular, the other biologically active compounds may be those for treating, alleviating or preventing the diseases.

[0754] The above-mentioned combination can be conveniently used in the form of a pharmaceutical preparation. The individual components of such a combination can be administered sequentially or simultaneously in a separate or combined pharmaceutical preparation by any convenient route. When administered sequentially, the compound of the present invention or the other biologically active compound can be administered first. When administered simultaneously, the combination can be administered in the same or different pharmaceutical compositions. When combined in the same formulation, it should be understood that the two compounds must be stable and compatible with each other and with the other components of the formulation. When formulated separately, they can be provided in any convenient formulation, conveniently provided in a manner known to the art for such compounds.

[0755] The pharmaceutical compositions of the invention can be prepared in a manner known per se to a person skilled in the art, for example as described in Remington's Pharmaceutical Sciences, 15th edition, Mack Publishing Company, New Jersey (1975).

[0756] The compounds of the present invention as disclosed herein may also be provided in admixture with at least one additional biologically active compound and / or a pharmaceutically acceptable carrier, diluent, adjuvant or vehicle. The compound and / or additional biologically active compound is preferably present in a therapeutically effective amount.

[0757] The nature of the additional biologically active compound will depend on the intended use of the mixture. The additional biologically active substance or compound may exert its biological effect by the same or similar mechanism as the compounds of the present invention or by an unrelated mechanism of action or by multiple related and / or unrelated mechanisms of action.

[0758] 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 a compound in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine and chlorine, for example, 2 H. 3 H. 13 C. 14 C. 15 N. 17 O. 18 O. 35S. 18 F and 36 Certain isotopic variants of the present invention, for example, wherein a radioactive isotope such as 3 H or 14 C, can be used for drug and / or substrate tissue distribution studies. 3 H and carbon- 14 ,Right now 14 C isotopes are particularly preferred for their ease of preparation and detectability. 18 F-labeled compounds are particularly suitable for imaging applications such as PET. 2 H substitution may provide certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and therefore may be preferred in some circumstances. Isotopic variations of the compounds of the invention can generally be prepared by conventional methods, for example, by the illustrative methods or by the preparation methods described in the Examples and Preparations below, using appropriate isotopic variations of suitable reagents.

[0759] Methods of using the present invention

[0760] There is evidence for a role for NLRP3-induced IL-1 and IL-18 in inflammatory responses that are associated with or occur as a result of a variety of different diseases, disorders, or abnormalities that respond to modulation of NLRP3 inflammasome pathway components and / or to modulation of IL-1β and / or IL-18 levels (Menu et al., Clinical and Experimental Immunology, 2011, 166, 1-15; Strowig et al., Nature, 2012, 481, 278-286).

[0761] The present invention provides compounds of formula (I'), (I), (II') or (II) as defined herein, or stereoisomers, racemic mixtures, tautomers, polymorphs, pharmaceutically acceptable salts, prodrugs, hydrates or solvates thereof, which exhibit valuable pharmacological properties, such as NRLP3 inhibitory properties on the NLRP3 inflammasome pathway. The compounds of the present invention can be used to treat, alleviate or prevent diseases or disorders or abnormalities that respond to modulation of NLRP3 inflammasome pathway components and / or to modulation of IL-1β and / or IL-18 levels. Many diseases, disorders or abnormalities have been shown to involve NLRP3, including, for example, one of the following:

[0762] 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 damage due to pneumococcal meningitis, motor neuron disease, traumatic brain injury, amyotrophic lateral sclerosis, or multiple sclerosis (MS);

[0763] B. Immune diseases, disorders, or abnormalities (e.g., autoimmune diseases, disorders, or abnormalities, and diseases, disorders, or abnormalities involving the immune system), such as type 1 diabetes, hidradenitis suppurativa (HS), Schnitzler syndrome, multiple sclerosis (MS), including primary progressive multiple sclerosis (PPMS), Sjögren's syndrome, secondary progressive multiple sclerosis (SPMS), TNF receptor-associated periodic syndrome (TRAPS), graft-versus-host disease, or relapsing-remitting multiple sclerosis (RRMS);

[0764] C. Inflammatory diseases, including autoinflammation and inflammation due to an inflammatory disease, disorder, or abnormality, such as mevalonate kinase deficiency (MKD), hyperimmunoglobulinemia D, cryptopyrin-associated periodic syndrome (CAPS), Muckle-Wells syndrome (MWS), familial 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-related antibody deficiency and immune dysregulation (PLAID), PLCG2-related autoinflammatory, antibody deficiency, and immune dysregulation (APLAID), septic arthritis, A20 haploinsufficiency (HA20), pediatric granulomatous arthritis (PGA), or sideroblastic anemia with B-cell immunodeficiency, periodic fever, or developmental delay (SIFD);

[0765] D. Skin diseases, disorders, or abnormalities, such as hidradenitis suppurativa (HS), dermatitis, psoriasis, contact allergy, 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), or alopecia areata;

[0766] E. Ocular diseases, disorders, or abnormalities, such as age-related macular degeneration (AMD), corneal infection, uveitis, glaucoma, dry eye, or demyelination;

[0767] F. Cardiovascular disease, disorder or abnormality (e.g., a disease, disorder or abnormality of the cardiovascular system), such as myocardial infarction, hypertension, ischemia-reperfusion injury, pericarditis (including Dressler syndrome), aneurysm (including abdominal aortic aneurysm) or stroke;

[0768] G. Metabolic diseases, disorders, or abnormalities, such as type 2 diabetes, obesity, atherosclerosis, gout, or pseudogout;

[0769] H. Respiratory diseases, disorders, or abnormalities (e.g., diseases, disorders, or abnormalities of the respiratory system), such as asbestosis, silicosis, cystic fibrosis, allergic inflammation, chronic obstructive pulmonary disease (COPD), steroid-resistant asthma, or asthma;

[0770] I. Liver diseases, disorders, or abnormalities (e.g., liver diseases, disorders, or abnormalities), such as alcoholic liver disease, alcoholic fatty liver disease (AFLD), alcoholic steatohepatitis (ASH), non-alcoholic fatty liver disease (NAFLD), or non-alcoholic steatohepatitis (NASH), including advanced fibrosis stages F3 and F4;

[0771] J. Kidney diseases, disorders or abnormalities (e.g., diseases, disorders or abnormalities of the renal system), such as oxalate-induced nephropathy, diabetic nephropathy, chronic kidney disease or nephropathy;

[0772] K. a cancer disease, disorder, or abnormality (e.g., cancer, tumor, or malignancy), such as lung cancer (e.g., lung cancer metastasis), pancreatic cancer, gastric cancer, leukemia, myelodysplastic syndrome (MOS), skin cancer, an endocrine system tumor, or thyroid cancer;

[0773] L. Infections, including viral infections, such as helminth infections (e.g., from schistosomes, roundworms, tapeworms, or flukes), viral encephalitis, bacterial infections, human immunodeficiency virus (HIV), HIV-associated neurocognitive disorder, 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 virus), coronavirus-associated inflammatory diseases, coronavirus, or influenza virus;

[0774] M. Psychological illness, disorder or abnormality, such as depression and psychological stress;

[0775] N. Inflammation, including inflammation that occurs as a result of an inflammatory disease, disorder, or abnormality, such as an autoinflammatory disease, inflammation that occurs as a symptom of a non-inflammatory condition, 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 caused by the following diseases:

[0776] i. Joint diseases, disorders, or abnormalities, such as periodic fever syndrome (HIDS), rheumatoid arthritis, impetigo, synovitis, osteoarthritis, chronic relapsing multifocal osteomyelitis (CRMO), systemic juvenile idiopathic arthritis, osteoarthritis syndrome (SAPHO), hyperostosis, relapsing polychondritis, or adult-onset Still's disease;

[0777] ii. Gastrointestinal diseases, disorders or abnormalities (e.g., diseases, disorders or abnormalities of the gastrointestinal tract), such as colitis, ulcerative colitis or inflammatory bowel disease;

[0778] iii. Muscle diseases, disorders or abnormalities, such as polymyositis or myasthenia gravis;

[0779] iv. a disease, disorder or abnormality of the endocrine system, such as diabetes, parathyroid disease (e.g., hypothyroidism), an endocrine system tumor, thyroid cancer or hypoglycemia; and / or

[0780] v. Vascular diseases, disorders or abnormalities, such as Behçet's disease.

[0781] In one embodiment, the disease, disorder or abnormality is selected from Alzheimer's disease, Parkinson's disease, cryopyrin-associated periodic syndrome (CAPS), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH) and gout.

[0782] In particular, the disease, disorder or abnormality is selected from the group consisting of: Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, demyelination, viral encephalitis, epilepsy, stroke, atherosclerosis, asthma, allergic inflammation, cryptopyrin-associated periodic syndrome (CAPS), Muckle-Wells syndrome (MWS), familial 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, rheumatoid arthritis, myelodysplastic syndrome, family Familial Mediterranean fever (FMF), TNF 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 (PAPA), A20 haploinsufficiency (HA20), PLCG2-related antibody deficiency and immune dysregulation (PLAID), pediatric granulomatous arthritis (PGA), PLCG2-related autoinflammatory, antibody deficiency, and immune dysregulation (APLAID), sideroblastic anemia with B-cell immunodeficiency, periodic fever, and developmental delay (SIFD), chronic nonbacterial osteomyelitis (CNO), Sweet's syndrome, chronic relapsing multifocal osteomyelitis (CRMO), synovitis, impetigo, acne, eczema, alopecia areata, actinic keratosis, hyperostosis, syndrome of osteoarthritis (SAPHO), multiple sclerosis (MS), psoriasis, Behçet's disease, Sjögren's syndrome, Schnitzler syndrome, chronic obstructive pulmonary disease (COPD), steroid-resistant asthma, asbestosis, silicosis, cystic fibrosis, motor neuron disease, Huntington's disease, cerebral malaria, brain damage due to pneumococcal meningitis, obesity, age-related macular degeneration (AMD), corneal infection, uveitis, dry eye, chronic kidney disease, diabetes mellitus nephropathy, alcoholic liver disease, contact allergy, 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, helminthic 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 pathologies, and traumatic brain injury;Preferably, the disorder is selected from the group consisting of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, demyelination, viral encephalitis, epilepsy, stroke, atherosclerosis, asthma, allergic inflammation, cryptopyrin-associated periodic 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, glomerular basement membrane (GMB) disease, IgA nephropathy, glomerulonephritis (GN), systemic lupus erythematosus (SLE), focal segmental glomerulosclerosis, minimal change disease (MCD), psoriatic arthritis, and hereditary recurrent fever (HRF).

[0783] In yet another embodiment, the disease, disorder or abnormality is preferably an inflammatory disease, disorder or abnormality; or an autoimmune disease, disorder or abnormality; or a disease, disorder or abnormality of the skin (such as, but not limited to, psoriasis, acne, eczema, alopecia areata or actinic keratosis); or a disease, disorder or abnormality of the cardiovascular system; or a disease, disorder or abnormality such as cancer, a tumor or a malignancy; or a disease, disorder or abnormality of the renal system; a disease, disorder or abnormality of the gastrointestinal tract; a disease, disorder or abnormality of the respiratory system; or a disease, disorder or abnormality of the endocrine system; or a disease, disorder or abnormality of the central nervous system (CNS); or a disease, disorder or abnormality of the liver.

[0784] definition

[0785] Within the meaning of this application, the following definitions apply unless otherwise indicated; and where appropriate, terms used in the singular shall include the plural and vice versa:

[0786] "Alkyl" refers to a saturated straight or branched organic moiety consisting of carbon and hydrogen atoms. Examples of suitable alkyl groups have 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, and include methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, and isobutyl. In the present invention, any alkyl group may optionally be substituted with one or more (preferably 1 or 2) substituents defined below as "optional substituents." The term "C1-C6 alkyl" refers to an alkyl group having 1 to 6 carbon atoms. The terms "C1-C4 alkyl," "C1-C3 alkyl," or "C1 alkyl" should be interpreted accordingly.

[0787] "Hal" or "halogen" refers to F, Cl, Br, and I. Preferably, halogen is F or Cl. More preferably, halogen is Cl. Even more preferably, halogen is F.

[0788] "-O-C1-C6 alkyl" refers to a group having the formula -O-Ra, where Ra is a "C1-C6 alkyl" group as generally defined above. Examples of "-O-C1-C6 alkyl" include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, pentoxy, and hexoxy.

[0789] "C1-C6 alkyl-OH" refers to a C1-C6 alkyl group as defined above, wherein one of the hydrogen atoms of the C1-C6 alkyl group is replaced by "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.

[0790] "Cycloalkyl" refers to a saturated monocyclic, bicyclic, or tricyclic hydrocarbon radical (each ring having 3 to 6 ring carbon atoms). Preferably, "cycloalkyl" refers to a saturated monocyclic hydrocarbon radical. The term "C3-C6 cycloalkyl" refers to a saturated monocyclic hydrocarbon radical having 3 to 6 carbon atoms. The term "C5-C6 cycloalkyl" should be interpreted accordingly. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0791] "HeteroC3-C6 cycloalkyl" refers to a stable 5- or 6-membered non-aromatic monocyclic group containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Preferably, the 5- or 6-membered non-aromatic monocyclic group contains 1 heteroatom. More preferably, the heteroatom is oxygen. Examples include, but are not limited to, tetrahydropyran and tetrahydrofuran.

[0792] "Aryl" refers to an aromatic hydrocarbon group having 3 to 8 carbon atoms in the ring portion ("3- to 8-membered ring" means a three-membered, four-membered, five-membered, six-membered, seven-membered, or eight-membered ring). Preferably, the term "aryl" refers to an aromatic hydrocarbon group having 6 carbon atoms. Preferably, "aryl" is phenyl.

[0793] "Heteroaryl" refers to an aromatic "3- to 8-membered ring", i.e., a three-, four-, five-, six-, seven-, or eight-membered ring, wherein none or one or more of the carbon atoms in the ring are substituted by 1 or 2 (for a three-membered ring), 1, 2 or 3 (for a four-membered ring), 1, 2, 3 or 4 (for a five-membered ring), or 1, 2, 3, 4 or 5 (for a six-membered ring), 1, 2, 3, 4, 5 or 6 (for a seven-membered ring), or 1, 2, 3, 4, 5, 6 or 7 (for an eight-membered ring) of the same or different heteroatoms, wherein the heteroatoms are selected from O, N, and S. Preferably, "heteroaryl" refers to an aromatic 5- to 10-membered ring. More preferably, "heteroaryl", such as C5-C6 heteroaryl, refers to an aromatic 5- to 6-membered aromatic monocyclic group containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, wherein the heteroaryl group can be bonded via a carbon atom or a heteroatom. Examples of heteroaryl groups include, but are not limited to, furanyl, oxazolyl, isoxazolyl, thienyl, isothiazolyl, thiazolyl, pyrazolyl, pyrrolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl.

[0794] "Optionally substituted with..." with respect to a group means that the group is optionally substituted with one or more substituents (i.e., the substituents may be present or absent). Such "optional substituents" may be selected from: optionally substituted C1-C 10 alkyl (eg, optionally substituted C1-C6 alkyl); optionally substituted C3-C6 cycloalkyl (eg, optionally substituted cyclopropyl); optionally substituted hydroxyalkyl; optionally substituted C1-C 10 Alkoxy (eg, optionally substituted C1-C6 alkoxy); optionally substituted C2-C 10 Alkenyl; optionally substituted C2-C 10 Alkynyl; optionally substituted C6-C 12 Aryl; aryloxy; optionally substituted heteroaryl; optionally substituted heterocyclyl; halogen (e.g., F, CI, Br, I); hydroxy; haloalkyl (e.g., CH2F, CHF2, CF3, 2-Br-ethyl, CH2CF3, and CF2CF3); amino (e.g., NH2, NR 30 H and NR 30 R 31 ); alkylamino; arylamino; acyl; acylamino; OH; CN; N3; NO2; CH2OH; CONH2; CONR 32 R 33 ;CO2R 32 ;CH2OR 32 ;NHCOR 32 ;NHCO2R 32C1-C3 alkylthio; sulfate; sulfonic acid; sulfonate, such as alkyl or aralkylsulfonyl; phosphonic acid; phosphate; phosphonate; monophosphate, diphosphate or triphosphate; trityl or monomethoxytrityl; R 32 SO;R 32 SO2; CF3S; and CF3SO2; trialkylsilyl, such as dimethyl-tert-butylsilyl or diphenylmethylsilyl; wherein R 30 、R 31 、R 32 and R 33 are each independently selected from H and optionally substituted C1-C 10 Alkyl (eg, optionally substituted C1-C6 alkyl or C1-C4 alkyl).

[0795] The term "compound of the present invention" refers to a compound of formula (I'), (I), (II') or (II) as disclosed herein or a subformula thereof as disclosed herein, or a stereoisomer thereof, or a racemic mixture thereof, or a tautomer thereof, or a polymorph thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a hydrate thereof, or a solvate thereof, unless otherwise indicated. Compounds of the present 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, and conformer mixtures and single conformers), tautomers, atropisomers, and rotamers. The present invention includes all isomeric forms. Compounds containing olefinic double bonds described herein include E and Z geometric isomers. The present invention also includes all pharmaceutically acceptable salts, prodrugs, hydrates, and solvates of compounds of formula (I') or (I).

[0796] Tautomers are isomers of a compound that differ only in the position of protons and electrons. The skeleton of the compound remains unchanged. Common tautomeric pairs include: keto-enol Enamine-imine

[0797] The present invention also encompasses solvates, hydrates and anhydrous forms of the salts. The solvent included in the solvate is not particularly limited and may be any pharmaceutically acceptable solvent. Examples include water and C 1-4 Alcohol (such as methanol or ethanol).

[0798] "Pharmaceutically acceptable salts" are defined as derivatives of the disclosed compounds wherein the parent compound is modified by preparing acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali metal or organic salts of acidic residues such as carboxylic acids; and the like. Pharmaceutically acceptable salts include, for example, the conventional non-toxic salts or quaternary ammonium salts of the parent compound formed from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, etc.; 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, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, etc. Pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing alkaline or acidic moieties. Typically, such salts can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of a suitable base or acid in water or in an organic solvent or in a mixture thereof. 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's Pharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, PA, 1990, p. 1445, the disclosure of which is incorporated herein by reference.

[0799] The compounds of the present invention as defined herein may also be provided in the form of prodrugs (i.e., compounds that are metabolized in vivo to active metabolites). As used hereinafter in the specification and claims, the term "prodrug" refers to any covalently bonded compound that releases the active parent drug as a result of in vivo biotransformation. Goodman and Gilman (The Pharmacological Basis of Therapeutics, 8th edition, McGraw-Hill, Int. Ed. 1992, "Biotransformation of Drugs", pp. 13-15) is incorporated herein by reference for descriptions of prodrugs.

[0800] "Pharmaceutically acceptable" is defined as those compounds, materials, compositions and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication and commensurate with a reasonable benefit / risk ratio.

[0801] As used herein, the term "patient" or "subject" referred to in the present invention generally refers to an animal, particularly a mammal (e.g., rabbit, rat, dog, mouse, guinea pig, pig), more particularly a primate (e.g., human, male or female). In certain embodiments, the subject is a human.

[0802] As used herein, "NLRP3" refers to the pyrin domain-containing protein 3 component of the NOD-like receptor (NLR) family inflammasome. Inflammasomes are intracellular supramolecular complexes that contain sensor molecules, CARD-containing apoptosis-associated speckle-like proteins (ASC), and effector proteases, caspase 1. When inflammasome sensor molecules are activated, ASC self-assembles into helical fibril assemblies, resulting in the formation of so-called ASC specks or pyroptotic bodies, which act as molecular platforms for activating pro-caspase 1 through proximity-induced autocatalytic activation. Active caspase 1 triggers the activation and release of interleukin-1 (IL-1) family proteins, making it possible for the unconventional secretion of a variety of cytoplasmic proteins. Among the proinflammatory mediators released upon NLRP3 activation are IL-1β, IL-18, high mobility group protein B1 (HMGB1), leukotrienes, and prostaglandins.

[0803] Activation of the NLRP3 inflammasome pathway is an important driver of inflammation that interacts with different cytokine pathways that shape the immune response to infection and injury. The production of several proinflammatory cytokines is triggered by activation of the NLRP3 inflammasome pathway.

[0804] The term "inhibit" refers to a reduction or suppression of a given condition, symptom or disorder or disease or abnormality or a significant decrease in the baseline activity of a biological activity or process that is responsive to modulation of a component of the NLRP3 inflammasome pathway.

[0805] The term "treat," "treat," or "treating" with respect to any disease, disorder, or abnormality refers to alleviating, ameliorating, or modulating the disease, disorder, or abnormality (i.e., slowing or arresting the development of the disease, disorder, or abnormality, or at least one clinical symptom thereof); or alleviating, ameliorating, or modulating at least one physical parameter or biomarker associated with the disease, disorder, or abnormality, including those that may not be discernible by an individual (e.g., a patient).

[0806] The term "prevention" of any disease, disorder, or abnormality responsive to modulation of a component of the NLRP3 inflammasome pathway refers to prophylactic treatment of the disease, disorder, or abnormality; or delaying the onset or progression of the disease or disorder.

[0807] The term "in need of treatment" means that the individual would benefit biologically, medically, or in quality of life from such treatment.

[0808] As used herein, "modulate" refers to an alteration, such as upregulation, downregulation, increase or decrease, preferably a decrease.

[0809]

[0810]

[0811] Unless stated otherwise, the definitions and preferred definitions given in the "Definitions" section apply to all embodiments described herein.

[0812] The compounds of the present invention can be synthesized by those skilled in the art by using generally known preparative steps, such as those of the general methods shown in the following schemes. These methods are given for illustrative purposes only and should not be considered limiting.

[0813] General synthetic schemes for preparing compounds of the present invention

[0814] Solution 1

[0815]

[0816] Option 2

[0817]

[0818] From commercially available aryl ketoesters, nitro derivatives have been synthesized using nitroalkanes such as nitromethane and suitable alkali and solvent. Then, the reduction of the nitro group is achieved by hydrogen and a suitable catalyst or by using a metal (e.g., iron or zinc in acetic acid) under acidic conditions. Subsequently, thiourea or urea derivatives are obtained by optionally treating the amine intermediate with isothiocyanates or isocyanates in the presence of a base. Finally, cyclization is carried out as known in the art, for example, using N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDC) and a base, mukaiyama reagent and a base, iodomethane and a base or TsCl and a base to carry out cyclization. Alternatively, the R2 functional group can also be introduced by a two-step strategy of saponification / esterification process at the end of the synthesis. Ultimately, enantiomers can be separated by chiral supercritical fluid chromatography (SFC) to obtain the desired single enantiomer.

[0819] It should be noted that in the present invention, the R groups of the compounds of formula (I') or (I) and the compounds of formula (II') or (II) are similar, especially R 2 and R 8 are the same groups and are used interchangeably throughout the general schemes. 1 and R 6 are the same groups and are used interchangeably throughout the general schemes. 3 and R 7 are the same groups and are used interchangeably throughout the general schemes. Example

[0820] The present disclosure is further illustrated by the following examples and synthetic schemes, which should not be viewed as limiting the scope of the specific methods described herein. It should be understood that the examples are provided to illustrate certain embodiments and are not intended to limit the scope of the present disclosure thereby.

[0821] All reagents and solvents were obtained from commercial sources and used without further purification. Spectra were recorded in deuterated solvents on a Bruker 400 MHz-AVANCE III HD NMR, a Bruker 500 MHz-AVANCE III HD NMR spectrometer, or a Spinsolve 80 MHz spectrometer. 1 H-NMR spectra. Chemical shifts (δ) are reported in parts per million, and coupling constants (J values) are reported 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 Water 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 specific examples. Rapid purification was performed using a Biotage Isolera One or Reveris X2 with a KP-NH SNAP column (Biotage) or a Reveris silica column (Grace) and the solvent gradients indicated in the specific examples. Thin layer chromatography (TLC) was performed on silica gel plates (Merck) with UV detection.

[0822] Intermediate 1: 1-(4-isopropylthiazol-2-yl)ethan-1-one

[0823]

[0824] Step A

[0825] To a stirred solution of 2,4-dibromothiazole (20 g, 82.833 mmol) in anhydrous ether (200 mL) at -78°C was added n-BuLi (2.5 M in hexanes) (36.2 mL, 90.572 mmol) dropwise. After 30 minutes, N-acetylmorpholine (14.4 mL, 123.507 mmol) was added dropwise to the reaction mixture, and stirring was continued at -78°C for 1 hour and 30 minutes. The reaction mixture was warmed to room temperature and stirred for 16 hours. The reaction mixture was quenched with water and extracted with ether (2 x 300 mL). The organic layer was concentrated under reduced pressure. The resulting residue was purified by flash chromatography (SiO2 column, 0-20% ethyl acetate in hexanes) to afford 1-(4-bromothiazol-2-yl)ethan-1-one (11.1 g, 65.6%) as an off-white solid. 1 H-NMR (400MHz CDC13): δ=7.58 (s, 1H), 2.71 (s, 3H). MS:205.94[(M+H)] + .

[0826] Step B

[0827] To a stirred solution of the compound from Step-A (5.0 g, 24.271 mmol) and isopropenyl borate (8.2 mL, 43.689 mmol) in 1,4-dioxane (75 mL) was added 2M Na2CO3 solution (24 mL, 48.543 mmol); the resulting mixture was degassed for 5 minutes. Pd(dppf)Cl2 DCM (0.99 g, 1.213 mmol) was added to the reaction mixture, which was further degassed for 10 minutes. After stirring at 90°C for 16 hours, the reaction mixture was cooled to room temperature and filtered through a bed of celite. The filtrate was diluted with ethyl acetate (50 mL) and washed with water (50 mL). The organic layer was dried and concentrated under reduced pressure. The resulting crude material was purified by flash chromatography (SiO2 column, 0-20% ethyl acetate in hexanes) to afford 1-(4-(prop-1-en-2-yl)thiazol-2-yl)ethan-1-one (3.1 g, 77.5%) as a light yellow liquid. 1 H-NMR (400MHz, CDCl3): δ = 7.45 (s, 1H), 6.00 (d, 1H), 5.26 (m, 1H), 2.73 (s, 3H), 2.17 (m, 3H). MS:167.99[(M+H)] + .

[0828] Step-C

[0829] At room temperature, 10% Pd / C (1.5 g) was added to a stirred solution of the compound (3.1 g, 18.562 mmol) of step-B in ethanol (31 mL). The resulting reaction mixture was stirred for 3 hours under a 10 psi hydrogen atmosphere, and progress was subsequently monitored by TLC. After the starting material was completely consumed, the reaction mixture was filtered through diatomaceous earth, washed with EtOH, and the filtrate was concentrated under vacuum to obtain 1- (4- isopropylthiazol-2-yl) ethane-1-one (2.8 g, 90.3%) as a colorless liquid. 1 H-NMR (400MHz, CDCl3): δ = 7.23 (s, 1H), 3.2-3.13 (m, 1H), 2.70 (s, 3H), 1.34 (d, 6H). MS:170.03(M+H) + .

[0830] Intermediate 2: 1-(1-isopropyl-1H-pyrazol-3-yl)ethan-1-one

[0831]

[0832] Step A

[0833] To a stirred solution of but-3-yn-2-one (15 g, 0.2203 mol) in anhydrous THF (150 mL) was added TMSCHN2 (110 mL, 0.2203 mol) at 0 ° C. The reactants were warmed to room temperature and then stirred for another 4 hours. The reaction mixture was diluted with water (500 mL) and extracted with EtOAc (2 × 250 mL). The organic layer was dried and concentrated under reduced pressure. The resulting crude residue was purified by flash chromatography (SiO2 column, 0-30% ethyl acetate in hexane) to give 1-(1H-pyrazol-3-yl)ethane-1-one (4.6 g, 19%) as an off-white solid. 1 H-NMR (400MHz, CDCl3): δ=9.5 to 8.0 (bs, 1H), 7.66 (d, 1H), 6.85 (d, 1H), 2.6 (s, 3H). MS:111.03(M+H) + .

[0834] Step B

[0835] At room temperature, to a stirred solution of the compound from step-A (4.6 g, 0.0417 mol) in acetonitrile (50 mL) was added 2-bromopropane (5.13 g, 0.0417 mol), followed by CS2CO3 (13.6 g, 0.0417 mol), and stirred at 90 ° C for 4 hours under an N2 atmosphere. The reaction mixture was filtered through diatomaceous earth and the filtrate was concentrated under reduced pressure. The resulting crude residue was purified by flash chromatography (SiO2 column, 0-10% ethyl acetate in hexane) to obtain 4.0 g of 1- (1-isopropyl -1H- pyrazol-3-yl) ethane -1- one (4 g, 62%) as a colorless liquid. 1 H-NMR (400MHz, CDCl3): δ = 7.42 (d, 1H), 6.77 (d, 1H), 4.60-4.51 (m, 1H), 2.57 (s, 3H), 1.53 (d, 6H). MS:153.05[(M+H)] + .

[0836] Example 1: 2-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)amino)-5-phenyl-4,5-dihydrooxazole- 5-Ethyl formate (Indacene)

[0837]

[0838] Step-A:

[0839] To a stirred solution of ethyl 2-oxo-2-phenylacetate (1.0 g, 5.612 mmol) in nitromethane (0.601 mL, 11.224 mmol) was added triethylamine (0.156 mL, 1.122 mmol). After stirring at room temperature for 48 hours, the reaction mixture was concentrated to dryness under reduced pressure. The crude compound was purified by flash chromatography (silica, 80 g Reveleris column; 0-50% ethyl acetate in hexanes) to give ethyl 2-hydroxy-3-nitro-2-phenylpropanoate (900 mg, 67%) as an off-white solid. 1 H-NMR (500MHz, DMSO-d6)δ=7.55-7.54(d,2H),7.41-7.34(m,3H),6.80(s,1H),5.59 -5.57(d,1H),4.83-4.80(d,1H),4.21-4.15(m,2H),1.19–1.17(t,3H).

[0840] Step B:

[0841] To a stirred solution of the compound from step-A (500 mg, 2.090 mmol) in ethanol (20 mL) was added 10% Pd / C (250 mg) at room temperature. The reaction mixture was stirred under a hydrogen atmosphere (~15 psi pressure) for 16 hours. The crude mixture was then filtered through a pad of celite and the residue was washed with ethanol. The filtrate was evaporated under reduced pressure to give ethyl 3-amino-2-hydroxy-2-phenylpropanoate (420 mg) as a colorless gum. 1 H-NMR (400MHz, DMSO-d6)δ=7.53-7.48(m,2H),7.39-7.32(m,2H),7.29-7.25(m,1H),5.8 4(brs,1H),4.13-4.08(m,2H),3.24-3.21(d,1H),2.78-2.75(d,1H),1.18-1.14(t,3H). MS:210.31[M+H] +

[0842] Step C:

[0843] To a stirred solution of the compound from Step-B (420 mg, 2.0071 mmol) and triethylamine (0.84 mL, 6.021 mmol) in dichloromethane (10 mL) was added 4-isothiocyanato-1,2,3,5,6,7-hexahydro-s-indacenes (432.16 mg, 2.0071 mmol). After stirring at room temperature for 16 hours, the reaction mixture was concentrated to dryness under reduced pressure. The crude compound was purified by flash chromatography (silica, 80 g Reveleris column, 0%-50% ethyl acetate in hexanes) to give ethyl 3-(3-(1,2,3,5,6,7-hexahydro-s-indacenes-4-yl)thioureido)-2-hydroxy-2-phenylpropanoate (520 mg) as a colorless gum. 1 H-NMR (500MHz, DMSO-d6)δ=9.27(brs,1H),7.48-7.29(m,5H),6.99(s,1H),6.45(brs,1H), 4.19-4.03(m,4H),2.80-2.78(t,4H),2.55-2.49(m,4H),1.91(brs,4H),1.17-1.13(t,3H). MS:425.49[M+H] +

[0844] Step D:

[0845] At 0 ° C, triethylamine (0.414 mL, 1.22 mmol) was added to a stirred solution of the compound (420 mg, 0.989 mmol) from step-C in acetonitrile (20 mL), followed by EDC.HCl (379.2 mg, 1.978 mmol). The reaction mixture was then warmed to room temperature. After 48 hours, the reaction mixture was diluted with ice water (30 mL) and the crude product was stirred for 30 minutes. The solid was collected by filtration and dried under reduced pressure to obtain a crude compound. The crude compound was triturated with diethyl ether (10 mL), filtered, and dried under reduced pressure to obtain ethyl 2-((1,2,3,5,6,7-hexahydro-s-indoxane-4-yl)amino)-5-phenyl-4,5-dihydrooxazole-5-carboxylate (320 mg, 83%) as a white solid. 1 H-NMR (400MHz, DMSO-d6)δ=8.60(brs,1H),7.43-7.38(m,5H),6.83(brs,1H),4.21-4.19(brs,1H),4.1 9-4.15(m,2H),3.83(brs,1H),2.80-2.76(t,4H),2.66(brs,4H),1.97-1.90(m,4H),1.18-1.15(t,3H). MS:391.52[M+H] +

[0846] Example 2: Enantiomerically pure 2-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)amino)-5-phenyl- Ethyl 4,5-dihydrooxazole-5-carboxylate

[0847] Starting from the racemic mixture of Example 1, the enantiomerically pure compound was separated by chiral SFC as an off-white solid (Chiralpak IG (4.6*250) mm, 5μ; cosolvent: 50% (0.5% isopropylamine in 2-propanol), total flow rate: 70 mg / ml; outlet pressure: 120 bar; temperature: 30°C); second eluting peak. 1 H-NMR (500MHz, CDCl3) δ = 7.58 (brs, 1H), 7.49-7.46 (d, 2H), 7.40-7.33 (m, 3H), 6.96 (s, 1H), 4.55-4.52 (d,1H),4.26-4.22(q,2H),4.09-4.06(d,1H),2.89-2.79(m,8H),2.08-2.00(m,4H),1.28-1.25(t,3H). MS:391.48[M+H] + 99.4% ee

[0848] Example 3: 2-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)amino)-5-(1-methyl-1H-imidazole-2- (4,5-dihydrooxazole-5-carboxylic acid ethyl ester)

[0849]

[0850] Step A:

[0851] To a stirred solution of ethyl 2-(1-methyl-1H-imidazol-2-yl)-2-oxoacetate (0.9 g, 4.945 mmol) in nitromethane (2.5 mL) was added triethylamine (0.142 mL, 0.989 mmol). After stirring at room temperature for 16 hours, the reaction mixture was concentrated under reduced pressure to afford ethyl 2-hydroxy-2-(1-methyl-1H-imidazol-2-yl)-3-nitropropanoate (900 mg, 82%) as an off-white solid. 1 H-NMR (400MHz, CDCl3)δ=7.17(s,1H),7.04(s,1H),6.81(d,1H),5.59 -5.56(d,1H),5.12 -5.09(d,1H),4.26 -4.14(m,2H),3.67(s,3H),1.19–1.15(t,3H). MS:244.26[M+H] +

[0852] Step-B:

[0853] To a stirred solution of the compound from step-A (400 mg, 1.639 mmol) in ethanol (10 mL) was added 10% Pd / C (220 mg) at room temperature. The reaction mixture was stirred under a hydrogen atmosphere (~15 psi pressure) for 12 hours. The crude mixture was then filtered through a pad of celite and the residue was washed with ethanol. The filtrate was evaporated under reduced pressure to give ethyl 3-amino-2-hydroxy-2-(1-methyl-1H-imidazol-2-yl)propanoate (200 mg) as a colorless gum. MS: 214.15 [M+H] +

[0854] Step-C:

[0855] To a stirred solution of the compound from step-B (450 mg, 2.10 mmol) and triethylamine (637.14 mg, 6.30 mmol) in dichloromethane (DCM) (10 mL) was added 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (452.10 mg, 2.10 mmol). After stirring at room temperature for 12 hours, the reaction mixture was concentrated to dryness under reduced pressure. The crude compound was purified by flash chromatography (silica, silica 25 g column; 0-50% ethyl acetate in hexane) to give ethyl 3-(3-(1,2,3,5,6,7-hexahydro-s-indacene-4-yl)thiourea)-2-hydroxy-2-(1-methyl-1H-imidazol-2-yl)propanoate (370 mg) as an off-white solid. MS: 429.61 [M+H] +

[0856] Step-D:

[0857] To a stirred solution of the compound (350 mg, 0.81 mmol) from step-C in acetonitrile (5 mL) was added triethylamine (123.59 mg, 1.22 mmol), followed by EDC.HCl (467.72 mg, 2.447 mmol). The reaction mixture was then warmed to room temperature. After 48 hours, the reaction mixture was diluted with ice water (30 mL) and the crude product was stirred for 30 minutes. The solid was collected by filtration and dried under reduced pressure to give a crude compound. The crude compound was ground with n-pentane (10 mL), filtered, and dried under reduced pressure to give ethyl 2-((1,2,3,5,6,7-hexahydro-s-indazole-4-yl)amino)-5-(1-methyl-1H-imidazole-2-yl)-4,5-dihydrooxazole-5-carboxylate (123 mg, 38%) as a white solid. 1 H-NMR (500MHz, DMSO-d6) δ = 8.42 (s, 1H), 7.26 (s, 1H), 6.88 (m, 2H), 4.88 (brs, 1H), 4.25-4.21 (m,2H),3.39(brs,1H),3.54(s,3H),2.79-2.55(m,8H),1.94-1.91(m,4H),1.20-1.17(t,3H). MS:395.61[M+H] +

[0858] Example 4: Enantiomerically pure 2-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)amino)-5-(1-methyl (1H-imidazol-2-yl)-4,5-dihydrooxazole-5-carboxylic acid ethyl ester

[0859] Starting from the racemic mixture of Example 3, the enantiomerically pure compound was separated by chiral SFC as an off-white solid (Chiralpak IG (4.6*250) mm, 5μ; cosolvent: 50% (100% ethanol), outlet pressure: 100 bar; temperature: 30°C); first eluting peak. 1 H-NMR (500MHz, DMSO-d6)δ=8.44(s,1H),7.26(s,1H),6.88(s,2H),4.88(brs,1H),4.25-4.2 1(m,2H),3.96(s,1H),3.55(s,3H),2.79-2.55(m,8H),1.95-1.90(m,4H)1.20-1.17(t,3H). MS:395.61[M+H] + .97.54% ee

[0860] Example 5: Enantiomerically pure 2-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)amino)-5-(1-methyl (1H-imidazol-2-yl)-4,5-dihydrooxazole-5-carboxylic acid ethyl ester

[0861] Starting from the racemic mixture of Example 3, the enantiomerically pure compound was separated by chiral SFC as an off-white solid (Chiralpak IG (4.6*250) mm, 5μ; co-solvent: 50% (100% ethanol), outlet pressure: 100 bar; temperature: 30°C); second eluting peak. 1 H-NMR, (500MHz, DMSO-d6)δ=8.43(s,1H),7.26(s,1H),6.88(s,2H),4.88(brs,1H),4.25-4. 21(m,2H),3.96(s,1H),3.55(s,3H),2.79-2.55(m,8H),1.94-1.91(t,4H)1.20-1.17(t,3H). MS:395.61[M+H] + 96.56% ee

[0862] Example 6: 2-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)amino)-5-(6-methoxypyridine-3- (4,5-dihydrooxazole-5-carboxylic acid ethyl ester)

[0863]

[0864] Step-A:

[0865] To a stirred solution of ethyl 2-(6-methoxypyridin-3-yl)-2-oxoacetate (1 g, 4.78 mmol) in nitromethane (10 mL) was added triethylamine (0.67 mL, 4.78 mmol). After stirring at room temperature for 16 hours, the reaction mixture was concentrated under reduced pressure. The crude compound was purified by flash chromatography (silica, 80 g Reveleris column; 0-50% ethyl acetate in hexanes) to afford ethyl 2-hydroxy-2-(6-methoxypyridin-3-yl)-3-nitropropanoate (0.85 g, 66%) as a light yellow liquid. 1 H-NMR (400MHz, CDCl3) δ = 8.38-8.37 (m, 1H), 7.82-7.79 (dd, 1H), 6.78-6.76 (d, 1H), 5.23-5.1 7(d,1H),4.68-4.65(d,1H),4.44-4.33(m,2H),4.22(s,1H),3.94(s,3H),1.37-1.33(t,3H). MS:371.12[M+H] +

[0866] Step-B:

[0867] To a stirred solution of the compound from step-A (0.75 g, 2.77 mmol) in ethanol (15 mL) was added 10% Pd / C (0.38 g) at room temperature. The reaction mixture was stirred under a hydrogen atmosphere (~15 psi pressure) for 16 hours. The crude compound was then filtered through a pad of celite and the residue was washed with ethanol. The filtrate was evaporated under reduced pressure to give ethyl 3-amino-2-hydroxy-2-(6-methoxypyridin-3-yl)propanoate (345 mg, 52%) as a light yellow gum. MS: 214.13 [M+H] +

[0868] Step-C:

[0869] To a stirred solution of the compound from Step B (0.34 g, 1.41 mmol) and triethylamine (0.6 mL, 4.249 mmol) in dichloromethane (20 mL) was added 4-isothiocyanato-1,2,3,5,6,7-hexahydro-s-indacenes (0.335 g, 1.558 mmol). After stirring at room temperature for 16 hours, the reaction mixture was concentrated to dryness under reduced pressure. The crude compound was purified by flash chromatography (12 g silica, Reveleris column; 0-70% ethyl acetate in hexanes) to afford ethyl 3-(3-(1,2,3,5,6,7-hexahydro-s-indacenes-4-yl)thioureido)-2-hydroxy-2-(6-methoxypyridin-3-yl)propanoate (0.26 g, 40%) as an off-white solid.1 H-NMR, (400MHz, CDCl3)δ=8.32(d,1H),7.81-7.78(dd,1H),7.29(s,1H),7.09(s,1H),6.74-6.71(d,1H),5.95(s,1H),4.52-4.50(m,1H) ,4.31-4.20(m,3H),4.19-4.08(m,1H),3.94(s,3H),3.49(d,1H),2.88(t,4H),2.70-2.58(m,4H),2.07-2.00(m,4H),1.31-1.26(m,3H). MS:456.55[M+H]+

[0870] Step-D:

[0871] To a stirred solution of the compound (0.26 g, 0.57 mmol) from step-C in acetonitrile (5 mL) was added triethylamine (0.24 mL, 1.71 mmol), followed by EDC.HCl (0.218 g, 1.14 mmol). The reaction mixture was then warmed to room temperature. After 48 hours, the reaction mixture was diluted with ice water (10 mL) and the crude product was stirred for 30 minutes. The solid was collected by filtration and dried under reduced pressure to give a crude compound. The crude compound was purified by flash chromatography (silica, 12 g Reveleris column; 0-70% ethyl acetate in hexane) to give 2-((1,2,3,5,6,7-hexahydro-s-indacene-4-yl)amino)-5-(6-methoxypyridin-3-yl)-4,5-dihydrooxazole-5-carboxylic acid ethyl ester (0.12 g, 52%) as an off-white solid. 1 H-NMR (500MHz, CDCl3)δ=8.27(d,1H),7.65(dd,1H),6.97(s,1H),6.77(d,1H),4.50-4.47(d,1H) ,4.28-4.23(m,2H),4.07(d,1H),3.95(s,3H),2.89-2.80(m,8H),2.07-2.05(m,4H),1.28(t,3H). MS:422.58[M+H] +

[0872] Example 7: Enantiomerically pure 2-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)amino)-5-(6-methyl)- (3-Pyridin-3-yl)-4,5-dihydrooxazole-5-carboxylic acid ethyl ester

[0873] Starting from the racemic mixture of Example 6, the enantiomerically pure compound was separated by chiral SFC as an off-white solid (Chiralpak IG (4.6*250) mm, 5μ; cosolvent: 50% (0.5% triethylamine in ethanol), outlet pressure: 100 bar; temperature: 30°C); second eluting peak.

[0874] 1 H-NMR, (500MHz, CDCl3)δ=8.27(d,1H),7.65(dd,1H),6.97(s,1H),6.77(d,1H),4.48(d,1H),4 .28-4.24(m,2H),4.06(d,1H),3.95(s,3H),2.89-2.77(m,8H),2.09-2.00(m,4H),1.28(t,3H). MS:422.55[M+H] + .99.79%ee

[0875] Example 8: 2-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)amino)-5-(pyridin-2-yl)-4,5-dihydro- Ethyl hydrooxazole-5-carboxylate

[0876]

[0877] Step-A:

[0878] To a stirred solution of ethyl 2-oxo-2-(pyridin-2-yl)acetate (0.9 g, 5.02 mmol) in nitromethane (10 mL) was added triethylamine (0.7 mL, 5.02 mmol). After stirring at room temperature for 16 hours, the reaction mixture was concentrated under reduced pressure. The crude compound was purified by flash chromatography (silica 25 g column, 0-50% ethyl acetate in hexane) to give ethyl 2-hydroxy-3-nitro-2-(pyridin-2-yl)propanoate (1 g, 83%) as a colorless liquid. MS: 241.32 [M+H] +

[0879] Step-B:

[0880] To a stirred solution of the compound from Step-A (1 g, 4.16 mmol) in ethanol (20 mL) was added 10% Pd / C (0.6 g) at room temperature. The reaction mixture was stirred under a hydrogen atmosphere (~15 psi pressure) for 16 hours. The crude compound was then filtered through a pad of Celite, and the residue was washed with ethanol. The filtrate was evaporated under reduced pressure to give ethyl 3-amino-2-hydroxy-2-(pyridin-2-yl)propanoate (0.6 g, 69%) as a colorless gum. 1H-NMR (400MHz, CDCl3) δ = 8.57 (d, 1H), 7.78-7.74 (m, 1H), 7.63 (d, 1H), 7.3 0-7.26(m,1H),4.23(q,2H),3.49(d,1H),3.18(d,1H),1.26-1.22(m,3H). MS:211.33[M+H] +

[0881] Step-C:

[0882] To a stirred solution of the compound from Step-B (0.6 g, 2.85 mmol) and triethylamine (1.19 mL, 8.56 mmol) in dichloromethane (4 mL) was added a solution of 4-isothiocyanato-1,2,3,5,6,7-hexahydro-s-indacenes (0.613 g, 2.85 mmol) in dichloromethane (4 mL). After stirring at room temperature for 16 hours, the reaction mixture was concentrated to dryness under reduced pressure. The crude compound was purified by flash chromatography (silica 12 g, Reveris column; 0-50% ethyl acetate in hexanes) to give ethyl 3-(3-(1,2,3,5,6,7-hexahydro-s-indacenes-4-yl)thioureido)-2-hydroxy-2-(pyridin-2-yl)propanoate (0.48 g, 40%) as an off-white solid. 1 H-NMR, (400MHz, DMSO-d6)δ=9.27(s,1H),8.40(s,1H),7.84-7.79(m,1H),7.54-7.52(d,1H),7.34-7.31(m,1H),7 .00(s,1H),6.62(s,1H),4.17-4.04(m,4H),2.82-2.78(m,4H),2.55-2.49(m,4H),1.94-1.89(m,4H),1.09(t,3H). MS:426.28[M+H]+

[0883] Step-D:

[0884] To a stirred solution of the compound (0.480 g, 1.12 mmol) from step-C in acetonitrile (5 mL) was added triethylamine (0.47 mL, 3.38 mmol), followed by EDC.HCl (0.432 g, 2.25 mmol). The reaction mixture was then warmed to room temperature. After 24 hours, the reaction mixture was diluted with ice water (10 mL) and the crude product was stirred for 30 minutes. The solid was collected by filtration and dried under reduced pressure to give a crude compound. The crude compound was purified by flash chromatography (silica, 12 g Reveleris column; 0-70% ethyl acetate in hexane) to give 2-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)amino)-5-(pyridin-2-yl)-4,5-dihydrooxazole-5-carboxylic acid ethyl ester (0.28 g, 63%) as an off-white solid. 1 H-NMR (400MHz, DMSO-d6) δ = 8.59 (d, 1H), 7.94-7.91 (m, 1H), 7.50 (s, 1H), 7.44-7.41 (m, 1H), 6.81 (s,1H),4.21-4.16(m,4H),2.79-2.75(m,4H),2.67-2.66(m,4H),1.96-1.89(m,4H),1.15(t,3H). MS:392.57[M+H] +

[0885] Example 9: Enantiomerically pure 2-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)amino)-5-(pyridine- 2-amino)-4,5-dihydrooxazole-5-carboxylic acid ethyl ester

[0886] Starting from the racemic mixture of Example 8, the enantiomerically pure compound was separated by chiral SFC as an off-white solid (Chiralpak IG (4.6*250) mm, 5μ; co-solvent: 30% (100% ethanol), outlet pressure: 100 bar; temperature: 30°C); second eluting peak. 1 H-NMR (400MHz, DMSO-d6) δ = 8.59 (d, 1H), 7.94-7.91 (m, 1H), 7.50 (s, 1H), 7.44-7.41 (m, 1H), 6.81 (s,1H),4.21-4.16(m,4H),2.79-2.75(m,4H),2.67-2.66(m,4H),1.96-1.90(m,4H),1.15(t,3H). MS:392.57[M+H] + .99.76% ee

[0887] Example 10: 5-(4-chlorophenyl)-2-((1,2,3,5,6,7-hexahydro-s-indacene-4-yl)amino)-4,5-dichlorophenyl Ethyl hydrooxazole-5-carboxylate

[0888]

[0889] Step-A:

[0890] To a stirred solution of ethyl 2-(4-chlorophenyl)-2-oxoacetate (2 g, 9.4 mmol) in nitromethane (10 mL) was added triethylamine (1.31 mL, 9.4 mmol). After stirring at room temperature for 16 hours, the reaction mixture was concentrated under reduced pressure. The crude compound was purified by flash chromatography (silica, 80 g column; 0-50% EtOAc in hexanes) to give ethyl 2-(4-chlorophenyl)-2-hydroxy-3-nitropropanoate (2.4 g, 94%) as a colorless liquid. MS 272.11 [M+H] +

[0891] Step-B:

[0892] To a stirred solution of the compound from step-A (0.2 g, 0.73 mmol) in acetic acid (5 mL) was added zinc powder (0.2 g, 7.32 mmol) at 0 ° C. The reaction mixture was then warmed to room temperature. After 16 hours, the crude mixture was filtered through a pad of celite and the residue was washed with ethyl acetate. The filtrate was evaporated under reduced pressure to give ethyl 3-amino-2-(4-chlorophenyl)-2-hydroxypropanoate (0.16 g, 90%) as a colorless gum. 1 H-NMR (500 MHz, chloroform-d) δ = 7.51 (d, 2H), 7.34 (d, 2H), 4.31–4.22 (m, 2H), 3.44 (d, 1H), 3.12 (d, 1H), 1.27 (t, 3H). MS: 244.10 [M+H] +

[0893] Step-C:

[0894] To a stirred solution of the compound from Step-B (0.160 g, 0.65 mmol) and triethylamine (0.27 mL, 1.97 mmol) in dichloromethane (2 mL) was added a solution of 4-isothiocyanato-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)thioureido)-2-hydroxypropanoic acid ethyl ester (0.2 g, 66%). After stirring at room temperature for 16 hours, the reaction mixture was concentrated to dryness under reduced pressure. The crude compound was purified by flash chromatography (silica 12 g, Reveleris column; 0-50% ethyl acetate in hexanes) to give ethyl 2-(4-chlorophenyl)-3-(3-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)thioureido)-2-hydroxypropanoate (0.2 g, 66%) as an off-white solid. 1H-NMR (400MHz, DMSO-d6) δ = 9.23 (brs, 1H), 7.49 (d, 2H), 7.41 (d, 2H), 6.98 (s, 1H) 6.5 8(s,1H),4.17-4.02(m,4H),2.86-2.67(m,8H),1.97-1.90(m,4H),1.17-1.14(m,3H). MS:459.33[M+H]+

[0895] Step-D:

[0896] To a stirred solution of the compound from step-C (0.20 g, 0.43 mmol) in acetonitrile (4 mL) was added triethylamine (0.18 mL, 1.3 mmol), followed by EDC.HCl (0.167 g, 0.87 mmol). The reaction mixture was then warmed to room temperature. After 20 hours, the reaction mixture was diluted with ice water (30 mL) and the crude product was stirred for 30 minutes. The solid was collected by filtration and dried under reduced pressure to give a crude compound. The crude compound was triturated with diethyl ether (10 mL), filtered, and dried under reduced pressure to give 5-(4-chlorophenyl)-2-((1,2,3,5,6,7-hexahydro-s-indoxane-4-yl)amino)-4,5-dihydrooxazole-5-carboxylic acid ethyl ester (70 mg, 38%) as a white solid. 1 H-NMR (500MHz, DMSO-d6) δ = 8.66 (s, 1H), 7.53-7.45 (m, 4H), 6.85-6.75 (m, 1H),4.27-3.86(m,4H),2.8-2.63(m,8H),1.97-1.91(m,4H),1.17(t,3H). MS:425.55[M+H] +

[0897] Example 10a: Enantiomerically pure 5-(4-chlorophenyl)-2-((1,2,3,5,6,7-hexahydro-s-indacene-4- (4,5-dihydrooxazole-5-carboxylic acid ethyl ester)

[0898] Starting from the racemic mixture of Example 10, the enantiomerically pure compound was separated by chiral SFC as an off-white solid (Lux Amylose-3 (30*250) mm, 5μ; co-solvent: 35% (ethanol), outlet pressure: 100 bar; temperature: 30°C); the second eluting peak. 1H-NMR(500MHz,DMSO-d6)δ8.67(br s,1H),7.59–7.38(m,4H),6.85(s,1H),4.36–4.08(m,3H),3.95–3.62(m,1H),2.88–2.57(m,8H),2.03–1.86(m,4H),1.17(t,3H). MS:425.52[M+H] +

[0899] Example 11a: 2-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)amino)-5-(pyridin-3-yl)-4,5- Ethyl dihydrooxazole-5-carboxylate

[0900]

[0901] Step-A:

[0902] To a stirred solution of ethyl 2-oxo-2-(pyridin-3-yl)acetate (0.5 g, 2.79 mmol) in nitromethane (5 mL) was added triethylamine (0.38 mL, 2.79 mmol). After stirring at room temperature for 16 hours, the reaction mixture was concentrated under reduced pressure. The crude compound was purified by flash chromatography (silica, 12 g column, 0-50% EtOAc in hexanes) to give ethyl 2-hydroxy-3-nitro-2-(pyridin-3-yl)propanoate (0.580 g, 87%) as a colorless liquid. 1 H-NMR (500MHz, CDCl3) δ = 8.87 (d, 1H), 8.64 (dd, 1H), 7.99-7.97 (m, 1H), 7. 37-7.35(m,1H),5.26(d,1H),4.70(d,1H),4.45-4.35(m,2H),1.36(t,3H). MS241.28[M+H] +

[0903] Step-B:

[0904] To a stirred solution of the compound from step-A (0.450 g, 1.87 mmol) in acetic acid (5 mL) was added zinc powder (1.21 g, 18.75 mmol) at 0 ° C. The reaction mixture was then warmed to room temperature. After 16 hours, the crude mixture was filtered through a pad of celite and the residue was washed with ethyl acetate. The filtrate was evaporated under reduced pressure to give ethyl 3-amino-2-hydroxy-2-(pyridin-3-yl)propanoate as a colorless gum. MS: 211.2 [M+H] +

[0905] Step-C:

[0906] To a stirred solution of the compound from Step-B (0.360 g, 1.71 mmol) and triethylamine (0.71 mL, 5.13 mmol) in dichloromethane (5 mL) was added a solution of 4-isothiocyanato-1,2,3,5,6,7-hexahydro-s-indacenes (0.368 g, 1.71 mmol) in dichloromethane (3 mL). After stirring at room temperature for 16 hours, the reaction mixture was concentrated to dryness under reduced pressure. The crude compound was purified by flash chromatography (silica 12 g, Reveris column; 0-50% ethyl acetate in hexanes) to give ethyl 3-(3-(1,2,3,5,6,7-hexahydro-s-indacenes-4-yl)thioureido)-2-hydroxy-2-(pyridin-3-yl)propanoate (0.450 g, 61%) as an off-white solid. 1 H-NMR (500MHz, CDCl3) δ = 8.80 (d, 1H), 8.57 (dd, 1H), 7.98-7.95 (m, 1H), 7.38-7.29 (m, 2H), 7.10 (s, 1H), 4.54 -4.53(m,1H),4.32-4.09(m,4H),2.90-2.86(m,4H),2.71-2.56(m,4H),2.10-2.01(m,4H),1.30-1.22(m,3H). MS:426.3[M+H]+

[0907] Step-D:

[0908] To a stirred solution of the compound (0.4 g, 0.93 mmol) from step-C in acetonitrile (5 mL) was added triethylamine (0.39 mL, 2.81 mmol), followed by EDC.HCl (0.54 g, 2.81 mmol). The reaction mixture was then warmed to room temperature. After 20 hours, the reaction mixture was diluted with ice water (30 mL) and the crude product was stirred for 30 minutes. The solid was collected by filtration and dried under reduced pressure to give a crude compound. The crude compound was triturated with diethyl ether (20 mL), filtered, and dried under reduced pressure to give ethyl 2-((1,2,3,5,6,7-hexahydro-s-indoxane-4-yl)amino)-5-(pyridin-3-yl)-4,5-dihydrooxazole-5-carboxylate (207 mg, 56%) as a white solid. 1H-NMR(500MHz, CDCl3)δ8.82–8.72(m,1H),8.61(dd,1H),7.81(dt,1H),7.33(ddd,1H),6.98(s, 1H),4.54(d,1H),4.27(q,2H),4.09(d,1H),2.95–2.77(m,8H),2.16–1.99(m,4H),1.29(t,3H). MS:392.54[M+H]+.

[0909] Example 11: Enantiomerically pure 2-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)amino)-5-(pyrrolidone) (3-pyridin-4,5-dihydrooxazole-5-carboxylic acid ethyl ester

[0910] Starting from the racemic mixture of Example 11a, the enantiomerically pure compound was separated by chiral SFC as an off-white solid (Chiralpak IG (4.6*250) mm, 5μ; cosolvent: 30% (ethanol), outlet pressure: 100 bar; temperature: 30°C); second eluting peak. 1 H-NMR (500MHz, CDCl3) δ = 8.77 (d, 1H), 8.61 (dd, 2H), 7.80 (d, 1H), 7.34-7.32 (m, 1H), 6.97 (s, 1H) ,4.54(d,1H),4.29-4.24(m,2H),4.09(d,1H),2.89-2.78(m,8H),2.09-2.03(m,4H),1.29(t,3H). MS:392.57[M+H]+.99.91%ee

[0911] Example 12: Enantiomerically pure 2-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)amino)-5-(tetrahydro- 2H-pyran-4-yl)-4,5-dihydrooxazole-5-carboxylic acid ethyl ester

[0912]

[0913] Step-A:

[0914] To a stirred solution of ethyl 2-oxo-2-(tetrahydro-2H-pyran-4-yl)acetate (0.5 g, 2.69 mmol) in nitromethane (5 mL) was added triethylamine (0.075 mL, 0.537 mmol). After stirring at room temperature for 48 hours, the reaction mixture was concentrated under reduced pressure. The crude compound was purified by flash chromatography (silica, 40 g column, 0-50% EtOAc in hexanes) to give 2-hydroxy-3-nitro-2-(tetrahydro-2H-pyran-4-yl)propanoate (0.620 g, 93%) as a colorless gum. 1H-NMR (400MHz, CDCl3) δ = 4.83 (d, 1H), 4.66 (d, 1H), 4.39-4.33 (m, 2H), 4.05-3.98 (m, 2H), 3.68 ( s,1H),3.38-3.32(m,2H),1.91-1.88(m,1H),1.70-1.58(m,3H),1.35(t,3H),1.26-1.23(m,1H). MS 248.31[M+H] +

[0915] Step-B:

[0916] To a stirred solution of the compound from Step-A (500 mg, 2.022 mmol) in ethanol (15 mL) was added 10% Pd / C (0.25 g) at room temperature. The reaction mixture was stirred under a hydrogen atmosphere (~15 psi pressure) for 16 hours. The crude mixture was then filtered through a pad of Celite, and the residue was washed with ethanol. The filtrate was evaporated under reduced pressure to give ethyl 3-amino-2-hydroxy-2-(tetrahydro-2H-pyran-4-yl)propanoate as a colorless gum.

[0917] Step-C:

[0918] To a stirred solution of the compound from Step B (260 mg, 1.196 mmol) and triethylamine (0.5 mL, 3.590 mmol) in dichloromethane (5 mL) was added a solution of 4-isothiocyanato-1,2,3,5,6,7-hexahydro-s-indacen-4-yl) (257.6 mg, 1.196 mmol). After stirring at room temperature for 16 hours, the reaction mixture was concentrated to dryness under reduced pressure. The crude compound was purified by flash chromatography (24 g silica, Reveleris column; 0-50% ethyl acetate in hexanes) to give ethyl 3-(3-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)thioureido)-2-hydroxy-2-(tetrahydro-2H-pyran-4-yl)propanoate (0.270 g, 52%). MS: 433.3 [M+H]. + .

[0919] Step-D:

[0920] To a stirred solution of the compound (270 mg, 0.624 mmol) from step-C in acetonitrile (12 mL) was added triethylamine (0.261 mL, 1.872 mmol), followed by EDC.HCl (299 mg, 1.560 mmol). The reaction mixture was then warmed to room temperature. After 20 hours, the reaction mixture was diluted with ice water (30 mL) and the crude product was stirred for 30 minutes. The solid was collected by filtration and dried under reduced pressure to give a crude compound. The crude compound was ground with diethyl ether (20 mL) in pentane, filtered, and dried under reduced pressure to give ethyl 2-((1,2,3,5,6,7-hexahydro-s-indoxane-4-yl)amino)-5-(tetrahydro-2H-pyran-4-yl)-4,5-dihydrooxazole-5-carboxylate (220 mg, 89%) as a white solid. Starting from the racemic mixture of Example 8, the enantiomerically pure compound was separated by chiral SFC as an off-white solid (Lux Cellulose-4 (30*250) mm, 5μ; co-solvent: 45% (ethanol), outlet pressure: 120 bar; temperature: 30°C); the first eluting peak. 1 H-NMR (500MHz, CDCl3) δ = 6.95 (s, 1H), 4.29-4.25 (m, 2H), 4.05 (m, 2H), 3.95 (d, 1H), 3.84 (d, 1H), 3.41 -3.37(m,2H),2.88-2.79(m,8H),2.12-2.03(m,5H)1.68-1.62(m,2H),1.51-1.46(m,2H),1.32(t,3H). MS:399.60[M+H] + .99.94%ee

[0921] Example 13: 5-(3-chlorophenyl)-2-((1,2,3,5,6,7-hexahydro-s-indacene-4-yl)amino)-4,5-dihydro- Ethyl hydrooxazole-5-carboxylate

[0922]

[0923] Step-A:

[0924] To a stirred solution of ethyl 2-(3-chlorophenyl)-2-oxoacetate (0.50 g, 2.35 mmol) in nitromethane (5 mL) was added triethylamine (0.32 mL, 2.35 mmol). After stirring at room temperature for 16 hours, the reaction mixture was concentrated under reduced pressure. The crude compound was purified by flash chromatography (silica, 25 g column; 0-50% EtOAc in hexanes) to afford 2-hydroxy-3-nitro-2-(tetrahydro-2H-pyran-4-yl)propanoate (0.62 g, 68%) as a colorless gum. 1H-NMR (400MHz, CDCl3)δ=7.67–7.63(m,1H),7.52–7.48(m,1H),7.38–7.33(m, 2H),5.22(dd,1H),4.65(d,1H),4.47–4.32(m,2H),4.26(d,1H),1.36(t,3H).

[0925] Step-B:

[0926] To a stirred solution of the compound from step-A (0.6 g, 2.19 mmol) in acetic acid (7 mL) was added zinc powder (1.41 g, 21.9 mmol) at 5 ° C. The reaction mixture was then warmed to room temperature. After 16 hours, the crude mixture was filtered through a pad of celite and the residue was washed with ethyl acetate. The filtrate was evaporated under reduced pressure to give ethyl 3-amino-2-(3-chlorophenyl)-hydroxypropanoate as a colorless gum. MS: 244.10 [M+H] +

[0927] Step-C:

[0928] To a stirred solution of the compound from step B (0.5 g, 2.05 mmol) and triethylamine (0.85 mL, 6.15 mmol) in dichloromethane (7 mL) was added a solution of 4-isothiocyanato-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)thioureido)-2-hydroxypropanoic acid ethyl ester (0.6 g, 82%). After stirring at room temperature for 16 hours, the reaction mixture was concentrated to dryness under reduced pressure. The crude compound was purified by flash chromatography (silica 12 g, Reveris column; 0-50% ethyl acetate in hexanes) to give ethyl 2-(3-chlorophenyl)-3-(3-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)thioureido)-2-hydroxypropanoate (0.6 g, 82%) as an off-white solid. 1 H-NMR (400MHz, CDCl3) δ = 7.57 (s, 1H), 7.47-7.46 (m, 1H), 7.29-7.26 (m, 2H), 7.09 (s, 1H), 5.92 (s, 1H), 4.52-4.47 ( m,1H),4.28-4.20(m,2H),4.14-4.09(m,1H),2.89-2.86(m,4H),2.68-2.57(m,4H),2.10-1.99(m,4H),1.28(t,3H). MS:459.27[M+H] + .

[0929] Step-D:

[0930] To a stirred solution of the compound from step-C (0.60 g, 1.3 mmol) in acetonitrile (10 mL) was added triethylamine (0.54 mL, 3.92 mmol), followed by EDC.HCl (0.751 g, 3.92 mmol). The reaction mixture was then warmed to room temperature. After 20 hours, the reaction mixture was diluted with ice water (20 mL) and the crude product was stirred for 30 minutes. The solid was collected by filtration and dried under reduced pressure to give a crude compound. The crude compound was triturated with diethyl ether (20 mL), filtered, and dried under reduced pressure to give 5-(3-chlorophenyl)-2-((1,2,3,5,6,7-hexahydro-s-indoxane-4-yl)amino)-4,5-dihydrooxazole-5-carboxylic acid ethyl ester (340 mg, 61%) as a white solid. 1 H-NMR (500MHz, DMSO-d6) δ = 8.69 (s, 1H), 7.48-7.41 (m, 4H), 7.00-6.62 (m, 1H),4.27-3.88(m,4H),2.80-2.63(m,8H),1.96-1.93(m,4H),1.18(t,3H). MS:425.52[M+H] + .

[0931] Example 13a: Enantiomerically pure 5-(3-chlorophenyl)-2-((1,2,3,5,6,7-hexahydro-s-indacene-4- (4,5-dihydrooxazole-5-carboxylic acid ethyl ester)

[0932] Starting from the racemic mixture of Example 13, the enantiomerically pure compound was obtained by chiral SFC separation as an off-white solid (Chiralpak AD-H (30*250) mm, 5μ; co-solvent: 20% (ethanol), outlet pressure: 120 bar; temperature: 30°C); the first eluting peak. 1 H-NMR(500MHz, CDCl3)δ7.50(s,1H),7.39–7.31(m,3H),6.97(s,1H),4.52(d,1H) ),4.25(q,2H),4.04(d,1H),2.93–2.80(m,8H),2.13–2.00(m,4H),1.28(t,3H). MS:425.2[M+H]+.

[0933] Example 14: 3-(3-(1,2,3,5,6,7-hexahydro-s-indacene-4-yl)thiourea)-2-hydroxy-2-(5-(2- Ethyl hydroxypropan-2-yl)isoxazol-3-yl)propanoate

[0934]

[0935] Step-A:

[0936] At room temperature, a round-bottom flask was charged with acetone (52.3 mL, 706 mmol), 2-methylbut-3-yn-2-ol (2.304 mL, 23.30 mmol) and tert-butyl nitrite (3.39 mL, 25.6 mmol). Under argon, the solution was stirred at 60 ° C overnight. The reaction mixture was then evaporated under reduced pressure. The crude compound was purified by flash chromatography (silica, 50 g column; 0-40% ethyl acetate in hexane) to give 1- (5- (2-hydroxypropan-2-yl) isoxazol-3-yl) ethanone (1.44 g, 37%) as a yellow oil. 1 H-NMR (80MHz, DMSO-d6) δ6.59(s,1H),5.73(s,1H),2.56(s,3H),1.49(s,6H).

[0937] Step-B:

[0938] To a stirred solution of the compound (50 mg, 0.296 mmol) from step-A in THF (1 mL) was added phenyltrimethylammonium tribromide (89 mg, 0.236 mmol) at room temperature. The reaction mixture was stirred at 70 ° C for 3 hours. Water and ethyl acetate were added and the layers were separated. The aqueous layer was extracted with EtOAc (3x). The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude compound was purified by flash chromatography (silica, 12 g column; 0-40% ethyl acetate in hexane) to give 2-bromo-1-(5-(2-hydroxypropan-2-yl)isoxazol-3-yl)ethanone (80 mg, 87%) as an orange oil. 1 H-NMR (80MHz, DMSO-d6) δ6.72(s,1H),4.83(s,2H),1.50(s,6H).

[0939] Step-C:

[0940] To a solution of the compound (1g, 3.39mmol) from step-B in ethanol (10mL) was added selenium dioxide (0.751g, 6.77mmol). The reaction mixture was heated for 18 hours. The crude mixture was cooled to room temperature and concentrated to dryness under reduced pressure. The oily compound was purified by flash chromatography (silica, 0-40% ethyl acetate in heptane) to obtain ethyl 2-(5-(2-hydroxypropan-2-yl)isoxazol-3-yl)-2-oxoacetate (680mg.74%) as an orange oil. 1 H-NMR (80MHz, DMSO-d6) δ6.87(s,1H),4.40(q,2H),1.54(s,6H),1.34(t,3H).

[0941] Step-D:

[0942] To a stirred solution of the compound from Step-C (600 mg, 2.64 mmol) in nitromethane (5 mL, 93 mmol) was added Amberlyst A-21 (500 mg) at room temperature. After stirring for 5 hours, the reaction mixture was filtered, rinsed with ethyl acetate (3x), and the resulting filtrate was evaporated under reduced pressure. The crude compound was purified by flash chromatography (silica, 25 g column; 0-40% ethyl acetate in hexanes) to give ethyl 2-hydroxy-2-(5-(2-hydroxypropan-2-yl)isoxazol-3-yl)-3-nitropropanoate (663 mg, 83%). 1 H-NMR (80MHz, DMSO-d6) δ7.23(d,1H),6.42(s,1H),5.68(s,1H),5.49(dd,1H),5.04(d,1H),4.23(q,2H),1.45(s,6H),1.20(t,3H). MS:289.04[M+H] +

[0943] Step-E:

[0944] Zinc (1.266g, 19.36mmol) is added to a cooling solution of the compound (558mg, 1.936mmol) from step-D in acetic acid (11mL). The reaction mixture is slowly warmed to room temperature. After stirring for 1 hour and 30 minutes, the mixture is filtered through diatomaceous earth. The diatomaceous earth pad is washed with ethyl acetate (3x), and the resulting filtrate is evaporated under reduced pressure to obtain 3-amino-2-hydroxy-2-(5-(2-hydroxypropyl-2-yl)isoxazole-3-yl)ethyl propionate as a yellow oil. The crude compound is used directly in the next step without further purification. MS: 259.07[M+H] +

[0945] Step-F:

[0946] To a stirred solution of the compound from Step E (500 mg, 1.936 mmol) and triethylamine (0.837 mL, 6.01 mmol) in THF (11 mL) was added 4-isothiocyanato-1,2,3,5,6,7-hexahydro-s-indacene (453 mg, 2.103 mmol) at room temperature. After 1 hour and 30 minutes, the reaction mixture was concentrated under reduced pressure. The crude compound was purified by flash chromatography (silica, 25 g column; 0-80% ethyl acetate in hexanes) to give ethyl 3-(3-(1,2,3,5,6,7-hexahydro-s-indacene-4-yl)thioureido)-2-hydroxy-2-(5-(2-hydroxypropan-2-yl)isoxazol-3-yl)propanoate (570 mg, 56%) as a white foam. 1 H-NMR(80MHz,DMSO-d6)δ9.34(s,1H),7.00(s,1H),6.80(s,1H),6.32(s,1H),5.63(s,1H),4.22 -3.96(m,4H),2.94 -2.60(m,8H),1.96(d,4H),1.45(s,6H),1.16(t,3H). MS:474.07[M+H] +

[0947] Example 14a: Enantiomerically pure 3-(3-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)thioureido)-2- Ethyl hydroxy-2-(5-(2-hydroxypropan-2-yl)isoxazol-3-yl)propanoate

[0948] Starting from the racemic mixture of Example 14, the enantiomerically pure compound was separated by chiral SFC as an off-white solid (Lux Amylose IG (30*250) mm, 5μ; mobile phase: 30n-hexane:ethanol (90:10), temperature: 30°C); the first eluting peak. 1 H-NMR, (400MHz, DMSO-d6δ9.35(s,1H),7.00(s,1H),6.81(s,1H),6.32(s,1H),5.64(s,1H),4.42(s,1H),4.24–4 .07(m,2H),4.05–3.89(m,1H),2.89–2.58(m,8H),2.04–1.89(m,4H),1.45(s,6H),1.17(t,3H) MS:474.45[M+H]+.

[0949] Example 15: 2-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)amino)-5-(5-(2-hydroxypropane-2- (4-(2-Yl)isoxazol-3-yl)-4,5-dihydrooxazole-5-carboxylic acid ethyl ester

[0950]

[0951] To a cooled (0°C) solution of the compound from Example 14 (100 mg, 0.211 mmol) in acetonitrile (3.5 mL) was added triethylamine (0.088 mL, 0.633 mmol), followed by N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (81 mg, 0.422 mmol). The reaction mixture was allowed to slowly warm to room temperature. After stirring at room temperature for 48 hours, ice was added to the reaction mixture, which was stirred for 30 minutes. The acetonitrile was concentrated under reduced pressure, and the resulting solid was filtered. The solid was rinsed twice with water and diethyl ether, then dried in vacuo to yield ethyl 2-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)amino)-5-(5-(2-hydroxypropan-2-yl)isoxazol-3-yl)-4,5-dihydrooxazole-5-carboxylate (42 mg, 45%) as an off-white solid. 1 H-NMR(80MHz,DMSO-d6)δ6.86(s,1H),6.42(s,1H),5.71(s,1H),4.44-4.1 0(m,4H),2.91-2.62(m,8H),2.14-1.80(m,4H),1.48(s,6H),1.22(t,3H). MS:440.12[M+H] +

[0952] Example 16: Enantiomerically pure 2-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)amino)-5-(5- Ethyl (2-hydroxypropan-2-yl)isoxazol-3-yl)-4,5-dihydrooxazole-5-carboxylate

[0953] Starting from the racemic mixture of Example 15, the enantiomerically pure compound was separated by chiral SFC as an off-white solid (Chiralpak IG (4.6*250) mm, 5μ; co-solvent: 50% (0.5% triethylamine in ethanol), outlet pressure: 100 bar; temperature: 30°C); second eluting peak. 1 H-NMR,(400MHz,DMSO-d6)δ8.64(s,1H),6.86(s,1H),6.40(s,1H),5.71(s,1H),4 .27-4.00(m,4H),2.80-2.55(m,8H),1.98-1.93(m,4H),1.47(s,6H),1.22(t,3H). MS:440.43[M+H] + .99.52%ee

[0954] According to the above method, the following preparation examples were prepared.

[0955]

[0956]

[0957]

[0958] Example 22 :2-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)amino)-5-(5-(2-hydroxypropan-2-yl)isoxazol-3-yl)-4,5-dihydrooxazole-5-carboxylic acid

[0959]

[0960] To a stirred solution of the ester of Example 15 (20 mg, 0.0455 mmol) in THF (1 mL) was added sodium trimethylsilanol (6.125 mg, 0.0546 mmol) at 0 ° C. The reaction mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. The reaction mixture was concentrated and triturated in diethyl ether. The resulting solid was dried under reduced pressure to give 2-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)amino)-5-(5-(2-hydroxypropyl-2-yl)isoxazol-3-yl)-4,5-dihydrooxazole-5-carboxylic acid (20 mg, 99%) as an off-white solid. 1 H-NMR (400MHz, DMSO-d6) δ6.67(s,1H),6.11(s,1H),5.57(s,1H),4.00-3.70(m,2H),2.77 -2.50(m,8H),1,93–1,85(m,4H),1.44(s,6H). MS:412.3[M+H] +

[0961] Following the saponification method as described in Example 22, the following preparation examples were synthesized.

[0962]

[0963]

[0964]

[0965]

[0966] According to the above method, the following preparation examples were also prepared.

[0967]

[0968]

[0969]

[0970]

[0971]

[0972]

[0973] Example 56: 2-((1,2,3,5,6,7-hexahydro-5-indacene-4-yl)amino)-5-(isoxazol-3-yl)-4-nitropropene Isopropyl 5-dihydrooxazole-5-carboxylate

[0974]

[0975] To a stirred solution of the ethyl ester of Example 49 (0.200 g, 0.524 mmol) in THF (5 mL) was added titanium tetraisopropoxide (0.447 g, 1.573 mmol). After stirring at room temperature for 72 hours, the reaction mixture was diluted with water and filtered through a pad of celite. The filtrate was extracted with ethyl acetate (2 x 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude residue was triturated with n-pentane, filtered, and dried under reduced pressure to afford isopropyl 2-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)amino)-5-(isoxazol-3-yl)-4,5-dihydrooxazole-5-carboxylate (190 mg, 91%) as an off-white solid. (ACI-16456) 1 H-NMR(400MHz DMSO-D6δ9.04(d,1H),8.65(s,1H),6.87(s,1H),6.72(s,1H),5.14–4.94(m,1H),4.32– 4.01(m,2H),2.89–2.59(m,8H),2.03–1.82(m,4H),1.26–1.16(m,6H) MS:396.06(M+H). + .

[0976] Example 57: 2-((1,2,3,5,6,7-hexahydro-5-indacene-4-yl)amino)-5-(isoxazol-3-yl)-4, Cyclopentyl 5-dihydrooxazole-5-carboxylate

[0977]

[0978] To a stirred solution of the ethyl ester from Example 21B (0.5 g, 1.3108 mmol) in cyclopentanol (5 mL) was added Et3N (0.091 mL, 0.655 mmol) at room temperature and stirred at 80°C for 72 hours. The reaction mixture was concentrated under reduced pressure. The crude compound thus obtained was purified by preparative HPLC (XSELECT PHENYL-HEXYL (150*19) mm 5u; mobile phase A: 10 mM ammonium bicarbonate (Aq), mobile phase B: 100% acetonitrile; flow rate: 19 mL / min) to afford cyclopentyl 2-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)amino)-5-(isoxazol-3-yl)-4,5-dihydrooxazole-5-carboxylate (0.19 g, 34%) as a white solid.1 H-NMR(400MHz,DMSO-d6)δ9.04(d,1H),8.64(s,1H),6.86(s,1H),6.71(s,1H),5.33–5.16(m,1H) ,4.34–4.03(m,2H),2.89–2.58(m,8H),2.00–1.89(m,4H),1.88–1.77(m,2H),1.69–1.48(m,6H). MS:422.17[M+H] +

[0979] Example 58: Enantiomerically pure 2-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)amino)-5-(isoxazol- (3-oxazol-4,5-dihydrooxazole-5-carboxylic acid cyclopentyl ester

[0980] Starting from the racemic mixture of Example 61, chiral SFC separation afforded the enantiomerically pure compound as an off-white solid. (Chiralpak IG (30*250) mm, 5μ; cosolvent: 30% (100% isopropanol), outlet pressure: 100 bar; temperature: 30°C); second eluting peak. 1 H-NMR(400MHz,DMSO-d6)δ9.04(s,1H),6.84(s,1H),6.72(s,1H),5.30–5.17(m, 1H),4.31–4.01(m,2H),2.88–2.61(m,8H),2.02–1.79(m,6H),1.78–1.50(m,6H). MS:422.06[M+H] +

[0981] According to the above method, the following preparation examples were prepared.

[0982]

[0983]

[0984]

[0985]

[0986]

[0987]

[0988]

[0989] Biological assay description

[0990] NLRP3 inhibition assay

[0991] The following assay was used to determine the inhibitory activity of test compounds on the NLRP3 inflammasome pathway using the conventional stimulator nigericin (Invivogen) or monosodium urate crystals (MSU) (Invivogen).

[0992] Cell culture

[0993] 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).

[0994] NLRP3 inflammasome pathway activation assay

[0995] Human monocyte-like cells were seeded at 75,000 cells per well in a 96-well plate and differentiated into macrophages overnight with 10 ng / mL PMA (phorbol myristate acetate). The next day, medium containing 10 ng / mL LPS (lipopolysaccharide) was added. After 3 hours of LPS treatment, test compounds were added at concentrations ranging from 100 μM to 6 nM. 30 minutes later, the NLRP3 inflammasome pathway was stimulated with either 3.75 μM nigericin or 150 μg / mL MSU for 3 hours.

[0996] Human whole blood assay

[0997] Cultivation setting operation

[0998] Before performing the assay, perform a preliminary blood hemolysis assessment. Centrifuge the blood sample at 1000 g for 10 minutes. Then, transfer 50 to 100 μL of blood to a Corning TM 96-well clear flat-bottom plates. Hemolysis was assessed at 414 nm using a Tecan. The OD value for hemolysis should be less than 1.

[0999] • Add 10 μL of LPS 9x or CTRL according to the plate layout.

[1000] Add 80 μL of whole blood to each well of a PP low-binding 96-well plate.

[1001] Incubate at 37°C and 5% CO2 for 2 hours 30 minutes to 3 hours.

[1002] • Add 10 μL of compound 10x or control to the wells according to the plate layout.

[1003] Incubate at 37°C and 5% CO2 for 30 minutes.

[1004] • Add 11 μL of ATP 10x or control to all wells according to the plate layout.

[1005] Incubate at 37°C and 5% CO2 for 1 hour.

[1006] • Collection at 1 hour time point → Centrifuge the plate at 1000 g for 10 minutes and collect plasma (40 to 50 μL) and store at -20°C.

[1007] • IL-1β levels were measured by AlphaLISA.

[1008] LPS-ATP-induced peritonitis mouse model

[1009] 6-8 week old C57BL / 6 female mice were randomly divided into experimental groups. Mice were challenged intraperitoneally with 50 μg / kg of LPS. Two hours later, mice received an intraperitoneal injection of 200 μL of ATP (adenosine triphosphate) 50 mM, pH 7.2. 15 minutes before ATP injection, each compound was administered intraperitoneally at 1 mg / kg or 3 mg / kg. 30 minutes after ATP injection, animals were sacrificed by CO2. Cardiac blood was collected by cardiac puncture. Peritoneal lavage was performed on the entire peritoneum with a total volume of 4 mL of sterile saline solution. IL-1b levels in peritoneal lavage samples were assessed by AlphaLisa. Results are expressed as a % reduction compared to the vehicle-treated group.

[1010] Determination of IL-1β

[1011] For IL-1β quantification, supernatants were analyzed using an AlphaLISA kit according to the manufacturer's instructions (Perkin Elmer AlphaLISA AL220F). TM In a microplate, 5 μl of sample was mixed with 20 μl of AlphaLISA anti-analyte acceptor beads (final concentration: 10 μg / ml) and biotinylated anti-analyte antibody (final concentration: 1 nM). The mixture was then incubated at room temperature for 60 minutes, followed by the addition of 25 μl of 2X SA-donor beads (final concentration: 40 μg / mL) and incubation at room temperature in the dark for 30 minutes. The samples were read using an EnVision-Alpha reader (PerkinElmer).

[1012] IC was determined using GraphPad Prism 8. 50 (Concentration corresponding to 50% inhibition).

[1013] The following example compounds were measured:

[1014] Table 1

[1015]

[1016]

[1017]

[1018]

[1019] Legend:+++IC 50 <1μM; ++IC 50 1<x<10μM;+IC 50 10<x<30μM.

[1020] The test compounds were shown to inhibit IL-1β 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; and (C) by peritoneal lavage from a mouse model of LPS-ATP-induced peritonitis, see Tables 1 and Figure 1 (as described below).

[1021] In particular, Figure 1 It was shown that in the LPS-ATP-induced peritonitis model, IL-1β release was significantly inhibited in peritoneal lavage samples from mice given (1 mg / kg or 3 mg / kg) of Example 16 and Example 23 by intraperitoneal injection. Data are expressed as % cytokine release compared to the vehicle-treated group, which represents 100% secretion capacity. n = 6 mice per group. ****p < 0.0001, compared to the vehicle-treated group; one-way ANOVA, followed by Dunnett's post hoc test.

Claims

1. Compound of formula (I') or a stereoisomer, racemic mixture, or pharmaceutically acceptable salt thereof; in X is independently selected from O, N and S; Y is independently selected from N and O; When valence permits, It is a combination of single and double bonds or two single bonds; n is 1; R 0 is H or C1-C3 alkyl; R 1 yes in Z is independently selected from CH2 and O, provided that no more than two Z are O; R 5 independently selected from hydrogen and halogen; R 2 independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl; and R 3 yes They may each be optionally substituted by -C1-C6 alkyl, -O-C1-C6 alkyl, -Hal or -C1-C6 alkyl-OH, and R 4 Independently selected from hydrogen and C1-C6 alkyl.

2. The compound according to claim 1, which is a compound of formula (Ic) or a compound of formula (Ic') or a stereoisomer, racemic mixture, or pharmaceutically acceptable salt thereof, in X, Y, R 1 、R 2 and R 3 As defined in claim 1, and wherein R 0 It is a C1-C3 alkyl group.

3. The compound according to claim 1, which is a compound of formula (Ic) in X, Y, R 1 、R 2 and R 3 As defined in claim 1.

4. A compound according to any one of claims 1 to 3, wherein X is O; Y is N; When valence permits, It is a combination of single and double bonds; R 1 yes Where Z is CH2; R 5 It is hydrogen; R 3 yes They may each be optionally substituted by -C1-C6 alkyl, -O-C1-C6 alkyl, -Hal or -C1-C6 alkyl-OH, and R 4 Independently selected from hydrogen and C1-C6 alkyl.

5. A compound according to claim 1, selected from or a stereoisomer, racemic mixture, or pharmaceutically acceptable salt thereof.

6. Compound of formula (II') or a stereoisomer, racemic mixture, or pharmaceutically acceptable salt thereof, in W is independently selected from O and S; m is 1; R 0 is H or C1-C3 alkyl; R 6 yes in Z 1 are independently selected from CH2 and O, provided that no more than two Z 1 It is O; R 9 independently selected from hydrogen and halogen; R 8 independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl; and R 7 yes They may each be optionally substituted by -C1-C6 alkyl, -O-C1-C6 alkyl, -Hal or -C1-C6 alkyl-OH, and R 4 Independently selected from hydrogen and C1-C6 alkyl.

7. The compound according to claim 6, which is or a stereoisomer, racemic mixture, or pharmaceutically acceptable salt thereof.

8. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 7 or a stereoisomer, racemic mixture, pharmaceutically acceptable salt thereof, and optionally at least one pharmaceutically acceptable carrier, diluent, adjuvant or vehicle.

9. Use of a compound according to any one of claims 1 to 7, or a stereoisomer, racemic mixture, or pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating, alleviating, or preventing a disease, disorder, or abnormality that responds to modulation of NLRP3 inflammasome pathway components and / or to modulation of IL-1β and / or IL-18 levels.

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

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

12. The use according to claim 11, wherein activation of the NLRP3 inflammasome pathway is inhibited.

13. The method of claim 11 or 12, wherein the disease, disorder or abnormality is selected from the group consisting of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, demyelination, viral encephalitis, epilepsy, stroke, atherosclerosis, asthma, allergic inflammation, cryptopyrin-associated periodic syndrome (CAPS), gout, pseudogout, inflammatory bowel disease, non-alcoholic fatty liver disease, hypertension, myocardial infarction, oxalate-induced nephropathy, graft-versus-host disease, type 1 diabetes, type 2 diabetes, rheumatoid arthritis, myelodysplastic syndrome, familial Mediterranean fever (FMF), TNF receptor-associated periodic syndrome (TRAPS). , mevalonate kinase deficiency (MKD), hyperimmunoglobulinemia D, periodic fever syndrome (HIDS), interleukin-1 receptor antagonist deficiency (DIRA), Majeed syndrome, pyogenic arthritis-pyoderma gangrenosum and acne (PAPA), A20 haploinsufficiency (HA20), PLCG2-related antibody deficiency and immune dysregulation (PLAID), pediatric granulomatous arthritis (PGA), PLCG2-related autoinflammatory, antibody deficiency and immune dysregulation (APLAID), sideroblastic anemia with B-cell immunodeficiency, periodic fever, developmental delay (SIFD), chronic nonbacterial bone marrow disease Osteitis nigra (CNO), Sweet's syndrome, chronic recurrent multifocal osteomyelitis (CRMO), synovitis, impetigo, acne, eczema, alopecia areata, actinic keratosis, hyperostosis, inflammatory osteomyelitis syndrome (SAPHO), multiple sclerosis (MS), psoriasis, Behçet's disease, Sjögren's syndrome, Schnitzler syndrome, chronic obstructive pulmonary disease (COPD), asbestosis, silicosis, cystic fibrosis, motor neuron disease, Huntington's disease, cerebral malaria, brain damage due to pneumococcal meningitis, obesity, age-related macular degeneration (AMD), corneal infection, uveitis, dry eye, chronic kidney disease, diabetic nephropathy , alcoholic liver disease, contact allergy, 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, helminthic infection, bacterial infection, abdominal aortic aneurysm, wound healing, depression, psychological stress, pericarditis, ischemia-reperfusion injury, frontotemporal dementia, HIV-related neurocognitive disorders, coronavirus-related inflammatory pathology and traumatic brain injury.

14. The method of claim 11 or 12, wherein the disease, disorder or abnormality is selected from the group consisting of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, demyelination, viral encephalitis, epilepsy, stroke, atherosclerosis, asthma, allergic inflammation, cryptopyrin-associated periodic syndrome (CAPS), gout, inflammatory bowel disease, non-alcoholic fatty liver disease (NAFLD), 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, 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 fevers (HRFs).

15. The use according to claim 11 or 12, wherein the disease, disorder or abnormality is selected from the group consisting of: Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), neonatal-onset multisystem inflammatory disease (NOMID), non-alcoholic steatohepatitis (NASH), steroid-resistant asthma and Dressler's syndrome.

16. The use according to claim 13, wherein the disease, disorder or abnormality is selected from the group consisting of Alzheimer's disease, Parkinson's disease, cryopyrin-associated periodic syndrome (CAPS), non-alcoholic fatty liver disease (NAFLD) and gout.

17. The use according to any one of claims 9 to 12, wherein the disease, disorder or abnormality is a disease, disorder or abnormality of the immune system.

18. The use according to any one of claims 9 to 12, wherein the disease, disorder or abnormality is an inflammatory disease, disorder or abnormality.

19. The use according to any one of claims 9 to 12, wherein the disease, disorder or abnormality is an autoimmune disease, disorder or abnormality.

20. The use according to any one of claims 9 to 12, wherein the disease, disorder or abnormality is a disease, disorder or abnormality of the skin.

21. The use according to claim 20, wherein the disease, disorder or abnormality of the skin is selected from psoriasis, acne, eczema, alopecia areata or actinic keratosis.

22. The use according to any one of claims 9 to 12, wherein the disease, disorder or abnormality is a disease, disorder or abnormality of the cardiovascular system.

23. The use according to any one of claims 9 to 12, wherein the disease, disorder or abnormality is cancer, a tumor or a malignancy.

24. The use according to any one of claims 9 to 12, wherein the disease, disorder or abnormality is a disease, disorder or abnormality of the renal system.

25. The use according to any one of claims 9 to 12, wherein the disease, disorder or abnormality is a disease, disorder or abnormality of the gastrointestinal tract.

26. The use according to any one of claims 9 to 12, wherein the disease, disorder or abnormality is a disease, disorder or abnormality of the respiratory system.

27. The use according to any one of claims 9 to 12, wherein the disease, disorder or abnormality is a disease, disorder or abnormality of the endocrine system.

28. The use of any one of claims 9 to 12, wherein the disease, disorder or abnormality is a disease, disorder or abnormality of the central nervous system (CNS).

29. The use according to any one of claims 9 to 12, wherein the disease, disorder or abnormality is a disease, disorder or abnormality of the liver.

30. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7 or a stereoisomer, racemic mixture, pharmaceutically acceptable salt thereof and at least one additional biologically active compound, and optionally at least one pharmaceutically acceptable carrier, diluent, adjuvant or vehicle.

31. A combination comprising a therapeutically effective amount of a compound according to any one of claims 1 to 7 or a stereoisomer, racemic mixture, pharmaceutically acceptable salt thereof and at least one additional biologically active compound, and optionally at least one pharmaceutically acceptable carrier, diluent, adjuvant or vehicle.

32. Use of a pharmaceutical composition according to claim 30 or a combination product according to claim 31 in the preparation of a medicament for treating, alleviating or preventing a disease, disorder or abnormality responsive to modulation of NLRP3 inflammasome pathway components and / or responsive to modulation of IL-1β and / or IL-18 levels.

33. Use of a compound according to any one of claims 1 to 7 or a stereoisomer, racemic mixture, pharmaceutically acceptable salt thereof as an analytical reference or in vitro screening tool.

Images