Pyrrolotriazine and imidazolotriazine derivatives as NLRP3 inflammasome pathway modulators

Abstract

The present application relates to pyrrolo-triazine and imidazo-triazine derivatives of general formula (I) for use in the treatment, amelioration or prevention of a group of diseases, disorders and abnormalities responsive to modulation of components of the NLRP3 inflammasome pathway or inhibition of activation thereof. Specifically, the component of the inflammasome pathway is an NOD-like receptor (NLR) family, a protein 3 (NLRP3) inflammasome containing a thermal protein domain. More specifically, the compounds have the ability to modulate the NLRP3 inflammasome pathway and are suitable for treating, ameliorating or preventing a group of diseases, disorders and abnormalities responsive to modulation, in particular reduction, of IL-1 beta and / or IL-18 levels, such as Alzheimer's disease, Parkinson's disease, non-alcoholic fatty liver disease and gout. # imgabs0 #

Description

Field of the Invention

[0001] The present invention relates to novel compounds that can be used to treat, reduce or prevent diseases, disorders or abnormalities that respond to the regulation of components of the NLRP3 inflammasome pathway, especially the inhibition of activation. In particular, the components of the inflammasome pathway are NOD-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3) inflammasomes. More particularly, the compounds of the present invention have the ability to regulate, for example, inhibit the activation of the NLRP3 inflammasome pathway. In addition, the compounds of the present invention have the ability to regulate, especially reduce IL-1β and / or IL-18 levels. The present invention relates to novel compounds for treating, reducing or preventing diseases, disorders or abnormalities that respond to the inhibition of NLRP3 inflammasome pathway activation. The present invention relates to novel compounds for treating, reducing or preventing diseases, disorders or abnormalities that respond to the regulation 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 regulation, drugs containing them and their uses. Background of the Invention

[0003] Inflammasome protein complex is the key component of inflammatory signal transduction.These complex assemblies are in response to a variety of danger signals, such as molecules from pathogens (pathogen-associated molecular patterns, PAMPs) and host molecules, sterile tissue damage products and environmental factors (danger associated molecular patterns, DAMPs) of changes.Inflammasome family is composed of NALP1-14, IPAF and NAIP1-6, wherein each family member provides specificity (Sharma, D. & Kanneganti, TD The cell biology of inflammasomes: mechanisms of inflammasome activation and regulation. J. Cell Biol. 213, 617-629 (2016)) to different PAMP / DAMPs (including nucleic acids, bacterial proteins, metabolites, protein aggregates and toxin activity). 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 family members. It is a tripartite protein of the NLR family and contains an amino-terminal PYRIN (PYD) domain, a nucleotide-binding NACHT domain, and a carboxyl-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 apoptosis-associated speck-like proteins containing a caspase activation and recruitment domain (ASC, also known as PYCARD) adaptor protein. The polymerization of ASC proteins into large complexes (ASC specks) leads to the activation of caspase-1 effector proteins, followed by the cleavage of pro-IL1β and pro-IL18 into their active secreted forms, and mediates pyroptosis (Heneka et al., 2018 Nat Rev Neurosci). IL-1β acts through the IL-1β receptor and induces secondary proinflammatory signals including IL-6 and TNF-α secretion, and attracts and activates cells of the adaptive immune system at the site of infection. NLRP3 / ASC complexes appear 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 Muir-Wei syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), and neonatal-onset multisystem inflammatory disease (NOMID).

[0006] 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 amount 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 NLRP3-inflammasomes has shown protective effects in the following models: 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 October; 19(10): 610-621; Mangan et al., Nat Rev Drug Discov. 2018 August; 17(8): 588-606).

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

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

[0010] Several small molecules have been shown to inhibit the NLRP3 inflammasome pathway (Baldwin, AG, Brough, D. & Freeman, S. Inhibition of 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 (aka CRID3 and MCC950) and their derivatives); the phenamates of nonsteroidal anti-inflammatory drugs; the hydroxysulfonamide analog JC-171; a series of new 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-keto; and Michael acceptors. Most of these compounds have promiscuous modes of action and limited potency.

[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) which are useful for the treatment and prevention of medical disorders and diseases, most particularly through NLRP3 inhibition.

[0013] WO2017184604, WO2017184623, WO2017184624, WO2019023145, WO2019023147 and WO2019079119 relate to chemical entities for use in treating a condition, disease or disorder, wherein a decrease or increase in NLRP3 activity contributes to the pathology and / or symptoms and / or progression of the condition, disease or disorder in an individual.

[0014] WO2019211463, WO2020021447, and WO2021043966, WO2021239885, WO2021219784, WO2021214284, WO2021209552, and WO2021209539 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 responsive 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 thus useful in methods of treating the human or animal body.

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

[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] WO2020 / 234715 discloses pyridazine-3-ylphenol compounds defined as inhibitors of NOD-like receptor protein 3 (NLRP3) inflammasome activity.

[0022] WO2021 / 193897 relates to substituted pyridazine compounds which are described as having an inhibitory effect on NLRP3 inflammasome activity.

[0023] Recently, the mutual interference between the NLRP3 inflammasome pathway and Tau pathology has been deciphered. Ising et al. (Nature 2019 November; 575(7784): 669-673) investigated the important role of microglia and NLRP3 inflammasome pathway activation in the pathogenesis of tau pathology in the Tau22 mouse model of frontotemporal dementia (FTD). Genetic ablation of components of the NLRP3 inflammasome pathway in Tau22 mice reduced Tau aggregation / phosphorylation and improved cognition. Stancu et al. (Acta Neuropathol. 2019; 137(4): 599-617) studied the role of inflammasome activation in prion-like or templated inoculation of Tau pathology. Significant inhibition of exogenously inoculated Tau pathology was found in ASC-deficient-PS19 Tau transgenic mice. In addition, long-term intracerebral administration of the NLRP3 inhibitor MCC950 has been shown to inhibit exogenously inoculated Tau pathology. Finally, ASC deficiency also reduced non-exogenously seeded Tau pathology in PS19 mice.

[0024] There is a need to identify and develop specific NLRP3 inflammasome pathway inhibitors and / or interleukin activity modulators having beneficial pharmacological and / or physiological and / or physicochemical properties.

[0025] The present invention provides compounds of Formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie), which have surprisingly been found to modulate the activation of components of the NLRP3 inflammasome pathway, in particular to inhibit the activation of components of the NLRP3 inflammasome pathway, such as the NLRP3 inflammasome. Therefore, such compounds are useful for treating diseases, disorders or abnormalities that respond to modulation of components of the NLRP3 inflammasome pathway and / or to modulation of IL-1β and / or IL-18 levels that typically lead to pathological inflammation. SUMMARY OF THE INVENTION

[0027] Thus, the present invention provides compounds that can be used to treat, reduce or prevent diseases, disorders or abnormalities that are responsive to the modulation, particularly inhibition, of components of the NLRP3 inflammasome pathway, or to the modulation, particularly reduction, of IL-1β and / or IL-18 levels.

[0028] Various embodiments of the invention are described herein.

[0029] In one aspect, provided herein is a compound of formula (I)

[0030]

[0031] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof;

[0032] in

[0033] Z 1 and Z 2 are each selected from N and C, wherein if Z 1 is N, then Z 2 is C, and if Z 1 is C, then Z 2 is N;

[0034] V, X and E are each independently selected from N and CR a ;

[0035] At least one of V, X and E is CR a ;

[0036] R a Independently selected from -H, -C 1 -C 3 Alkyl, -CF 3 and halo;

[0037] R 0 Selected from -H, C 1 -C 3 Alkyl and halo;

[0038] R 1 Selected from -CF 3 、-OCF 3 、-OCHF 2 and halo;

[0039] R 2 Selected from -OH, -H and -CF 3 ;

[0040] Y is selected from NH and O; and

[0041] R 3 Selected from

[0042] A 4-, 5- or 6-membered heterocycloalkyl group containing one or two heteroatoms, preferably one heteroatom, wherein the heteroatom is N, which is optionally substituted with one or two substituents independently selected from: C 1 -C 4 Alkyl, halogenated C 1 -C 4 Alkyl, hydroxyl C 1 -C 4Alkyl, -OH and halo;

[0043] A 5- or 6-membered aryl or heteroaryl group, wherein the heteroaryl group contains one or two heteroatoms, wherein the heteroatom is N, which is optionally substituted with one or two substituents independently selected from: C 1 -C 4 Alkyl, hydroxyl C 1 -C 4 Alkyl, halogenated C 1 -C 4 Alkyl, -CN and halo;

[0044] C 3 -C 6 Cycloalkyl, which is optionally substituted by one or two substituents independently selected from the following: 1 -C 4 Alkyl, halogenated C 1 -C 4 Alkyl, hydroxyl C 1 -C 4 Alkyl, -OH and halo; and

[0045] C 1 -C 6 Alkyl, which is substituted by one or two substituents independently selected from the following: -OH, halo, halo 1 -C 4 Alkyl and C 1 -C 4 Alkoxy.

[0046] In a preferred aspect, provided herein is a compound of formula (I')

[0047]

[0048] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof;

[0049] in

[0050] Z 1 is N;

[0051] Z 2 It is C;

[0052] V, X and E are each independently selected from N and CR a ;

[0053] At least one of V, X and E is CR a ;

[0054] R a Independently selected from -H, -C 1-C 3 Alkyl, -CF 3 and halo;

[0055] R 0 Selected from -H, C 1 -C 3 Alkyl and halo;

[0056] R 1 Selected from -CF 3 、-OCF 3 、-OCHF 2 and halo;

[0057] R 2 Selected from -OH, -H and -CF 3 ;

[0058] Y is selected from NH and O;

[0059] R 3 Selected from

[0060] A 4-, 5- or 6-membered heterocycloalkyl group containing one or two heteroatoms, preferably one heteroatom, wherein the heteroatom is N, which is optionally substituted with one or two substituents independently selected from: C 1 -C 4 Alkyl, halogenated C 1 -C 4 Alkyl, hydroxyl C 1 -C 4 Alkyl, -OH and halo;

[0061] A 5- or 6-membered aryl or heteroaryl group, wherein the heteroaryl group contains one or two heteroatoms, wherein the heteroatom is N, which is optionally substituted with one or two substituents independently selected from: C 1 -C 4 Alkyl, hydroxyl C 1 -C 4 Alkyl, halogenated C 1 -C 4 Alkyl, -CN and halo;

[0062] C 3 -C 6 Cycloalkyl, substituted by one or two substituents independently selected from the group consisting of: 1 -C 4 Alkyl, halogenated C 1 -C 4 Alkyl, hydroxyl C 1 -C 4 Alkyl, -OH and halo; and

[0063] C 1 -C 6Alkyl, which is substituted by one or two substituents independently selected from the following: -OH, halo, halo 1 -C 4 Alkyl and C 1 -C 4 Alkoxy.

[0064] In one aspect provided herein is a compound of formula (Ib)

[0065]

[0066] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof;

[0067] in

[0068] E is selected from N and CR a ;

[0069] R a Selected from -H, -C 1 -C 3 Alkyl, -CF 3 and halo;

[0070] R 0 Selected from -H, C 1 -C 3 Alkyl and halo;

[0071] R 1 Selected from -CF 3 、-OCF 3 、-OCHF 2 and halo;

[0072] R 2 Selected from -OH, -H and -CF 3 ;

[0073] Y is selected from NH and O; and

[0074] R 3 Selected from

[0075] A 4-, 5- or 6-membered heterocycloalkyl group containing one or two heteroatoms, preferably one heteroatom, wherein the heteroatom is N, which is optionally substituted with one or two substituents independently selected from: C 1 -C 4 Alkyl, halogenated C 1 -C 4 Alkyl, hydroxyl C 1 -C 4 Alkyl, -OH and halo;

[0076] A 5- or 6-membered aryl or heteroaryl group, wherein the heteroaryl group contains one or two heteroatoms, wherein the heteroatom is N, which is optionally substituted with one or two substituents independently selected from: C 1 -C 4 Alkyl, hydroxyl C 1 -C 4 Alkyl, halogenated C 1 -C 4 Alkyl, -CN and halo;

[0077] C 3 -C 6 Cycloalkyl, which is optionally substituted by one or two substituents independently selected from the following: 1 -C 4 Alkyl, halogenated C 1 -C 4 Alkyl, hydroxyl C 1 -C 4 Alkyl, -OH and halo; and

[0078] C 1 -C 6 Alkyl, which is substituted by one or two substituents independently selected from the following: -OH, halo, halo 1 -C 4 Alkyl and C 1 -C 4 Alkoxy.

[0079] In another aspect provided herein is a compound of formula (Ic)

[0080]

[0081] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof;

[0082] in

[0083] E is selected from N and CR a ;

[0084] R a Selected from -H, -C 1 -C 3 Alkyl, -CF 3 and halo;

[0085] R 0 Selected from -H, C 1 -C 3 Alkyl and halo;

[0086] R 1 Selected from -CF 3 、-OCF3 、-OCHF 2 and halo;

[0087] R 2 Selected from -OH, -H and -CF 3 ;

[0088] Y is selected from NH and O; and

[0089] R 3 Selected from

[0090] A 4-, 5- or 6-membered heterocycloalkyl group containing one or two heteroatoms, preferably one heteroatom, wherein the heteroatom is N, which is optionally substituted with one or two substituents independently selected from: C 1 -C 4 Alkyl, halogenated C 1 -C 4 Alkyl, hydroxyl C 1 -C 4 Alkyl, -OH and halo;

[0091] A 5- or 6-membered aryl or heteroaryl group, wherein the heteroaryl group contains one or two heteroatoms, wherein the heteroatom is N, which is optionally substituted with one or two substituents independently selected from: C 1 -C 4 Alkyl, hydroxyl C 1 -C 4 Alkyl, halogenated C 1 -C 4 Alkyl, -CN and halo;

[0092] C 3 -C 6 Cycloalkyl, which is optionally substituted by one or two substituents independently selected from the following: 1 -C 4 Alkyl, halogenated C 1 -C 4 Alkyl, hydroxyl C 1 -C 4 Alkyl, -OH and halo; and

[0093] C 1 -C 6 Alkyl, which is substituted by one or two substituents independently selected from the following: -OH, halo, halo 1 -C 4 Alkyl and C 1 -C 4 Alkoxy.

[0094] In another aspect provided herein is a compound of formula (Ie)

[0095]

[0096] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof;

[0097] in

[0098] X is selected from N and CR a ;

[0099] R a Selected from -C 1 -C 3 Alkyl, -CF 3 and halo;

[0100] R 0 Selected from -H, C 1 -C 3 Alkyl and halo;

[0101] R 1 Selected from -CF 3 、-OCF 3 、-OCHF 2 and halo;

[0102] R 2 Selected from -OH, -H and -CF 3 ;

[0103] Y is selected from NH and O; and

[0104] R 3 Selected from

[0105] A 4-, 5- or 6-membered heterocycloalkyl group containing one or two heteroatoms, preferably one heteroatom, wherein the heteroatom is N, which is optionally substituted with one or two substituents independently selected from: C 1 -C 4 Alkyl, halogenated C 1 -C 4 Alkyl, hydroxyl C 1 -C 4 Alkyl, -OH and halo;

[0106] A 5- or 6-membered aryl or heteroaryl group, wherein the heteroaryl group contains one or two heteroatoms, wherein the heteroatom is N, which is optionally substituted with one or two substituents independently selected from: C 1 -C 4 Alkyl, hydroxyl C 1 -C 4 Alkyl, halogenated C 1 -C 4 Alkyl, -CN and halo;

[0107] C 3 -C 6 Cycloalkyl, which is optionally substituted by one or two substituents independently selected from the following: 1 -C 4 Alkyl, halogenated C 1 -C 4 Alkyl, hydroxyl C 1 -C 4 Alkyl, -OH and halo; and

[0108] C 1 -C 6 Alkyl, which is substituted by one or two substituents independently selected from the following: -OH, halo, halo 1 -C 4 Alkyl and C 1 -C 4 Alkoxy.

[0109] In one aspect provided herein is a compound of formula (Ia)

[0110]

[0111] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof;

[0112] in

[0113] E is selected from N and CR a ;

[0114] R a Selected from -H, -C 1 -C 3 Alkyl and -CF 3 ;

[0115] R 0 Selected from -H, C 1 -C 3 Alkyl and halo;

[0116] R 1 Selected from -CF 3 、-OCF 3 、-OCHF 2 and halo;

[0117] R 2 Selected from -OH, -H and -CF 3 ;

[0118] Y is selected from NH and O; and

[0119] R 3 Selected from

[0120] A 4-, 5- or 6-membered heterocycloalkyl group containing one or two heteroatoms, preferably one heteroatom, wherein the heteroatom is N, which is optionally substituted with one or two substituents independently selected from: C 1 -C 4 Alkyl, halogenated C 1 -C 4 Alkyl, hydroxyl C 1 -C 4 Alkyl, -OH and halo;

[0121] A 5- or 6-membered aryl or heteroaryl group, wherein the heteroaryl group contains one or two heteroatoms, wherein the heteroatom is N, which is optionally substituted with one or two substituents independently selected from: C 1 -C 4 Alkyl, hydroxyl C 1 -C 4 Alkyl, halogenated C 1 -C 4 Alkyl, -CN and halo;

[0122] C 3 -C 6 Cycloalkyl, which is optionally substituted by one or two substituents independently selected from the following: 1 -C 4 Alkyl, halogenated C 1 -C 4 Alkyl, hydroxyl C 1 -C 4 Alkyl, -OH and halo; and

[0123] C 1 -C 6 Alkyl, which is substituted by one or two substituents independently selected from the following: -OH, halo, halo 1 -C 4 Alkyl and C 1 -C 4 Alkoxy.

[0124] In another aspect provided herein is a compound of formula (Id)

[0125]

[0126] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof;

[0127] in

[0128] X is selected from N and CR a ;

[0129] R a Selected from -H, -C1 -C 3 Alkyl, -CF 3 and halo;

[0130] R 0 Selected from -H, C 1 -C 3 Alkyl and halo;

[0131] R 1 Selected from -CF 3 、-OCF 3 、-OCHF 2 and halo;

[0132] R 2 Selected from -OH, -H and -CF 3 ;

[0133] Y is selected from NH and O; and

[0134] R 3 Selected from

[0135] A 4-, 5- or 6-membered heterocycloalkyl group containing one or two heteroatoms, preferably one heteroatom, wherein the heteroatom is N, which is optionally substituted with one or two substituents independently selected from: C 1 -C 4 Alkyl, halogenated C 1 -C 4 Alkyl, hydroxyl C 1 -C 4 Alkyl, -OH and halo;

[0136] A 5- or 6-membered aryl or heteroaryl group, wherein the heteroaryl group contains one or two heteroatoms, wherein the heteroatom is N, which is optionally substituted with one or two substituents independently selected from: C 1 -C 4 Alkyl, hydroxyl C 1 -C 4 Alkyl, halogenated C 1 -C 4 Alkyl, -CN and halo;

[0137] C 3 -C 6 Cycloalkyl, which is optionally substituted by one or two substituents independently selected from the following: 1 -C 4 Alkyl, halogenated C 1 -C 4 Alkyl, hydroxyl C 1 -C 4 Alkyl, -OH and halo; and

[0138] C 1-C 6 Alkyl, which is substituted by one or two substituents independently selected from the following: -OH, halo, halo 1 -C 4 Alkyl and C 1 -C 4 Alkoxy.

[0139] In the present invention, any reference to a compound of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie) or a preferred embodiment thereof is also meant to refer to its stereoisomers, or racemic mixtures, or tautomers, or polymorphs, or pharmaceutically acceptable salts, or prodrugs, or hydrates, or solvates.

[0140] The compounds of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie) 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 modulation, particularly inhibition, of components of the NLRP3 inflammasome pathway and / or to the modulation, particularly reduction, of IL-1β and / or IL-18 levels. Specifically, the component of the inflammasome pathway is the NLRP3 inflammasome. Activation of the NLRP3 inflammasome pathway can trigger the formation of ASC spots, cleavage and activation of caspase-1 and caspase-8, followed by activation and release of IL-1β, IL-18, gasedermin D cleavage and pore formation, pyroptosis and release of IL-1α, IL-33, IL-17 and high mobility group box (HMGB) proteins. The compounds of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie) or their stereoisomers, racemic mixtures, tautomers, polymorphs, pharmaceutically acceptable salts, prodrugs, hydrates or solvates have the ability to modulate, in particular reduce, the levels of IL-1β and / or IL-18.

[0141] The compounds of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie) or their stereoisomers, racemic mixtures, tautomers, polymorphs, pharmaceutically acceptable salts, prodrugs, hydrates or solvates exhibit a high ability to modulate NLRP3 inflammasome pathway components, particularly to inhibit activation of NLRP3 inflammasome pathway components, particularly wherein the inflammasome pathway component is NLRP3 inflammasome. Due to their unique design features, these compounds exhibit properties such as modulating the NLRP3 inflammasome pathway or inhibiting activation of the NLRP3 inflammasome pathway, making them successful drugs for treating, alleviating or preventing diseases, disorders and abnormalities that respond to modulation or inhibition of NLRP3 inflammasome pathway components, for example, Alzheimer's disease, Parkinson's disease, CAPS, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH) and gout.

[0142] In another embodiment, the present invention is directed to a pharmaceutical composition comprising a compound of Formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie) 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.

[0143] In another embodiment, the present invention is directed to a compound of Formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie) or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof for use as a medicament.

[0144] In another embodiment, the present invention relates to a compound of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie) or its stereoisomers, racemic mixtures, tautomers, polymorphs, pharmaceutically acceptable salts, prodrugs, hydrates or solvates for use in treating, alleviating or preventing diseases, disorders or abnormalities that respond to the modulation of components of the NLRP3 inflammasome pathway, particularly the inhibition of activation and / or the modulation of IL-1β and / or IL-18 levels, particularly the reduction.

[0145] Another embodiment relates to the use of a compound of Formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie) 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 the modulation of components of the NLRP3 inflammasome pathway, particularly inhibition of activation, and / or to the modulation of IL-1β and / or IL-18 levels, particularly reduction.

[0146] In 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 components of the NLRP3 inflammasome pathway, particularly the inhibition of activation, or to the modulation of IL-1β and / or IL-18 levels, particularly the reduction, the method comprising administering to an individual in need thereof (e.g., a patient) a therapeutically effective amount of a compound of Formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie) or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof.

[0147] The present invention also relates to pharmaceutical compositions comprising a compound of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie), 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 a compound of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie), or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, optionally comprising at least one pharmaceutically acceptable carrier, diluent, adjuvant or excipient.

[0148] In particular, the additional biologically active compound may be one that is used to treat a disease, disorder or abnormality associated with a disease that targets a different pathological mechanism, such as an anti-amyloid β antibody, an anti-Tau antibody, an amyloid β 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 invention is used in combination with an additional biologically active compound, the dosage of each compound may differ from that when the compound is used as a monotherapy.

[0149] Additional embodiments relate to the use of a compound of Formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie) or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof as an analytical reference or in vitro screening tool.

[0150] The present invention is described below. BRIEF DESCRIPTION OF THE DRAWINGS

[0152] Figure 1 Inhibition of IL-1β release by compounds of the present invention in LPS / ATP-induced acute peritonitis mouse model DETAILED DESCRIPTION OF THE INVENTION

[0154] The present invention relates to compounds of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie), including stereoisomers, racemic mixtures, tautomers, polymorphs, pharmaceutically acceptable salts, prodrugs, hydrates or solvates thereof.

[0155] With respect to compounds of formula (I), R 0 , R 1 , R 2、 R 3 , R a Any definitions of , E, V, X and Y apply analogously to compounds of formula (I'), (Ia), (Ib), (Ic), (Id) and (Ie), provided that R 0 , R 1 , R 2、 R 3 , R a , E, V, X and / or Y are used.

[0156] The present invention relates to compounds of formula (I') as defined below

[0157]

[0158] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof;

[0159] in

[0160] Z 1 is N;

[0161] Z 2 It is C;

[0162] V, X and E are each independently selected from N and CR a ;

[0163] At least one of V, X and E is CRa ;

[0164] R a Independently selected from -H, -C 1 -C 3 Alkyl, -CF 3 and halo;

[0165] R 0 Selected from -H, C 1 -C 3 Alkyl and halo;

[0166] R 1 Selected from -CF 3 、-OCF 3 、-OCHF 2 and halo;

[0167] R 2 Selected from -OH, -H and -CF 3 ;

[0168] Y is selected from NH and O;

[0169] R 3 Selected from

[0170] A 4-, 5- or 6-membered heterocycloalkyl group containing one or two heteroatoms, preferably one heteroatom, wherein the heteroatom is N, which is optionally substituted with one or two substituents independently selected from: C 1 -C 4 Alkyl, halogenated C 1 -C 4 Alkyl, hydroxyl C 1 -C 4 Alkyl, -OH and halo;

[0171] A 5- or 6-membered aryl or heteroaryl group, wherein the heteroaryl group contains one or two heteroatoms, wherein the heteroatom is N, which is optionally substituted with one or two substituents independently selected from: C 1 -C 4 Alkyl, hydroxyl C 1 -C 4 Alkyl, halogenated C 1 -C 4 Alkyl, -CN and halo;

[0172] C 3 -C 6 Cycloalkyl, which is optionally substituted by one or two substituents independently selected from the following: 1 -C 4 Alkyl, halogenated C 1 -C 4 Alkyl, hydroxyl C 1 -C4 Alkyl, -OH and halo; and

[0173] C 1 -C 6 Alkyl, which is substituted by one or two substituents independently selected from the following: -OH, halo, halo 1 -C 4 Alkyl and C 1 -C 4 Alkoxy.

[0174] The present invention relates to compounds of formula (I) as defined below

[0175]

[0176] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof;

[0177] in

[0178] Z 1 and Z 2 are each selected from N and C, wherein if Z 1 is N, then Z 2 is C, and if Z 1 is C, then Z 2 is N;

[0179] V, X and E are each independently selected from N and CR a ;

[0180] At least one of V, X and E is CR a ;

[0181] R a Selected from -H, -C 1 -C 3 Alkyl, -CF 3 and halo;

[0182] R 0 Selected from -H, C 1 -C 3 Alkyl and halo;

[0183] R 1 Selected from -CF 3 、-OCF 3 、-OCHF 2 and halo;

[0184] R 2 Selected from -OH, -H and -CF 3 ;

[0185] Y is selected from NH and O; and

[0186] R 3 Selected from

[0187] A 4-, 5- or 6-membered heterocycloalkyl group containing one or two heteroatoms, preferably one heteroatom, wherein the heteroatom is N, which is optionally substituted with one or two substituents independently selected from: C 1 -C 4 Alkyl, halogenated C 1 -C 4 Alkyl, hydroxyl C 1 -C 4 Alkyl, -OH and halo;

[0188] A 5- or 6-membered aryl or heteroaryl group, wherein the heteroaryl group contains one or two heteroatoms, wherein the heteroatom is N, which is optionally substituted with one or two substituents independently selected from: C 1 -C 4 Alkyl, hydroxyl C 1 -C 4 Alkyl, halogenated C 1 -C 4 Alkyl, -CN and halo;

[0189] C 3 -C 6 Cycloalkyl, which is optionally substituted by one or two substituents independently selected from the following: 1 -C 4 Alkyl, halogenated C 1 -C 4 Alkyl, hydroxyl C 1 -C 4 Alkyl, -OH and halo; and C 1 -C 6 Alkyl, which is substituted by one or two substituents independently selected from the following: -OH, halo, halo 1 -C 4 Alkyl and C 1 -C 4 Alkoxy.

[0190] In a preferred embodiment, R 0 Selected from -H and C 1 -C 3 In a preferred embodiment, R 0 In another preferred embodiment, R 0 It is C 1 -C 3 Alkyl group, preferably methyl or ethyl group, more preferably methyl group.

[0191] In a preferred embodiment, R 1Selected from -CF 3 、-OCF 3 and-OCHF 2 In a preferred embodiment, R 1 Yes - CF 3 In another preferred embodiment, R 1 Yes - OCF 3 In another preferred embodiment, R 1 Yes - OCHF 2 .

[0192] In another embodiment, R 1 is a halogenated group. 1 is a halo group, wherein the halogen (halo group) is preferably chlorine.

[0193] In a preferred embodiment, R 2 is -OH or H, more preferably -OH. In another embodiment, R 2 is -H. In another embodiment, R 2 Yes - CF 3 .

[0194] In a preferred embodiment, R 0 Yes - H, R 1 Selected from -CF 3 、-OCF 3 and-OCHF 2 , and R 2 In a preferred embodiment, R 0 Yes - H, R 1 Yes - CF 3 , and R 2 It is -OH.

[0195] In a preferred embodiment, R 3 Selected from

[0196] A 4-, 5- or 6-membered heterocycloalkyl group containing one or two heteroatoms, preferably one heteroatom, wherein the heteroatom is N, which is optionally substituted with one or two substituents independently selected from: C 1 -C 4 Alkyl, halogenated C 1 -C 4 Alkyl, hydroxyl C 1 -C 4 Alkyl, -OH and halo;

[0197] 6-membered aryl or heteroaryl, wherein the heteroaryl contains one or two heteroatoms, wherein the heteroatom is N, which is optionally substituted with one or two substituents independently selected from: C 1-C 4 Alkyl, hydroxyl C 1 -C 4 Alkyl, halogenated C 1 -C 4 Alkyl, -CN and halo;

[0198] C 3 -C 6 Cycloalkyl, which is optionally substituted by one or two substituents independently selected from the following: 1 -C 4 Alkyl, halogenated C 1 -C 4 Alkyl, hydroxyl C 1 -C 4 Alkyl, -OH and halo; and

[0199] C 1 -C 6 Alkyl, which is substituted by one or two substituents independently selected from the following: -OH, halo, halo 1 -C 4 Alkyl and C 1 -C 4 Alkoxy.

[0200] R 3 Selected from

[0201]

[0202] Where R 4 Independently selected from -H or -C 1 -C 3 alkyl; and

[0203] n is selected from 0, 1 or 2.

[0204] Preferably, R 3 Selected from

[0205]

[0206] Where R 4 Independently selected from -H or -C 1 -C 3 alkyl; and

[0207] n is selected from 0, 1 or 2.

[0208] In a preferred embodiment, R 3 is selected from 5- or 6-membered heterocycloalkyl groups containing one or two heteroatoms, preferably one heteroatom, wherein the heteroatom is N. In a preferred embodiment, R 3is a 6-membered heterocycloalkyl group containing one heteroatom, wherein the heteroatom is N. The 5- or 6-membered heterocycloalkyl group may be substituted by one or two substituents independently selected from the following: 1 -C 4 Alkyl, halogenated C 1 -C 4 Alkyl, hydroxyl C 1 -C 4 The substituents may be at any possible position on the heterocyclic group.

[0209] In a preferred embodiment, R 3 yes Where R 4 Independently selected from -H or C 1 -C 3 In a preferred embodiment, R 4 is H. In another embodiment, R 4 It is C 1 -C 3 In a preferred embodiment, R 4 It's methyl.

[0210] In a preferred embodiment, R 3 yes Where R 4 Independently selected from -H or C 1 -C 3 In a preferred embodiment, R 4 is H. In another embodiment, R 4 It is C 1 -C 3 In a preferred embodiment, R 4 It's methyl.

[0211] In another preferred embodiment, R 3 yes Where R 4 Independently selected from -H or C 1 -C 3 In a preferred embodiment, R 4 is H. In another embodiment, R 4 It is C 1 -C 3 In a preferred embodiment, R 4 is a methyl group, where R 3 yes

[0212] In another preferred embodiment, R 3 yes

[0213] In another embodiment, R 3 is selected from 6-membered aryl or heteroaryl, wherein the heteroaryl contains one or two heteroatoms, wherein the heteroatom is N. The 6-membered aryl or heteroaryl may be substituted by one or two substituents independently selected from the following: 1 -C 4 Alkyl, hydroxyl C 1 -C 4 Alkyl, halogenated C 1 -C 4 The substituents may be at any possible position on the aryl or heteroaryl group.

[0214] In one embodiment, R 3 is a 6-membered heteroaryl group having two N heteroatoms. The 6-membered heteroaryl group may be substituted by one or two substituents independently selected from the following: 1 -C 4 Alkyl, hydroxyl C 1 -C 4 Alkyl, halogenated C 1 -C 4 In one embodiment, R 3 Selected from

[0215]

[0216] In another embodiment, R 3 It is C 3 -C 6 Cycloalkyl, preferably cyclopropyl or cyclobutyl. 3 -C 6 The cycloalkyl group may be substituted with one or two substituents independently selected from the group consisting of: 1 -C 4 Alkyl, halogenated C 1 -C 4 Alkyl, hydroxyl C 1 -C 4 The substituents may be at any possible position on the cycloalkyl group.

[0217] In a preferred embodiment, R 3 yes Where R 4 Independently selected from -H or C 1 -C 3 In a preferred embodiment, R 4is H. In another embodiment, R 4 It is C 1 -C 3 In a preferred embodiment, R 4 In a preferred embodiment, R 3 yes In another preferred embodiment, R 3 yes

[0218] In another preferred embodiment, R 3 It is C 1 -C 6 Alkyl, preferably C 1 -C 3 The alkyl group may be substituted with one or two substituents independently selected from the following: -OH, halo, halo-C 1 -C 4 Alkyl and C 1 -C 4 In a preferred embodiment, R 3 It is hydroxyl C 1 -C 6 Alkyl (i.e. C substituted by -OH) 1 -C 6 Alkyl), more preferably hydroxyl C 1 -C 3 Alkyl, preferably hydroxyethyl.

[0219] In a preferred embodiment, R 3 yes wherein n is 0, 1 or 2. In another preferred embodiment, R 3 yes Where n is 0, 1 or 2.

[0220] In some embodiments, one of V, X, and E is CR a , where R a As defined above. In a preferred embodiment, two of V, X and E are CR a , where R a As defined above. In another preferred embodiment, V, X and E are each CR a , where R a As defined above.

[0221] In a preferred embodiment, X is CR a , where R a Selected from H and -C 1 -C 3In a preferred embodiment, X is CH.

[0222] In a preferred embodiment, Z 1 is N. In a preferred embodiment, Z 1 is N and V is CH, and X and E are independently selected from N and CR a , where R a As defined above.

[0223] In another preferred embodiment, Z 1 is N, and V, X, and E are all CR a , where R a As defined above. In some preferred embodiments, Z 1 is N, and at least two of V, X, and E are CR a , where R a As defined above. In a preferred embodiment, Z 1 is N, and V, X and E are all CH.

[0224] In another preferred embodiment, Z 1 is N, E is N, and V and X are each CR a , where R a As defined above. In one embodiment, Z 1 is N, E is N, and V and X are both CH. In another preferred embodiment, Z 1 is N, V ​​is N, and E and X are each CR a , where R a As defined above. In one embodiment, Z 1 is N, V ​​is N, and E and X are both CH. In another embodiment, Z 1 is N, X is N, and V and E are each CR a , where R a As defined above. In another embodiment, Z 1 is N, X is N, and V and E are both CH.

[0225] In a preferred embodiment, Z 1 is N and Z 2 It is C.

[0226] In a more preferred embodiment:

[0227] Z 1 is N, V ​​is N, X and E are CR a , and Z 2 is C; or

[0228] Z 1is N, V, X, E are CR a , and Z 2 is C; or

[0229] Z 1 is N, E is N, X and V are CR a , and Z 2 It is C.

[0230] In other aspects, Z 2 is N. In one embodiment, Z 2 is N, E is CH, and V and X are independently selected from N and CR a , where R a In one embodiment, Z 2 is N, and V, X, and E are all CR a , where R a As defined above. In some embodiments, Z 2 is N, and at least two of V, X, and E are CR a , where R a As defined above. In one embodiment, Z 2 is N, and V, X and E are all CH. In another embodiment, Z 2 is N, E is N, and V and X are each CR a , where R a As defined above. In one embodiment, Z 2 is N, E is N, and V and X are both CH. In another embodiment, Z 2 is N, V ​​is N, and E and X are each CR a , where R a As defined above. In one embodiment, Z 2 is N, V ​​is N, and E and X are both CH. In another embodiment, Z 2 is N, X is N, and V and E are each CR a , where R a As defined above. In another embodiment, Z 2 is N, X is N, and V and E are both CH.

[0231] In one embodiment provided herein is a compound of formula (I) having the structure of formula (Ia):

[0232]

[0233] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof;

[0234] in

[0235] E is selected from N and CR a ; R a Selected from -H, -C 1 -C 3 Alkyl and -CF 3 , and R 0 , R 1 , R 2、 R 3 , and Y is as defined in any of the above embodiments.

[0236] In a preferred embodiment of the compounds of formula (Ia), E is N. In another preferred embodiment of the compounds of formula (Ia), E is CR a , where R a As defined above. In a preferred embodiment of the compounds of formula (Ia), E is CH.

[0237] In a preferred embodiment, R 0 Selected from -H and C 1 -C 3 In a preferred embodiment, R 0 In another preferred embodiment, R 0 It is C 1 -C 3 Alkyl group, preferably methyl or ethyl group, more preferably methyl group.

[0238] In a preferred embodiment, R 1 Selected from -CF 3 、-OCF 3 and-OCHF 2 In a preferred embodiment, R 1 Yes - CF 3 In another preferred embodiment, R 1 Yes - OCF 3 In another preferred embodiment, R 1 Yes - OCHF 2 .

[0239] In another embodiment, R 1 is a halogenated group. 1 When it is a halo group, the halogen (halo group) is preferably chlorine.

[0240] In a preferred embodiment, R 2 In another embodiment, R 2 is -H. In another embodiment, R 2 Yes - CF 3 .

[0241] In a preferred embodiment, R 0 Yes - H, R 1 Selected from -CF 3 、-OCF 3 and-OCHF 2 , and R 2 In a preferred embodiment, R 0 Yes - H, R 1 Yes - CF 3 , and R 2 It is -OH.

[0242] In a preferred embodiment, R 3 Independently selected from

[0243] A 4-, 5- or 6-membered heterocycloalkyl group containing one or two heteroatoms, preferably one heteroatom, wherein the heteroatom is N, which is optionally substituted with one or two substituents independently selected from: C 1 -C 4 Alkyl, halogenated C 1 -C 4 Alkyl, hydroxyl C 1 -C 4 Alkyl, -OH and halo;

[0244] 6-membered aryl or heteroaryl, wherein the heteroaryl contains one or two heteroatoms, wherein the heteroatom is N, which is optionally substituted with one or two substituents independently selected from: C 1 -C 4 Alkyl, hydroxyl C 1 -C 4 Alkyl, halogenated C 1 -C 4 Alkyl, -CN and halo;

[0245] C 3 -C 6 Cycloalkyl, which is optionally substituted by one or two substituents independently selected from the following: 1 -C 4 Alkyl, halogenated C 1 -C 4 Alkyl, hydroxyl C 1 -C 4 Alkyl, -OH and halo; and

[0246] C 1 -C 6 Alkyl, which is substituted by one or two substituents independently selected from the following: -OH, halo, halo 1 -C 4 Alkyl and C 1 -C4 Alkoxy.

[0247] In a preferred embodiment, R 3 is selected from 5- or 6-membered heterocycloalkyl groups containing one or two heteroatoms, preferably one heteroatom, wherein the heteroatom is N. In a preferred embodiment, R 3 is a 6-membered heterocycloalkyl group containing one heteroatom, wherein the heteroatom is N. The 5- or 6-membered heterocycloalkyl group may be substituted by one or two substituents independently selected from the following: 1 -C 4 Alkyl, halogenated C 1 -C 4 Alkyl, hydroxyl C 1 -C 4 The substituents may be at any possible position on the heterocyclic group.

[0248] In a preferred embodiment, R 3 yes Where R 4 Independently selected from -H or C 1 -C 3 In a preferred embodiment, R 4 is H. In another embodiment, R 4 It is C 1 -C 3 In a preferred embodiment, R 4 It's methyl.

[0249] In a preferred embodiment, R 3 yes Where R 4 Independently selected from -H or C 1 -C 3 In a preferred embodiment, R 4 is H. In another embodiment, R 4 It is C 1 -C 3 In a preferred embodiment, R 4 It's methyl.

[0250] In another preferred embodiment, R 3 yes

[0251] In another preferred embodiment, R 3 yes Where R 4 Independently selected from -H or C 1 -C3 In a preferred embodiment, R 4 is H. In another embodiment, R 4 It is C 1 -C 3 In a preferred embodiment, R 4 is a methyl group, where R 3 yes In another embodiment, R 3 is selected from 6-membered aryl or heteroaryl, wherein the heteroaryl contains one or two heteroatoms, wherein the heteroatom is N. The 6-membered aryl or heteroaryl may be substituted by one or two substituents independently selected from the following: 1 -C 4 Alkyl, hydroxyl C 1 -C 4 Alkyl, halogenated C 1 -C 4 The substituents may be at any possible position on the aryl or heteroaryl group.

[0252] In one embodiment, R 3 is a 6-membered heteroaryl group having two N heteroatoms. The 6-membered heteroaryl group may be substituted by one or two substituents independently selected from the following: 1 -C 4 Alkyl, hydroxyl C 1 -C 4 Alkyl, halogenated C 1 -C 4 In one embodiment, R 3 Selected from

[0253]

[0254] In another embodiment, R 3 It is C 3 -C 6 Cycloalkyl, preferably cyclopropyl or cyclobutyl. 3 -C 6 The cycloalkyl group may be substituted with one or two substituents independently selected from the group consisting of: 1 -C 4 Alkyl, halogenated C 1 -C 4 Alkyl, hydroxyl C 1 -C 4 The substituents may be at any possible position on the cycloalkyl group.

[0255] In a preferred embodiment, R 3yes Where R 4 Independently selected from -H or C 1 -C 3 In a preferred embodiment, R 4 is H. In another embodiment, R 4 It is C 1 -C 3 In a preferred embodiment, R 4 In a preferred embodiment, R 3 yes In another preferred embodiment, R 3 yes

[0256] In another preferred embodiment, R 3 It is C 1 -C 6 Alkyl, preferably C 1 -C 3 The alkyl group may be substituted with one or two substituents independently selected from the following: -OH, halo, halo-C 1 -C 4 Alkyl and C 1 -C 4 In a preferred embodiment, R 3 It is hydroxyl C 1 -C 6 Alkyl (i.e. C substituted by -OH) 1 -C 6 Alkyl), more preferably hydroxyl C 1 -C 3 Alkyl, preferably hydroxyethyl.

[0257] In a preferred embodiment, R 3 yes wherein n is 0, 1 or 2. In another preferred embodiment, R 3 yes Where n is 0, 1 or 2.

[0258] In a preferred embodiment, a compound of formula (I) or (I') is provided, which has the structure of formula (Ib)

[0259]

[0260] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof;

[0261] Where R a, R 0 , R 1 , R 2、 R 3 , E and Y are as defined in any of the above embodiments.

[0262] In a preferred embodiment of the compound of formula (Ib), E is N. In another preferred embodiment of the compound of formula (Ib), E is CR a , where R a As defined above. In a preferred embodiment of the compounds of formula (Ib), E is CH.

[0263] In a preferred embodiment, R 0 Selected from -H and C 1 -C 3 In a preferred embodiment, R 0 In another preferred embodiment, R 0 It is C 1 -C 3 Alkyl group, preferably methyl or ethyl group, more preferably methyl group.

[0264] In a preferred embodiment, R 1 Selected from -CF 3 、-OCF 3 and-OCHF 2 In a preferred embodiment, R 1 Yes - CF 3 In another preferred embodiment, R 1 Yes - OCF 3 In another preferred embodiment, R 1 Yes - OCHF 2 .

[0265] In another embodiment, R 1 is a halogenated group. 1 When it is a halo group, the halogen (halo group) is preferably chlorine.

[0266] In a preferred embodiment, R 2 In another embodiment, R 2 is -H. In another embodiment, R 2 Yes - CF 3 .

[0267] In a preferred embodiment, R 0 Yes - H, R 1 Selected from -CF 3 、-OCF 3 and-OCHF 2, and R 2 In a preferred embodiment, R 0 Yes - H, R 1 Yes - CF 3 , and R 2 It is -OH.

[0268] In a preferred embodiment, R 3 Independently selected from

[0269] A 4-, 5- or 6-membered heterocycloalkyl group containing one or two heteroatoms, preferably one heteroatom, wherein the heteroatom is N, which is optionally substituted with one or two substituents independently selected from: C 1 -C 4 Alkyl, halogenated C 1 -C 4 Alkyl, hydroxyl C 1 -C 4 Alkyl, -OH and halo;

[0270] 6-membered aryl or heteroaryl, wherein the heteroaryl contains one or two heteroatoms, wherein the heteroatom is N, which is optionally substituted with one or two substituents independently selected from: C 1 -C 4 Alkyl, hydroxyl C 1 -C 4 Alkyl, halogenated C 1 -C 4 Alkyl, -CN and halo;

[0271] C 3 -C 6 Cycloalkyl, which is optionally substituted by one or two substituents independently selected from the following: 1 -C 4 Alkyl, halogenated C 1 -C 4 Alkyl, hydroxyl C 1 -C 4 Alkyl, -OH and halo; and

[0272] C 1 -C 6 Alkyl, which is substituted by one or two substituents independently selected from the following: -OH, halo, halo 1 -C 4 Alkyl and C 1 -C 4 Alkoxy.

[0273] In a preferred embodiment, R 3is selected from 5- or 6-membered heterocycloalkyl groups containing one or two heteroatoms, preferably one heteroatom, wherein the heteroatom is N. In a preferred embodiment, R 3 is a 6-membered heterocycloalkyl group containing one heteroatom, wherein the heteroatom is N. The 5- or 6-membered heterocycloalkyl group may be substituted by one or two substituents independently selected from the following: 1 -C 4 Alkyl, halogenated C 1 -C 4 Alkyl, hydroxyl C 1 -C 4 The substituents may be at any possible position on the heterocyclic group.

[0274] In a preferred embodiment, R 3 yes Where R 4 Independently selected from -H or C 1 -C 3 In a preferred embodiment, R 4 is H. In another embodiment, R 4 It is C 1 -C 3 In a preferred embodiment, R 4 It's methyl.

[0275] In a preferred embodiment, R 3 yes Where R 4 Independently selected from -H or C 1 -C 3 In a preferred embodiment, R 4 is H. In another embodiment, R 4 It is C 1 -C 3 In a preferred embodiment, R 4 It's methyl.

[0276] In another preferred embodiment, R 3 yes

[0277] In another preferred embodiment, R 3 yes Where R 4 Independently selected from -H or C 1 -C 3 In a preferred embodiment, R 4 is H. In another embodiment, R 4It is C 1 -C 3 In a preferred embodiment, R 4 is a methyl group, where R 3 yes

[0278] In another embodiment, R 3 is selected from 6-membered aryl or heteroaryl, wherein the heteroaryl contains one or two heteroatoms, wherein the heteroatom is N. The 6-membered aryl or heteroaryl may be substituted by one or two substituents independently selected from the following: 1 -C 4 Alkyl, hydroxyl C 1 -C 4 Alkyl, halogenated C 1 -C 4 The substituents may be at any possible position on the aryl or heteroaryl group.

[0279] In one embodiment, R 3 is a 6-membered heteroaryl group having two N heteroatoms. The 6-membered heteroaryl group may be substituted by one or two substituents independently selected from the following: 1 -C 4 Alkyl, hydroxyl C 1 -C 4 Alkyl, halogenated C 1 -C 4 In one embodiment, R 3 Selected from

[0280]

[0281] In another embodiment, R 3 It is C 3 -C 6 Cycloalkyl, preferably cyclopropyl or cyclobutyl. 3 -C 6 The cycloalkyl group may be substituted with one or two substituents independently selected from the group consisting of: 1 -C 4 Alkyl, halogenated C 1 -C 4 Alkyl, hydroxyl C 1 -C 4 The substituents may be at any possible position on the cycloalkyl group.

[0282] In a preferred embodiment, R 3 yes Where R 4 Independently selected from -H or C1 -C 3 In a preferred embodiment, R 4 is H. In another embodiment, R 4 It is C 1 -C 3 In a preferred embodiment, R 4 In a preferred embodiment, R 3 yes In another preferred embodiment, R 3 yes

[0283] In another preferred embodiment, R 3 It is C 1 -C 6 Alkyl, preferably C 1 -C 3 The alkyl group may be substituted with one or two substituents independently selected from the following: -OH, halo, halo-C 1 -C 4 Alkyl and C 1 -C 4 In a preferred embodiment, R 3 It is hydroxyl C 1 -C 6 Alkyl (i.e. C substituted by -OH) 1 -C 6 Alkyl), more preferably hydroxyl C 1 -C 3 Alkyl, preferably hydroxyethyl.

[0284] In a preferred embodiment, R 3 yes wherein n is 0, 1 or 2. In another preferred embodiment, R 3 yes Where n is 0, 1 or 2.

[0285] In another preferred embodiment, there is provided a compound of formula (I) or (I') having the structure of formula (Ic)

[0286]

[0287] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof;

[0288] in

[0289] E is selected from N and CR a ;

[0290] R a Selected from -H, -C 1 -C 3 Alkyl, -CF 3 and halo;

[0291] R 0 Selected from -H, C 1 -C 3 Alkyl and halo;

[0292] R 1 Selected from -CF 3 、-OCF 3 、-OCHF 2 and halo;

[0293] R 2 Selected from -OH, -H and -CF 3 ;

[0294] Y is selected from NH and O;

[0295] R 3 Selected from

[0296] A 4-, 5- or 6-membered heterocycloalkyl group containing one or two heteroatoms, preferably one heteroatom, wherein the heteroatom is N, which is optionally substituted with one or two substituents independently selected from: C 1 -C 4 Alkyl, halogenated C 1 -C 4 Alkyl, hydroxyl C 1 -C 4 Alkyl, -OH and halo;

[0297] A 5- or 6-membered aryl or heteroaryl group, wherein the heteroaryl group contains one or two heteroatoms, wherein the heteroatom is N, which is optionally substituted with one or two substituents independently selected from: C 1 -C 4 Alkyl, hydroxyl C 1 -C 4 Alkyl, halogenated C 1 -C 4 Alkyl, -CN and halo;

[0298] C 3 -C 6 Cycloalkyl, which is optionally substituted by one or two substituents independently selected from the following: 1 -C 4 Alkyl, halogenated C 1 -C 4 Alkyl, hydroxyl C 1 -C 4Alkyl, -OH and halo; and

[0299] C 1 -C 6 Alkyl, which is substituted by one or two substituents independently selected from the following: -OH, halo, halo 1 -C 4 Alkyl and C 1 -C 4 Alkoxy.

[0300] In a preferred embodiment of the compound of formula (Ic), E is CR a , where R a As defined above. In a preferred embodiment of the compounds of formula (Ic), E is CH. In another embodiment of the compounds of formula (Ic), E is N.

[0301] In a preferred embodiment, R 0 Selected from -H and C 1 -C 3 In a preferred embodiment, R 0 In another preferred embodiment, R 0 It is C 1 -C 3 Alkyl group, preferably methyl or ethyl group, more preferably methyl group.

[0302] In a preferred embodiment, R 1 Selected from -CF 3 、-OCF 3 and-OCHF 2 In a preferred embodiment, R 1 Yes - CF 3 In another preferred embodiment, R 1 Yes - OCF 3 In another preferred embodiment, R 1 Yes - OCHF 2 .

[0303] In another embodiment, R 1 is a halogenated group. 1 When it is a halo group, the halogen (halo group) is preferably chlorine.

[0304] In a preferred embodiment, R 2 In another embodiment, R 2 is -H. In another embodiment, R 2 Yes - CF 3 .

[0305] In a preferred embodiment, R0 Yes - H, R 1 Selected from -CF 3 、-OCF 3 and-OCHF 2 , and R 2 In a preferred embodiment, R 0 Yes - H, R 1 Yes - CF 3 , and R 2 It is -OH.

[0306] In a preferred embodiment, R 3 Independently selected from

[0307] A 4-, 5- or 6-membered heterocycloalkyl group containing one or two heteroatoms, preferably one heteroatom, wherein the heteroatom is N, which is optionally substituted with one or two substituents independently selected from: C 1 -C 4 Alkyl, halogenated C 1 -C 4 Alkyl, hydroxyl C 1 -C 4 Alkyl, -OH and halo;

[0308] 6-membered aryl or heteroaryl, wherein the heteroaryl contains one or two heteroatoms, wherein the heteroatom is N, which is optionally substituted with one or two substituents independently selected from: C 1 -C 4 Alkyl, hydroxyl C 1 -C 4 Alkyl, halogenated C 1 -C 4 Alkyl, -CN and halo;

[0309] C 3 -C 6 Cycloalkyl, which is optionally substituted by one or two substituents independently selected from the following: 1 -C 4 Alkyl, halogenated C 1 -C 4 Alkyl, hydroxyl C 1 -C 4 Alkyl, -OH and halo; and

[0310] C 1 -C 6 Alkyl, which is substituted by one or two substituents independently selected from the following: -OH, halo, halo 1 -C 4 Alkyl and C 1 -C 4 Alkoxy.

[0311] In a preferred embodiment, R 3 is selected from 5- or 6-membered heterocycloalkyl groups containing one or two heteroatoms, preferably one heteroatom, wherein the heteroatom is N. In a preferred embodiment, R 3 is a 6-membered heterocycloalkyl group containing one heteroatom, wherein the heteroatom is N. The 5- or 6-membered heterocycloalkyl group may be substituted by one or two substituents independently selected from the following: 1 -C 4 Alkyl, halogenated C 1 -C 4 Alkyl, hydroxyl C 1 -C 4 The substituents may be at any possible position on the heterocyclic group.

[0312] In a preferred embodiment, R 3 yes Where R 4 Independently selected from -H or C 1 -C 3 In a preferred embodiment, R 4 is H. In another embodiment, R 4 It is C 1 -C 3 In a preferred embodiment, R 4 It's methyl.

[0313] In a preferred embodiment, R 3 yes Where R 4 Independently selected from -H or C 1 -C 3 In a preferred embodiment, R 4 is H. In another embodiment, R 4 It is C 1 -C 3 In a preferred embodiment, R 4 It's methyl.

[0314] In another preferred embodiment, R 3 yes

[0315] In another preferred embodiment, R 3 yes Where R 4 Independently selected from -H or C 1 -C 3 In a preferred embodiment, R4 is H. In another embodiment, R 4 It is C 1 -C 3 In a preferred embodiment, R 4 is a methyl group, where R 3 yes

[0316] In another embodiment, R 3 is selected from 6-membered aryl or heteroaryl, wherein the heteroaryl contains one or two heteroatoms, wherein the heteroatom is N. The 6-membered aryl or heteroaryl may be substituted by one or two substituents independently selected from the following: 1 -C 4 Alkyl, hydroxyl C 1 -C 4 Alkyl, halogenated C 1 -C 4 The substituents may be at any possible position on the aryl or heteroaryl group.

[0317] In one embodiment, R 3 is a 6-membered heteroaryl group having two N heteroatoms. The 6-membered heteroaryl group may be substituted by one or two substituents independently selected from the following: 1 -C 4 Alkyl, hydroxyl C 1 -C 4 Alkyl, halogenated C 1 -C 4 In one embodiment, R 3 Selected from

[0318]

[0319] In another embodiment, R 3 It is C 3 -C 6 Cycloalkyl, preferably cyclopropyl or cyclobutyl. 3 -C 6 The cycloalkyl group may be substituted with one or two substituents independently selected from the group consisting of: 1 -C 4 Alkyl, halogenated C 1 -C 4 Alkyl, hydroxyl C 1 -C 4 The substituents may be at any possible position on the cycloalkyl group.

[0320] In a preferred embodiment, R 3 yes Where R 4 Independently selected from -H or C 1 -C 3 In a preferred embodiment, R 4 is H. In another embodiment, R 4 It is C 1 -C 3 In a preferred embodiment, R 4 In a preferred embodiment, R 3 yes In another preferred embodiment, R 3 yes

[0321] In another preferred embodiment, R 3 It is C 1 -C 6 Alkyl, preferably C 1 -C 3 The alkyl group may be substituted with one or two substituents independently selected from the following: -OH, halo, halo-C 1 -C 4 Alkyl and C 1 -C 4 In a preferred embodiment, R 3 It is hydroxyl C 1 -C 6 Alkyl (i.e. C substituted by -OH) 1 -C 6 Alkyl), more preferably hydroxyl C 1 -C 3 Alkyl, preferably hydroxyethyl.

[0322] In a preferred embodiment, R 3 yes wherein n is 0, 1 or 2. In another preferred embodiment, R 3 yes Where n is 0, 1 or 2.

[0323] In another embodiment, a compound of formula (I) is provided, which has the structure of formula (Id)

[0324]

[0325] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof;

[0326] Where R a , R0 , R 1 , R 2、 R 3 , X and Y are as defined in any of the above embodiments.

[0327] In a preferred embodiment of the compound of formula (Id), X is CR a , where R a As defined above. In a preferred embodiment of the compounds of formula (Id), X is CH. In another embodiment of the compounds of formula (Id), X is N.

[0328] In a preferred embodiment, R 0 Selected from -H and C 1 -C 3 In a preferred embodiment, R 0 In another preferred embodiment, R 0 It is C 1 -C 3 Alkyl group, preferably methyl or ethyl group, more preferably methyl group.

[0329] In a preferred embodiment, R 1 Selected from -CF 3 、-OCF 3 and-OCHF 2 In a preferred embodiment, R 1 Yes - CF 3 In another preferred embodiment, R 1 Yes - OCF 3 In another preferred embodiment, R 1 Yes - OCHF 2 .

[0330] In another embodiment, R 1 is a halogenated group. 1 When it is a halo group, the halogen (halo group) is preferably chlorine.

[0331] In a preferred embodiment, R 2 In another embodiment, R 2 is -H. In another embodiment, R 2 Yes - CF 3 .

[0332] In a preferred embodiment, R 0 Yes - H, R 1 Selected from -CF 3 、-OCF 3 and-OCHF 2 , and R2 In a preferred embodiment, R 0 Yes - H, R 1 Yes - CF 3 , and R 2 It is -OH.

[0333] In a preferred embodiment, R 3 Independently selected from

[0334] A 4-, 5- or 6-membered heterocycloalkyl group containing one or two heteroatoms, preferably one heteroatom, wherein the heteroatom is N, which is optionally substituted with one or two substituents independently selected from: C 1 -C 4 Alkyl, halogenated C 1 -C 4 Alkyl, hydroxyl C 1 -C 4 Alkyl, -OH and halo;

[0335] 6-membered aryl or heteroaryl, wherein the heteroaryl contains one or two heteroatoms, wherein the heteroatom is N, which is optionally substituted with one or two substituents independently selected from: C 1 -C 4 Alkyl, hydroxyl C 1 -C 4 Alkyl, halogenated C 1 -C 4 Alkyl, -CN and halo;

[0336] C 3 -C 6 Cycloalkyl, which is optionally substituted by one or two substituents independently selected from the following: 1 -C 4 Alkyl, halogenated C 1 -C 4 Alkyl, hydroxyl C 1 -C 4 Alkyl, -OH and halo; and

[0337] C 1 -C 6 Alkyl, which is substituted by one or two substituents independently selected from the following: -OH, halo, halo 1 -C 4 Alkyl and C 1 -C 4 Alkoxy.

[0338] In a preferred embodiment, R 3is selected from 5- or 6-membered heterocycloalkyl groups containing one or two heteroatoms, preferably one heteroatom, wherein the heteroatom is N. In a preferred embodiment, R 3 is a 6-membered heterocycloalkyl group containing one heteroatom, wherein the heteroatom is N. The 5- or 6-membered heterocycloalkyl group may be substituted by one or two substituents independently selected from the following: 1 -C 4 Alkyl, halogenated C 1 -C 4 Alkyl, hydroxyl C 1 -C 4 The substituents may be at any possible position on the heterocyclic group.

[0339] In a preferred embodiment, R 3 yes Where R 4 Independently selected from -H or C 1 -C 3 In a preferred embodiment, R 4 is H. In another embodiment, R 4 It is C 1 -C 3 In a preferred embodiment, R 4 It's methyl.

[0340] In a preferred embodiment, R 3 yes Where R 4 Independently selected from -H or C 1 -C 3 In a preferred embodiment, R 4 is H. In another embodiment, R 4 It is C 1 -C 3 In a preferred embodiment, R 4 It's methyl.

[0341] In another preferred embodiment, R 3 yes

[0342] In another preferred embodiment, R 3 yes Where R 4 Independently selected from -H or C 1 -C 3 In a preferred embodiment, R 4 is H. In another embodiment, R 4It is C 1 -C 3 In a preferred embodiment, R 4 is a methyl group, where R 3 yes

[0343] In another embodiment, R 3 is selected from 6-membered aryl or heteroaryl, wherein the heteroaryl contains one or two heteroatoms, wherein the heteroatom is N. The 6-membered aryl or heteroaryl may be substituted by one or two substituents independently selected from the following: 1 -C 4 Alkyl, hydroxyl C 1 -C 4 Alkyl, halogenated C 1 -C 4 The substituents may be at any possible position on the aryl or heteroaryl group.

[0344] In one embodiment, R 3 is a 6-membered heteroaryl group having two N heteroatoms. The 6-membered heteroaryl group may be substituted by one or two substituents independently selected from the following: 1 -C 4 Alkyl, hydroxyl C 1 -C 4 Alkyl, halogenated C 1 -C 4 In one embodiment, R 3 Selected from

[0345]

[0346] In another embodiment, R 3 It is C 3 -C 6 Cycloalkyl, preferably cyclopropyl or cyclobutyl. 3 -C 6 The cycloalkyl group may be substituted with one or two substituents independently selected from the group consisting of: 1 -C 4 Alkyl, halogenated C 1 -C 4 Alkyl, hydroxyl C 1 -C 4 The substituents may be at any possible position on the cycloalkyl group.

[0347] In a preferred embodiment, R 3 yes Where R 4 Independently selected from -H or C1 -C 3 In a preferred embodiment, R 4 is H. In another embodiment, R 4 It is C 1 -C 3 In a preferred embodiment, R 4 In a preferred embodiment, R 3 yes In another preferred embodiment, R 3 yes

[0348] In another preferred embodiment, R 3 It is C 1 -C 6 Alkyl, preferably C 1 -C 3 The alkyl group may be substituted with one or two substituents independently selected from the following: -OH, halo, halo-C 1 -C 4 Alkyl and C 1 -C 4 In a preferred embodiment, R 3 It is hydroxyl C 1 -C 6 Alkyl (i.e. C substituted by -OH) 1 -C 6 Alkyl), more preferably hydroxyl C 1 -C 3 Alkyl, preferably hydroxyethyl.

[0349] In a preferred embodiment, R 3 yes wherein n is 0, 1 or 2. In another preferred embodiment, R 3 yes Where n is 0, 1 or 2.

[0350] In another preferred embodiment, there is provided a compound of formula (I) or (I') having the structure of formula (Ie)

[0351]

[0352] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof;

[0353] in

[0354] X is selected from N and CR a ;

[0355] R a Selected from -C 1 -C 3 Alkyl, -CF 3 and halo;

[0356] R 0 Selected from -H, C 1 -C 3 Alkyl and halo;

[0357] R 1 Selected from -CF 3 、-OCF 3 、-OCHF 2 and halo;

[0358] R 2 Selected from -OH, -H and -CF 3 ;

[0359] Y is selected from NH and O;

[0360] R 3 Selected from

[0361] A 4-, 5- or 6-membered heterocycloalkyl group containing one or two heteroatoms, preferably one heteroatom, wherein the heteroatom is N, which is optionally substituted with one or two substituents independently selected from: C 1 -C 4 Alkyl, halogenated C 1 -C 4 Alkyl, hydroxyl C 1 -C 4 Alkyl, -OH and halo;

[0362] A 5- or 6-membered aryl or heteroaryl group, wherein the heteroaryl group contains one or two heteroatoms, wherein the heteroatom is N, which is optionally substituted with one or two substituents independently selected from: C 1 -C 4 Alkyl, hydroxyl C 1 -C 4 Alkyl, halogenated C 1 -C 4 Alkyl, -CN and halo;

[0363] C 3 -C 6 Cycloalkyl, which is optionally substituted by one or two substituents independently selected from the following: 1 -C 4 Alkyl, halogenated C 1 -C 4 Alkyl, hydroxyl C 1 -C 4Alkyl, -OH and halo; and

[0364] C 1 -C 6 Alkyl, which is substituted by one or two substituents independently selected from the following: -OH, halo, halo 1 -C 4 Alkyl and C 1 -C 4 Alkoxy.

[0365] In a preferred embodiment of the compound of formula (Ie), X is N. In another preferred embodiment of the compound of formula (Ie), X is CR a .

[0366] In a preferred embodiment, R 0 Selected from -H and C 1 -C 3 In a preferred embodiment, R 0 In another preferred embodiment, R 0 It is C 1 -C 3 Alkyl group, preferably methyl or ethyl group, more preferably methyl group.

[0367] In a preferred embodiment, R 1 Selected from -CF 3 、-OCF 3 and-OCHF 2 In a preferred embodiment, R 1 Yes - CF 3 In another preferred embodiment, R 1 Yes - OCF 3 In another preferred embodiment, R 1 Yes - OCHF 2 .

[0368] In another embodiment, R 1 is a halogenated group. 1 When it is a halo group, the halogen (halo group) is preferably chlorine.

[0369] In a preferred embodiment, R 2 In another embodiment, R 2 is -H. In another embodiment, R 2 Yes - CF 3 .

[0370] In a preferred embodiment, R 0 Yes - H, R 1 Selected from -CF 3、-OCF 3 and-OCHF 2 , and R 2 In a preferred embodiment, R 0 Yes - H, R 1 Yes - CF 3 , and R 2 It is -OH.

[0371] In a preferred embodiment, R 3 Independently selected from

[0372] A 4-, 5- or 6-membered heterocycloalkyl group containing one or two heteroatoms, preferably one heteroatom, wherein the heteroatom is N, which is optionally substituted with one or two substituents independently selected from: C 1 -C 4 Alkyl, halogenated C 1 -C 4 Alkyl, hydroxyl C 1 -C 4 Alkyl, -OH and halo;

[0373] 6-membered aryl or heteroaryl, wherein the heteroaryl contains one or two heteroatoms, wherein the heteroatom is N, which is optionally substituted with one or two substituents independently selected from: C 1 -C 4 Alkyl, hydroxyl C 1 -C 4 Alkyl, halogenated C 1 -C 4 Alkyl, -CN and halo;

[0374] C 3 -C 6 Cycloalkyl, which is optionally substituted by one or two substituents independently selected from the following: 1 -C 4 Alkyl, halogenated C 1 -C 4 Alkyl, hydroxyl C 1 -C 4 Alkyl, -OH and halo; and

[0375] C 1 -C 6 Alkyl, which is substituted by one or two substituents independently selected from the following: -OH, halo, halo 1 -C 4 Alkyl and C 1 -C 4 Alkoxy.

[0376] In a preferred embodiment, R 3is selected from 5- or 6-membered heterocycloalkyl groups containing one or two heteroatoms, preferably one heteroatom, wherein the heteroatom is N. In a preferred embodiment, R 3 is a 6-membered heterocycloalkyl group containing one heteroatom, wherein the heteroatom is N. The 5- or 6-membered heterocycloalkyl group may be substituted by one or two substituents independently selected from the following: 1 -C 4 Alkyl, halogenated C 1 -C 4 Alkyl, hydroxyl C 1 -C 4 The substituents may be at any possible position on the heterocyclic group.

[0377] In a preferred embodiment, R 3 yes Where R 4 Independently selected from -H or C 1 -C 3 In a preferred embodiment, R 4 is H. In another embodiment, R 4 It is C 1 -C 3 In a preferred embodiment, R 4 It's methyl.

[0378] In a preferred embodiment, R 3 yes Where R 4 Independently selected from -H or C 1 -C 3 In a preferred embodiment, R 4 is H. In another embodiment, R 4 It is C 1 -C 3 In a preferred embodiment, R 4 It's methyl.

[0379] In another preferred embodiment, R 3 yes

[0380] In another preferred embodiment, R 3 yes Where R 4 Independently selected from -H or C 1 -C 3 In a preferred embodiment, R 4 is H. In another embodiment, R 4It is C 1 -C 3 In a preferred embodiment, R 4 is a methyl group, where R 3 yes

[0381] In another embodiment, R 3 is selected from 6-membered aryl or heteroaryl, wherein the heteroaryl contains one or two heteroatoms, wherein the heteroatom is N. The 6-membered aryl or heteroaryl may be substituted by one or two substituents independently selected from the following: 1 -C 4 Alkyl, hydroxyl C 1 -C 4 Alkyl, halogenated C 1 -C 4 The substituents may be at any possible position on the aryl or heteroaryl group.

[0382] In one embodiment, R 3 is a 6-membered heteroaryl group having two N heteroatoms. The 6-membered heteroaryl group may be substituted by one or two substituents independently selected from the following: 1 -C 4 Alkyl, hydroxyl C 1 -C 4 Alkyl, halogenated C 1 -C 4 In one embodiment, R 3 Selected from

[0383]

[0384] In another embodiment, R 3 It is C 3 -C 6 Cycloalkyl, preferably cyclopropyl or cyclobutyl. 3 -C 6 The cycloalkyl group may be substituted with one or two substituents independently selected from the group consisting of: 1 -C 4 Alkyl, halogenated C 1 -C 4 Alkyl, hydroxyl C 1 -C 4 The substituents may be at any possible position on the cycloalkyl group.

[0385] In a preferred embodiment, R 3 yes Where R 4 Independently selected from -H or C1 -C 3 In a preferred embodiment, R 4 is H. In another embodiment, R 4 It is C 1 -C 3 In a preferred embodiment, R 4 In a preferred embodiment, R 3 yes In another preferred embodiment, R 3 yes

[0386] In another preferred embodiment, R 3 It is C 1 -C 6 Alkyl, preferably C 1 -C 3 The alkyl group may be substituted with one or two substituents independently selected from the following: -OH, halo, halo-C 1 -C 4 Alkyl and C 1 -C 4 In a preferred embodiment, R 3 It is hydroxyl C 1 -C 6 Alkyl (i.e. C substituted by -OH) 1 -C 6 Alkyl), more preferably hydroxyl C 1 -C 3 Alkyl, preferably hydroxyethyl.

[0387] In a preferred embodiment, R 3 yes wherein n is 0, 1 or 2. In another preferred embodiment, R 3 yes Where n is 0, 1 or 2.

[0388] In another embodiment, the present invention relates to compounds of formula (I') or (I)

[0389]

[0390]

[0391] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof.

[0392] The present invention also relates to a pharmaceutical composition comprising a compound of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie) as defined in the present invention or its stereoisomers, racemic mixtures, tautomers, polymorphs, pharmaceutically acceptable salts, prodrugs, hydrates or solvates, and optionally at least one pharmaceutically acceptable carrier, diluent, adjuvant or excipient.

[0393] In one embodiment, the pharmaceutical composition comprises a compound of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie) as defined in the present invention or its stereoisomers, racemic mixtures, tautomers, polymorphs, pharmaceutically acceptable salts, prodrugs, hydrates or solvates, and optionally at least one pharmaceutically acceptable carrier, diluent, adjuvant or excipient.

[0394] Having described various embodiments of the invention, it will be recognized that features specified in each embodiment may be combined with other specified features to provide further embodiments of the invention.

[0395] The present invention relates to compounds of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie) as defined in the present invention or their stereoisomers, racemic mixtures, tautomers, polymorphs, pharmaceutically acceptable salts, prodrugs, hydrates or solvates for use as medicaments.

[0396] The present invention relates to a compound of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie) 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 a disease, disorder or abnormality that responds to the modulation, in particular inhibition of activation, of a component of the NLRP3 inflammasome pathway and / or to the modulation, in particular reduction, of IL-1β and / or IL-18 levels. In one embodiment, the modulation is a reduction and / or inhibition of IL-1β and / or IL-1β levels. In particular, the modulation is a reduction and / or inhibition of IL-1β.

[0397] In another embodiment, the invention relates to a compound of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie) 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.

[0398] The present invention relates to compounds of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie) as defined in the present invention or their stereoisomers, racemic mixtures, tautomers, polymorphs, pharmaceutically acceptable salts, prodrugs, hydrates or solvates, which are used to treat, alleviate or prevent diseases, disorders or abnormalities that respond to the modulation of components of the NLRP3 inflammasome pathway, in particular the inhibition of activation.

[0399] The present invention relates to compounds of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie) as defined in the present invention or their stereoisomers, racemic mixtures, tautomers, polymorphs, pharmaceutically acceptable salts, prodrugs, hydrates or solvates, which are used to treat, alleviate or prevent diseases, disorders or abnormalities that respond to the modulation of the NLRP3 inflammasome pathway, especially the inhibition of activation.

[0400] The present invention relates to compounds of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie) as defined in the present invention or their stereoisomers, racemic mixtures, tautomers, polymorphs, pharmaceutically acceptable salts, prodrugs, hydrates or solvates, for use in treating, alleviating or preventing diseases, disorders or abnormalities responsive to the regulation, in particular reduction, of IL-1β and / or IL-18 levels.

[0401] In other words, the present invention relates to a method for treating, alleviating or preventing diseases, disorders or abnormalities responsive to the modulation of components of the NLRP3 inflammasome pathway, in particular the inhibition of activation, and / or diseases, disorders or abnormalities responsive to the modulation of IL-1β and / or IL-18 levels, in particular the reduction, 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), (Ia), (Ib), (Ic), (Id) or (Ie) as defined in the present invention, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof.

[0402] In one embodiment, the present invention relates to a method for treating, preventing or alleviating a disease, disorder or abnormality that responds to the modulation of a component of the NLRP3 inflammasome pathway, in particular the inhibition of 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), (Ia), (Ib), (Ic), (Id) or (Ie) as defined herein, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof.

[0403] The present invention also relates to a method for treating, preventing or alleviating a disease, disorder or abnormality that responds to the modulation of the NLRP3 inflammasome pathway, in particular the inhibition of 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), (Ia), (Ib), (Ic), (Id) or (Ie) as defined in the present invention, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof.

[0404] In one embodiment, the invention relates to a method for treating, preventing or alleviating a disease, disorder or abnormality responsive to the regulation, 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), (Ia), (Ib), (Ic), (Id) or (Ie) as defined herein, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof.

[0405] The present invention relates to the use of a compound of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie) 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 another embodiment, the present invention relates to the use of a compound of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie) 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 responsive to modulation, in particular inhibition of activation, of a component of the NLRP3 inflammasome pathway and / or a disease, disorder or abnormality responsive to modulation, in particular reduction, of IL-1β and / or IL-18 levels. In one embodiment, the disease, disorder or abnormality is selected from the list disclosed herein.

[0406] The present invention relates to the use of a compound of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie) 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 responsive to the modulation of a component of the NLRP3 inflammasome pathway, in particular the inhibition of activation.

[0407] The present invention relates to the use of a compound of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie) 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 responsive to the modulation of the NLRP3 inflammasome pathway, in particular the inhibition of activation.

[0408] The present invention relates to the use of a compound of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie) 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 regulation, in particular the reduction, of IL-1β and / or IL-18 levels.

[0409] The present invention relates to the use of a compound of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie) 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 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.

[0410] In one embodiment, the present invention relates to a compound of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie) 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.

[0411] 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.

[0412] In yet another embodiment, the disease, disorder or abnormality is a disease, disorder or abnormality selected from Alzheimer's disease, Parkinson's disease, multiple sclerosis, cryptopyrin-associated periodic syndrome (CAPS), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH) and gout, such as Alzheimer's disease, Parkinson's disease, cryptopyrin-associated periodic syndrome (CAPS), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH) and gout.

[0413] In another 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 malignant tumor. 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.

[0414] In one embodiment, the disease, disorder or abnormality responsive to modulation of a component of the NLRP3 inflammasome pathway, in particular inhibition of activation, can be selected from Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, demyelination, viral encephalitis, epilepsy, stroke, cerebral hemorrhage, atherosclerosis, asthma, allergic inflammation, cryptopyrin-associated periodic syndrome (CAPS), Mueller-Weiss 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, suppurative arthritis, pyoderma gangrenosum, and acne (PAPA), A20 haploinsufficiency (HA20), PLCG2-related antibody deficiency and immune dysregulation (PLAID) , Pediatric granulomatous arthritis (PGA), PLCG2-associated autoinflammatory, antibody deficiency and immune dysregulation (APLAID), Sideroblastic anemia with B-cell immunodeficiency, periodic fever, developmental delay (SIFD), chronic nonbacterial osteomyelitis (CNO), Sweet syndrome, chronic relapsing multifocal osteomyelitis (CRMO), synovitis, impetigo, acne, eczema, alopecia areata, actinic keratosis, hyperostosis, osteoarthritis syndrome (SAPHO), multiple sclerosis (MS), psoriasis, Behcet's disease, Sjögren's syndrome, Schnitzler syndrome, chronic obstructive pulmonary disorder (COPD), steroid resistance 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 eyes, 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 infections, bacterial infections, abdominal aortic aneurysm, wound healing, depression, psychological stress, pericarditis including Dressler syndrome, ischemia-reperfusion injury, frontotemporal dementia, HIV-related neurocognitive disorders, coronavirus-related inflammatory lesions, traumatic brain and spinal cord injury, inflammatory pain, chronic pain, neuropathic pain, metastatic cancer-induced bone pain, chemotherapy-induced peripheral neuropathy, migraine and amyloidosis (including AL amyloidosis, AA amyloidosis, ATTR amyloidosis, hereditary amyloidosis (including apolipoprotein AI (AApoAI), apolipoprotein A-II (AApoAII), gelsolin (AGel), fibrinogen (AFib) and lysozyme (ALys)), beta-2 microglobulin amyloidosis, iAPP amyloidosis). ;

[0415] In one embodiment, the disease, disorder or abnormality responsive to modulation of a component of the NLRP3 inflammasome pathway, in particular inhibition of 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), Mueller-Weiss 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- Cellular immunodeficiency, periodic fever, sideroblastic anemia with delayed development (SIFD), chronic nonbacterial osteomyelitis (CNO), Sweet syndrome, chronic relapsing multifocal osteomyelitis (CRMO), synovitis, impetigo, acne, eczema, alopecia areata, actinic keratosis, hyperostosis, osteoarthritis syndrome (SAPHO), multiple sclerosis (MS), psoriasis, Behcet's disease, Sjögren's syndrome, Schnitzler syndrome, chronic obstructive pulmonary disorder (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, eye color Laminitis, dry eyes, 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, helminth infection, bacterial infection, abdominal aortic aneurysm, wound healing, depression, psychological stress, pericarditis including Dressler syndrome, ischemia-reperfusion injury, frontotemporal dementia, HIV-related neurocognitive disorders, coronavirus-related inflammatory lesions, and traumatic brain injury.

[0416] Preferably, the disease, disorder or abnormality is selected from Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, demyelination, viral encephalitis, epilepsy, stroke, chronic pain, atherosclerosis, asthma and 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, anti-glomerular basement membrane (GMB) disease, IgA nephropathy, glomerulonephritis (GN), systemic lupus erythematosus (SLE), focal segmental glomerulosclerosis, minimal change disease (MCD), psoriatic arthritis and hereditary paroxysmal relapsing fever (HRF).

[0417] In one embodiment, 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, 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, anti-glomerular basement membrane (GMB) disease, IgA nephropathy, glomerulonephritis (GN), systemic lupus erythematosus (SLE), focal segmental glomerulosclerosis, minimal change disease (MCD), psoriatic arthritis and hereditary paroxysmal relapsing fever (HRF).

[0418] More preferably, the disease, disorder or abnormality is selected from Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, demyelination, viral encephalitis, epilepsy, stroke, atherosclerosis, asthma and 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 and myelodysplastic syndrome.

[0419] In one embodiment, 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, 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 and myelodysplastic syndrome.

[0420] Even more preferably, the disease, disorder or abnormality is selected from Alzheimer's disease, Parkinson's disease, multiple sclerosis, 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, multiple sclerosis, cryptopyrin-associated periodic syndrome (CAPS), rheumatoid arthritis and gout.

[0421] In one embodiment, 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; such as Alzheimer's disease, Parkinson's disease, cryptopyrin-associated periodic syndrome (CAPS), rheumatoid arthritis and gout.

[0422] In one embodiment, the present invention relates to a compound of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie) 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 IL-18 and / or IL-1β related diseases by modulating components of the NLRP3 inflammasome pathway, in particular by modulating the NLRP3 inflammasome pathway. The level of IL-18 and / or IL-1β in an individual is reduced due to the administration of a compound of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie) as defined in the present invention, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof.

[0423] The IL-18 and / or IL-1β related disease, disorder or abnormality 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, 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) including primary, secondary and relapsing MAS, hemophagocytic lymphohistiocytosis (HLH), familial (hereditary) hemophagocytic lymphohistiocytosis associated with genetic defects in perforin (FHLH), munc 13-4 and 18-2, synthaxin 11. Immunodeficiency such as Cheyenne syndrome (CHS), Griesli syndrome (GS), X-linked lymphoproliferative syndrome (XLP2), X-linked inhibitor of apoptosis protein deficiency (XIAP), acquired hemophagocytic lymphohistiocytosis associated with infectious conditions, especially herpes viruses such as EBV and other pathogens, autoinflammatory syndromes associated with NLRC4 mutations, giant cell arteritis (GCA), acne, suppurative arthritis, pyoderma gangrenosum and acne (PAPA), pulmonary sarcoidosis, heart failure, ischemic heart disease, dry eye disease (DED), keratitis, corneal ulcers and abrasions, iritis, glaucoma, Sjögren's syndrome, auto Immune uveitis, Behcet'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 syndrome (TRAPS), hyper-lgD 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 advanced EOIBD (VEOIBD), infantile IBD, neonatal IBD, ulcerative colitis, and Blau syndrome (NOD-2 mutation).

[0424] Modulation of the NLRP3 inflammasome pathway has been shown to be beneficial in diseases or disorders and abnormalities with altered IL-18 levels and / or IL-1β levels, which lead to pathological inflammation.

[0425] The present invention relates to compounds of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie) as defined in the present invention, which are modulators of NLRP3 inflammasome activity and / or modulators of IL-18 and / or IL-1b levels in an individual.

[0426] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie) 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 defined herein.

[0427] In another embodiment, the invention relates to a pharmaceutical composition comprising a compound of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie) 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), (Ia), (Ib), (Ic), (Id) or (Ie), and optionally comprising at least one pharmaceutically acceptable carrier, diluent, adjuvant or excipient.

[0428] In another embodiment, the invention relates to a pharmaceutical composition comprising a compound of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie) 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), (Ia), (Ib), (Ic), (Id) or (Ie), and optionally comprising at least one pharmaceutically acceptable carrier, diluent, adjuvant or excipient.

[0429] In particular, additional biologically active compounds can be used to treat 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 compounds of the present invention are used in combination with additional biologically active compounds, the dosage of each compound may be different from the dosage when the compound is used as a monotherapy. These biologically active compounds are well known in the literature. Such biologically active compounds are, for example, compounds, peptides, antibody fragments or nucleic acids, which have therapeutic activity or enhance therapeutic activity when applied to an individual (e.g., a patient) in combination with the compounds of the present invention.

[0430] In another embodiment, the invention relates to a pharmaceutical composition for use as a medicament, comprising a compound of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie) 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), (Ia), (Ib), (Ic), (Id) or (Ie), and optionally comprising at least one pharmaceutically acceptable carrier, diluent, adjuvant or excipient.

[0431] The term "combination" refers to a fixed combination in the form of one dosage unit, or to 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, may be administered simultaneously and independently or separately within time intervals.

[0432] 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), (Ia), (Ib), (Ic), (Id) or (Ie) 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 excipient. In particular, the at least one additional biologically active compound is a compound different from formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie).

[0433] In another embodiment, the invention relates to a combination for use as a medicament comprising a therapeutically effective amount of a compound of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie) 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 which is different from the compound of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie), and optionally comprising at least one pharmaceutically acceptable carrier, diluent, adjuvant or excipient.

[0434] The present invention relates to the use of compounds of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie) as defined in the present invention or their stereoisomers, racemic mixtures, tautomers, polymorphs, pharmaceutically acceptable salts, prodrugs, hydrates or solvates as analytical references or in vitro screening tools. The compounds of the present invention or their stereoisomers, racemic mixtures, tautomers, polymorphs, pharmaceutically acceptable salts, prodrugs, hydrates or solvates can be used as analytical references or in vitro screening tools for characterizing cells with activated NLRP3 inflammasome pathways and for testing compounds targeting the NLRP3 inflammasome pathway.

[0435] Therefore, the present invention provides a compound of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie) 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 components of the NLRP3 inflammasome pathway or to modulation of IL-1β and / or IL-18 levels, particularly to reduction in response, wherein the medicament is prepared for administration with another biologically active agent. The present invention also provides the use of another biologically active agent for treating, alleviating or preventing disorders or abnormalities that respond to modulation of components of the NLRP3 inflammasome pathway or to modulation of IL-1β and / or IL-18 levels, particularly to reduction in response, wherein the other biologically active agent is administered together with the compound of the present invention or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof.

[0436] In another embodiment, the present invention provides a compound of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie) as defined herein or its stereoisomers, racemic mixtures, tautomers, polymorphs, pharmaceutically acceptable salts, prodrugs, hydrates or solvates for use in treating, alleviating or preventing disorders or abnormalities responsive to modulation of components of the NLRP3 inflammasome pathway or to modulation, in particular reduction, of IL-1β and / or IL-18 levels, 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 an inhibition of IL-1β. In another embodiment, the present invention provides a compound of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie) as defined in the present invention or its stereoisomers, racemic mixtures, tautomers, polymorphs, pharmaceutically acceptable salts, prodrugs, hydrates or solvates, for use as a medicament, in particular for inhibiting IL-1β.

[0437] In another embodiment, the present invention also provides a compound of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie) as defined in the present invention, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, for use in a method of treating, alleviating or preventing a disease, disorder or abnormality responsive to modulation of a component of the NLRP3 inflammasome pathway or to modulation, in particular reduction, of IL-1β and / or IL-18 levels, wherein the compound of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie) is prepared for administration with an additional biologically active compound (as defined herein).

[0438] In another embodiment, the present invention also provides a method for treating, reducing or preventing a disease, disorder or abnormality that is responsive to modulation of a component of the NLRP3 inflammasome pathway or to modulation, particularly reduction, of IL-1β and / or IL-18 levels, 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), Mueller-Weiss syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), neonatal onset multisystem inflammatory disease (NOMID), pain rheumatoid arthritis, 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 vulgaris (PAPA), haploinsufficiency of A20 (HA20), P LCG2-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 syndrome, chronic relapsing multifocal osteomyelitis (CRMO), synovitis, impetigo, acne, eczema, alopecia areata, actinic keratosis, hyperostosis, osteoarthritis syndrome (SAPHO), multiple sclerosis (MS), psoriasis, Behcet's disease, Sjögren's syndrome, Schnitzler syndrome, chronic obstructive pulmonary disorder ( 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 eyes, 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 including Dressler syndrome, ischemia-reperfusion injury, frontotemporal dementia, HIV-related neurocognitive disorders, coronavirus-related inflammatory lesions 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 (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, anti-glomerular basement membrane (GMB) disease, IgA nephropathy , glomerulonephritis (GN), systemic lupus erythematosus (SLE), focal segmental glomerulosclerosis, minimal change disease (MCD), psoriatic arthritis, hereditary paroxysmal relapsing fever (HRF), and amyloidosis (including AL amyloidosis, AA amyloidosis, ATTR amyloidosis, hereditary amyloidosis (including apolipoprotein AI (AApoAI), apolipoprotein A-II (AApoAII), gelsolin (AGel), fibrinogen (AFib) and lysozyme (ALys)), beta-2 microglobulin amyloidosis, iAPP amyloidosis), the method comprising administering to the individual a therapeutically effective amount of a compound of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie) as defined herein, or a stereoisomer, or racemic mixture, or tautomer, or polymorph, or pharmaceutically acceptable salt, or hydrate, or solvate thereof. ;

[0439] In another embodiment, the present invention also provides a method of inhibiting IL-1β in an individual in need thereof, the method comprising administering to an individual in need thereof a therapeutically effective amount of a compound of Formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie) or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof.

[0440] In particular, the disease, disorder or abnormality is a disease, disorder or abnormality that responds to inhibition of NLRP3 inflammasome pathway activation. More particularly, the disease, disorder or abnormality responds to modulation of one or more, such as but not limited to IL-1β or IL-18, for example, the disease, disorder or abnormality responds to modulation of one or more 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.

[0441] Any combination of embodiments, preferred embodiments and more preferred embodiments disclosed herein is also contemplated in the present invention.

[0442] Pharmaceutical composition

[0443] Although the compounds of the invention or their stereoisomers, racemic mixtures, tautomers, polymorphs, pharmaceutically acceptable salts, prodrugs, hydrates or solvates may be administered alone, it is preferred to formulate them as 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), (Ia), (Ib), (Ic), (Id) or (Ie) or its stereoisomers, racemic mixtures, tautomers, polymorphs, pharmaceutically acceptable salts, prodrugs, hydrates or solvates, optionally in admixture with a pharmaceutically acceptable carrier, diluent, adjuvant or excipient.

[0444] The term "therapeutically effective amount" of a compound of the invention refers to an amount of a compound of the invention (a compound of Formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie) or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof) that will elicit a biological or medical response in a subject, such as reduction or inhibition of enzyme or protein activity, or improvement of symptoms, alleviation of symptoms, slowing or delaying disease progression, or prevention of a disease, disorder or abnormality, etc. In one embodiment, the term "therapeutically effective amount" refers to an amount of a compound of the 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 responds to modulation of a component of the NLRP3 inflammasome pathway or to modulation, particularly reduction, of IL-1β and / or IL-18.

[0445] Pharmaceutically acceptable carriers, diluents, adjuvants and excipients are well known in the pharmaceutical art and are described, for example, in the following literature: Remington's Pharmaceutical Sciences, 18th edition (Alfonso R. Gennaro, ed.; Mack Publishing Company, Easton, PA, 1990); Remington: the Science and Practice of Pharmacy 19th edition (Lippincott, Williams & Wilkins, 1995); Handbook of Pharmaceutical Excipients, 3rd edition (Arthur H. Kibbe, ed.; Amer. Pharmaceutical Assoc, 1999); Pharmaceutical Codex: Principles and Practice of Pharmaceutics 12th edition (Walter Lund ed.; Pharmaceutical Press, London, 1994); The United States Pharmacopeia: The National Formulary (United States Pharmacopeial Convention); Fiedler's "Lexikon der Hilfsstoffe", 5th edition, Cantor Verlag Aulendorf 2002; "The Handbook of Pharmaceutical Excipients", 4th edition, American Pharmaceuticals 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.

[0446] The 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.

[0447] 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, isopropanol, and polyhydric alcohols such as ethylene glycol), edible oils (e.g., soybean oil, coconut oil, olive oil, safflower oil, and cottonseed oil), oil 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., cross-linked polyvinylpyrrolidone, or XL), alginic acid, sodium alginate, guar gum, cross-linked CMC (cross-linked sodium carboxymethylcellulose, such as Ac-Di- ), carboxymethyl starch-Na (sodium starch glycolate) (e.g. or ), preferably cross-linked PVP and / or cross-linked sodium carboxymethylcellulose), a glidant (e.g. colloidal SiO2 (e.g. 200), magnesium trisilicate, powdered cellulose, talc, and combinations thereof), lubricants (e.g., magnesium stearate, aluminum silicate 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, flavoring agents, 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, low melting point waxes, and ion exchange resins.

[0448] There is no particular limitation on the carrier and 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 agents 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 the target.

[0449] There are no particular limitations on the diluent and 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.

[0450] Adjuvants are additives which themselves have little or no pharmacological effect, but which, if administered together with the compounds of the invention, increase the efficacy or effectiveness of the compounds of the invention.

[0451] 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.

[0452] For example, the compounds may be administered orally in the form of tablets, capsules, ovules, elixirs, solutions or suspensions, which may contain flavorings or coloring agents for immediate, delayed, modified, sustained, pulsed or controlled-release applications.

[0453] Tablets may include excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, calcium hydrogen phosphate and glycine, disintegrants such as starch (preferably corn, potato or tapioca starch), sodium starch glycolate, cross-linked sodium carboxymethylcellulose and certain 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 may be included. Similar types of solid compositions may 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 active agent may be combined with a variety of sweeteners or flavoring agents, coloring substances or dyes, with emulsifiers and / or suspending agents and with diluents such as water, ethanol, propylene glycol and glycerol and combinations thereof.

[0454] If the compounds of the 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 salt or glucose to make the solution isotonic with the blood. If necessary, the aqueous solution should be appropriately buffered (preferably pH 3-9). The preparation of suitable parenteral formulations under sterile conditions is easily accomplished by standard pharmaceutical techniques well known to those skilled in the art.

[0455] 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, 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 propellant as a solvent, which may additionally contain a lubricant, for example sorbitan trioleate. Capsules and cartridges (for example 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 (for example lactose or starch).

[0456] Alternatively, the compounds of the invention as defined herein may be administered in the form of a suppository or vaginal suppository, or 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.

[0457] They may also be administered by the pulmonary or rectal routes. They may also be administered by the ocular route. For ophthalmic use, the compounds may 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 may be formulated in an ointment, such as vaseline.

[0458] For topical application to the skin, the compounds of the invention may be formulated into suitable ointments comprising the active compound suspended or dissolved in, for example, a mixture with one or more of: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, emulsifying wax, and water. Alternatively, they may be formulated into suitable lotions or creams suspended or dissolved in, for example, a mixture with one or more of: mineral oil, sorbitan monostearate, polyethylene glycol, liquid paraffin, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0459] Generally, the clinician will determine the actual dosage most suitable 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.

[0460] The claimed compounds as defined herein can be used alone or in combination with one or more other biologically active compounds as defined herein for treating, alleviating or preventing the conditions. In particular, the other biologically active compounds can be compounds for treating, alleviating or preventing the diseases.

[0461] The above-mentioned combination involved can be conveniently used in the form of a pharmaceutical preparation. The individual components of such combinations can be applied sequentially or simultaneously in a separate or combined pharmaceutical preparation by any convenient approach. When applied sequentially, the compounds of the invention or another biologically active compound can be applied first. When applied simultaneously, the combination can be applied in the form of the same or different pharmaceutical compositions. When combined in the same preparation, it is understood that the two compounds must be stable and compatible with each other and with the other components of the preparation. When formulated separately, they can be provided in any convenient formulation form, conveniently provided in a manner known to this area to such compounds.

[0462] 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 Co., New Jersey (1975).

[0463] The compounds of the 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 excipient. The compounds and / or additional biologically active compounds are preferably present in a therapeutically effective amount.

[0464] 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 invention or by an unrelated mechanism of action or by multiple related and / or unrelated mechanisms of action.

[0465] 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 variation 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. 35 S. 18 F and 36 For example, certain isotopic variants of the invention are such isotopes in which a radioactive isotope is incorporated, such as 3 H or 14 C, they can be used for drug and / or substrate tissue distribution studies. 3 H and carbon-14, i.e. 14 The C isotope is particularly preferred due to its ease of preparation and detectability. 18 F-labeled compounds are particularly suitable for imaging applications such as PET. 2 H substitution may offer certain therapeutic advantages due to greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and may therefore 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.

[0466] Invention application method

[0467] There is evidence for a role for NLRP3-induced IL-1 and IL-18 in inflammatory responses that occur in association with or as a result of a variety of different diseases, disorders, or abnormalities that respond to modulation of components of the NLRP3 inflammasome pathway 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).

[0468] The present invention provides compounds of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie) 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 are responsive to modulation of components of the NLRP3 inflammasome pathway and / or to modulation of IL-1β and / or IL-18 levels. NLRP3 has been shown to be involved in many diseases, disorders or abnormalities, including, for example, one of the following:

[0469] 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);

[0470] 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);

[0471] C. Inflammatory diseases, including autoinflammation and inflammation due to inflammatory diseases, disorders or abnormalities, such as mevalonate kinase deficiency (MKD), hyperimmunoglobulinemia D, cryptopyrin-associated periodic syndrome (CAPS), Mueller-Weiss syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), neonatal-onset multisystem inflammatory disease (NOMID), familial Mediterranean fever (FMF), acne, suppurative 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), suppurative arthritis, A20 haploinsufficiency (HA20), pediatric granulomatous arthritis (PGA), or sideroblastic anemia with B-cell immunodeficiency, periodic fever, developmental delay (SIFD);

[0472] D. Skin diseases, disorders, or abnormalities, such as hidradenitis suppurativa (HS), dermatitis, psoriasis, contact allergy, acne, periodic fever syndrome (HIDS), Sweet syndrome, eczema, skin lesions, burns, wounds, wound healing, trauma, sunburn, actinic keratosis, interleukin 1 receptor antagonist deficiency (DIRA), or alopecia areata;

[0473] E. Eye diseases, disorders or abnormalities, such as age-related macular degeneration (AMD), corneal infection, uveitis, glaucoma, dry eyes or demyelination;

[0474] F. Cardiovascular disease, disorder or abnormality (e.g., 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;

[0475] G. Metabolic diseases, disorders or abnormalities, such as type 2 diabetes, obesity, atherosclerosis, gout or pseudogout;

[0476] 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 disorder (COPD), steroid-resistant asthma or asthma;

[0477] 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;

[0478] J. renal 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;

[0479] K. cancer diseases, disorders or abnormalities (e.g., cancer, tumors or malignancies), such as lung cancer (e.g., lung cancer metastasis), pancreatic cancer, gastric cancer, leukemia, myelodysplastic syndrome (MOS), skin cancer, tumors of the endocrine system or thyroid cancer;

[0480] L. Infection, including viral infection, such as helminth infection (e.g., from schistosomes, roundworms, tapeworms, or flukes), viral encephalitis, bacterial infection, human immunodeficiency virus (HIV), HIV-associated neurocognitive disorder, chronic nonbacterial osteomyelitis (CNO), chronic bacterial osteomyelitis, interleukin 1 receptor antagonist deficiency (DIRA), or epilepsy; type alpha viruses (e.g., Chikungunya virus and Ross River virus), arboviruses (e.g., dengue and Zika virus), coronavirus-associated inflammatory disorders, coronavirus, or influenza virus;

[0481] M. Mental illness, disorder or abnormality, such as depression and psychological stress;

[0482] 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 disorder, inflammation that occurs as a result of infection, or inflammation secondary to trauma, injury, or autoimmunity. Examples of inflammation include inflammatory responses associated with or occurring as a result of:

[0483] 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;

[0484] ii. a gastrointestinal disease, disorder or abnormality (e.g., a disease, disorder or abnormality of the gastrointestinal tract), such as colitis, ulcerative colitis or inflammatory bowel disease;

[0485] iii. Muscle diseases, disorders or abnormalities, such as polymyositis or myasthenia gravis;

[0486] iv. diseases, disorders or abnormalities of the endocrine system, such as diabetes, parathyroid disease (e.g. hypothyroidism), tumors of the endocrine system, thyroid cancer or hypoglycemia; and / or

[0487] v. Vascular diseases, disorders or abnormalities, such as Behcet's disease.

[0488] In one embodiment, 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) and gout.

[0489] In particular, the disease, disorder or abnormality is selected from the group consisting of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, demyelination, viral encephalitis, epilepsy, stroke, cerebral hemorrhage, atherosclerosis, asthma, allergic inflammation, cryptopyrin-associated periodic syndrome (CAPS), Mueller-Weiss 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 dysplasia, 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, developmental delay (SIFD), chronic nonbacterial bone disease Myelitis (CNO), Sweet syndrome, chronic recurrent multifocal osteomyelitis (CRMO), synovitis, impetigo, acne, eczema, alopecia areata, actinic keratosis, hyperostosis, osteoarthritis syndrome (SAPHO), multiple sclerosis (MS), psoriasis, Behcet's disease, Sjögren's syndrome, Schnitzler syndrome, chronic obstructive pulmonary disorder (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 eyes, chronic kidney disease, diabetic nephropathy, alcoholic liver disease, skin 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 infections, bacterial infections, abdominal aortic aneurysm, wound healing, depression, psychological stress, pericarditis including Dressler syndrome, ischemia-reperfusion injury, frontotemporal dementia, HIV-associated neurocognitive disorders, coronavirus-associated inflammatory lesions and traumatic brain and spinal cord injury, inflammatory pain, chronic pain, neuropathic pain, metastatic cancer-induced bone pain, chemotherapy-induced peripheral neuropathy, and migraine;Preferably, the disorder is selected from the group consisting of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple 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, anti-glomerular basement membrane ( GMB) disease, IgA nephropathy, glomerulonephritis (GN), systemic lupus erythematosus (SLE), focal segmental glomerulosclerosis, minimal change disease (MCD), psoriatic arthritis, hereditary paroxysmal relapsing fever (HRF), and amyloidosis (including AL amyloidosis, AA amyloidosis, ATTR amyloidosis, hereditary amyloidosis (including apolipoprotein AI (AApoAI), apolipoprotein A-II (AApoAII), gelsolin (AGel), fibrinogen (AFib) and lysozyme (ALys)), beta-2 microglobulin amyloidosis, iAPP amyloidosis). ;

[0490] In one embodiment, 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), Mueller-Weiss 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 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, developmental delay sideroblastic anemia (SIFD), chronic nonbacterial osteomyelitis (CNO), Sweet syndrome, chronic recurrent multifocal osteomyelitis (CRMO), synovitis, impetigo, acne, eczema, alopecia areata, actinic keratosis, hyperostosis, osteoarthritis syndrome (SAPHO), multiple sclerosis (MS), psoriasis, Behcet's disease, Sjögren's syndrome, Schnitzler syndrome, chronic obstructive pulmonary disorder (COPD), steroid-resistant asthma, asbestosis, silicosis, cystic fibrosis, motor neuron disease, Huntington's disease, cerebral malaria, brain damage caused by pneumococcal meningitis, obesity, age-related macular degeneration (AMD), corneal infection, uveitis, dry eyes, Chronic kidney disease, diabetic nephropathy, alcoholic liver disease, skin 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, helminth infection, bacterial infection, abdominal aortic aneurysm, wound healing, depression, psychological stress, pericarditis including Dressler syndrome, ischemia-reperfusion injury, frontotemporal dementia, HIV-related neurocognitive disorders, coronavirus-related inflammatory lesions 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, anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV), lupus nephritis, anti-glomerular basement membrane (GMB) disease, IgA nephropathy, glomerulonephritis (GN), systemic lupus erythematosus (SLE), focal segmental glomerulosclerosis, minimal change disease (MCD), psoriatic arthritis, and hereditary paroxysmal relapsing fever (HRF). ;

[0491] In yet another embodiment, the disease, disorder or abnormality is preferably an inflammatory disease, disorder or abnormality; or the autoimmune disease, disorder or abnormality; or a disease, disorder or abnormality of the skin (such as, for example 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.

[0492] definition

[0493] Within the meaning of this application, unless otherwise indicated, the following definitions apply and, where appropriate, terms used in the singular shall also include the plural and vice versa:

[0494] "Alkyl" refers to a saturated straight or branched chain organic group consisting of carbon and hydrogen atoms. Examples of suitable alkyl groups have 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, and include, as appropriate, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl and isobutyl. The term "C 1 -C 6 "Alkyl" refers to an alkyl group having 1 to 6 carbon atoms. 1 -C 4 Alkyl", "C 1 -C 3 Alkyl" or "C 1 "Alkyl" should be interpreted accordingly.

[0495] "Hal", "halo" 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.

[0496] “-OC 1 -C 6 Alkyl", where "C 1 -C 6 "Alkyl" is as generally defined above. "-OC 1 -C 6 Examples of "alkyl" include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, pentyloxy, and hexyloxy.

[0497] The term "C 3 -C 6 "Cycloalkyl" refers to a saturated monocyclic hydrocarbon group having 3 to 6 carbon atoms. 5 -C 6 "Cycloalkyl" should be interpreted accordingly. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0498] "4-, 5- or 6-membered heterocycloalkyl" refers to a stable 4-, 5- or 6-membered non-aromatic monocyclic ring radical containing 1 or 2 heteroatoms. The heteroatom is nitrogen. Examples include piperidine.

[0499] "Aryl" refers to an aromatic hydrocarbon group having 5 or 6 carbon atoms in the ring portion. Preferably, "aryl" is phenyl.

[0500] "Heteroaryl" refers to an aromatic "5 or 6-membered ring" in which one or two carbon atoms in the ring are replaced by heteroatoms. In the context of the present invention, the heteroatom is N, and the heteroaryl group can be bonded via a carbon atom or a heteroatom. Examples of heteroaryl groups include, but are not limited to, pyridine and pyrimidine.

[0501] Reference to a group as "optionally substituted" means that the group is optionally substituted with one or more substituents (ie, the substituents may or may not be present).

[0502] Unless otherwise indicated, the term "compound of the present invention" refers to a compound of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie) 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. The 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 single diastereomers, enantiomeric mixtures and single enantiomers, mixtures of conformers and single conformers), tautomers, atropisomers and rotamers. All isomeric forms are included in the present invention. The compounds containing olefinic double bonds described in the present invention include E and Z geometric isomers. The present invention also includes all pharmaceutically acceptable salts, prodrugs, polymorphs, hydrates and solvates of the compounds of Formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie).

[0503] Tautomers are isomers of a compound that differ only in the position of their protons and electrons. The skeleton of the compound does not change. Common tautomeric pairs include: keto-enol and

[0504] The present invention also includes solvates, hydrates and anhydrous forms of the salts. There is no particular limitation on the solvent contained in the solvate and it can be any pharmaceutically acceptable solvent. Examples include water and C 1-4 Alcohol (eg methanol or ethanol).

[0505] "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, inorganic or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids and the like. Pharmaceutically acceptable salts include conventional non-toxic salts or quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids, such as but not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, 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. The 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 an appropriate base or acid in water or an organic solvent or a mixture of the two. Organic solvents include but are not limited to non-aqueous media, such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile. Lists of suitable salts can be found in Remington's Pharmaceutical Sciences, 18th edition, Mack Publishing Company, Easton, PA, 1990, p. 1445, the disclosure of which is incorporated herein by reference.

[0506] The compounds of the present invention as defined herein can also be provided in the form of prodrugs, i.e. compounds that are metabolized into active metabolites in vivo. As used in the following and claims of the present specification, the term "prodrug" refers to any covalently bonded compound that releases an active parent drug due to in vivo biotransformation. The references of Goodman and Gilman (The Pharmacological Basis of Therapeutics, 8th edition, McGraw-Hill, Int. Ed. 1992, "Biotransformation of Drugs", pp. 13-15) generally describing prodrugs are incorporated herein by reference.

[0507] "Pharmaceutically acceptable" is defined as those compounds, materials, compositions, and / or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0508] 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.

[0509] As used herein, "NLRP3" refers to the NOD-like receptor (NLR) family of inflammasomes, a protein 3 component containing a pyrin domain. Inflammasomes are intracellular supramolecular complexes that contain sensor molecules, apoptosis-associated speck-like proteins (ASC) containing CARDs as connectors, 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 pyroptosomes, which act as molecular platforms for activating pro-caspase 1 by proximity-induced autocatalytic activation. Active caspase 1 triggers the activation and release of interleukin 1 (IL-1) family proteins and enables the unconventional secretion of numerous cytosolic proteins. Proinflammatory mediators released upon NLRP3 activation are IL-1β (β), IL-18, high mobility group protein B1 (HMGB1), leukotrienes, and prostaglandins.

[0510] Activation of the NLRP3 inflammasome pathway is an important driver of inflammation that interacts with different cytokine pathways to form immune responses to infection and injury. The formation of several proinflammatory cytokines is triggered by activation of the NLRP3 inflammasome pathway.

[0511] The term "inhibit" refers to a reduction or suppression of a given condition, symptom or disorder, or disease or abnormality that is responsive to modulation of a component of the NLRP3 inflammasome pathway, or to a significant decrease in the baseline activity of a biological activity or process.

[0512] The term "treating" or "treatment" of any disease, disorder or abnormality refers to alleviating or 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 or 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).

[0513] The term "preventing" any disease or disorder or abnormality responsive to modulation of a component of the NLRP3 inflammasome pathway refers to preventive treatment of the disease or disorder or abnormality; or delaying the onset or progression of the disease or disorder.

[0514] The term "in need of" treatment means that an individual would benefit biologically, medically, or in quality of life from such treatment.

[0515] As used herein, "modulate" refers to alteration, such as upregulation, downregulation, increase or decrease, preferably decrease.

[0516]

[0517] Unless stated otherwise, the definitions and preferred definitions given in the "Definitions" section apply to all embodiments described below.

[0518] General Synthetic Scheme for the Preparation of Compounds of the Invention

[0519] The compounds of the present invention can be synthesized by one skilled in the art using known preparative procedures, for example, those of the general methods shown in the following schemes. These methods are given for illustrative purposes only and should not be considered limiting.

[0520] In all methods, it should be understood that, according to the general principles of chemistry, the protecting group for sensitive or reactive groups can be used if necessary. Protecting group is operated according to the standard method of organic synthesis (TW Green and PGM Wuts (2014) Protective Groups in Organic Synthesis, the fifth edition, John Wiley & Sons). These groups are removed using methods that are easily understood by those skilled in the art at the convenient stage of compound synthesis.

[0521] In the following general method, R 0 , R 1 , R 2 , R 3 , Z 1 , Z 2 , E, V, X and Y are as defined in the previous embodiments.

[0522]

[0523]

[0524] Process 1:

[0525]

[0526] Commercially available 5-membered heterocyclic esters can be condensed with hydrazine to form carbamates, thereby synthesizing intermediate B. The cyclization can be carried out under basic conditions such as KOH in an appropriate solvent to give the bicyclic system intermediate C. Subsequent use of POCl 3 Or any halogenating agent halogenation can give the intermediate D. YR 3 The introduction of substituents can be carried out by palladium-catalyzed amination using standard palladium catalysts, bases and solvents. Intermediate E can be prepared using POCl 3Finally, intermediate F can be further functionalized using a palladium-catalyzed Suzuki reaction to give compounds of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie).

[0527] Process 2:

[0528]

[0529] Starting from intermediate B, CS 2 Cyclization can provide intermediate G. Selective alkylation using standard conditions followed by chlorination can provide intermediate J. Finally, SNAr followed by metal coupling using, for example, boronic acid and a palladium catalyst can provide compounds of formula (I).

[0530] Process 3:

[0531]

[0532] Another method may include cyclizing intermediate A with an orthoformate reagent to give intermediate L. Benzylation of the backbone using standard conditions can give intermediate M. The alkyl ether can then be converted to a leaving group by a two-step process. Finally, the pyridone is converted to a leaving group in a one-pot reaction to give intermediate P. Finally, compounds of formula (I) can be obtained by SNAr reaction using standard conditions. Example

[0533] The present disclosure is further illustrated by the following examples and synthetic schemes, which should not be construed as limiting the scope of the specific procedures described herein. It should be understood that the examples are provided to illustrate certain embodiments, and the scope of the present disclosure is not thereby limited.

[0534] Unless otherwise stated, all reagents and solvents were obtained from commercial sources and used without further purification. Chemical names were generated using ChemDraw from CambridgeSoft. Temperatures are given in degrees Celsius. If not otherwise mentioned, all evaporations were carried out under reduced pressure, typically between about 15 mmHg and 100 mmHg (=20-133 mbar). The structures of final products, intermediates and starting materials were confirmed by standard analytical methods, such as microanalysis and spectral characteristics, such as MS, IR, NMR. 1H-NMR spectra were recorded on a Bruker 400MHz-Avance Neo Nanobay NMR spectrometer in deuterated solvents. 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 (MS) were obtained on Waters Alliance HPLC (Waters e2695 separation module), Waters Arc HPLC or Waters AcquityUPLC. Chromatography was performed using silica gel (SRL: silica gel 100-200 mesh) and a suitable solvent as shown in the specific examples. Rapid purification was performed using the CombiFlash system and solvent gradients were given in the specific examples. Thin layer chromatography (TLC) was performed on silica gel plates with UV detection.

[0535] Intermediate 1

[0536]

[0537] Step 1: To a mixture of 1H-imidazole-2-carboxylic acid ethyl ester (100 g, 713.57 mmol, 1 eq.) in EtOH (1 L) was slowly added N 2 H 4 ·H 2 O (225.41 mL, 3.72 mol, 5.21 equiv.). The mixture was stirred at 25 °C for 4 h. The reaction mixture was filtered. The filter cake was washed with H 2 O (300 mL x 3), and dried to give 1H-imidazole-2-carbohydrazide (70 g, 77%) as a white solid.

[0538] 1 H NMR: (400MHz, DMSO-d6) δ = 12.64 (br s, 1H), 9.66 (s, 1H), 7.14 (s, 2H), 4.60 (s, 2H).

[0539] MS:127.3[M+H] + .

[0540] Step 2: To a mixture of 1H-imidazole-2-carbohydrazide (60 g, 475.75 mmol, 1 eq.) in pyridine (1.6 L) was added CS 2 (573.60 mL, 8.52 mol, 20.0 equiv.). The mixture was stirred at 100 °C for 16 h. The reaction mixture was concentrated in vacuo and the residue was purified by HPLC. 2O (500mL), and then the pH was adjusted to pH = 2 with 1M HCl. The resulting yellow solid was filtered and dried. The crude product was ground with MeOH (200mL) at 25°C for 16 hours. The mixture was filtered, and the filter cake was washed with MeOH (20mL*3) and freeze-dried to give 5-mercaptoimidazo[1,2-d][1,2,4]triazine-8-ol (25.5g, 31%) as a yellow solid.

[0541] 1 H NMR: (400MHz, DMSO-d6) δ = 8.21 (d, 1H), 7.72 (d, 1H).

[0542] MS:169.0[M+H] + .

[0543] Embodiment 1: (R)-2-(1-((1-methylpiperidin-3-yl)amino)pyrrolo[1,2-d][1,2,4]triazin-4-yl)-5-(trifluoromethyl)phenol

[0544]

[0545] Step A: A solution of 1H-pyrrole-2-carboxylic acid methyl ester (10 g, 79.92 mmol) in hydrazine hydrate (76.86 mL, 2397.51 mmol) was stirred at room temperature for 1 hour and then heated to 100 °C for 2 hours. After the starting material was consumed, the reaction mixture was treated with H 2 O (50 mL), and the solid was cooled and precipitated. The solid was filtered through a Buchner funnel and washed with H 2 O (20 mL), and dried to give 1H-pyrrole-2-carbohydrazide (8.0 g, 80%) as an off-white solid.

[0546] 1 H NMR (400MHz, CDCl3): δ=11.42(brs,1H),9.22(brs,1H),6.83-6.82(m,1H),6.73(brs,1H),6.05-6.03(m,1H),4.28-4.27(brs,2H).

[0547] MS:125.98[M+H]+.

[0548] Step B: Methyl chloroformate (7.428 ml, 95.90 mmol) was added dropwise to a stirred solution of 1H-pyrrole-2-carbohydrazide (derived from step A) (8.0 g, 63.93 mmol) and N,N-diisopropylethylamine (33.41 ml, 191.80 mmol) in DCM (350 mL) at room temperature over 15 minutes. The mixed solution was stirred at room temperature for 2 hours. After the raw material was consumed, the raw material was evaporated under reduced pressure to obtain a crude compound. The crude compound was co-distilled with DCM (50 mL) and fully dried under reduced pressure to obtain a crude product, 2-(1H-pyrrole-2-carbonyl)hydrazine-1-methyl formate (8.0 g, 68%), which was an oil.

[0549] MS:184.07[M+H]+.

[0550] Step C: To a stirred solution of methyl 2-(1H-pyrrole-2-carbonyl)hydrazine-1-carboxylate (from step B) (8.0 g, 43.68 mmol) in EtOH (800 mL) was added KOH (8.58 g, 152.87 mmol) and heated to reflux for 2 hours. The reaction was monitored by TLC. After the starting material was consumed, the reaction mixture was cooled to room temperature. The formed precipitate was filtered and the solid was dissolved in H 2 O (50 mL), then acidified to pH-4 with 1.0 N HCl (aq.), and extracted with EtOAc (2 x 300 mL). The combined organic layers were evaporated under reduced pressure to give 2,3-dihydropyrrolo[1,2-d][1,2,4]triazine-1,4-dione (6.3 g, 95%) as an off-white solid.

[0551] 1 H NMR (400MHz, DMSO-d6): δ=11.42(s,2H),7.67-7.66(s,1H),6.81-6.80(m,1H),6.73-6.71(m,1H).

[0552] MS:152.04[M+H] + .

[0553] Step D: 2,3-dihydropyrrolo[1,2-d][1,2,4]triazine-1,4-dione (from step C) (2.5 g, 16.54 mmol) was added to POCl at room temperature. 3To the stirred solution in 4% paraformaldehyde (15.56 mL, 165.42 mmol) was added DIPEA (2.3 mL, 13.23 mmol) dropwise, and the mixture was stirred at 120 ° C for 16 hours. The reaction progress was monitored by TLC. After the starting material was consumed, the reaction mixture was added dropwise to ice under stirring and then stirred for 15 minutes. The off-white solid was filtered off through a Büchner funnel and dried to give the desired product, 1-chloropyrrolo[1,2-d][1,2,4]triazine-4(3H)-one (1.8 g, 64%), as an off-white solid.

[0554] 1 H NMR (400MHz DMSO-d6): δ = 12.53 (s, 1H), 7.88 -7.86 (m, 1H), 6.92 - 6.87 (m, 2H).

[0555] MS:168.01[MH] - .

[0556] Step E: To a stirred, degassed solution of 1-chloropyrrolo[1,2-d][1,2,4]triazine-4(3H)-one (from Step D) (1.0 g, 5.93 mmol) and (R)-1-methylpiperidin-3-amine (1.36 g, 11.86 mmol) in tetrahydrofuran (10 mL) was added BrettPhos Pd G3 (0.54 g, 0.59 mmol) and BrettPhos (0.318 g, 0.59 mmol), followed by a single addition of 1 M solution of lithium bis(trimethylsilyl)amide in THF (17.80 ml, 17.80 mmol) at room temperature. The mixture was stirred at 65 °C for 16 h. The reaction was monitored by TLC. After the starting material was consumed, the reaction mixture was washed with saturated NH 4 The solution was quenched with Cl solution (70 mL) and extracted with ethyl acetate (2 x 200 mL). The combined organic layers were washed with Na 2 SO 4 Dry, filter, and evaporate under reduced pressure to give the crude compound as a light brown solid. The crude compound was triturated with ether (2x20 mL) to give a brown solid. The resulting solid was filtered through a Buchner funnel and dried to give (R)-1-((1-methylpiperidin-3-yl)amino)pyrrolo[1,2-d][1,2,4]triazine-4(3H)-one (1.2 g, 82%) as a light brown solid.

[0557] 1H NMR (400MHz, DMSO-d6): δ = 11.20 (s, 1H), 7.60-7.59 (q, 1H), 6.99-6.98 (dd, 1H), 6.67-6.65 (t, 1H), 6.28-6.26 (d, 1H), 5.75 (s, 1H) ),3.78-3.71(m,1H),2.96-2.94(m,1H),2.65-2.62(m,1H),2.15(s,3H),1.91-1.66(m,4H),1.55-1.45(m,1H),1.30-1.20(m,1H).

[0558] MS:248.11[M+H] + .

[0559] Step F: (R)-1-((1-methylpiperidin-3-yl)amino)pyrrolo[1,2-d][1,2,4]triazine-4(3H)-one (from Step E) (500 mg, 2.02 mmol) in POCl at room temperature 3 N, N-diisopropylethylamine (0.28mL, 1.62mmol) was added dropwise to the stirred solution in (3mL), and the mixture was stirred at 120°C for 6 hours. The reaction was monitored by TLC. After the raw material was consumed, the reaction mixture was evaporated, quenched with ice, alkalized with a saturated sodium bicarbonate solution (50ml), and extracted with EtOAc (2x150mL). The combined organic layers were washed with saline solution (100mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product (R)-4-chloro-N-(1-methylpiperidin-3-yl)pyrrolo[1,2-d][1,2,4]triazine-1-amine (380mg, 70%), which was an off-white jelly.

[0560] MS:266.06[M+H] + .

[0561] Step G: To a stirred, degassed solution of (R)-4-chloro-N-(1-methylpiperidin-3-yl)pyrrolo[1,2-d][1,2,4]triazine-1-amine (from Step F) (250 mg, 0.94 mmol) and (2-hydroxy-4-(trifluoromethyl)phenyl)boronic acid (232.47 mg, 1.13 mmol) in 1,4-dioxane (3 mL) and water (3 mL) was added potassium carbonate (390.18 mg, 2.82 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane adduct (76.78 mg, 0.27 mmol) at room temperature and the mixture was heated to 100 °C for 16 hours. The reaction was monitored by TLC. After the starting material was consumed, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2x30 mL). The combined organic layer was separated, washed with brine solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude compound.The crude compound was purified by preparative HPLC.

[0562] Preparative HPLC purification conditions

[0563] Mobile phase: 10 mM ammonium bicarbonate in water / acetonitrile

[0564] Column: Mobile phase-Inertsil ODS-3V (25x 150) mm 10μm

[0565] Flow rate: 18mL / min

[0566] Gradient method: T / %B-0 / 30, 4 / 55, 12 / 55, 12.05 / 99, 14.05 / 99, 14.10 / 30.18.10 / 30.

[0567] The pure fractions were collected and freeze-dried to afford (R)-2-(1-((1-methylpiperidin-3-yl)amino)pyrrolo[1,2-d][1,2,4]triazin-4-yl)-5-(trifluoromethyl)phenol (22 mg, 6%) as an off-white solid.

[0568] 1H NMR (400MHz, DMSO-d6): δ = 10.81 (brs, 1H), 7.65-7.63 (d, 1H), 7.32-7.29 (m, 2H), 7.08-7.04 (dd, 2H), 6.99-6.97 (d, 1H), 6.72-6.70 (t, 1H), 4. 25(brs,1H),3.04-3.02(d,1H),2.71-2.67(brs,1H),2.21(s,3H),1.92 -1.90(m,3H),1.76-1.72(m,1H),1.62-1.56(m,1H),1.41-1.36(m,1H),

[0569] MS:392.26[M+H] + .

[0570] Embodiment 2 to 5:

[0571] Similar to the method of above Example 1, the following examples were synthesized:

[0572]

[0573]

[0574] Embodiment 6: 5-(4-Chlorophenyl)-N-[(3R)-1-methyl-3-piperidinyl]imidazo[1,2-d][1,2,4]triazine-8-amine

[0575]

[0576] Step 1: To a solution of 5-sulfanylimidazo[1,2-d][1,2,4]triazine-8-ol (Intermediate 1) (15 g, 89.19 mmol, 1.0 eq.) in acetone (150 mL) was added K 2 CO 3 (24.65 g, 178.38 mmol, 2 equivalents) and MeI (15.19 g, 107.03 mmol, 6.66 mL, 1.2 equivalents). The resulting reaction mixture was stirred at 20°C for 3 hours. The reaction solution was filtered to remove K 2 CO 3 , and then concentrated to give the crude product. The crude product was triturated with DCE (1000 mL) at 80°C for 30 minutes to give 5-methylsulfanylimidazo[1,2-d][1,2,4]triazine-8-ol (12 g, crude) as a yellow solid.

[0577] 1H NMR (400MHz, DMSO-d6) δ = 12.62 (br s, 1H), 7.88 (d, 1H), 7.62 (d, 1H), 2.63 (s, 3H).

[0578] MS:183.1[M+H] + .

[0579] Step 2: 5-Methylsulfanylimidazo[1,2-d][1,2,4]triazine-8-ol (4 g, 21.95 mmol, 1 eq.) was reacted with POCl 3 The solution of 1,4-dihydro-1,4-dihydro-2-nitropropene (58.49 g, 381.46 mmol, 35.56 mL, 17.38 equiv) was heated at 100 °C for 5 h. The reaction mixture was poured into 100 mL of saturated NaHCO 3 , followed by 20 mL of DCM. The aqueous phase was then separated and extracted with DCM (30 mL x 3). The combined organic layers were washed with water (20 mL x 2) and brine (20 ml x 1) and then with anhydrous Na 2 SO 4 The residue was purified by column chromatography (SiO 2 , DCM:MeOH=100 / 1 to 10 / 1). 8-Chloro-5-methylsulfanyl-imidazo[1,2-d][1,2,4]triazine (4.4 g, 50% yield) was obtained as a yellow solid.

[0580] 1 H NMR (400MHz, DMSO-d6) δ = 8.22 (d, 1H), 7.97 (d, 1H), 2.84 (s, 3H).

[0581] MS:200.09[M+H] + .

[0582] Step 3: To a solution of 8-chloro-5-methylsulfanyl-imidazo[1,2-d][1,2,4]triazine (2 g, 9.97 mmol, 1.0 eq) in DMSO (10 mL) was added (3R)-1-methylpiperidin-3-amine (1.37 g, 11.96 mmol, 1.2 eq) and KF (1.16 g, 19.94 mmol, 467.01 μL, 2 eq). The resulting reaction mixture was stirred at 100 °C for 12 h. The reaction mixture was poured into 30 mL of saturated Na 2 CO 3 The resulting solution was then extracted with EtOAc (20 mL x 6) (keeping the pH of the aqueous phase at 12). The combined organic layers were washed with saturated Na 2 CO 3(20 mL x 3) and brine (20 ml x 3) were washed successively (keeping the pH of the aqueous phase at 12), and the mixture was washed with anhydrous Na 2 SO 4 The residue was purified by flash silica gel chromatography (SiO 2 , DCM / MeOH=100 / 1 to 5 / 1), and then re-purified by preparative HPLC (column: Waters Xbridge BEH C18 250 x 70 mm x 10 μm; mobile phase: [H 2 O(0.05% NH 3 H 2 O)-ACN]; gradient: 15%-45% B over 20.0 minutes) to give the title product. N-[(3R)-1-methyl-3-piperidinyl]-5-methylsulfanyl-imidazo[1,2-d][1,2,4]triazine-8-amine (2.34 g, 42% yield) was obtained as a yellow oil.

[0583] 1 H NMR (400MHz, DMSO-d6)δ=7.88(d,1H),7.67(d,1H),7.02(br d,1H),4.24-4.13(m,1H),2.84-2.76(m,1H),2.71(s,3H),2.55-2.53(m ,1H),2.21-2.16(s,3H),2.11-1.99(m,2H),1.80-1.74(m,1H),1.67(br dd,1H),1.58-1.47(m,2H).

[0584] MS:279.2[M+H] + .

[0585] Step 4: To a solution of N-[(3R)-1-methyl-3-piperidinyl]-5-methylsulfanyl-imidazo[1,2-d][1,2,4]triazine-8-amine (0.3 g, 1.08 mmol, 1.0 eq.) in THF (5 mL) were added (4-chlorophenyl)boronic acid (252.78 mg, 1.62 mmol, 1.5 eq.), cuprous 2-hydroxy-3-methyl-benzoate (578.40 mg, 2.69 mmol, 2.5 eq.), Pd(PPh 3 ) 4(373.60 mg, 323.30 μmol, 0.3 eq.). The resulting reaction mixture was stirred at 100 °C for 1 hour. The reaction mixture was poured into 20 mL of saturated EDTA, followed by 10 mL of EtOAc. The solution was stirred at 20 °C for 0.5 h. Afterwards, the aqueous phase was separated and extracted with EtOAc (20 mL x 5). The combined organic layers were washed with saturated Na 2 CO 3 (20mL x 1) washed continuously with anhydrous Na 2 SO 4 The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 3 / 1 to DCM / MeOH = 10 / 1), to obtain 0.5 g of 20% pure product. Repurified by preparative HPLC (column: Phenomenex Luna C18 100 x 30 mm x 5 μm; mobile phase: [H 2 O (0.2% FA)-ACN]; gradient: 5%-30% B over 8.0 minutes) to give the pure product. 5-(4-chlorophenyl)-N-[(3R)-1-methyl-3-piperidinyl]imidazo[1,2-d][1,2,4]triazine-8-amine (45 mg, 12% yield) was obtained as an off-white solid.

[0586] 1H NMR (400MHz, DMSO) δ7.92(s,1H),7.87(d,2H),7.71-7.63(m,3H),7.31(d,1H),4.41-4.23(m,1H),2.84( d,1H),2.60-2.51(m,1H),2.22(s,3H),2.11(d,2H),1.79(s,1H),1.74-1.66(m,1H),1.66-1.49(m,2H).

[0587] MS:343.1[M+H] + .

[0588] Embodiment 7: 5-Chloro-2-[8-[[(3R)-1-methyl-3-piperidinyl]amino]imidazo[1,2-d][1,2,4]triazin-5-yl]phenol formate

[0589]

[0590] To a solution of N-[(3R)-1-methyl-3-piperidinyl]-5-methylsulfanyl-imidazo[1,2-d][1,2,4]triazine-8-amine (0.3 g, 1.08 mmol, 1.0 eq) in THF (5 mL) were added (4-chloro-2-hydroxy-phenyl)boronic acid (278.65 mg, 1.62 mmol, 1.5 eq), 2-hydroxy-3-methyl-benzoic acid cuprous acid (578.40 mg, 2.69 mmol, 2.5 eq) and Pd(PPh 3 ) 4 (373.60 mg, 323.30 μmol, 0.3 eq.). The resulting reaction mixture was stirred at 100 °C for 1 hour in a sealed tube. The reaction mixture was poured into 20 mL of saturated EDTA followed by 10 mL of EtOAc. The solution was stirred at 20 °C for 0.5 hour. Afterwards, the aqueous phase was separated and extracted with EtOAc (20 mL x 5). The combined organic layers were washed with saturated Na 2 CO 3 (20mL x 1) and washed with anhydrous Na 2 SO 4 The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 3 / 1 to DCM / MeOH = 10 / 1), to obtain 0.25 g of 30% pure product. Repurified by preparative HPLC (column: Phenomenex luna C18 100 x 40 mm x 3 μm; mobile phase: [H 2 O (0.2% FA)-ACN]; gradient: 2%-25% B over 8.0 min) to give 5-chloro-2-[8-[[(3R)-1-methyl-3-piperidinyl]amino]imidazo[1,2-d][1,2,4]triazin-5-yl]phenol (42 mg, 11%) as a white solid.

[0591] 1H NMR(400MHz,DMSO)δ10.88(s,1H),8.19(s,1H),7.59(d,1H),7.49(dd,2H),7.25(d,1H),7.14-6.97(m,2H ),4.32(s,1H),2.87(d,1H),2.57(s,1H),2.24(s,3H),2.21-2.04(m,2H),1.87-1.68(m,2H),1.58(q,2H).

[0592] MS:359.1[M+H] + .

[0593] Embodiment 8:2-(1-((1s,3s)-3-hydroxy-3-methylcyclobutyloxy)pyrrolo[1,2-d][1,2,4]triazin-4-yl)-5-(trifluoromethyl)phenol

[0594]

[0595] Step 1: Lawesson's reagent (3.578 g, 8.846 mmol) was added to a stirred solution of 1-chloropyrrolo[1,2-d][1,2,4]triazine-4(3H)-one (1.0 g, 5.897 mmol) in toluene (20 mL) at room temperature, and the reaction mixture was stirred at 120 ° C for 3 hours. The reaction process was monitored by TLC. The reaction mixture was concentrated under reduced pressure to obtain a crude compound as a brown colloid. The crude product was purified by column silica gel (100-200) chromatography and eluted with 0-30% EtOAc gradient in petroleum ether. The product was eluted in 8% EtOAc in petroleum ether. Pure compound fractions were collected and concentrated under reduced pressure to obtain 1-chloropyrrolo[1,2-d][1,2,4]triazine-4(3H)-thione (0.66 g, 60%) as a white solid.

[0596] MS:186.06[M+H] + .

[0597] Step 2: Add ethyl 2-bromoacetate (0.429mL, 3.879mmol) and potassium carbonate (670.073mg, 4.848mmol) to a stirred degassed solution of 1-chloropyrrolo[1,2-d][1,2,4]triazine-4(3H)-thione (600mg, 3.232mmol) in THF (10.0mL) and water (5.0mL) at room temperature, and stir the reaction mixture at room temperature for 3 hours. Monitor the reaction process by TLC. The reaction mixture was diluted with ice-cold water (30mL), and the solid was filtered and dried in vacuo to give ethyl 2-((1-chloropyrrolo[1,2-d][1,2,4]triazine-4-yl)thio)acetate (660mg, 75%) as an off-white solid.

[0598] MS:272.39[M+H] + .

[0599] Step 3: To a stirred degassed solution of ethyl 2-((1-chloropyrrolo[1,2-d][1,2,4]triazine-4-yl)thio)acetate (660 mg, 2.429 mmol), (2-methoxy-4-(trifluoromethyl)phenyl)boric acid (1175.359 mg, 5.344 mmol) and copper(I) 3-methylsalicylate (1147.251 mg, 5.344 mmol) in THF (8 mL) was added tetrakis(triphenylphosphine)palladium(0) (140.344 mg, 0.121 mmol) at room temperature and the reaction mixture was stirred at 70 °C for 3 hours. The progress of the reaction was monitored by TLC. The crude material was filtered through a bed of celite and washed with THF (10 mL). The filtrate was evaporated and dried under vacuum to give a brown gum. The crude product was purified by column silica gel (100-200) chromatography and eluted with 0-50% EtOAc gradient in petroleum ether. The product was eluted in 25% EtOAc in petroleum ether. The pure fractions were collected and concentrated under reduced pressure to give 1-chloro-4-(2-methoxy-4-(trifluoromethyl)phenyl)pyrrolo[1,2-d][1,2,4]triazine (600 mg, 75.38%) as a yellow solid.

[0600] MS:328.43[M+H] + .

[0601] Step 4: To a stirred solution of 1-chloro-4-(2-methoxy-4-(trifluoromethyl)phenyl)pyrrolo[1,2-d][1,2,4]triazine (600 mg, 1.831 mmol) in DCM (12 mL) was added a solution of 1M boron tribromide in DCM (6 mL) at -10 °C, and the reaction mixture was stirred at 0 °C for 1 hour. The reaction progress was monitored by TLC. The crude material was evaporated under reduced pressure and distilled with DCM (5 mL) to give a crude residue as a brown gum. It was further ground with DCM (5 mL), and the resulting solid was filtered and fully dried under reduced pressure to give 2-(1-chloropyrrolo[1,2-d][1,2,4]triazine-4-yl)-5-(trifluoromethyl)phenol (480 mg, 83.58%) as an off-white solid.

[0602] MS:314.08[M+H] + .

[0603] Step 5: To a stirred degassed solution of 1-methylcyclobutane-1,3-diol (374.010 mg, 3.662 mmol) in THF (6 mL) was added LiHMDS 1M solution in THF (4.577 mL, 4.577 mmol) at 60 ° C, and the reaction mixture was stirred at 60 ° C for 30 minutes and then cooled to room temperature. 1-Chloro-4-(2-methoxy-4-(trifluoromethyl)phenyl)pyrrolo[1,2-d][1,2,4]triazine (300 mg, 0.915 mmol) was added, and the reaction mixture was stirred at 60 ° C for 16 hours. The reaction process was monitored by LCMS. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2x 80 mL). The combined organic layer was separated, washed with brine solution (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product as a brown oil. The crude product is purified by column silica gel (100-200) chromatography and eluted with 0-10% MeOH gradient in DCM. The product is eluted in 7% MeOH in DCM. Pure fractions are collected and concentrated under reduced pressure. The obtained residue is ground with ether (5mL), and the precipitated solid is filtered and dried in vacuo to obtain 2-(1-((1s, 3s)-3-hydroxy-3-methylcyclobutyloxy)pyrrolo[1,2-d][1,2,4]triazine-4-yl)-5-(trifluoromethyl)phenol (25mg, 7%), which is an off-white solid.

[0604] 1H NMR(400MHz,DMSO)δ10.94(s,1H),7.70(d,1H),7.38-7.29(m,2H),7.22(dd,1H),6.91(dd,1 H),6.87(dd,1H),5.21(s,1H),5.09(p,1H),2.61(ddd,2H),2.31-2.22(m,2H),1.30(s,3H).

[0605] MS:380.24[M+H] + .

[0606] Embodiment 9: 5-Chloro-2-[8-[[(3R)-1-methylpyrrolidin-3-yl]amino]imidazo[1,2-d][1,2,4]triazin-5-yl]phenol

[0607]

[0608] Step 1: To a solution of 8-chloro-5-methylsulfanyl-imidazo[1,2-d][1,2,4]triazine (800 mg, 3.99 mmol, 1 eq) and (3R)-1-methylpyrrolidin-3-amine (798.70 mg, 7.97 mmol, 2 eq) in DMSO (8 mL) was added KF (463.27 mg, 7.97 mmol, 186.80 μL, 2 eq). The mixture was stirred at 100 °C for 1 hour. The mixture was heated to 40 °C with 20 mL of saturated Na 2 CO 3 The reaction mixture was adjusted to pH 12 and then extracted with EtOAc (30 mL x 3). The combined organic layers were washed with 20 mL of brine and purified by Na 2 SO 4 The residue was purified by column chromatography (SiO 2 , DCM:MeOH=1 / 0 to 90 / 10) to give N-[(3R)-1-methylpyrrolidin-3-yl]-5-methylsulfanyl-imidazo[1,2-d][1,2,4]triazine-8-amine (700 mg, 2.65 mmol, 66.41) as a yellow oil.

[0609] 1 H NMR (400MHz, DMSO-d 6 )δ=7.87(d,1H),7.67(d,1H),7.33(br d,1H),4.56-4.46(m,1H),2.82(dd,1H),2.71(s,3H),2.63-2.58(m,1H),2.54- 2.53(m,1H),2.46-2.41(m,1H),2.26(s,3H),2.24-2.16(m,1H),1.89(tdd,1H)

[0610] MS:265.5[M+H] + .

[0611] Step 2: To a solution of N-[(3R)-1-methylpyrrolidin-3-yl]-5-methylsulfanyl-imidazo[1,2-d][1,2,4]triazine-8-amine (300 mg, 1.13 mmol, 1 eq) and (4-chloro-2-hydroxy-phenyl)boronic acid (293.43 mg, 1.70 mmol, 1.5 eq) in THF (5 mL) was added Pd(PPh 3 ) 4(393.42 mg, 340.46 μmol, 0.3 eq.) and CuMeSal (609.09 mg, 2.84 mmol, 2.5 eq.). The mixture was stirred at 100 °C in a sealed tube for 8 hours. The reaction mixture was quenched by adding 10 mL of EDTA and then extracted with EtOAc (10 mL x 3). The combined organic layer was washed with 10 mL of brine and purified by Na 2 SO 4 The residue was purified by column chromatography (SiO 2 , DCM / MeOH=1 / 0 to 5 / 1), and then further purified by preparative HPLC (column: Phenomenex Luna C18 100x30mm x 5μm; mobile phase: [H 2 O (0.2% FA)-ACN]; gradient: 1%-25% B over 8.0 min) to afford 5-chloro-2-[8-[[(3R)-1-methylpyrrolidin-3-yl]amino]imidazo[1,2-d][1,2,4]triazin-5-yl]phenol (20.8 mg, 5%) as an off-white solid.

[0612] 1 H NMR (400 MHz, DMSO-d 6 )δ=11.51-10.30(m,1H),7.60(s,2H),7.49(t,2H),7.11-7.01(m,2H),4.66(br d,1H),2.93(br d,1H),2.73-2.61(m,2H),2.55(br d,1H),2.34(brd,3H),2.30-2.21(m,1H),2.03-1.91(m,1H).

[0613] 1 H NMR (400 MHz, CDCl 3 )δ=8.55(br s,1H),7.96(s,1H),7.74-7.69(m,2H),7.53(br s,1H),7.20(d,1H),7.05-7.00(m,1H),5.08(br s,1H),3.53-3.47(m,2H),3.10-3.05(m,1H),2.74(br d,1H),2.68(s,3H),2.65(br d,1H),2.32-2.22(m,1H).

[0614] MS:345.1[M+H] + .

[0615] Embodiment 10: 2-(8-Fluoro-1-(((1s,3s)-3-hydroxy-3-methylcyclobutyl)amino)pyrrolo[1,2-d][1,2,4]triazin-4-yl)-5-(trifluoromethyl)phenol

[0616] Similar to the method of Example 8 above, the following examples were synthesized:

[0617]

[0618]

[0619] Embodiment 11: 2-(4-(((1s,3s)-3-hydroxy-3-methylcyclobutyl)amino)pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol

[0620]

[0621] Step 1: To a stirred degassed solution of 1-chloropyrrolo[1,2-d][1,2,4]triazine-4(3H)-one (0.60 g, 3.538 mmol) in 1,4-dioxane (12 mL) and water (1.2 mL) was added (2-methoxy-4-(trifluoromethyl)phenyl)boronic acid (0.778 g, 3.538 mmol), potassium phosphate (0.751 g, 3.538 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (0.144 g, 0.177 mmol) at room temperature and the reaction mixture was heated to 100° C. for 1 hour. The reaction progress was monitored by TLC. The reaction mixture was quenched with ice-cold water (50 mL) and stirred for 10 minutes. The precipitate was filtered, washed with water (50 mL), and dried in vacuo to afford 1-(2-methoxy-4-(trifluoromethyl)phenyl)pyrrolo[1,2-d][1,2,4]triazin-4(3H)-one (0.90 g, 82.25%) as an off-white solid.

[0622] MS:310.35[M+H] + .

[0623] Step 2: To a stirred solution of 1-(2-methoxy-4-(trifluoromethyl)phenyl)pyrrolo[1,2-d][1,2,4]triazine-4(3H)-one (0.60 g, 1.940 mmol) in pyridine (6.0 mL) was added phosphorus pentasulfide (1.725 g, 3.880 mmol) at room temperature and the reaction mixture was heated to 150 ° C in a sealed tube for 3 hours. The reaction progress was monitored by TLC. The reaction mixture was diluted with ice-cold water (50 mL) and stirred for 10 minutes. The precipitated solid was filtered, washed with water (50 mL), and dried in vacuo to give 1-(2-methoxy-4-(trifluoromethyl)phenyl)pyrrolo[1,2-d][1,2,4]triazine-4(3H)-thione (0.50 g, 79.22%) as an off-white solid.

[0624] MS:326.26[M+H] + .

[0625] Step 3: Add ethyl 2-bromoacetate (0.513g, 3.074mmol) and potassium carbonate (1.062g, 7.685mmol) to a stirred degassed solution of 1-(2-methoxy-4-(trifluoromethyl)phenyl)pyrrolo[1,2-d][1,2,4]triazine-4(3H)-thione (0.50g, 1.537mmol) in tetrahydrofuran (20.0mL) and water (10.0mL) at room temperature, and stir the reaction mixture for 3 hours. Monitor the reaction process by TLC. The reaction mixture is diluted with water (50mL) and extracted with EtOAc (2x100 mL). The combined organic layer is washed with saline solution (50mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product as a brown oil.

[0626] MS:412.28[M+H] + .

[0627] Step 4: To a stirred solution of ethyl 2-((1-(2-methoxy-4-(trifluoromethyl)phenyl)pyrrolo[1,2-d][1,2,4]triazine-4-yl)thio)acetate (0.50 g, 1.215 mmol) and (1s,3s)-3-amino-1-methylcyclobutane 1-ol hydrochloride (0.334 g, 2.431 mmol) in N,N-dimethylformamide (10.0 mL) was added N,N-diisopropylethylamine (0.635 mL, 3.646 mmol) at room temperature, and the reaction mixture was heated to 100 ° C and stirred in a sealed tube for 16 hours. The reaction progress was monitored by TLC. The reaction mixture was diluted with ice-cold water (50 mL) and extracted with EtOAc (2x100 mL). The combined organic layer was washed with cold brine solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product as a brown gum. The crude product was purified by column silica gel (100-200) chromatography and eluted with 0-10% MeOH gradient in DCM. Pure fractions were collected and concentrated under reduced pressure to give (1s, 3s) -3- ((1- (2- methoxy -4- (trifluoromethyl) phenyl) pyrrolo [1, 2-d] [1, 2, 4] triazine -4- bases) amino) -1- methylcyclobutane 1-ol (0.30 g, 63%) as an off-white solid.

[0628] MS:393.36[M+H] + .

[0629] Step 5: To a stirred solution of (1s,3s)-3-((1-(2-methoxy-4-(trifluoromethyl)phenyl)pyrrolo[1,2-d][1,2,4]triazine-4-yl)amino)-1-methylcyclobutane 1-ol (0.150 g, 0.382 mmol) in dichloromethane (7.5 mL) was added boron tribromide 1.0 M (1.147 mL, 1.147 mmol) in dichloromethane at -78 °C and the reaction mixture was stirred for 10 minutes. The progress of the reaction was monitored by TLC. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2x5 0 mL). The combined organic layers were washed with brine solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product as a yellow solid. The crude product was purified by preparative HPLC (column: Luna C18 (25 x 150 mm) 10 μm; buffer A: 10 mm ABC buffer B: acetonitrile mobile phase conditions (T / %B): 0 / 30, 2 / 30, 10 / 70, 15 / 70, 15.1 / 98, 20 / 98, 20.1 / 98 flow rate: 19 mL / min, fraction volume: 200 mL). The fractions were collected, concentrated under reduced pressure, and freeze-dried to give 2-(4-(((1s,3s)-3-hydroxy-3-methylcyclobutyl)amino)pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol (0.047 g, 32%) as an off-white solid.

[0630] 1H NMR (400MHz, DMSO) δ13.60(s,1H),8.14(d,1H),8.09(d,1H),8.06-7.90(m,1H),7.36-7.24(m,2H),7.21( d,1H),7.14-7.06(m,1H),5.08(s,1H),4.30-4.13(m,1H),2.49-2.46(m,2H),2.21(dd,2H),1.34(s,3H).

[0631] MS:379.25[M+H] + .

[0632] Embodiment 12: 2-(1-(((1s,3s)-3-hydroxy-3-methylcyclobutyl)amino)pyrrolo[1,2-d][1,2,4]triazin-4-yl)-5-(trifluoromethyl)phenol

[0633]

[0634] Step 1: Aluminum isopropoxide (4.897 g, 23.975 mmol) was added to a stirred solution of 1H-pyrrole-2-carbohydrazide (15 g, 119.874 mmol) and tetramethyl orthocarbonate (24.239 mL, 179.812 mmol) in acetonitrile (250 mL) at room temperature, and the reaction mixture was stirred at 120 ° C for 5 days in a sealed tube. The reaction process was monitored by TLC. The reaction mixture was cooled to room temperature and diluted with ACN (40 mL), the formed precipitate was filtered, and thoroughly dried under vacuum to give 4-methoxypyrrolo[1,2-d][1,2,4]triazine-1(2H)-one (7.5 g, 38%) as a yellow solid.

[0635] MS:166.31[M+H] + .

[0636] Step 2: To a stirred solution of sodium hydride, 60% (3.270 g, 136.238 mmol) in N,N-dimethylformamide (60 mL) was added 4-methoxypyrrolo[1,2-d][1,2,4]triazine-1(2H)-one (7.5 g, 45.413 mmol) at 0°C, the reaction mixture was stirred for 10 minutes, and then benzyl bromide (6.473 mL, 54.495 mmol) was added at 0°C. The resulting mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. The reaction mixture was quenched with ice-cold water (120 mL) and stirred for 30 minutes. The precipitated solid was filtered, washed with water (10 mL), and dried in vacuo to give 2-benzyl-4-methoxypyrrolo[1,2-d][1,2,4]triazine-1(2H)-one (6 g, 55%) as an off-white solid.

[0637] MS:256.11[M+H] + .

[0638] Step 3: To a stirred solution of 2-benzyl-4-methoxypyrrolo[1,2-d][1,2,4]triazine-1(2H)-one (6 g, 23.504 mmol) in acetonitrile (120 mL) was added trimethylchlorosilane (6.563 mL, 51.709 mmol) and sodium iodide (7.751 g, 51.709 mmol) at room temperature, and the reaction mixture was stirred at 80 ° C for 1 hour. The reaction process was monitored by TLC. The reaction mixture was quenched with ice-cold water (150 mL) and stirred for 30 minutes. The solid was precipitated, filtered, washed with water (20 mL), and dried in vacuo to give 2-benzyl-4-hydroxypyrrolo[1,2-d][1,2,4]triazine-1(2H)-one (5 g, 88%) as an off-white solid.

[0639] MS:242.07[M+H] + .

[0640] Step 4: Triethylamine (2.311 mL, 16.580 mmol) and trifluoromethanesulfonic anhydride (2.784 mL, 16.580 mmol) were added dropwise to a stirred solution of 2-benzyl-4-hydroxypyrrolo[1,2-d][1,2,4]triazine-1(2H)-one (2.0 g, 8.290 mmol) in DCM (200 mL) at 0 °C, and the reaction mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by TLC. The reaction mixture was diluted with water (60 mL) and extracted with DCM (2 x 60 ml). The combined organic layers were purified by Na 2 SO 4 The crude compound was purified by column silica gel (100-200) chromatography and gradient elution with DCM. The product was eluted in 100% DCM. The pure fractions were collected and concentrated under reduced pressure to give trifluoromethanesulfonic acid 2-benzyl-1-oxo-1,2-dihydropyrrolo[1,2-d][1,2,4]triazine-4-yl ester (1.9 g, 61%) as an off-white solid.

[0641] MS:374.36[M+H] + .

[0642] Step 5: To a degassed solution of (2-methoxy-4-(trifluoromethyl)phenyl)boronic acid (1.679 g, 7.634 mmol) and triethylamine (2.128 mL, 15.269 mmol) in 1,4-dioxane (10 mL) was added Xantphos Pd G 4 (0.490g, 0.509mmol), and the reaction mixture was stirred at 100 ° C for 3 minutes. Then trifluoromethanesulfonic acid 2-benzyl-1-oxo-1,2-dihydropyrrolo[1,2-d][1,2,4]triazine-4-yl ester (1.9g, 5.090mmol) in 1,4-dioxane (10mL) was added dropwise for 20 minutes, and the reaction mixture was stirred at the same temperature for 20 minutes. The reaction process was monitored by TLC. The reaction mixture was diluted with water (30mL) and extracted with EtOAc (2x 70ml). The combined organic layer was filtered through Na 2 SO 4Dried, filtered, and evaporated under reduced pressure to give a crude compound as a brown gum. The crude product was purified by column silica gel (100-200) chromatography and gradient elution with EtOAc in petroleum ether. The product was eluted in 20% EtOAc in petroleum ether. Pure fractions were collected and concentrated under reduced pressure to give 2-benzyl-4-(2-methoxy-4-(trifluoromethyl)phenyl)pyrrolo[1,2-d][1,2,4]triazine-1(2H)-one (1.5 g, 73.79%) as an off-white solid.

[0643] MS:400.20[M+H] + .

[0644] Step 6: Phosphorus oxychloride (6 mL) was added dropwise to compound 2-benzyl-4-(2-methoxy-4-(trifluoromethyl)phenyl)pyrrolo[1,2-d][1,2,4]triazine-1(2H)-one (500 mg, 1.252 mmol) at 0 ° C, and the reaction mixture was stirred at 110 ° C for 48 hours. The reaction process was monitored by LCMS. The crude material was evaporated under reduced pressure. The reaction mixture was quenched with a saturated ice-cold bicarbonate solution (12 mL) and extracted with EtOAc (2 x 30 mL). The combined organic layer was washed with a saline solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product as a brown jelly. The crude product was purified by column silica gel (100-200) chromatography and gradient elution with EtOAc in petroleum ether. The product was eluted in 20% EtOAc in petroleum ether. The pure fractions were collected and concentrated under reduced pressure to afford 1-chloro-4-(2-methoxy-4-(trifluoromethyl)phenyl)pyrrolo[1,2-d][1,2,4]triazine (60 mg, 14.62%) as an off-white solid.

[0645] MS:328.10[M+H] + .

[0646] Step 7: Add 1M boron tribromide (0.366mL, 0.366mmol) in dichloromethane to a stirred solution of 1-chloro-4-(2-methoxy-4-(trifluoromethyl)phenyl)pyrrolo[1,2-d][1,2,4]triazine (40mg, 0.122mmol) in DCM (4mL) at -78°C, and slowly warm the reaction mixture to room temperature and stir for 2 hours. Monitor the reaction process by LCMS. The reaction mixture was diluted with water (10mL) and extracted with EtOAc (2x 30mL). The combined organic layer was washed with saline solution (20mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product as an off-white jelly.

[0647] MS:314.12[M+H] + .

[0648] Step 8: In a sealed tube, 2-(1-chloropyrrolo[1,2-d][1,2,4]triazine-4-yl)-5-(trifluoromethyl)phenol (45mg, 0.143mmol) was added to a stirred solution of N,N-diisopropylethylamine (0.5mL) (1s, 3s)-3-amino-1-methylcyclobutane 1-ol hydrochloride (23.690mg, 0.172mmol), and the reaction mixture was stirred at 120°C for 3 hours. The reaction process was monitored by LCMS. The reaction mixture was evaporated under reduced pressure to obtain a crude residue as a yellow solid. The product was purified by preparative HPLC (mobile phase: 10 mM ammonium bicarbonate (Aq): MeCN, column: X select-CSH, flow rate 5 ml / min, gradient method: 0 / 30, 10 / 60, 10.01 / 100, 16 / 100, 16.01, 30, 21 / 30). The fractions were collected, concentrated under reduced pressure, and freeze-dried to give 2-(1-(((1s,3s)-3-hydroxy-3-methylcyclobutyl)amino)pyrrolo[1,2-d][1,2,4]triazin-4-yl)-5-(trifluoromethyl)phenol (5 mg, 9.2%) as an off-white solid.

[0649] 1H NMR (400MHz, DMSO) δ10.82(s,1H),7.64(d,1H),7.43(d,1H),7.38-7.24(m,2H),7.14-6.99(m,2 H),6.71(dd,1H),5.01(s,1H),4.15(h,1H),2.47-2.39(m,2H),2.22-2.04(m,2H),1.31(s,3H).

[0650] MS:379.30[M+H] + .

[0651] Embodiment 13: 2-(4-((1s,3s)-3-hydroxy-3-methylcyclobutyloxy)pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol

[0652]

[0653] Step 1: To a stirred solution of 1-(2-methoxy-4-(trifluoromethyl)phenyl)pyrrolo[1,2-d][1,2,4]triazine-4(3H)-thione (0.30 g, 0.922 mmol) in DCM (15.0 mL) was added 1.0 M boron tribromide (2.767 mL, 2.767 mmol) in DCM at -78 °C and the reaction mixture was stirred for 1 hour. The reaction progress was monitored by TLC. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2x100 mL). The combined organic layers were washed with brine solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product as a light yellow solid.

[0654] MS:312.33[M+H] + .

[0655] Step 2: Add ethyl 2-bromoacetate (0.134g, 0.803mmol) and potassium carbonate (0.166g, 1.205mmol) to a stirred degassed solution of 1-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrrolo[1,2-d][1,2,4]triazine-4(3H)-thione (0.25g, 0.803mmol) in THF (10.0mL) and water (5.0mL) at room temperature, and stir the reaction mixture for 2 hours. Monitor the reaction process by TLC. The reaction mixture is diluted with water (100mL) and extracted with EtOAc (2x200mL). The combined organic layer is washed with saline solution (50mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product as a yellow solid.

[0656] MS:398.23[M+H] + .

[0657] Step 3: To a stirred solution of 1-methylcyclobutane-1,3-diol (0.964 g, 9.437 mmol) in THF (6.0 mL) was added a solution of LiHMDS 1M in THF (3.146 mL, 3.146 mmol) at room temperature, and the reaction mixture was heated to 65 ° C for 10 minutes. Then, ethyl 2-((1-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrrolo[1,2-d][1,2,4]triazine-4-yl)thio)acetate (0.250 g, 0.629 mmol) in THF (4.0 mL) was added to the suspension at room temperature, the reaction mixture was heated to 65 ° C, and stirred in a sealed tube for 16 hours. The reaction process was monitored by TLC. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2x 200 mL). The combined organic layers were washed with brine solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product as a brown gum. The crude product was purified by preparative HPLC. (Buffer A: 10 mm ABC, Buffer B: ACN, mobile phase conditions (% of B): 0 / 40, 2 / 40, 10 / 70, 16 / 70, 16.01 / 9, column: inersil flow rate -19 mL / min). Pure fractions were collected, concentrated under reduced pressure, and freeze-dried to give 2-(4-((1s, 3s)-3-hydroxy-3-methylcyclobutyloxy)pyrrolo[1,2-d][1,2,4]triazine-1-yl)-5-(trifluoromethyl)phenol (0.017 g, 7%) as an off-white solid.

[0658] 1H NMR(400MHz,DMSO)δ12.23(s,1H),7.84(d,1H),7.77(dd,1H),7.25(s,1H),7.20(d,1H),7.05 (dd,1H),6.96(dd,1H),5.46-5.10(m,2H),2.74-2.61(m,2H),2.44-2.33(m,2H),1.32(s,3H).

[0659] MS:380.26[M+H] + .

[0660] Embodiment 14: 2-[8-[[(3R)-1-ethyl-3-piperidinyl]amino]imidazo[1,2-d][1,2,4]triazin-5-yl]-5-(trifluoromethyl)phenol

[0661]

[0662] Step 1: A mixture of 8-chloro-5-methylsulfanyl-imidazo[1,2-d][1,2,4]triazine (0.5 g, 2.49 mmol, 1 eq), (3R)-1-ethylpiperidin-3-amine (1.00 g, 4.98 mmol, 2 eq, 2HCl), DIEA (1.29 g, 9.97 mmol, 1.74 mL, 4 eq), and KF (289.54 mg, 4.98 mmol, 116.75 μL, 2 eq) in DMSO (5 mL) was degassed and heated to 40 ℃ for 1 hr. 2 The mixture was purified three times and then heated under N 2 The reaction mixture was stirred at 100°C for 14 hours under a 37°C atmosphere. 2 O (50 mL) quenched, and then extracted with EtOAc (30 mL x 3). The combined organic layer was washed with brine (50 mL x 3) and purified by Na 2 SO 4 The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 4 / 1 to 1 / 1, then DCM:MeOH:TEA = 40:2:1 to DCM:MeOH:TEA = 20:2:1, TLC (PE:EtOAc = 1:1, R f =0, DCM:MeOH:TEA = 20:2:1, R f =0.2). The purified product was diluted with EtOAc 50 mL, and then washed with brine 150 mL (50 mL*3) to give the title compound N-[(3R)-1-ethyl-3-piperidinyl]-5-methylsulfanyl-imidazo[1,2-d][1,2,4]triazine-8-amine (470 mg, 43%) as a yellow oil.

[0663] 1 H NMR (400 MHz, DMSO-d 6 )δ=7.90-7.85(m,1H),7.67(d,J=1.3Hz,1H),7.14-6.95(m,1H),4.25-4.13(m,1H),2.93-2.85(m,1H),2.71(s,3H),2.66-2. 60(m,1H),2.43-2.33(m,2H),2.21-2.03(m,2H),1.84-1.74(m,1H),1.72-1.64(m,1H),1.62-1.46(m,2H),1.05-0.98(m,3H).

[0664] MS:293.0[M+H] + .

[0665] Step 2: N-[(3R)-1-ethyl-3-piperidinyl]-5-methylsulfanyl-imidazo[1,2-d][1,2,4]triazine-8-amine (0.18 g, 615.59 μmol, 1 eq.), [2-hydroxy-4-(trifluoromethyl)phenyl]boronic acid (253.53 mg, 1.23 mmol, 2 eq.), 2-hydroxy-3-methyl-benzoic acid cuprous acid (660.79 mg, 3.08 mmol, 5 eq.) and Pd(PPh 3 ) 4 A mixture of 426.81 mg, 369.35 μmol, 0.6 eq.) in THF (10 mL) was degassed and heated with N 2 The mixture was purified three times and then heated under N 2 The reaction mixture was poured into EDTA (50 mL) and stirred at room temperature for 1 hour. The mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL x 3) and purified by Na 2 SO 4 The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 2 / 1 to 1 / 2, then DCM:MeOH:TEA = 20:2:1, TLC (PE:EtOAc = 1:1, R f =0, DCM:MeOH:TEA = 20:2:1, R f =0.2)) and then purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 2 / 1 to 1 / 2, then DCM:MeOH:TEA = 20:2:1, TLC (PE:EtOAc = 1:1, R f =0, DCM:MeOH:TEA = 20:2:1, R f =0.2)), and then purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um; mobile phase: [H 2 O(10 mM NH 4 HCO 3 )-ACN]; gradient: 15%-45% B over 8.0 minutes) to give 2-[8-[[(3R)-1-ethyl-3-piperidinyl]amino]imidazo[1,2-d][1,2,4]triazin-5-yl]-5-(trifluoromethyl)phenol (36.75 mg, 14%) as a white solid.

[0666] LC-MS (ES+, m / z): 407.1 [(M+H)+ ].

[0667] 1H NMR (400MHz, DMSO-d 6 )δ=11.41-10.70(m,1H),7.77-7.66(m,1H),7.64-7.57(m,1H),7.56-7.49(m,1H),7.39-7.20(m,3H),4.44-4.22(m,1H), 2.99-2.83(m,1H),2.74-2.57(m,1H),2.39(q,2H),2.25-2.02(m,2H),1.88-1.79(m,1H),1.77-1.46(m,3H),1.02(t,3H).

[0668] MS:407.1[M+H] + .

[0669] Embodiment 15: 5-Chloro-2-[8-[[(3R)-1-ethyl-3-piperidinyl]amino]imidazo[1,2-d][1,2,4]triazin-5-yl]phenol

[0670]

[0671] N-[(3R)-1-ethyl-3-piperidinyl]-5-methylsulfanyl-imidazo[1,2-d][1,2,4]triazine-8-amine (0.18 g, 615.59 μmol, 1 eq), (4-chloro-2-hydroxy-phenyl)boronic acid (212.22 mg, 1.23 mmol, 2 eq), 2-hydroxy-3-methyl-benzoic acid cuprous acid (660.79 mg, 3.08 mmol, 5 eq) and Pd(PPh 3 ) 4 A mixture of 426.81 mg, 369.35 μmol, 0.6 eq.) in THF (10 mL) was degassed and heated with N 2 The mixture was purified three times and then placed in a sealed tube under N 2 The reaction mixture was poured into EDTA (50 mL) and stirred at room temperature for 1 hour. The mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL x 3) and purified by Na 2 SO 4 The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 2 / 1 to 1 / 2, then DCM:MeOH:TEA = 20:2:1, TLC (PE:EtOAc = 1:1, Rf =0, DCM:MeOH:TEA = 20:2:1, R f =0.2)) and further purified by preparative HPLC (column: Waters Xbridge Prep OBD C18150*40mm*10um; mobile phase: [H 2 O (10 mM NH 4 HCO 3 )-ACN]; gradient: 15%-45% B over 8.0 minutes) to afford 5-chloro-2-[8-[[(3R)-1-ethyl-3-piperidinyl]amino]imidazo[1,2-d][1,2,4]triazin-5-yl]phenol (42.27 mg, 18%) as a white solid.

[0672] 1 H NMR (400 MHz, DMSO-d 6 )δ=11.30-10.15(m,1H),7.66-7.56(m,1H),7.50(br s,2H),7.32-7.15(m,1H),7.09-6.97(m,2H),4.37-4.19(m,1H),2.98-2.82(m,1H),2.71-2.56( m,1H),2.42-2.33(m,2H),2.24-2.01(m,2H),1.88-1.77(m,1H),1.76-1.45(m,3H),1.01(t,3H).

[0673] MS:373.1[M+H] + .

[0674] Bioassay Description

[0675] 1.1 NLRP3 inhibition assay

[0676] The following assay was used to determine the inhibitory activity of the test compounds on the NLRP3 inflammasome pathway using the common stimulants nigericin (Invivogen) or monosodium urate crystals (MSU) (Invivogen).

[0677] Cell culture

[0678] Human monocyte-like cells were cultured in RPMI-1640 Glutamax medium supplemented with 10% heat-inactivated FBS (fetal bovine serum) and 50 U / ml penicillin-streptomycin (Life Technologies).

[0679] NLRP3 inflammasome pathway activation assay

[0680] Human monocyte-like cells were seeded at 25,000 cells / well in a 384-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 induction, test compounds were added at concentrations ranging from 100 μM to 380 pM, and 30 minutes later, nigericin 3.75 μM or MSU 200 μg / ml was used to stimulate the NLRP3 inflammasome pathway for 3 hours.

[0681] Determination of IL-1β

[0682] For IL-1β quantification, supernatants were analyzed using the HTRF kit according to the manufacturer's instructions (Cisbio 62HIL1BPEH). TM In a microplate, 8 μl of sample was mixed with 5 μl of anti-IL1β Cryptate antibody (40×) and anti-IL1β XL antibody (40×), and then incubated overnight at room temperature. The reading was performed using an Envision reader (PerkinElmer).

[0683] IC 50 (Concentration corresponding to 50% inhibition) was determined using GraphPad Prism 9.

[0684] The following example compounds were tested:

[0685] Table 1

[0686]

[0687]

[0688] legend:

[0689] ++++IC 50 ≤5nM;

[0690] +++IC 50 5nM <X<20nM;

[0691] ++IC 50 20nM <X<100nM;

[0692] +IC 50 >100nM;

[0693] ND Not determined.

[0694] The test compounds were shown to inhibit IL-1β release in human monocyte-like cells using MSU or nigericin as activators, see Table 1.

[0695] In human monocyte-like cells using MSU or nigericin as activator, Z 1 =C and Z 2 =N in the corresponding compounds 13 and 12, the test compounds 8 and 11 of the present invention (whose Z 1 =N and Z 2 =C) surprisingly showed a significant increase in the inhibition of IL-1β release, see Table 1.

[0696] The results showed that in human monocyte-like cells using MSU or nigericin as activator, Z 1 =C and Z 2 =N, compared with the corresponding compound with Z 1 =N and Z 2 =C surprisingly showed a significant increase in the inhibition of IL-1β release.

[0697] 1.2 Inhibition of IL-1β in LPS / ATP-induced acute peritonitis mouse model

[0698] Evaluation of the efficacy of Compound 5 in LPS / ATP-induced acute peritonitis: LPS (lipopolysaccharide) and ATP (adenosine triphosphate) were administered to BALB / c mice by intraperitoneal (ip) injection to induce an acute inflammatory response in the peritoneal cavity.

[0699] method

[0700] Mice (BALB / c mice, 6-8 weeks old, female) were challenged with 50 μg / kg LPS by intraperitoneal (ip) injection. ATP (50 mM, 200 μL) was injected intraperitoneally (ip) 120 minutes after LPS injection. Compound 5 was formulated in an aqueous solution of 0.5% carboxymethylcellulose sodium salt and 0.2% Tween 80 at a dose volume of 10 mL / kg. Compound 5 was administered 30 minutes before LPS injection. 30 minutes after ATP injection, CO 2 Animals were sacrificed. For peritoneal wash (PW) collection, 3 mL of cold phosphate buffered saline (PBS) / heparin (25 U / mL) was injected into the peritoneal cavity with a 25G needle and the abdominal area was gently massaged for 2 minutes. The lavage fluid was collected and the supernatant was harvested after centrifugation (300 x g, 4°C for 10 minutes). The volume of the supernatant was reported and aliquoted into three Eppendorf tubes, 250 μL each. The tubes were quickly frozen on dry ice.

[0701] Cytometric bead array (CBA) assays for IL-1β detection were performed on PW supernatants as follows: supernatants or cytokine standards were incubated with the capture bead mixture for 1 hour at room temperature. Dilution factor in peritoneal lavage: for TNF-α and IL-1b, samples were diluted 2-fold; for IL-6, samples were diluted 20-fold. The capture beads were then incubated with a mixture of phycoerythrin (PE) detection reagents containing PE-conjugated anti-mouse IL-1β, TNF, and IL-6 for 1 hour at room temperature. After washing in a wash buffer containing 1xPBS, blocking protein, and detergent, the beads were resuspended and analyzed by flow cytometry.

[0702] Data were exported and plotted using GraphPad Prism 7. Raw data were analyzed for cytokines using FACP. Data are presented as mean ± SD. One-way ANOVA was used to compare significance between groups.

[0703] result

[0704] LPS- and ATP-challenged mice showed elevated IL-1β levels in plasma and peritoneal washings (PW), indicating successful model induction. Figure 1 As shown, in the LPS-ATP acute peritonitis model, compound 5 significantly reduced IL-1β release in PW in a dose-responsive manner (n=8, one-way ANOVA with Dunnett's multiple comparison correction, compared with the following group: LPS-ATP, 0 mg / kg. ****p>0.0001). It was further observed that compound 5 did not show an inhibitory effect on IL-6 or TNF-α in plasma or PW (data not shown).

Claims

1. Compounds of formula (I) or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof; in Z1 and Z2 are each selected from N and C, wherein if Z1 is N, then Z2 is C, and if Z1 is C, then Z2 is N; V, X and E are each independently selected from N and CR a ; At least one of V, X and E is CR a ; R a Independently selected from -H, -C1-C3 alkyl, -CF3 and halo; R0 is selected from -H, C1-C3 alkyl and halo; R1 is selected from -CF3, -OCF3, -OCHF2 and halo; R2 is selected from -OH, -H and -CF3; Y is selected from NH and O; and R3 is selected from 4-, 5- or 6-membered heterocycloalkyl containing one or two heteroatoms, preferably one heteroatom, wherein the heteroatom is N, which is optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl, -OH and halo; 5- or 6-membered aryl or heteroaryl, wherein the heteroaryl comprises one or two heteroatoms, wherein the heteroatom is N, which is optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, hydroxyC1-C4 alkyl, haloC1-C4 alkyl, -CN and halo; C3-C6 cycloalkyl, optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, halo C1-C4 alkyl, hydroxy C1-C4 alkyl, -OH and halo; and C1-C6 alkyl, which is substituted by one or two substituents independently selected from the group consisting of -OH, halo, halo-substituted C1-C4 alkyl and C1-C4 alkoxy.

2. Compounds of formula (I') or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof; in Z1 is N; Z2 is C; V, X and E are each independently selected from N and CR a ; At least one of V, X and E is CR a ; R a Independently selected from -H, -C1-C3 alkyl, -CF3 and halo; R0 is selected from -H, C1-C3 alkyl and halo; R1 is selected from -CF3, -OCF3, -OCHF2 and halo; R2 is selected from -OH, -H and -CF3; Y is selected from NH and O; and R3 is selected from 4-, 5- or 6-membered heterocycloalkyl containing one or two heteroatoms, preferably one heteroatom, wherein the heteroatom is N, which is optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl, -OH and halo; 5- or 6-membered aryl or heteroaryl, wherein the heteroaryl comprises one or two heteroatoms, wherein the heteroatom is N, which is optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, hydroxyC1-C4 alkyl, haloC1-C4 alkyl, -CN and halo; C3-C6 cycloalkyl, optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, halo C1-C4 alkyl, hydroxy C1-C4 alkyl, -OH and halo; and C1-C6 alkyl, which is substituted by one or two substituents independently selected from the group consisting of -OH, halo, halo-substituted C1-C4 alkyl and C1-C4 alkoxy.

3. The compound according to claim 1, which has the structure of formula (Ib) or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof; Among them, R0, R1, R 2、 R3, E and Y are as defined in claim 1.

4. The compound according to claim 1, which has the structure of formula (Ic) or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof; Among them, R0, R1, R 2、 R3, E and Y are as defined in claim 1, preferably E is CR a , where CR a As defined in claim 1.

5. The compound according to claim 1, which has the structure of formula (Ie) or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof; in X is selected from N and CR a ; R a is selected from -C1-C3 alkyl, -CF3 and halo; and R0, R1, R 2、 R3 and Y are as defined in claim 1.

6. The compound according to claim 1, which has the structure of formula (Ia) or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof; in E is selected from N and CR a ; R a Selected from -H, -C1-C3 alkyl and -CF3; R0, R1, R 2、 R3 and Y are as defined in claim 1.

7. The compound according to claim 1, which has the structure of formula (Id): or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof; Among them, R0, R1, R 2、 R3, X and Y are as defined in claim 1, preferably X is CR a , where CR a As defined in claim 1.

8. A compound of formula I, I', Ia, Ib, Ic, Id or Ie according to any one of the preceding claims, wherein R3 is selected from A 4-, 5- or 6-membered heterocycloalkyl group containing one heteroatom, wherein the heteroatom is N, which is optionally substituted with one or two substituents independently selected from: C1-C4 alkyl; 5- or 6-membered heteroaryl, wherein the heteroaryl comprises one or two heteroatoms, wherein the heteroatom is N, which is optionally substituted with one or two substituents independently selected from: C1-C4 alkyl; C3-C6 cycloalkyl, optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, -OH and halo; and Hydroxy C1-C6 alkyl.

9. A compound of formula I, I', Ia, Ib, Ic, Id or Ie according to any one of the preceding claims, wherein R3 is selected from Best wherein R4 is independently selected from -H or -C1-C3 alkyl; and n is selected from 0, 1 or 2.

10. A compound of formula I, I', Ia, Ib, Ic, Id or Ie according to any one of the preceding claims (preferably a compound of formula I', Ib, Ic or Ie), wherein R0 is -H or -CH3; R1 is -CF3; and R2 is -OH.

11. A compound of formula I, I', Ia, Ib, Ic, Id or Ie according to any one of the preceding claims, selected from or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof.

12. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 11 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.

13. A compound according to any one of claims 1 to 11 or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof for use as a medicament.

14. A compound according to any one of claims 1 to 11 or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof for use in treating, alleviating or preventing a disease or disorder or abnormality that responds to modulation of a component of the NLRP3 inflammasome pathway and / or to modulation of IL-1β and / or IL-18 levels.

15. The compound for use according to claim 14, wherein the modulation is a reduction and / or inhibition of IL-1[beta].

16. The compound for use according to claim 14, wherein the component of the inflammasome pathway is the NLRP3 inflammasome.

17. The compound for use according to claim 14 or 16, wherein activation of the NLRP3 inflammasome pathway is inhibited.

18. A compound for use according to any one of claims 14 to 17, wherein the disease, disorder or abnormality is selected from Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, demyelination, viral encephalitis, epilepsy, stroke, cerebral hemorrhage, atherosclerosis, asthma, allergic inflammation, cryptopyrin-associated periodic syndrome (CAPS), Mueller-Weiss 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), sideroblastic anemia with B-cell immunodeficiency, periodic fever, developmental delay (SIFD), chronic nonbacterial osteomyelitis (CNO), Sweet syndrome, chronic relapsing multifocal osteomyelitis (CRMO), synovitis, impetigo, acne, eczema, alopecia areata, actinic keratosis, hyperostosis, osteoarthritis syndrome (SAPHO), multiple sclerosis (MS), psoriasis, Behcet's disease, Sjögren's syndrome, Schnitzler syndrome, chronic obstructive pulmonary disorder (COPD), steroid-resistant asthma 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 eyes, chronic kidney disease, diabetic nephropathy, alcoholic liver disease, skin 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 syndrome, ischemia-reperfusion injury, frontotemporal dementia, HIV-related neurocognitive disorders, coronavirus-related inflammatory lesions, and traumatic brain and spinal cord injury, inflammatory pain, chronic pain, neuropathic pain, metastatic cancer-induced bone pain, chemotherapy-induced peripheral neuropathy and migraine; preferably, the disorder is selected from Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple 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 renal failure, disease, graft-versus-host disease, type 1 diabetes, type 2 diabetes, rheumatoid arthritis, myelodysplastic syndrome, anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV), lupus nephritis, anti-glomerular basement membrane (GMB) disease, IgA nephropathy, glomerulonephritis (GN), systemic lupus erythematosus (SLE), focal segmental glomerulosclerosis, minimal change disease (MCD), psoriatic arthritis, hereditary paroxysmal relapsing fever (HRF) and amyloidosis (including AL amyloidosis, AA amyloidosis, ATTR amyloidosis, hereditary amyloidosis (including apolipoprotein AI (AApoAI), apolipoprotein A-II (AApoAII), gelsolin (AGel), fibrinogen (AFib) and lysozyme (ALys)), beta-2 microglobulin amyloidosis iAPP amyloidosis). ; 19. A compound for use according to claim 18, wherein the disease, disorder or abnormality is selected from Alzheimer's disease and Parkinson's disease.

20. The compound for use according to claim 18, wherein the disease, disorder or abnormality is selected from the group consisting of cryopyrin-associated periodic syndrome (CAPS), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH) and gout.

21. Use of a compound according to any one of claims 1 to 11 or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof as an analytical reference or in vitro screening tool.

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