Novel compounds

Abstract

The present invention relates to novel compounds for treating, ameliorating or preventing a group of diseases, disorders and abnormalities that are responsive to modulation of components of the NLRP3 inflammasome pathway, in particular inhibition of activation. In particular, the component of the inflammasome pathway is a NOD-like receptor (NLR) family, a protein 3 (NLRP3) inflammasome containing a thermal protein domain. More particularly, the compounds of the present invention have the ability to modulate the NLRP3 inflammasome pathway. Furthermore, the compounds of the invention 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.

Description

Field of the Invention

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

[0003] Inflammasome protein complex is the key component of inflammatory signal conduction.These complex assemblies are in response to a variety of danger signals, such as molecules from pathogens (pathogen-associated molecular patterns, PAMP) and the host molecules, sterile tissue damage products and environmental factors (danger associated molecular patterns, DAMP) of change. Inflammasome family is made up of NALP1-14, IPAF and NAIP1-6, and wherein each family member provides specificity (Sharma, D.&Kanneganti, TDThe cell biology ofinflammasomes:mechanisms of inflammasome activation and regulation.J.CellBiol.213,617-629(2016)) to different PAMP / DAMP (including nucleic acid, bacterial protein, metabolite, protein aggregate and toxin activity). Inflammasomes are typically composed of sensors (cytosolic pattern recognition receptors, PRRs) and an adaptor protein called apoptosis-associated speck-like protein (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 protein containing a caspase activation and recruitment domain (ASC, also known as PYCARD) adaptor protein. The polymerization of ASC proteins into large complexes (ASC speckles) leads to the activation of caspase-1 effector proteins, which subsequently cleave pro-IL1β and pro-IL18 into their active secreted forms and mediate pyroptosis (Heneka et al., 2018 Nat Rev Neurosci). IL-1β acts through the IL-1β receptor and induces pro-inflammatory signals, including IL-6 and TNF-α secretion, and attracts and activates cells of the adaptive immune system at the site of infection. The NLRP3 / ASC complex appears to be released into the extracellular environment, where it 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 Mueller-Weissler syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), and neonatal-onset multisystem inflammatory disease (NOMID).

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

[0007] A large 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 the NLRP3-inflammasome 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 outlined above, modulation of NLRP3 inflammasome activity represents a promising therapeutic approach.

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

[0010] Several small molecules have been shown to inhibit the NLRP3 inflammasome pathway (Baldwin, AG, Brough, D. & Freeman, S. Inhibiting the NLRP3 inflammasome pathway: a chemical perspective. J. Med. Chem. 59, 1691-1710 (2016); reviewed in Mangan et al., Nat Rev Drug Discov. 2018 Aug; 17(8): 588-606). These include a variety of chemical classes, such as sulfonylurea-based compounds (glyburide, CP 456,773 (aka CRID3 and MCC950) and their derivatives); the fenamates class 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-ketone; and Michael acceptors. Most of these compounds have mixed modes of action and limited efficacy.

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

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

[0013] WO2017184604, WO2017184623, WO2017184624, WO2019023145, WO2019023147 and WO2019079119 relate to chemical entities for 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, 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 that respond to modulation of cytokines such as IL-1β and IL-18, modulation of NLRP3, or inhibition of activation of NLRP3 or components associated with inflammatory processes.

[0016] WO2018225018 and WO2019043610 relate to the use of NLRP3 modulators and novel inhibitor compounds in the treatment of diseases or disorders and in the treatment of disease states mediated by NLRP3 and in the treatment of 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 and NLRP3 modulators associated with inflammatory processes.

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

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

[0021] WO2020 / 234715 discloses pyridazin-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] The mutual interference between the NLRP3 inflammasome pathway and Tau pathology has recently 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 with beneficial pharmacological and / or physiological and / or physicochemical properties.

[0025] The present invention provides compounds of formula (I) that have surprisingly been found to modulate components of the NLRP3 inflammasome pathway, in particular to inhibit the activation of components of the NLRP3 inflammasome pathway, such as activation of the NLRP3 inflammasome. Thus, 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, alleviate 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 of the present invention, 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] X' is selected from CH or N;

[0034] W is selected from N, CH or CR c ;

[0035] Q is selected from N and C;

[0036] E is selected from NR a and CR a ;

[0037] Z is selected from N and C;

[0038] Where at least one of Q and Z is C, and / or E is CR a ;

[0039] R c Selected from -C1-C4 alkyl, -O-C1-C4 alkyl, -C1-C4 alkyl-OH, -halo or -C1-C4 alkyl-Hal;

[0040] R a Selected from -H and -C1-C3 alkyl;

[0041] R A and R B Each selected

[0042] where R A and R B One of them is And R A and R B The other one is

[0043] R0 is selected from -H, C1-C3 alkyl and halo;

[0044] R1 is selected from -CF3, -OCF3, -OCHF2 and halo;

[0045] R2 is selected from -OH, -H and -CF3;

[0046] Y is selected from NH, NR d , O, or a key;

[0047] R d Selected from -C1-C4 alkyl, -C1-C4 alkyl-OH or -C1-C4 alkyl-Hal;

[0048] R3 is selected from

[0049] A 4-, 5-, or 6-membered heterocycloalkyl group comprising one or two heteroatoms independently selected from N and O, optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl, -OH, -NR5R6, and halo; or

[0050] An 8-, 9-, or 10-membered bicyclic fused heterocycloalkyl containing 1 to 3 heteroatoms, wherein the heteroatoms are independently selected from N and O, which is optionally substituted at any available position with one or two substituents independently selected from the group consisting of C1-C4 alkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl, -OH, -NR5R6, and halo; or

[0051] C3-C6 cycloalkyl, optionally substituted by 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; or

[0052] C1-C6 alkyl, optionally substituted with one or two substituents independently selected from the group consisting of -OH, halo, halo-substituted C1-C4 alkyl, C1-C4 alkoxy, and -NR5R6;

[0053] R5 and R6 are independently selected from H and C1-C3 alkyl; and

[0054] m is 0, 1, or 2.

[0055] In one aspect of the present invention, provided herein is a compound of formula (II')

[0056]

[0057] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof;

[0058] in

[0059] X' is selected from CH or N;

[0060] W is selected from N, CH or CR c ;

[0061] Q is selected from N and C;

[0062] E is selected from NR a and CR a ;

[0063] Z is selected from N and C;

[0064] Where at least one of Q and Z is C, and / or E is CR a ;

[0065] R c Selected from C1-C4 alkyl, -O-C1-C4 alkyl, C1-C4 alkyl-OH, halo or halogenated C1-C4 alkyl;

[0066] R a Selected from -H and -C1-C3 alkyl;

[0067] R0 is selected from -H, C1-C3 alkyl and halo;

[0068] R1 is selected from -CF3, -OCF3, -OCHF2 and halo;

[0069] R2 is selected from -OH, -H and -CF3;

[0070] R A yes

[0071] Y is selected from NH, NR d , O, or a key;

[0072] R d Selected from -C1-C4 alkyl, -C1-C4 alkyl-OH or -C1-C4 alkyl-Hal;

[0073] R3 is selected from

[0074] A 4-, 5- or 6-membered heterocycloalkyl group comprising one or two heteroatoms, preferably one heteroatom, wherein the heteroatoms are independently selected from N and O, 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, -NR5R6 and halo; or

[0075] An 8-, 9-, or 10-membered bicyclic fused heterocycloalkyl containing 1 to 3 heteroatoms, wherein the heteroatoms are independently selected from N and O, which is optionally substituted at any available position with one or two substituents independently selected from the group consisting of C1-C4 alkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl, -OH, -NR5R6, and halo; or

[0076] C3-C6 cycloalkyl, optionally substituted by 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; or

[0077] C1-C6 alkyl, optionally substituted with one or two substituents independently selected from the group consisting of -OH, halo, halo-substituted C1-C4 alkyl, C1-C4 alkoxy, and -NR5R6;

[0078] R5 and R6 are independently selected from H and C1-C3 alkyl; and

[0079] m is 0, 1, or 2.

[0080] In one aspect, provided herein are compounds of formula (I)

[0081]

[0082] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof;

[0083] in

[0084] Q is selected from N and C;

[0085] E is selected from NR a and CR a ;

[0086] Z is selected from N and C;

[0087] Where at least one of Q and Z is C, and / or E is CR a ;

[0088] R a Selected from -H and -C1-C3 alkyl;

[0089] R A and R B Each selected

[0090] where R A and R B One of them is And R A and R B The other one is

[0091] R0 is selected from -H, C1-C3 alkyl and halo;

[0092] R1 is selected from -CF3, -OCF3, -OCHF2 and halo;

[0093] R2 is selected from -OH, -H and -CF3;

[0094] Y is selected from NH and O; and

[0095] R3 is selected from

[0096] 4-, 5- or 6-membered heterocycloalkyl containing one or two heteroatoms, preferably one heteroatom, wherein the heteroatoms are independently selected from N and O, 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;

[0097] C3-C6 cycloalkyl, 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; and

[0098] C1-C6 alkyl, which is optionally substituted with one or two substituents independently selected from the group consisting of -OH, halo, halo C1-C4 alkyl, C1-C4 alkoxy, and -NR5R6, wherein R5 and R6 are independently selected from H and C1-C3 alkyl.

[0099] In another aspect, there is provided a compound of formula (II)

[0100]

[0101] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof;

[0102] in

[0103] Q is selected from N and C;

[0104] E is selected from NR a and CR a ;

[0105] Z is selected from N and C;

[0106] Where at least one of Q and Z is C, and / or E is CR a ;

[0107] R a Selected from -H and -C1-C3 alkyl;

[0108] R0 is selected from -H, C1-C3 alkyl and halo;

[0109] R1 is selected from -CF3, -OCF3, -OCHF2 and halo;

[0110] R2 is selected from -OH, -H and -CF3;

[0111] Y is selected from NH and O; and

[0112] R3 is selected from

[0113] 4-, 5- or 6-membered heterocycloalkyl containing one or two heteroatoms, preferably one heteroatom, wherein the heteroatoms are independently selected from N and O, 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;

[0114] 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

[0115] C1-C6 alkyl, which is optionally substituted with one or two substituents independently selected from the group consisting of -OH, halo, halo C1-C4 alkyl, C1-C4 alkoxy, and -NR5R6, wherein R5 and R6 are independently selected from H and C1-C3 alkyl.

[0116] In another aspect, there is provided a compound of formula (III)

[0117]

[0118] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof;

[0119] in

[0120] Q is selected from N and C;

[0121] E is selected from NR a and CR a ;

[0122] Z is selected from N and C;

[0123] Where at least one of Q and Z is C, and / or E is CR a ;

[0124] R a Selected from -H and -C1-C3 alkyl;

[0125] R0 is selected from -H, C1-C3 alkyl and halo;

[0126] R1 is selected from -CF3, -OCF3, -OCHF2 and halo;

[0127] R2 is selected from -OH, -H and -CF3;

[0128] Y is selected from NH and O; and

[0129] R3 is selected from

[0130] 4-, 5- or 6-membered heterocycloalkyl containing one or two heteroatoms, preferably one heteroatom, wherein the heteroatoms are independently selected from N and O, 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;

[0131] 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

[0132] C1-C6 alkyl, which is optionally substituted with one or two substituents independently selected from the group consisting of -OH, halo, halo C1-C4 alkyl, C1-C4 alkoxy, and -NR5R6, wherein R5 and R6 are independently selected from H and C1-C3 alkyl.

[0133] In another aspect, there is provided a compound of formula (II'a)

[0134]

[0135] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof;

[0136] in

[0137] X' is selected from CH or N;

[0138] W is selected from N, CH or CR c ;

[0139] R c Selected from C1-C4 alkyl, -O-C1-C4 alkyl, C1-C4 alkyl-OH, halo or halogenated C1-C4 alkyl;

[0140] R a Selected from -H and -C1-C3 alkyl;

[0141] R0 is selected from -H, C1-C3 alkyl and halo;

[0142] R1 is selected from -CF3, -OCF3, -OCHF2 and halo;

[0143] R2 is selected from -OH, -H and -CF3;

[0144] Y is selected from NH, NR d , O, or a key;

[0145] R dSelected from -C1-C4 alkyl, -C1-C4 alkyl-OH or -C1-C4 alkyl-Hal;

[0146] R3 is selected from

[0147] A 4-, 5- or 6-membered heterocycloalkyl group comprising one or two heteroatoms, preferably one heteroatom, wherein the heteroatoms are independently selected from N and O, 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, -NR5R6 and halo; or

[0148] An 8-, 9-, or 10-membered bicyclic fused heterocycloalkyl containing 1 to 3 heteroatoms, wherein the heteroatoms are independently selected from N and O, which is optionally substituted at any available position with one or two substituents independently selected from the group consisting of C1-C4 alkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl, -OH, -NR5R6, and halo; or

[0149] C3-C6 cycloalkyl, optionally substituted by 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; or

[0150] C1-C6 alkyl, optionally substituted with one or two substituents independently selected from the group consisting of -OH, halo, halo-substituted C1-C4 alkyl, C1-C4 alkoxy, and -NR5R6;

[0151] R5 and R6 are independently selected from H and C1-C3 alkyl; and

[0152] m is 0, 1, or 2.

[0153] In another aspect, there is provided a compound of formula (IIa)

[0154]

[0155] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof;

[0156] in

[0157] R a Selected from -H and -C1-C3 alkyl;

[0158] R0 is selected from -H, C1-C3 alkyl and halo;

[0159] R1 is selected from -CF3, -OCF3, -OCHF2 and halo;

[0160] R2 is selected from -OH, -H and -CF3;

[0161] Y is selected from NH and O; and

[0162] R3 is selected from

[0163] 4-, 5- or 6-membered heterocycloalkyl containing one or two heteroatoms, preferably one heteroatom, wherein the heteroatoms are independently selected from N and O, 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;

[0164] 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

[0165] C1-C6 alkyl, which is optionally substituted with one or two substituents independently selected from the group consisting of -OH, halo, halo C1-C4 alkyl, C1-C4 alkoxy, and -NR5R6, wherein R5 and R6 are independently selected from H and C1-C3 alkyl.

[0166] In another aspect, there is provided a compound of formula (II'b)

[0167]

[0168] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof;

[0169] in

[0170] X' is selected from CH or N;

[0171] W is selected from N, CH or CR c ;

[0172] R c Selected from -C1-C4 alkyl, -O-C1-C4 alkyl, -C1-C4 alkyl-OH, -halo or C1-C4 alkyl-Hal;

[0173] R a Selected from -H and -C1-C3 alkyl;

[0174] R0 is selected from -H, C1-C3 alkyl and halo;

[0175] R1 is selected from -CF3, -OCF3, -OCHF2 and halo;

[0176] R2 is selected from -OH, -H and -CF3;

[0177] Y is selected from NH, NR d , O, or a key;

[0178] R d Selected from -C1-C4 alkyl, -C1-C4 alkyl-OH or -C1-C4 alkyl-Hal;

[0179] R3 is selected from

[0180] A 4-, 5-, or 6-membered heterocycloalkyl group comprising one or two heteroatoms independently selected from N and O, optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl, -OH, -NR5R6, and halo; or

[0181] An 8-, 9-, or 10-membered bicyclic fused heterocycloalkyl containing 1 to 3 heteroatoms, wherein the heteroatoms are independently selected from N and O, which is optionally substituted at any available position with one or two substituents independently selected from the group consisting of C1-C4 alkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl, -OH, -NR5R6, and halo; or

[0182] C3-C6 cycloalkyl, optionally substituted by 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; or

[0183] C1-C6 alkyl, optionally substituted with one or two substituents independently selected from the group consisting of -OH, halo, halo-substituted C1-C4 alkyl, C1-C4 alkoxy, and -NR5R6;

[0184] R5 and R6 are independently selected from H and C1-C3 alkyl;

[0185] m is 0, 1, or 2.

[0186] In another aspect, there is provided a compound of formula (IIb)

[0187]

[0188] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof;

[0189] in

[0190] R a Selected from -H and -C1-C3 alkyl;

[0191] R0 is selected from -H, C1-C3 alkyl and halo;

[0192] R1 is selected from -CF3, -OCF3, -OCHF2 and halo;

[0193] R2 is selected from -OH, -H and -CF3;

[0194] Y is selected from NH and O; and

[0195] R3 is selected from

[0196] 4-, 5- or 6-membered heterocycloalkyl containing one or two heteroatoms, preferably one heteroatom, wherein the heteroatoms are independently selected from N and O, 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;

[0197] 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

[0198] C1-C6 alkyl, which is optionally substituted with one or two substituents independently selected from the group consisting of -OH, halo, halo C1-C4 alkyl, C1-C4 alkoxy, and -NR5R6, wherein R5 and R6 are independently selected from H and C1-C3 alkyl.

[0199] In another aspect, there is provided a compound of formula (IV)

[0200]

[0201] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof; wherein

[0202] R a Selected from -H and -C1-C3 alkyl;

[0203] R0 is selected from -H, C1-C3 alkyl and halo;

[0204] R1 is selected from -CF3, -OCF3, -OCHF2 and halo;

[0205] R2 is selected from -OH, -H and -CF3;

[0206] Y is selected from NH, NR d , O, or a key;

[0207] R d Selected from -C1-C4 alkyl, -C1-C4 alkyl-OH or -C1-C4 alkyl-Hal;

[0208] R3 is selected from

[0209] A 4-, 5-, or 6-membered heterocycloalkyl group comprising one or two heteroatoms independently selected from N and O, optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl, -OH, -NR5R6, and halo; or

[0210] An 8-, 9-, or 10-membered bicyclic fused heterocycloalkyl containing 1 to 3 heteroatoms, wherein the heteroatoms are independently selected from N and O, which is optionally substituted at any available position with one or two substituents independently selected from the group consisting of C1-C4 alkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl, -OH, -NR5R6, and halo; or

[0211] C3-C6 cycloalkyl, optionally substituted by 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; or

[0212] C1-C6 alkyl, optionally substituted with one or two substituents independently selected from the group consisting of -OH, halo, halo-substituted C1-C4 alkyl, C1-C4 alkoxy, and -NR5R6;

[0213] R5 and R6 are independently selected from H and C1-C3 alkyl;

[0214] m is 0, 1, or 2.

[0215] In another aspect, there is provided a compound of formula (V)

[0216]

[0217] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof;

[0218] in

[0219] R a Selected from -H and -C1-C3 alkyl;

[0220] R0 is selected from -H, C1-C3 alkyl and halo;

[0221] R1 is selected from -CF3, -OCF3, -OCHF2 and halo;

[0222] R2 is selected from -OH, -H and -CF3;

[0223] Y is selected from NH, NR d , O, or a key;

[0224] R d Selected from -C1-C4 alkyl, -C1-C4 alkyl-OH or -C1-C4 alkyl-Hal;

[0225] R3 is selected from

[0226] A 4-, 5-, or 6-membered heterocycloalkyl group comprising one or two heteroatoms independently selected from N and O, optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl, -OH, -NR5R6, and halo; or

[0227] An 8-, 9-, or 10-membered bicyclic fused heterocycloalkyl containing 1 to 3 heteroatoms, wherein the heteroatoms are independently selected from N and O, which is optionally substituted at any available position with one or two substituents independently selected from the group consisting of C1-C4 alkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl, -OH, -NR5R6, and halo; or

[0228] C3-C6 cycloalkyl, optionally substituted by 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; or

[0229] C1-C6 alkyl, optionally substituted with one or two substituents independently selected from the group consisting of -OH, halo, halo-substituted C1-C4 alkyl, C1-C4 alkoxy, and -NR5R6;

[0230] R5 and R6 are independently selected from H and C1-C3 alkyl;

[0231] m is 0, 1, or 2.

[0232] In the present invention, any reference to a compound of formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV) or (V) or a preferred embodiment thereof is also intended to refer to a stereoisomer, or a racemic mixture, or a tautomer, or a polymorph, or a pharmaceutically acceptable salt, or a prodrug, or a hydrate, or a solvate thereof.

[0233] Compounds of formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV) or (V), or stereoisomers, racemic mixtures, tautomers, polymorphs, pharmaceutically acceptable salts, prodrugs, hydrates or solvates thereof, are suitable for treating, alleviating or preventing diseases, disorders or abnormalities that are responsive to modulation, particularly inhibition, of a component of the NLRP3 inflammasome pathway and / or 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 specks, 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. Compounds of formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV), or (V), or stereoisomers, racemic mixtures, tautomers, polymorphs, pharmaceutically acceptable salts, prodrugs, hydrates, or solvates thereof, have the ability to modulate, in particular, reduce, IL-1β and / or IL-18 levels.

[0234] Compounds of Formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV) or (V) 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 the activation of NLRP3 inflammasome pathway components, particularly wherein the inflammasome pathway component is the NLRP3 inflammasome. Due to their unique design features, these compounds exhibit properties such as modulating the NLRP3 inflammasome pathway or inhibiting the activation of the NLRP3 inflammasome pathway, making them promising drugs for treating, alleviating or preventing diseases, disorders or abnormalities responsive to modulation or inhibition of NLRP3 inflammasome pathway components, such as Alzheimer's disease, Parkinson's disease, CAPS, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH) and gout.

[0235] In another embodiment, the present invention is directed to a pharmaceutical composition comprising a compound of Formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV) or (V) 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.

[0236] In another embodiment, the present invention relates to a compound of Formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV) or (V), or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, for use as a medicament.

[0237] In another embodiment, the present invention relates to a compound of formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV) or (V), or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, for use in treating, alleviating or preventing a disease, disorder or abnormality that responds to modulation, particularly inhibition of activation, of a component of the NLRP3 inflammasome pathway and / or to modulation, particularly reduction, of IL-1β and / or IL-18 levels.

[0238] Another embodiment relates to the use of a compound of Formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV) or (V), or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, in the preparation of a medicament for treating, alleviating or preventing a disease, disorder or abnormality that responds to modulation, particularly inhibition of activation, of a component of the NLRP3 inflammasome pathway and / or to modulation, particularly reduction, of IL-1β and / or IL-18 levels.

[0239] 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 a component 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, comprising administering to an individual (e.g., a patient) in need thereof a therapeutically effective amount of a compound of Formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV) or (V) or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof.

[0240] The present invention also provides pharmaceutical compositions comprising a compound of formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV) or (V), 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 which is different from a compound of formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV) or (V), 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.

[0241] 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 beta antibody, an anti-Tau antibody, an amyloid beta small molecule inhibitor, a Tau aggregation small molecule inhibitor, an anti-alpha synuclein antibody or an alpha synuclein aggregation small molecule inhibitor, an anti-TDP-43 antibody or an anti-TDP-43 aggregation small molecule inhibitor, etc. When a compound of the present invention is used in combination with an additional biologically active compound, the dosage of each compound may differ from the dosage when the compound is used as a monotherapy.

[0242] Additional embodiments relate to the use of a compound of Formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV) or (V), or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, as an analytical reference or in vitro screening tool.

[0243] The present invention is described below. BRIEF DESCRIPTION OF THE DRAWINGS

[0245] Figure 1 : Inhibition of IL-1β release by the compound of the present invention (Example Compound 53) in the LPS / ATP-induced acute peritonitis mouse model

[0246] Figure 2 : Inhibition of IL-1β release by the compound of the present invention (Compound 18) in the LPS / ATP-induced acute peritonitis mouse model Detailed Description of the Invention

[0248] The present invention relates to compounds of formula (I') and compounds of formula (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV) or (V), including stereoisomers, racemic mixtures, tautomers, polymorphs, pharmaceutically acceptable salts, prodrugs, hydrates or solvates thereof.

[0249] For compounds of formula (I') and its subformulas, R A 、R B , R0, R1, R 2、 R3, R4, R5, R6, R a 、R c 、R d Any definitions of , E, Q, W, X, X', Z, Y, m, n and / or a apply analogously to compounds of Formula (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV) or (V), provided that R A 、R B , R0, R1, R 2、 R3, R4, R5, R6, R a 、R c 、R d , E, Q, W, X, X', Z, Y, m, n and / or a are used.

[0250] In one aspect of the present invention, provided herein is a compound of formula (I')

[0251]

[0252] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof;

[0253] in

[0254] X' is selected from CH or N;

[0255] W is selected from N, CH or CR c ;

[0256] Q is selected from N and C;

[0257] E is selected from NR a and CR a ;

[0258] Z is selected from N and C;

[0259] Where at least one of Q and Z is C, and / or E is CR a ;

[0260] R c Selected from -C1-C4 alkyl, -O-C1-C4 alkyl, -C1-C4 alkyl-OH, -halo or C1-C4 alkyl-Hal;

[0261] R a Selected from -H and -C1-C3 alkyl;

[0262] R A and R B Each selected

[0263] where R A and R B One of them is And R A and R B The other one is

[0264] R0 is selected from -H, C1-C3 alkyl and halo;

[0265] R1 is selected from -CF3, -OCF3, -OCHF2 and halo;

[0266] R2 is selected from -OH, -H and -CF3;

[0267] Y is selected from NH, NR d , O, or a key;

[0268] R d Selected from -C1-C4 alkyl, -C1-C4 alkyl-OH or -C1-C4 alkyl-Hal;

[0269] R3 is selected from

[0270] A 4-, 5-, or 6-membered heterocycloalkyl group comprising one or two heteroatoms independently selected from N and O, optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl, -OH, -NR5R6, and halo; or

[0271] An 8-, 9-, or 10-membered bicyclic fused heterocycloalkyl containing 1 to 3 heteroatoms, wherein the heteroatoms are independently selected from N and O, which is optionally substituted at any available position with one or two substituents independently selected from the group consisting of C1-C4 alkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl, -OH, -NR5R6, and halo; or

[0272] C3-C6 cycloalkyl, optionally substituted by 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; or

[0273] C1-C6 alkyl, optionally substituted with one or two substituents independently selected from the group consisting of -OH, halo, halo-substituted C1-C4 alkyl, C1-C4 alkoxy, and -NR5R6;

[0274] R5 and R6 are independently selected from H and C1-C3 alkyl; and

[0275] m is 0, 1, or 2.

[0276] The present invention also relates to compounds of formula (I) as defined below

[0277]

[0278] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof;

[0279] in

[0280] Q is selected from N and C;

[0281] E is selected from NR a and CR a ;

[0282] Z is selected from N and C;

[0283] Where at least one of Q and Z is C, and / or E is CR a ;

[0284] R a Selected from -H and -C1-C3 alkyl;

[0285] R A and RB Each selected

[0286] where R A and R B One of them is And R A and R B The other one is

[0287] R0 is selected from -H, C1-C3 alkyl and halo;

[0288] R1 is selected from -CF3, -OCF3, -OCHF2 and halo;

[0289] R2 is selected from -OH, -H and -CF3;

[0290] Y is selected from NH and O; and

[0291] R3 is selected from

[0292] 4-, 5- or 6-membered heterocycloalkyl containing one or two heteroatoms, preferably one heteroatom, wherein the heteroatoms are independently selected from N and O, 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;

[0293] 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

[0294] C1-C6 alkyl, which is optionally substituted with one or two substituents independently selected from the group consisting of -OH, halo, halo C1-C4 alkyl, C1-C4 alkoxy, and -NR5R6, wherein R5 and R6 are independently selected from H and C1-C3 alkyl.

[0295] In a preferred embodiment, R0 is selected from -H and C1-C3 alkyl, more preferably -H or methyl. In a preferred embodiment, R0 is -H. In another preferred embodiment, R0 is C1-C3 alkyl, preferably methyl or ethyl, more preferably methyl.

[0296] In a preferred embodiment, R1 is selected from -CF3, -OCF3 and -OCHF2. In a preferred embodiment, R1 is -CF3. In another preferred embodiment, R1 is -OCF3. In another preferred embodiment, R1 is -OCHF2.

[0297] In another preferred embodiment, R1 is halo. When R1 is halo, halogen (halo) is preferably chlorine.

[0298] In a preferred embodiment, R2 is -OH or H, more preferably -OH. In another embodiment, R2 is -H. In another embodiment, R2 is -CF3.

[0299] In a preferred embodiment, R0 is -H, R1 is selected from -CF3, -OCF3, -OCHF2 and -Cl, and R2 is -OH or -H. In a preferred embodiment, R0 is -H, R1 is -CF3, and R2 is -OH.

[0300] In another preferred embodiment, R0 is -H or methyl, R1 is selected from -CF3 or -Cl, and R2 is -OH.

[0301] In a more preferred embodiment

[0302] R0 is -H, R1 is -CF3, and R2 is -OH; or

[0303] R0 is -H, R1 is -Cl, and R2 is -OH; or

[0304] R0 is -CH3, R1 is -Cl, and R2 is -OH.

[0305] R0 is -CH3, R1 is -CF3, and R2 is -OH.

[0306] In one embodiment, R3 is selected from

[0307] 4-, 5- or 6-membered heterocycloalkyl containing one or two heteroatoms, wherein the heteroatoms are independently selected from N and / or O, which is optionally substituted with one or two substituents independently selected from: -NR5R6, C1-C4 alkyl or OH;

[0308] An 8-, 9-, or 10-membered bicyclic fused heterocycloalkyl containing 1 to 3 heteroatoms, wherein the heteroatoms are independently selected from N and O, which is optionally substituted at any available position with one or two substituents independently selected from the group consisting of C1-C4 alkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl, -OH, -NR5R6, and halo;

[0309] C3-C6 cycloalkyl, optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, -OH, and halo;

[0310] Hydroxy C1-C6 alkyl;

[0311] Halogenated C1-C4 alkyl, preferably -CF3, or

[0312] C1-C6 alkyl optionally substituted with -NR5R6;

[0313] wherein R5 and R6 are independently selected from H and C1-C3 alkyl; and

[0314] m is 0 or 1.

[0315] In another specific embodiment, R3 is selected from

[0316] 4-, 5- or 6-membered heterocycloalkyl comprising one heteroatom, wherein the heteroatom is N or O, wherein the 4-, 5- or 6-membered heterocycloalkyl is optionally substituted with one or two substituents independently selected from C1-C4 alkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl, -OH and halo, preferably optionally substituted with one or two substituents independently selected from C1-C4 alkyl;

[0317] C3-C6 cycloalkyl, optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, -OH, and halo;

[0318] Hydroxy C1-C6 alkyl; and

[0319] C1-C6 alkyl optionally substituted with -NR5R6, wherein R5 and R6 are independently selected from H and C1-C3 alkyl.

[0320] In a preferred embodiment, R3 is selected from 4-, 5- or 6-membered heterocycloalkyl containing one or two heteroatoms, preferably one heteroatom, wherein the heteroatom is N or O. The 4-, 5- or 6-membered heterocycloalkyl may be substituted by 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. The substituents may be located at any available position on the heterocyclic group.

[0321] In a preferred embodiment, R3 is selected from

[0322]

[0323] Me and CF3;

[0324] in

[0325] X is selected from O and NR4;

[0326] R4 is independently selected from H, halo or C1-C3 alkyl;

[0327] R5 is independently selected from H or C1-C3 alkyl, preferably H or Me;

[0328] R6 is selected from C1-C4 alkyl; and

[0329] n is selected from 0, 1 or 2.

[0330] In another preferred embodiment, R3 is selected from

[0331]

[0332] Me and CF3;

[0333] X is selected from O and NR4;

[0334] R4 is independently selected from H, halo or C1-C3 alkyl;

[0335] R5 is independently selected from -H or -Me;

[0336] R6 is selected from C1-C4 alkyl; and

[0337] n is selected from 0, 1 or 2.

[0338] In a preferred embodiment, R3 is selected from

[0339]

[0340] Me and CF3;

[0341] in

[0342] R4 is independently selected from H, F or C1-C3 alkyl; and

[0343] R5 is methyl; and

[0344] n is selected from 0, 1 or 2.

[0345] In a more preferred embodiment, R3 is selected from

[0346]

[0347] Me and CF3;

[0348] wherein R4 is independently selected from -H, -F or -C1-C3 alkyl; R5 is methyl; and

[0349] n is selected from 0, 1 or 2.

[0350] In a preferred embodiment, R3 is selected from

[0351] in

[0352] X is selected from O and NR4;

[0353] R4 is independently selected from -H or -C1-C3 alkyl;

[0354] a is selected from 0 and 1; and

[0355] n is selected from 0, 1 or 2.

[0356] In a further preferred embodiment, R3 is selected from

[0357]

[0358] wherein R4 is independently selected from -H or -C1-C3 alkyl; and

[0359] n is selected from 0, 1 or 2.

[0360] In a further preferred embodiment, R3 is selected from

[0361]

[0362] wherein R4 is independently selected from -H or -C1-C3 alkyl; and

[0363] n is selected from 0, 1 or 2.

[0364] In a preferred embodiment, R is a 4-, 5- or 6-membered heterocycloalkyl group containing one heteroatom, wherein the heteroatom is N. The 4-, 5- or 6-membered heterocycloalkyl group may be 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 (preferably C1-C4 alkyl). The substituents may be located at any available position on the heterocyclic group.

[0365] In another embodiment, R is a 4-, 5-, or 6-membered heterocycloalkyl group containing one heteroatom, wherein the heteroatom is O. The 4-, 5-, or 6-membered heterocycloalkyl group may be 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 (preferably C1-C4 alkyl). The substituents may be located at any available position on the heterocyclic group.

[0366] In another preferred embodiment, R3 is C1-C6 alkyl.

[0367] In a preferred embodiment, R3 is Wherein X is selected from O and NR4, preferably X is NR4;

[0368] R4 is independently selected from -H or -C1-C3 alkyl;

[0369] a is selected from 0 and 1 (preferably a is 0); and

[0370] n is selected from 0, 1 or 2. In a preferred embodiment, n is 2. In a preferred embodiment, n is 1. In another preferred embodiment, n is 0.

[0371] In a preferred embodiment, R3 is wherein R4 is independently selected from -H or C1-C3 alkyl. In a preferred embodiment, R4 is H. In another embodiment, R4 is C1-C3 alkyl, such as methyl, ethyl or propyl. In a preferred embodiment, R4 is methyl.

[0372] In another preferred embodiment, R3 is wherein R4 is independently selected from -H or C1-C3 alkyl. In a preferred embodiment, R4 is H. In another embodiment, R4 is C1-C3 alkyl, such as methyl, ethyl or propyl. In a preferred embodiment, R4 is methyl.

[0373] In another embodiment, R3 is wherein R4 is independently selected from -H or C1-C3 alkyl. In a preferred embodiment, R4 is H. In another embodiment, R4 is C1-C3 alkyl, such as methyl, ethyl or propyl. In a preferred embodiment, R4 is methyl, wherein R3 is

[0374] In another embodiment, R3 is wherein R4 is independently selected from -H or C1-C3 alkyl. In a preferred embodiment, R4 is H. In another embodiment, R4 is C1-C3 alkyl, such as methyl, ethyl or propyl. In one embodiment, R4 is methyl, wherein R3 is

[0375] In another embodiment, R3 is wherein R4 is independently selected from -H or C1-C3 alkyl. In a preferred embodiment, R4 is H. In another embodiment, R4 is C1-C3 alkyl, such as methyl, ethyl or propyl. In a preferred embodiment, R4 is methyl, wherein R3 is

[0376] In another preferred embodiment, R3 is a 4, 5 or 6-membered heterocycloalkyl group containing one heteroatom, wherein the heteroatom is O. In a preferred embodiment, R3 is

[0377] In another embodiment, R is C-C cycloalkyl, preferably cyclohexyl, cyclopropyl or cyclobutyl, more preferably cyclopropyl or cyclobutyl. The C-C cycloalkyl may be substituted by one or two substituents independently selected from the group consisting of C-C alkyl, halo-C-C alkyl, hydroxy-C-C alkyl, -OH and halo. The substituent may be located at any available position on the cycloalkyl.

[0378] In a preferred embodiment, R3 is

[0379] In a preferred embodiment, R3 is wherein R4 is independently selected from -H or C1-C3 alkyl. In a preferred embodiment, R4 is H. In another embodiment, R4 is C1-C3 alkyl, such as methyl, ethyl or propyl. In a preferred embodiment, R4 is methyl. In a preferred embodiment, R3 is In another preferred embodiment, R3 is

[0380] In another preferred embodiment, R3 is In a preferred embodiment, R3 is In another preferred embodiment, R3 is

[0381] In another preferred embodiment, R is C1-C6 alkyl, for example C1-C3 alkyl, for example methyl, ethyl or propyl. In a preferred embodiment, R is methyl. In another preferred embodiment, alkyl can be substituted by one or two substituents independently selected from the following: -OH, halo, halogenated C1-C4 alkyl, C1-C4 alkoxy and -NR5R6, wherein R5 and R6 are independently selected from H and C1-C3 alkyl.

[0382] In a preferred embodiment, R3 is hydroxy C1-C6 alkyl (C1-C6 alkyl substituted by -OH), more preferably hydroxy C1-C3 alkyl, preferably hydroxyethyl.

[0383] In a preferred embodiment, R3 is wherein n is 0, 1 or 2. In another preferred embodiment, R3 is Where n is 0, 1, or 2.

[0384] In another embodiment, R3 is C1-C4 alkoxy C1-C6 alkyl (ie, C1-C6 alkyl substituted by C1-C4 alkoxy), preferably C1-C3 alkoxy C1-C4 alkyl.

[0385] In one embodiment, R3 is wherein R4 is -C1-C3 alkyl; and n is selected from 0, 1 or 2.

[0386] In another preferred embodiment, R is a C1-C6 alkyl substituted with -NR5R6, wherein R5 and R6 are independently selected from H and C1-C3 alkyl. In a preferred embodiment, R5 and R6 are both C1-C3 alkyl, such as methyl, ethyl or propyl, more preferably R5 and R6 are both methyl. In another embodiment, R5 and R6 are both H.

[0387] In one embodiment, R3 is wherein R5 and R6 are independently selected from H and C1-C3 alkyl and n is 0, 1 or 2. In a preferred embodiment, R5 and R6 are both C1-C3 alkyl, such as methyl, ethyl or propyl, more preferably R5 and R6 are both methyl. In another embodiment, R5 and R6 are both H.

[0388] In a preferred embodiment, R3 is Where n is 0, 1, or 2.

[0389] In another preferred embodiment, R3 is wherein R4 is independently selected from -H or C1-C3 alkyl. In a preferred embodiment, R4 is C1-C3 alkyl, such as methyl, ethyl or propyl, preferably methyl.

[0390] In another preferred embodiment, R3 is Wherein R5 is H and C1-C3 alkyl.

[0391] In a preferred embodiment, Z is C. In another embodiment, Z is N.

[0392] In a preferred embodiment, Q is C. In another embodiment, Q is N.

[0393] In some embodiments, one of Q and Z is C, and the other is N. In one embodiment, Q is N and Z is C. In another embodiment, one Q is C, and Z is N. In a preferred embodiment, Q and Z are both C.

[0394] In some embodiments, E is NR a , where R a In a preferred embodiment, R a is H. In another preferred embodiment, R a In a preferred embodiment, R a is methyl, in another preferred embodiment, R aIn another preferred embodiment, R a In another embodiment, E is CR a , where R a In a preferred embodiment, R a is H. In another preferred embodiment, R a is -C1-C3 alkyl, preferably R a It's methyl.

[0395] In one embodiment, Q and Z are both C, and E is CR a , where R a As defined above. In a preferred embodiment, Q and Z are both C, and E is NR a , where R a As defined above. In another preferred embodiment, Q is N, Z is C, and E is CR a , where R a As defined above.

[0396] In a preferred embodiment, X' is N. In another preferred embodiment, X' is CH.

[0397] In a preferred embodiment, W is N. In another preferred embodiment, W is CH. In another preferred embodiment, W is CR c , where R c It is -CH2-OH, -O-CH3 or F.

[0398] In a preferred embodiment, Y is NH. In another preferred embodiment, Y is O. In another embodiment, Y is N-CH3. In another preferred embodiment, Y is a bond.

[0399] In a preferred embodiment, R c In a further preferred embodiment, R c Selected from -O-C1-C2 alkyl, -C1-C4 alkyl-OH and -F, such as -C1-C4 alkyl-OH, -OCH3 and -F.

[0400] In a preferred embodiment, R d Selected from C1-C4 alkyl.

[0401] In a preferred embodiment, a compound having the structure of formula (II') is provided.

[0402]

[0403] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof;

[0404] Among them, Q, E, Z, X', W, R0, R1, R 2、 R3, m and Y are as defined in any of the above embodiments.

[0405] In a preferred embodiment, a compound having the structure of formula (II) is provided.

[0406]

[0407] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof;

[0408] in

[0409] Q, E, Z, R0, R1, R2, R3 and Y are as defined in any of the above embodiments.

[0410] The following paragraphs apply to formula (II') and / or (II).

[0411] In a preferred embodiment, R0 is selected from -H and C1-C3 alkyl, more preferably -H or methyl. In a preferred embodiment, R0 is -H. In another preferred embodiment, R0 is C1-C3 alkyl, preferably methyl or ethyl, more preferably methyl.

[0412] In a preferred embodiment, R1 is selected from -CF3, -OCF3 and -OCHF2. In a preferred embodiment, R1 is -CF3. In another preferred embodiment, R1 is -OCF3. In another preferred embodiment, R1 is -OCHF2.

[0413] In another embodiment, R1 is halo. When R1 is halo, halogen (halo) is preferably chlorine.

[0414] In a preferred embodiment, R2 is -OH or H, more preferably -OH. In another embodiment, R2 is -H. In another embodiment, R2 is -CF3.

[0415] In a preferred embodiment, R0 is -H, R1 is selected from -CF3, -OCF3, -OCHF2 and -Cl, and R2 is -OH or -H. In a preferred embodiment, R0 is -H, R1 is -CF3, and R2 is -OH.

[0416] In one embodiment, R3 is selected from

[0417] 4-, 5- or 6-membered heterocycloalkyl containing one or two heteroatoms, wherein the heteroatoms are independently selected from N and / or O, which is optionally substituted with one or two substituents independently selected from: -NR5R6, C1-C4 alkyl or OH;

[0418] An 8-, 9-, or 10-membered bicyclic fused heterocycloalkyl containing 1 to 3 heteroatoms, wherein the heteroatoms are independently selected from N and O, which is optionally substituted at any available position with one or two substituents independently selected from the group consisting of C1-C4 alkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl, -OH, -NR5R6, and halo; or

[0419] C3-C6 cycloalkyl, optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, -OH, and halo; or

[0420] Hydroxy C1-C6 alkyl; or

[0421] Halogenated C1-C4 alkyl, preferably -CF3, or

[0422] C1-C6 alkyl optionally substituted by -NR5R6,

[0423] wherein R5 and R6 are independently selected from H and C1-C3 alkyl; and

[0424] m is 0 or 1.

[0425] In a preferred embodiment, R3 is selected from

[0426] 4-, 5- or 6-membered heterocycloalkyl containing one heteroatom, wherein the heteroatom is N or O, 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, which is preferably optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl;

[0427] C3-C6 cycloalkyl, optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, -OH, and halo;

[0428] Hydroxy C1-C6 alkyl; and

[0429] C1-C6 alkyl optionally substituted with -NR5R6, wherein R5 and R6 are independently selected from H and C1-C3 alkyl.

[0430] In a preferred embodiment, R3 is selected from 4-, 5- or 6-membered heterocycloalkyl containing one or two heteroatoms, preferably one heteroatom, wherein the heteroatom is N or O. The 4-, 5- or 6-membered heterocycloalkyl may be substituted by 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. The substituents may be located at any available position on the heterocyclic group.

[0431] In a preferred embodiment, R3 is selected from

[0432]

[0433] Me and CF3;

[0434] in

[0435] X is selected from O and NR4;

[0436] R4 is independently selected from H, halo or C1-C3 alkyl;

[0437] R5 is independently selected from H or C1-C3 alkyl, preferably H or Me;

[0438] R6 is selected from C1-C4 alkyl; and

[0439] n is selected from 0, 1 or 2.

[0440] In a preferred embodiment, R3 is selected from

[0441]

[0442] wherein X is selected from O and NR4;

[0443] R4 is independently selected from -H or -C1-C3 alkyl;

[0444] n is selected from 0, 1 or 2; and a is selected from 0 or 1.

[0445] In a preferred embodiment, R3 is selected from

[0446]

[0447] Me and CF3;

[0448] X is selected from O and NR4;

[0449] R4 is independently selected from H, halo or C1-C3 alkyl; R5 is independently selected from -H or -Me;

[0450] R6 is selected from C1-C4 alkyl; and n is selected from 0, 1 or 2.

[0451] In a more preferred embodiment, R3 is selected from

[0452]

[0453] Me and CF3;

[0454] in

[0455] R4 is independently selected from H, F or C1-C3 alkyl; and

[0456] R5 is methyl; and

[0457] n is selected from 0, 1 or 2.

[0458] In a preferred embodiment, R3 is selected from

[0459] wherein X is selected from O and NR4;

[0460] R4 is independently selected from -H or -C1-C3 alkyl;

[0461] a is selected from 0 and 1; and

[0462] n is selected from 0, 1 or 2.

[0463] In a further preferred embodiment, R3 is selected from

[0464]

[0465] wherein R4 is independently selected from -H or -C1-C3 alkyl; and

[0466] n is selected from 0, 1 or 2.

[0467] In a further preferred embodiment, R3 is selected from

[0468]

[0469] wherein R4 is independently selected from -H or -C1-C3 alkyl; and

[0470] n is selected from 0, 1 or 2.

[0471] In a preferred embodiment, R is a 4-, 5- or 6-membered heterocycloalkyl group containing one heteroatom, wherein the heteroatom is N. The 4-, 5- or 6-membered heterocycloalkyl group may be 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 (preferably C1-C4 alkyl). The substituents may be located at any available position on the heterocyclic group.

[0472] In another embodiment, R is a 4-, 5-, or 6-membered heterocycloalkyl group containing one heteroatom, wherein the heteroatom is O. The 4-, 5-, or 6-membered heterocycloalkyl group may be 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 (preferably C1-C4 alkyl). The substituents may be located at any available position on the heterocyclic group.

[0473] In a preferred embodiment, R3 is Wherein X is selected from O and NR4, preferably X is NR4;

[0474] R4 is independently selected from -H or -C1-C3 alkyl;

[0475] a is selected from 0 and 1 (preferably a is 0); and

[0476] n is selected from 0, 1 or 2. In a preferred embodiment, n is 2. In a preferred embodiment, n is 1. In another preferred embodiment, n is 0.

[0477] In a preferred embodiment, R3 is wherein R4 is independently selected from -H or C1-C3 alkyl. In a preferred embodiment, R4 is H. In another embodiment, R4 is C1-C3 alkyl, such as methyl, ethyl or propyl. In a preferred embodiment, R4 is methyl.

[0478] In another preferred embodiment, R3 is wherein R4 is independently selected from -H or C1-C3 alkyl. In a preferred embodiment, R4 is H. In another embodiment, R4 is C1-C3 alkyl, such as methyl, ethyl or propyl. In a preferred embodiment, R4 is methyl.

[0479] In another embodiment, R3 is wherein R4 is independently selected from -H or C1-C3 alkyl. In a preferred embodiment, R4 is H. In another embodiment, R4 is C1-C3 alkyl, such as methyl, ethyl or propyl. In one embodiment, R4 is methyl, wherein R3 is

[0480] In another embodiment, R3 is wherein R4 is independently selected from -H or C1-C3 alkyl. In a preferred embodiment, R4 is H. In another embodiment, R4 is C1-C3 alkyl, such as methyl, ethyl or propyl. In a preferred embodiment, R4 is methyl, wherein R3 is

[0481] In another preferred embodiment, R3 is a 4, 5 or 6-membered heterocycloalkyl group containing one heteroatom, wherein the heteroatom is O. In a preferred embodiment, R3 is

[0482] In another embodiment, R is C-C cycloalkyl, preferably cyclohexyl, cyclopropyl or cyclobutyl, more preferably cyclopropyl or cyclobutyl. The C-C cycloalkyl may be substituted by one or two substituents independently selected from the group consisting of C-C alkyl, halo-C-C alkyl, hydroxy-C-C alkyl, -OH and halo. The substituent may be located at any available position on the cycloalkyl.

[0483] In a preferred embodiment, R3 is

[0484] In a preferred embodiment, R3 is wherein R4 is independently selected from -H or C1-C3 alkyl. In a preferred embodiment, R4 is H. In another embodiment, R4 is C1-C3 alkyl, such as methyl, ethyl or propyl. In a preferred embodiment, R4 is methyl. In a preferred embodiment, R3 is In another preferred embodiment, R3 is

[0485] In another preferred embodiment, R3 is In a preferred embodiment, R3 is In another preferred embodiment, R3 is

[0486] In another preferred embodiment, R is C1-C6 alkyl, for example C1-C3 alkyl, for example methyl, ethyl or propyl. In a preferred embodiment, R is methyl. In another preferred embodiment, alkyl can be substituted by one or two substituents independently selected from the following: -OH, halo, halogenated C1-C4 alkyl, C1-C4 alkoxy and -NR5R6, wherein R5 and R6 are independently selected from H and C1-C3 alkyl. In a preferred embodiment, R is hydroxy C1-C6 alkyl (C1-C6 alkyl substituted by -OH), more preferably hydroxy C1-C3 alkyl, preferably hydroxyethyl.

[0487] In a preferred embodiment, R3 is wherein n is 0, 1 or 2. In another preferred embodiment, R3 is Where n is 0, 1, or 2.

[0488] In another embodiment, R3 is C1-C4 alkoxy C1-C6 alkyl (ie, C1-C6 alkyl substituted by C1-C4 alkoxy), preferably C1-C3 alkoxy C1-C4 alkyl.

[0489] In one embodiment, R3 is wherein R4 is -C1-C3 alkyl; and n is selected from 0, 1 or 2.

[0490] In another preferred embodiment, R is a C1-C6 alkyl substituted with -NR5R6, wherein R5 and R6 are independently selected from H and C1-C3 alkyl. In a preferred embodiment, R5 and R6 are both C1-C3 alkyl, such as methyl, ethyl or propyl, more preferably R5 and R6 are both methyl. In another embodiment, R5 and R6 are both H.

[0491] In one embodiment, R3 is wherein R5 and R6 are independently selected from H and C1-C3 alkyl and n is 0, 1 or 2. In a preferred embodiment, R5 and R6 are both C1-C3 alkyl, such as methyl, ethyl or propyl, more preferably R5 and R6 are both methyl. In another embodiment, R5 and R6 are both H.

[0492] In a preferred embodiment, R3 is Where n is 0, 1, or 2.

[0493] In another preferred embodiment, R3 is wherein R4 is independently selected from -H or C1-C3 alkyl. In a preferred embodiment, R4 is C1-C3 alkyl, such as methyl, ethyl or propyl, preferably methyl.

[0494] In another preferred embodiment, R3 is Wherein R5 is H and C1-C3 alkyl.

[0495] In another preferred embodiment, R3 is C1-C6 alkyl.

[0496] In a preferred embodiment, Z is C. In another embodiment, Z is N. In a preferred embodiment, Q is C. In another embodiment, Q is N.

[0497] In some embodiments, one of Q and Z is C, and the other is N. In one embodiment, Q is N and Z is C. In another embodiment, one Q is C, and Z is N. In a preferred embodiment, Q and Z are both C.

[0498] In some embodiments, E is NR a , where R aIn a preferred embodiment, R a is H. In another preferred embodiment, R a is -C1-C3 alkyl, preferably R a In other embodiments, E is CR a , where R a In a preferred embodiment, R a is H. In another preferred embodiment, R a is -C1-C3 alkyl, preferably R a It's methyl.

[0499] In a preferred embodiment, Q and Z are both C, and E is NR a , where R a As defined above. In another embodiment, Q and Z are both C, and E is CR a , where R a As defined above. In another preferred embodiment, Q is N, Z is C, and E is CR a , where R a As defined above.

[0500] In formula (II'), in a preferred embodiment, X' is N. In another preferred embodiment, X' is CH.

[0501] In a preferred embodiment, W is N. In another preferred embodiment, W is CH. In another preferred embodiment, W is CR c , where R c It is -CH2-OH, -O-CH3 or F.

[0502] In a preferred embodiment, Y is NH. In another preferred embodiment, Y is O. In another embodiment, Y is N-CH3. In another preferred embodiment, Y is a bond.

[0503] In a preferred embodiment, R c In a further preferred embodiment, R c Selected from -O-C1-C2alkyl, C1-C4alkyl-OH and F, such as C1-C4alkyl-OH, OCH3 and F.

[0504] In a preferred embodiment, R d Selected from C1-C4 alkyl.

[0505] In another embodiment, there is provided a compound having the structure of formula (III')

[0506]

[0507] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof;

[0508] Among them, Q, E, Z, X', W, R0, R1, R 2、 R3, m and Y are as defined in any of the above embodiments.

[0509] In another embodiment, there is provided a compound having the structure of formula (III)

[0510]

[0511] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof;

[0512] Among them, Q, E, Z, R0, R1, R 2、 R3 and Y are as defined in any of the above embodiments.

[0513] The following paragraphs apply to formula (III') and / or (III).

[0514] In a preferred embodiment, R0 is selected from -H and C1-C3 alkyl, more preferably -H or methyl. In a preferred embodiment, R0 is -H. In another preferred embodiment, R0 is C1-C3 alkyl, preferably methyl or ethyl, more preferably methyl.

[0515] In a preferred embodiment, R1 is selected from -CF3, -OCF3 and -OCHF2. In a preferred embodiment, R1 is -CF3. In another preferred embodiment, R1 is -OCF3. In another preferred embodiment, R1 is -OCHF2.

[0516] In another embodiment, R1 is halo. When R1 is halo, halogen (halo) is preferably chlorine.

[0517] In a preferred embodiment, R2 is -OH or H, more preferably -OH. In another embodiment, R2 is -H. In another embodiment, R2 is -CF3.

[0518] In a preferred embodiment, R0 is -H, R1 is selected from -CF3, -OCF3, -OCHF2 and -Cl, and R2 is -OH or -H. In a preferred embodiment, R0 is -H, R1 is -CF3, and R2 is -OH.

[0519] In one embodiment, R3 is selected from

[0520] 4-, 5- or 6-membered heterocycloalkyl containing one or two heteroatoms, wherein the heteroatoms are independently selected from N and / or O, which is optionally substituted with one or two substituents independently selected from: -NR5R6, C1-C4 alkyl or OH; or

[0521] An 8-, 9-, or 10-membered bicyclic fused heterocycloalkyl containing 1 to 3 heteroatoms, wherein the heteroatoms are independently selected from N and O, which is optionally substituted at any available position with one or two substituents independently selected from the group consisting of C1-C4 alkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl, -OH, -NR5R6, and halo; or

[0522] C3-C6 cycloalkyl, optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, -OH, and halo; or

[0523] Hydroxy C1-C6 alkyl; or

[0524] Halogenated C1-C4 alkyl, preferably -CF3; or

[0525] C1-C6 alkyl optionally substituted by -NR5R6,

[0526] wherein R5 and R6 are independently selected from H and C1-C3 alkyl; and

[0527] m is 0 or 1.

[0528] In a preferred embodiment, R3 is selected from

[0529] 4-, 5- or 6-membered heterocycloalkyl containing one heteroatom, wherein the heteroatom is N or O, 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, which is preferably optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl;

[0530] C3-C6 cycloalkyl, optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, -OH, and halo;

[0531] Hydroxy C1-C6 alkyl; and

[0532] C1-C6 alkyl optionally substituted with -NR5R6, wherein R5 and R6 are independently selected from H and C1-C3 alkyl.

[0533] In a preferred embodiment, R3 is selected from 4-, 5- or 6-membered heterocycloalkyl containing one or two heteroatoms, preferably one heteroatom, wherein the heteroatom is N or O. The 4-, 5- or 6-membered heterocycloalkyl may be substituted by 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. The substituents may be located at any available position on the heterocyclic group.

[0534] In a preferred embodiment, R3 is selected from

[0535]

[0536] Me and CF3;

[0537] in

[0538] X is selected from O and NR4;

[0539] R4 is independently selected from H, halo or C1-C3 alkyl;

[0540] R5 is independently selected from H or C1-C3 alkyl, preferably H or Me;

[0541] R6 is selected from C1-C4 alkyl; and

[0542] n is selected from 0, 1 or 2.

[0543] In a preferred embodiment, R3 is selected from

[0544]

[0545] wherein X is selected from O and NR4;

[0546] R4 is independently selected from -H or -C1-C3 alkyl;

[0547] a is selected from 0 and 1; and

[0548] n is selected from 0, 1 or 2.

[0549] In a preferred embodiment, R3 is selected from

[0550]

[0551] Me and CF3;

[0552] X is selected from O and NR4;

[0553] R4 is independently selected from H, halo or C1-C3 alkyl;

[0554] R5 is independently selected from -H or -Me;

[0555] R6 is selected from C1-C4 alkyl; and

[0556] n is selected from 0, 1 or 2.

[0557] In a preferred embodiment, R3 is selected from

[0558]

[0559] wherein X is selected from O and NR4;

[0560] R4 is independently selected from -H or -C1-C3 alkyl;

[0561] a is selected from 0 and 1; and

[0562] n is selected from 0, 1 or 2.

[0563] In a further preferred embodiment, R3 is selected from

[0564]

[0565] Me and CF3;

[0566] in

[0567] R4 is independently selected from H, F or C1-C3 alkyl; and

[0568] R5 is methyl; and

[0569] n is selected from 0, 1 or 2.

[0570] In a further preferred embodiment, R3 is selected from

[0571]

[0572] wherein R4 is independently selected from -H or -C1-C3 alkyl; and

[0573] n is selected from 0, 1 or 2.

[0574] In a further embodiment, R3 is selected from

[0575]

[0576] wherein R4 is independently selected from -H or -C1-C3 alkyl; and

[0577] n is selected from 0, 1 or 2.

[0578] In a preferred embodiment, R is a 4-, 5- or 6-membered heterocycloalkyl group containing one heteroatom, wherein the heteroatom is N. The 4-, 5- or 6-membered heterocycloalkyl group may be 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 (preferably C1-C4 alkyl). The substituents may be located at any available position on the heterocyclic group.

[0579] In a preferred embodiment, R3 is Wherein X is selected from O and NR4, preferably X is NR4;

[0580] R4 is independently selected from -H or -C1-C3 alkyl;

[0581] a is selected from 0 and 1 (preferably a is 0); and

[0582] n is selected from 0, 1 or 2. In a preferred embodiment, n is 2. In a preferred embodiment, n is 1. In another preferred embodiment, n is 0.

[0583] In a preferred embodiment, R3 is wherein R4 is independently selected from -H or C1-C3 alkyl. In a preferred embodiment, R4 is H. In another embodiment, R4 is C1-C3 alkyl, such as methyl, ethyl or propyl. In a preferred embodiment, R4 is methyl.

[0584] In another preferred embodiment, R3 is wherein R4 is independently selected from -H or C1-C3 alkyl. In a preferred embodiment, R4 is H. In another embodiment, R4 is C1-C3 alkyl, such as methyl, ethyl or propyl. In a preferred embodiment, R4 is methyl.

[0585] In another embodiment, R3 is wherein R4 is independently selected from -H or C1-C3 alkyl. In a preferred embodiment, R4 is H. In another embodiment, R4 is C1-C3 alkyl, such as methyl, ethyl or propyl. In one embodiment, R4 is methyl, wherein R3 is

[0586] In another embodiment, R3 is wherein R4 is independently selected from -H or C1-C3 alkyl. In a preferred embodiment, R4 is H. In another embodiment, R4 is C1-C3 alkyl, such as methyl, ethyl or propyl. In a preferred embodiment, R4 is methyl, wherein R3 is

[0587] In another preferred embodiment, R3 is a 4, 5 or 6-membered heterocycloalkyl group containing one heteroatom, wherein the heteroatom is O. In a preferred embodiment, R3 is

[0588] In another embodiment, R is C-C cycloalkyl, preferably cyclohexyl, cyclopropyl or cyclobutyl, more preferably cyclopropyl or cyclobutyl. The C-C cycloalkyl may be substituted by one or two substituents independently selected from the group consisting of C-C alkyl, halo-C-C alkyl, hydroxy-C-C alkyl, -OH and halo. The substituent may be located at any available position on the cycloalkyl.

[0589] In a preferred embodiment, R3 is

[0590] In a preferred embodiment, R3 is wherein R4 is independently selected from -H or C1-C3 alkyl. In a preferred embodiment, R4 is H. In another embodiment, R4 is C1-C3 alkyl, such as methyl, ethyl or propyl. In a preferred embodiment, R4 is methyl. In a preferred embodiment, R3 is In another preferred embodiment, R3 is

[0591] In another preferred embodiment, R3 is In a preferred embodiment, R3 is In another preferred embodiment, R3 is

[0592] In another preferred embodiment, R is C1-C6 alkyl, for example C1-C3 alkyl, for example methyl, ethyl or propyl. In a preferred embodiment, R is methyl. In another preferred embodiment, alkyl can be substituted by one or two substituents independently selected from the following: -OH, halo, halogenated C1-C4 alkyl, C1-C4 alkoxy and -NR5R6, wherein R5 and R6 are independently selected from H and C1-C3 alkyl. In a preferred embodiment, R is hydroxy C1-C6 alkyl (C1-C6 alkyl substituted by -OH), more preferably hydroxy C1-C3 alkyl, preferably hydroxyethyl.

[0593] In a preferred embodiment, R3 is wherein n is 0, 1 or 2. In another preferred embodiment, R3 is Where n is 0, 1, or 2.

[0594] In another embodiment, R3 is C1-C4 alkoxy C1-C6 alkyl (ie, C1-C6 alkyl substituted by C1-C4 alkoxy), preferably C1-C3 alkoxy C1-C4 alkyl.

[0595] In one embodiment, R3 is wherein R4 is -C1-C3 alkyl; and n is selected from 0, 1 or 2.

[0596] In another preferred embodiment, R is a C1-C6 alkyl substituted with -NR5R6, wherein R5 and R6 are independently selected from H and C1-C3 alkyl. In a preferred embodiment, R5 and R6 are both C1-C3 alkyl, such as methyl, ethyl or propyl, more preferably R5 and R6 are both methyl. In another embodiment, R5 and R6 are both H.

[0597] In one embodiment, R3 is wherein R5 and R6 are independently selected from H and C1-C3 alkyl and wherein n is 0, 1 or 2. In a preferred embodiment, R5 and R6 are both C1-C3 alkyl, such as methyl, ethyl or propyl, more preferably R5 and R6 are both methyl. In another embodiment, R5 and R6 are both H.

[0598] In a preferred embodiment, R3 is Where n is 0, 1, or 2.

[0599] In a preferred embodiment, Z is C. In another embodiment, Z is N. In a preferred embodiment, Q is C. In another embodiment, Q is N.

[0600] In some embodiments, one of Q and Z is C, and the other is N. In one embodiment, Q is N and Z is C. In another embodiment, one Q is C, and Z is N.

[0601] In a preferred embodiment, Q and Z are both C.

[0602] In some embodiments, E is NR a , where R a In a preferred embodiment, R a is H. In another preferred embodiment, R a is -C1-C3 alkyl, preferably R a In other embodiments, E is CR a , where R a In a preferred embodiment, R a is H. In another preferred embodiment, Ra is -C1-C3 alkyl, preferably R a It's methyl.

[0603] In a preferred embodiment, Q and Z are both C, and E is NR a , where R a As defined above. In another embodiment, Q and Z are both C, and E is CR a , where R a As defined above. In another preferred embodiment, Q is N, Z is C, and E is CR a , where R a As defined above.

[0604] In a preferred embodiment, X' is N. In another preferred embodiment, X' is CH.

[0605] In a preferred embodiment, W is N. In another preferred embodiment, W is CH. In another preferred embodiment, W is CR c , where R c It is -CH2-OH, -O-CH3 or F.

[0606] In a preferred embodiment, Y is NH. In another preferred embodiment, Y is O. In another embodiment, Y is N-CH3. In another preferred embodiment, Y is a bond.

[0607] In a preferred embodiment, R c In a further preferred embodiment, R c Selected from -O-C1-C2alkyl, C1-C4alkyl-OH and F, such as C1-C4alkyl-OH, OCH3 and F.

[0608] In a preferred embodiment, R d Selected from C1-C4 alkyl.

[0609] In another preferred embodiment, R3 is wherein R4 is independently selected from -H or C1-C3 alkyl. In a preferred embodiment, R4 is C1-C3 alkyl, such as methyl, ethyl or propyl, preferably methyl.

[0610] In another preferred embodiment, R3 is Wherein R5 is H and C1-C3 alkyl.

[0611] In one embodiment, R3 is OH.

[0612] In another preferred embodiment, R3 is C1-C6 alkyl.

[0613] In another preferred embodiment, there is provided a compound of formula (II') having the structure of formula (II'a)

[0614]

[0615] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof;

[0616] Among them, X', W, R0, R1, R 2、 R3, R a , m and Y are as defined in any of the embodiments above.

[0617] In another preferred embodiment, there is provided a compound of formula (II) having the structure of formula (IIa)

[0618]

[0619] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof;

[0620] Among them, R0, R1, R 2、 R3, R a and Y are as defined in any of the embodiments above.

[0621] The following paragraphs apply to formula (IIa') and / or (IIa).

[0622] In a preferred embodiment, R0 is selected from -H and C1-C3 alkyl, more preferably -H or methyl. In a preferred embodiment, R0 is -H. In another preferred embodiment, R0 is C1-C3 alkyl, preferably methyl or ethyl, more preferably methyl.

[0623] In a preferred embodiment, R1 is selected from -CF3, -OCF3 and -OCHF2. In a preferred embodiment, R1 is -CF3. In another preferred embodiment, R1 is -OCF3. In another preferred embodiment, R1 is -OCHF2.

[0624] In another embodiment, R1 is halo. When R1 is halo, halogen (halo) is preferably chlorine.

[0625] In a preferred embodiment, R2 is -OH or H, more preferably -OH. In another embodiment, R2 is -H. In another embodiment, R2 is -CF3.

[0626] In a preferred embodiment, R0 is -H, R1 is selected from -CF3, -OCF3, -OCHF2 and -Cl, and R2 is -OH or -H. In a preferred embodiment, R0 is -H, R1 is -CF3, and R2 is -OH.

[0627] In one embodiment, R3 is selected from

[0628] 4-, 5- or 6-membered heterocycloalkyl containing one or two heteroatoms, wherein the heteroatoms are independently selected from N and / or O, which is optionally substituted with one or two substituents independently selected from: -NR5R6, C1-C4 alkyl or OH;

[0629] An 8-, 9-, or 10-membered bicyclic fused heterocycloalkyl containing 1 to 3 heteroatoms, wherein the heteroatoms are independently selected from N and O, which is optionally substituted at any available position with one or two substituents independently selected from the group consisting of C1-C4 alkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl, -OH, -NR5R6, and halo; or

[0630] C3-C6 cycloalkyl, optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, -OH, and halo; or

[0631] Hydroxy C1-C6 alkyl; or

[0632] Halogenated C1-C4 alkyl, preferably -CF3; or

[0633] C1-C6 alkyl optionally substituted by -NR5R6,

[0634] wherein R5 and R6 are independently selected from H and C1-C3 alkyl; and

[0635] m is 0 or 1.

[0636] In another embodiment, R3 is selected from

[0637] 4-, 5- or 6-membered heterocycloalkyl containing one heteroatom, wherein the heteroatom is N or O, 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, which is preferably optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl;

[0638] C3-C6 cycloalkyl, optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, -OH, and halo;

[0639] Hydroxy C1-C6 alkyl; and

[0640] C1-C6 alkyl optionally substituted with -NR5R6, wherein R5 and R6 are independently selected from H and C1-C3 alkyl.

[0641] In a preferred embodiment, R3 is selected from 4-, 5- or 6-membered heterocycloalkyl containing one or two heteroatoms, preferably one heteroatom, wherein the heteroatom is N or O. The 4-, 5- or 6-membered heterocycloalkyl may be substituted by 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. The substituents may be located at any available position on the heterocyclic group.

[0642] In a preferred embodiment, R3 is selected from

[0643]

[0644] Me and CF3;

[0645] in

[0646] X is selected from O and NR4;

[0647] R4 is independently selected from H, halo or C1-C3 alkyl;

[0648] R5 is independently selected from H or C1-C3 alkyl, preferably H or Me;

[0649] R6 is selected from C1-C4 alkyl; and

[0650] n is selected from 0, 1 or 2.

[0651] In a preferred embodiment, R3 is selected from

[0652]

[0653]

[0654] wherein X is selected from O and NR4;

[0655] R4 is independently selected from -H or -C1-C3 alkyl;

[0656] a is selected from 0 and 1; and

[0657] n is selected from 0, 1 or 2.

[0658] In a preferred embodiment, R3 is selected from

[0659]

[0660] Me and CF3;

[0661] X is selected from O and NR4;

[0662] R4 is independently selected from H, halo or C1-C3 alkyl;

[0663] R5 is independently selected from -H or -Me;

[0664] R6 is selected from C1-C4 alkyl; and

[0665] n is selected from 0, 1 or 2.

[0666] In a preferred embodiment, R3 is selected from

[0667]

[0668] wherein X is selected from O and NR4;

[0669] R4 is independently selected from -H or -C1-C3 alkyl;

[0670] a is selected from 0 and 1; and

[0671] n is selected from 0, 1 or 2.

[0672] In a further preferred embodiment, R3 is selected from

[0673]

[0674] Me and CF3;

[0675] in

[0676] R4 is independently selected from H, F or C1-C3 alkyl; and

[0677] R5 is methyl; and

[0678] n is selected from 0, 1 or 2.

[0679] In a further preferred embodiment, R3 is selected from

[0680]

[0681] wherein R4 is independently selected from -H or -C1-C3 alkyl; and

[0682] n is selected from 0, 1 or 2.

[0683] In a further preferred embodiment, R3 is selected from

[0684]

[0685] wherein R4 is independently selected from -H or -C1-C3 alkyl; and

[0686] n is selected from 0, 1 or 2.

[0687] In a preferred embodiment, R is a 4-, 5- or 6-membered heterocycloalkyl group containing one heteroatom, wherein the heteroatom is N. The 4-, 5- or 6-membered heterocycloalkyl group may be 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 (preferably C1-C4 alkyl). The substituents may be located at any available position on the heterocyclic group.

[0688] In a preferred embodiment, R3 is Wherein X is selected from O and NR4, preferably X is NR4;

[0689] R4 is independently selected from -H or -C1-C3 alkyl;

[0690] a is selected from 0 and 1 (preferably a is 0); and

[0691] n is selected from 0, 1 or 2. In a preferred embodiment, n is 2. In a preferred embodiment, n is 1. In another preferred embodiment, n is 0.

[0692] In a preferred embodiment, R3 is wherein R4 is independently selected from -H or C1-C3 alkyl. In a preferred embodiment, R4 is H. In another embodiment, R4 is C1-C3 alkyl, such as methyl, ethyl or propyl. In a preferred embodiment, R4 is methyl.

[0693] In another preferred embodiment, R3 is wherein R4 is independently selected from -H or C1-C3 alkyl. In a preferred embodiment, R4 is H. In another embodiment, R4 is C1-C3 alkyl, such as methyl, ethyl or propyl. In a preferred embodiment, R4 is methyl.

[0694] In another embodiment, R3 is wherein R4 is independently selected from -H or C1-C3 alkyl. In a preferred embodiment, R4 is H. In another embodiment, R4 is C1-C3 alkyl, such as methyl, ethyl or propyl. In one embodiment, R4 is methyl, wherein R3 is

[0695] In another embodiment, R3 is wherein R4 is independently selected from -H or C1-C3 alkyl. In a preferred embodiment, R4 is H. In another embodiment, R4 is C1-C3 alkyl, such as methyl, ethyl or propyl. In a preferred embodiment, R4 is methyl, wherein R3 is

[0696] In another preferred embodiment, R3 is a 4, 5 or 6-membered heterocycloalkyl group containing one heteroatom, wherein the heteroatom is O. In a preferred embodiment, R3 is

[0697] In another embodiment, R is C-C cycloalkyl, preferably cyclohexyl, cyclopropyl or cyclobutyl, more preferably cyclopropyl or cyclobutyl. The C-C cycloalkyl may be substituted by one or two substituents independently selected from the group consisting of C-C alkyl, halo-C-C alkyl, hydroxy-C-C alkyl, -OH and halo. The substituent may be located at any available position on the cycloalkyl.

[0698] In a preferred embodiment, R3 is

[0699] In a preferred embodiment, R3 is wherein R4 is independently selected from -H or C1-C3 alkyl. In a preferred embodiment, R4 is H. In another embodiment, R4 is C1-C3 alkyl, such as methyl, ethyl or propyl. In a preferred embodiment, R4 is methyl. In a preferred embodiment, R3 is In another preferred embodiment, R3 is

[0700] In another preferred embodiment, R3 is In a preferred embodiment, R3 is In another preferred embodiment, R3 is

[0701] In another preferred embodiment, R is C1-C6 alkyl, for example C1-C3 alkyl, for example methyl, ethyl or propyl. In a preferred embodiment, R is methyl. In another preferred embodiment, alkyl can be substituted by one or two substituents independently selected from the following: -OH, halo, halogenated C1-C4 alkyl, C1-C4 alkoxy and -NR5R6, wherein R5 and R6 are independently selected from H and C1-C3 alkyl. In a preferred embodiment, R is hydroxy C1-C6 alkyl (C1-C6 alkyl substituted by -OH), more preferably hydroxy C1-C3 alkyl, preferably hydroxyethyl.

[0702] In a preferred embodiment, R3 is wherein n is 0, 1 or 2. In another preferred embodiment, R3 is Where n is 0, 1, or 2.

[0703] In another embodiment, R3 is C1-C4 alkoxy C1-C6 alkyl (ie, C1-C6 alkyl substituted by C1-C4 alkoxy), preferably C1-C3 alkoxy C1-C4 alkyl.

[0704] In one embodiment, R3 is wherein R4 is -C1-C3 alkyl; and n is selected from 0, 1 or 2.

[0705] In another preferred embodiment, R is a C1-C6 alkyl substituted with -NR5R6, wherein R5 and R6 are independently selected from H and C1-C3 alkyl. In a preferred embodiment, R5 and R6 are both C1-C3 alkyl, such as methyl, ethyl or propyl, more preferably R5 and R6 are both methyl. In another embodiment, R5 and R6 are both H.

[0706] In one embodiment, R3 is wherein R5 and R6 are independently selected from H and C1-C3 alkyl and wherein n is 0, 1 or 2. In a preferred embodiment, R5 and R6 are both C1-C3 alkyl, such as methyl, ethyl or propyl, more preferably R5 and R6 are both methyl. In another embodiment, R5 and R6 are both H.

[0707] In a preferred embodiment, R3 is Where n is 0, 1, or 2.

[0708] R a In some embodiments, R a is H. In other embodiments, R a is -C1-C3 alkyl, such as methyl, ethyl or propyl, preferably methyl.

[0709] In a preferred embodiment, X' is N. In another preferred embodiment, X' is CH.

[0710] In a preferred embodiment, W is N. In another preferred embodiment, W is CH. In another preferred embodiment, W is CR c , where R c It is -CH2-OH, -O-CH3 or F.

[0711] In a preferred embodiment, Y is NH. In another preferred embodiment, Y is O. In another embodiment, Y is N-CH3. In another preferred embodiment, Y is a bond.

[0712] In a preferred embodiment, R c In a further preferred embodiment, R c Selected from -O-C1-C2alkyl, C1-C4alkyl-OH and F, such as C1-C4alkyl-OH, OCH3 and F.

[0713] In a preferred embodiment, R d Selected from C1-C4 alkyl.

[0714] In another preferred embodiment, R3 is wherein R4 is independently selected from -H or C1-C3 alkyl. In a preferred embodiment, R4 is C1-C3 alkyl, such as methyl, ethyl or propyl, preferably methyl.

[0715] In another preferred embodiment, R3 is wherein R5 is H or C1-C3 alkyl.

[0716] In another preferred embodiment, R3 is C1-C6 alkyl.

[0717] In another preferred embodiment, there is provided a compound of formula (II) having the structure of formula (IIb)

[0718]

[0719] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof;

[0720] Among them, X', W, R0, R1, R 2、 R3, R a , m and Y are as defined in any of the embodiments above.

[0721] In another preferred embodiment, there is provided a compound of formula (II) having the structure of formula (IIb)

[0722]

[0723] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof;

[0724] Among them, R0, R1, R 2、R3, R a and Y are as defined in any of the embodiments above.

[0725] The following paragraphs apply to formula (II'b) and / or (IIb).

[0726] In a preferred embodiment, R0 is selected from -H and C1-C3 alkyl, more preferably -H or methyl. In a preferred embodiment, R0 is -H. In another preferred embodiment, R0 is C1-C3 alkyl, preferably methyl or ethyl, more preferably methyl.

[0727] In a preferred embodiment, R1 is selected from -CF3, -OCF3 and -OCHF2. In a preferred embodiment, R1 is -CF3. In another preferred embodiment, R1 is -OCF3. In another preferred embodiment, R1 is -OCHF2.

[0728] In another embodiment, R1 is halo. When R1 is halo, halogen (halo) is preferably chlorine.

[0729] In a preferred embodiment, R2 is -OH or H, more preferably -OH. In another embodiment, R2 is -H. In another embodiment, R2 is -CF3.

[0730] In a preferred embodiment, R0 is -H, R1 is selected from -CF3, -OCF3, -OCHF2 and -Cl, and R2 is -OH or -H. In a preferred embodiment, R0 is -H, R1 is -CF3, and R2 is -OH.

[0731] In one embodiment, R3 is selected from

[0732] 4-, 5- or 6-membered heterocycloalkyl containing one or two heteroatoms, wherein the heteroatoms are independently selected from N and / or O, which is optionally substituted with one or two substituents independently selected from: -NR5R6, C1-C4 alkyl or OH;

[0733] An 8-, 9-, or 10-membered bicyclic fused heterocycloalkyl containing 1 to 3 heteroatoms, wherein the heteroatoms are independently selected from N and O, which is optionally substituted at any available position with one or two substituents independently selected from the group consisting of C1-C4 alkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl, -OH, -NR5R6, and halo; or

[0734] C3-C6 cycloalkyl, optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, -OH, and halo; or

[0735] Hydroxy C1-C6 alkyl; or

[0736] Halogenated C1-C4 alkyl, preferably -CF3, or

[0737] C1-C6 alkyl optionally substituted by -NR5R6,

[0738] R5 and R6 are independently selected from H and C1-C3 alkyl; and

[0739] m is 0 or 1.

[0740] In a preferred embodiment, R3 is selected from

[0741] 4-, 5- or 6-membered heterocycloalkyl containing one heteroatom, wherein the heteroatom is N or O, 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, which is preferably optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl;

[0742] C3-C6 cycloalkyl, optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, -OH, and halo;

[0743] Hydroxy C1-C6 alkyl;

[0744] and C1-C6 alkyl optionally substituted with -NR5R6, wherein R5 and R6 are independently selected from H and C1-C3 alkyl.

[0745] In a preferred embodiment, R3 is selected from 4-, 5- or 6-membered heterocycloalkyl containing one or two heteroatoms, preferably one heteroatom, wherein the heteroatom is N or O. The 4-, 5- or 6-membered heterocycloalkyl may be substituted by 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. The substituents may be located at any available position on the heterocyclic group.

[0746] In a preferred embodiment, R3 is selected from

[0747]

[0748] Me and CF3;

[0749] in

[0750] X is selected from O and NR4;

[0751] R4 is independently selected from H, halo or C1-C3 alkyl;

[0752] R5 is independently selected from H or C1-C3 alkyl, preferably H or Me;

[0753] R6 is selected from C1-C4 alkyl; and

[0754] n is selected from 0, 1 or 2.

[0755] In a preferred embodiment, R3 is selected from

[0756]

[0757] wherein X is selected from O and NR4;

[0758] R4 is independently selected from -H or -C1-C3 alkyl;

[0759] a is selected from 0 and 1; and

[0760] n is selected from 0, 1 or 2.

[0761] In a preferred embodiment, R3 is selected from

[0762]

[0763] Me and CF3;

[0764] X is selected from O and NR4;

[0765] R4 is independently selected from H, halo or C1-C3 alkyl;

[0766] R5 is independently selected from -H or -Me;

[0767] R6 is selected from C1-C4 alkyl; and

[0768] n is selected from 0, 1 or 2.

[0769] In a preferred embodiment, R3 is selected from

[0770] wherein X is selected from O and NR4;

[0771] R4 is independently selected from -H or -C1-C3 alkyl;

[0772] a is selected from 0 and 1; and

[0773] n is selected from 0, 1 or 2.

[0774] In a further preferred embodiment, R3 is selected from

[0775]

[0776] wherein R4 is independently selected from -H or -C1-C3 alkyl; and

[0777] n is selected from 0, 1 or 2.

[0778] In a further preferred embodiment, R3 is selected from

[0779]

[0780] Me and CF3;

[0781] in

[0782] R4 is independently selected from H, F or C1-C3 alkyl; and

[0783] R5 is methyl; and

[0784] n is selected from 0, 1 or 2.

[0785] In a further preferred embodiment, R3 is selected from

[0786]

[0787] wherein R4 is independently selected from -H or -C1-C3 alkyl; and

[0788] n is selected from 0, 1 or 2.

[0789] In a preferred embodiment, R is a 4-, 5- or 6-membered heterocycloalkyl group containing one heteroatom, wherein the heteroatom is N. The 4-, 5- or 6-membered heterocycloalkyl group may be 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 (preferably C1-C4 alkyl). The substituents may be located at any available position on the heterocyclic group.

[0790] In a preferred embodiment, R3 is Wherein X is selected from O and NR4, preferably X is NR4;

[0791] R4 is independently selected from -H or -C1-C3 alkyl;

[0792] a is selected from 0 and 1 (preferably a is 0); and

[0793] n is selected from 0, 1 or 2. In a preferred embodiment, n is 2. In a preferred embodiment, n is 1. In another preferred embodiment, n is 0.

[0794] In a preferred embodiment, R3 is wherein R4 is independently selected from -H or C1-C3 alkyl. In a preferred embodiment, R4 is H. In another embodiment, R4 is C1-C3 alkyl, such as methyl, ethyl or propyl. In a preferred embodiment, R4 is methyl.

[0795] In another preferred embodiment, R3 is wherein R4 is independently selected from -H or C1-C3 alkyl. In a preferred embodiment, R4 is H. In another embodiment, R4 is C1-C3 alkyl, such as methyl, ethyl or propyl. In a preferred embodiment, R4 is methyl.

[0796] In another embodiment, R3 is wherein R4 is independently selected from -H or C1-C3 alkyl. In a preferred embodiment, R4 is H. In another embodiment, R4 is C1-C3 alkyl, such as methyl, ethyl or propyl. In one embodiment, R4 is methyl, wherein R3 is

[0797] In another embodiment, R3 is wherein R4 is independently selected from -H or C1-C3 alkyl. In a preferred embodiment, R4 is H. In another embodiment, R4 is C1-C3 alkyl, such as methyl, ethyl or propyl. In a preferred embodiment, R4 is methyl, wherein R3 is

[0798] In another preferred embodiment, R3 is a 4, 5 or 6-membered heterocycloalkyl group containing one heteroatom, wherein the heteroatom is O. In a preferred embodiment, R3 is

[0799] In another embodiment, R is C-C cycloalkyl, preferably cyclohexyl, cyclopropyl or cyclobutyl, more preferably cyclopropyl or cyclobutyl. The C-C cycloalkyl may be substituted by one or two substituents independently selected from the group consisting of C-C alkyl, halo-C-C alkyl, hydroxy-C-C alkyl, -OH and halo. The substituent may be located at any available position on the cycloalkyl.

[0800] In a preferred embodiment, R3 is

[0801] In a preferred embodiment, R3 is wherein R4 is independently selected from -H or C1-C3 alkyl. In a preferred embodiment, R4 is H. In another embodiment, R4 is C1-C3 alkyl, such as methyl, ethyl or propyl. In a preferred embodiment, R4 is methyl. In a preferred embodiment, R3 is In another preferred embodiment, R3 is

[0802] In another preferred embodiment, R3 is In a preferred embodiment, R3 is In another preferred embodiment, R3 is

[0803] In another preferred embodiment, R is C1-C6 alkyl, for example C1-C3 alkyl, for example methyl, ethyl or propyl. In a preferred embodiment, R is methyl. In another preferred embodiment, the alkyl may be substituted by one or two substituents independently selected from the following: -OH, halo, halogenated C1-C4 alkyl, C1-C4 alkoxy and -NR5R6, wherein R5 and R6 are independently selected from H and C1-C3 alkyl. In a preferred embodiment, R is hydroxy C1-C6 alkyl (C1-C6 alkyl substituted by -OH), more preferably hydroxy C1-C3 alkyl, preferably hydroxyethyl.

[0804] In a preferred embodiment, R3 is wherein n is 0, 1 or 2. In another preferred embodiment, R3 is Where n is 0, 1, or 2.

[0805] In another embodiment, R3 is C1-C4 alkoxy C1-C6 alkyl (ie, C1-C6 alkyl substituted by C1-C4 alkoxy), preferably C1-C3 alkoxy C1-C4 alkyl.

[0806] In one embodiment, R3 is wherein R4 is -C1-C3 alkyl; and n is selected from 0, 1 or 2.

[0807] In another preferred embodiment, R is a C1-C6 alkyl substituted with -NR5R6, wherein R5 and R6 are independently selected from H and C1-C3 alkyl. In a preferred embodiment, R5 and R6 are both C1-C3 alkyl, such as methyl, ethyl or propyl, more preferably R5 and R6 are both methyl. In another embodiment, R5 and R6 are both H.

[0808] In one embodiment, R3 is wherein R5 and R6 are independently selected from H and C1-C3 alkyl and wherein n is 0, 1 or 2. In a preferred embodiment, R5 and R6 are both C1-C3 alkyl, such as methyl, ethyl or propyl, more preferably R5 and R6 are both methyl. In another embodiment, R5 and R6 are both H.

[0809] In a preferred embodiment, R3 is Where n is 0, 1, or 2.

[0810] R a In some embodiments, R a is H. In other embodiments, R a is -C1-C3 alkyl, such as methyl, ethyl or propyl, preferably methyl.

[0811] In a preferred embodiment, X' is N. In another preferred embodiment, X' is CH.

[0812] In a preferred embodiment, W is N. In another preferred embodiment, W is CH. In another preferred embodiment, W is CR c , where R c It is -CH2-OH, -O-CH3 or F.

[0813] In a preferred embodiment, Y is NH. In another preferred embodiment, Y is O. In another embodiment, Y is N-CH3. In another preferred embodiment, Y is a bond.

[0814] In a preferred embodiment, R c In a further preferred embodiment, R c Selected from -O-C1-C2alkyl, C1-C4alkyl-OH and F, such as C1-C4alkyl-OH, OCH3 and F.

[0815] In a preferred embodiment, R d Selected from C1-C4 alkyl.

[0816] In another preferred embodiment, R3 is wherein R4 is independently selected from -H or C1-C3 alkyl. In a preferred embodiment, R4 is C1-C3 alkyl, such as methyl, ethyl or propyl, preferably methyl.

[0817] In another preferred embodiment, R3 is wherein R5 is H or C1-C3 alkyl.

[0818] In another preferred embodiment, R3 is C1-C6 alkyl.

[0819] In another preferred embodiment, there is provided a compound of formula (IV) having the structure

[0820]

[0821] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof;

[0822] Among them, X', W, R0, R1, R 2、 R d and R a As defined in the above embodiments, and R A yes

[0823] Y is selected from NH, NR d , O, or a key;

[0824] R3 is selected from

[0825] 4-, 5- or 6-membered heterocycloalkyl containing one or two heteroatoms, preferably one heteroatom, wherein the heteroatoms are independently selected from N and O, 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, -NR5R6 and halo;

[0826] An 8-, 9-, or 10-membered bicyclic fused heterocycloalkyl containing 1 to 3 heteroatoms, wherein the heteroatoms are independently selected from N and O, which is optionally substituted at any available position with one or two substituents independently selected from the group consisting of C1-C4 alkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl, -OH, -NR5R6, and halo; or

[0827] C3-C6 cycloalkyl, optionally substituted by 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; or

[0828] C1-C6 alkyl, which is optionally substituted by one or two substituents independently selected from the group consisting of -OH, halo, halo-substituted C1-C4 alkyl, C1-C4 alkoxy, and -NR5R6,

[0829] wherein R5 and R6 are independently selected from H and C1-C3 alkyl; and

[0830] m is 0, 1, or 2.

[0831] In another preferred embodiment, there is provided a compound of formula (V) having the structure of formula (V),

[0832]

[0833] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof;

[0834] Among them, R0, R1, R2, R 3、 R a , m and Y are as defined in the above embodiments.

[0835] In a preferred embodiment, the present invention relates to the following compounds of formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV) or (V) above, wherein

[0836] R0 is -H or -CH3;

[0837] R1 is -CF3 or halo, preferably Cl; and

[0838] R2 is -OH.

[0839] Throughout this application, if Q is N, and R B yes Then Y is preferably a bond.

[0840] In a further embodiment, the present invention relates to the following compounds of formula (I)

[0841]

[0842]

[0843]

[0844]

[0845]

[0846] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof.

[0847] The present invention also relates to a pharmaceutical composition comprising a compound of formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV) or (V) as defined herein, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, and optionally at least one pharmaceutically acceptable carrier, diluent, adjuvant or excipient.

[0848] Having described various embodiments of the present invention, it will be recognized that features specified within each embodiment may be combined with other specified features to provide further embodiments of the invention.

[0849] The present invention relates to compounds of formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV) or (V) as defined herein, or stereoisomers, racemic mixtures, tautomers, polymorphs, pharmaceutically acceptable salts, prodrugs, hydrates or solvates thereof for use as medicaments.

[0850] The present invention relates to compounds of formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV) or (V) as defined herein, or stereoisomers, racemic mixtures, tautomers, polymorphs, pharmaceutically acceptable salts, prodrugs, hydrates or solvates thereof, for use in treating, alleviating or preventing diseases, disorders or abnormalities that respond to modulation, particularly inhibition of activation, of components of the NLRP3 inflammasome pathway and / or modulation, particularly reduction, of IL-1β and / or IL-18 levels. In one embodiment, modulation is reduction and / or inhibition of IL-1β and / or IL-18β levels. In particular, modulation is reduction and / or inhibition of IL-1β.

[0851] The present invention relates to compounds of formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV) or (V) as defined herein, or stereoisomers, racemic mixtures, tautomers, polymorphs, pharmaceutically acceptable salts, prodrugs, hydrates or solvates thereof, for use in treating, alleviating or preventing diseases, disorders or abnormalities that respond to modulation, in particular reduction, of IL-1β and / or IL-18 levels.

[0852] In another embodiment, the invention relates to a compound of formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV) or (V) 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 and / or IL-18. In one embodiment, the invention relates to a compound of formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV) or (V) 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.

[0853] The present invention relates to compounds of formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV) or (V) as defined in the present invention, or stereoisomers, racemic mixtures, tautomers, polymorphs, pharmaceutically acceptable salts, prodrugs, hydrates or solvates thereof, for use in treating, alleviating or preventing diseases, disorders or abnormalities that respond to modulation of components of the NLRP3 inflammasome pathway, particularly inhibition of activation.

[0854] The present invention relates to compounds of formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV) or (V) as defined in the present invention, or stereoisomers, racemic mixtures, tautomers, polymorphs, pharmaceutically acceptable salts, prodrugs, hydrates or solvates thereof, for use in treating, alleviating or preventing diseases, disorders or abnormalities responsive to modulation of the NLRP3 inflammasome, particularly inhibition of activation.

[0855] In other words, the present invention relates to a method for treating, alleviating or preventing diseases, disorders or abnormalities that are responsive to modulation, in particular inhibition of activation, of components of the NLRP3 inflammasome pathway and / or to modulation, in particular reduction, of IL-1β and / or IL-18 levels, wherein the method comprises administering to an individual in need thereof (e.g., a patient) a therapeutically effective amount of a compound of formula (I'), (I), (II'), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV) or (V) as defined herein, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof. In one embodiment, modulation is reduction and / or inhibition of IL-1β and / or IL-18β levels. In particular, modulation is reduction and / or inhibition of IL-1β.

[0856] In one embodiment, the present invention relates to a method for treating, preventing or alleviating a disease, disorder or abnormality that responds to modulation of a component of the NLRP3 inflammasome pathway, particularly 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), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV) or (V) as defined herein, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof.

[0857] The present invention also relates to a method for treating, preventing or alleviating a disease, disorder or abnormality that responds to modulation of the NLRP3 inflammasome, particularly 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), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV) or (V) as defined herein, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof.

[0858] In one embodiment, the present invention relates to a method for treating, preventing or alleviating a disease, disorder or abnormality that is responsive to modulation, in particular reduction, of IL-1β and / or IL-18 levels, wherein the method comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I'), (I), (II'), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV) or (V) as defined herein, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof. In one embodiment, modulation is reduction and / or inhibition of IL-1β and / or IL-18β levels. In particular, modulation is reduction and / or inhibition of IL-1β.

[0859] The present invention relates to the use of a compound (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV) or (V) as defined in the present invention, 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), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV) or (V) as defined herein, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, for 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, modulation is reduction and / or inhibition of IL-1β and / or IL-18β levels. In particular, modulation is reduction and / or inhibition of IL-1β.

[0860] The present invention relates to the use of a compound of formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV) or (V) 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.

[0861] The present invention relates to the use of a compound of formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV) or (V) as defined in the present invention, 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, particularly inhibition of activation, of the NLRP3 inflammasome.

[0862] The present invention relates to the use of a compound of formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV) or (V) as defined herein, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, in the preparation of a medicament for treating, alleviating or preventing a disease, disorder or abnormality that is responsive to the modulation, in particular the reduction, of IL-1β and / or IL-18 levels.

[0863] The present invention relates to the use of a compound of formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV) or (V) as defined herein, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof in the preparation of a medicament for reducing and / or inhibiting IL-1β and / or IL-18β 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 or inhibiting IL-1β.

[0864] In one embodiment, the present invention relates to a compound of formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV) or (V) as defined herein, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, for use in treating, alleviating or preventing tauopathy by modulating components of the inflammasome pathway, particularly by modulating the NLRP3 inflammasome pathway.

[0865] 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.

[0866] In yet another embodiment, the disease, disorder or abnormality is a disease, disorder or abnormality selected from Alzheimer's disease, Parkinson's disease, cryopyrin-associated periodic syndrome (CAPS), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH) and gout.

[0867] 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.

[0868] In one embodiment, the disease, disorder or abnormality responsive to modulation of a component of the NLRP3 inflammasome pathway, particularly inhibition of activation, can be selected from Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, demyelination, viral encephalitis, epilepsy, stroke, atherosclerosis, 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 (IBD) (including Crohn's disease, ulcerative colitis), hepatitis, non-alcoholic fatty liver disease disease, nonalcoholic steatohepatitis, hypertension, myocardial infarction, heart failure, coronary artery disease, oxalate-induced nephropathy, graft-versus-host disease, type 1 diabetes mellitus, type 2 diabetes mellitus, edema (DME), geographic atrophy (GA), 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, septic arthritis, pyoderma gangrenosum, and acne vulgaris (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 recurrent multifocal osteomyelitis (CRMO), synovitis, impetigo, skin contact allergy, sunburn, Psoriasis, hidradenitis suppurativa (HS), epidermolysis bullosa, acne, eczema, alopecia areata, actinic keratosis, hyperostosis, inflammatory bone disease syndrome (SAPHO), vitiligo, atopic dermatitis, cutaneous lupus, multiple sclerosis (MS), Behçet's disease, Sjögren's syndrome, Schnitzler syndrome, chronic obstructive pulmonary disease (COPD), asthma, steroid-resistant asthma, coronavirus-associated inflammatory diseases, including coronavirus-associated respiratory distress syndrome (CARDS), asbestosis, silicosis, cystic fibrosis, motor neurone disease Huntington's disease, cerebral malaria, brain damage due to pneumococcal meningitis, obesity, age-related macular degeneration (AMD), corneal infection, uveitis, dry eye, acute kidney injury, chronic kidney disease, lupus nephritis, diabetic nephropathy, alcoholic liver disease, osteoarthritis, systemic juvenile idiopathic arthritis, adult-onset Still's disease, relapsing polychondritis, Chikungunya virus, Ross River virus, influenza, HIV, coronavirus, dengue fever, Zika virus, primary biliary cholangitis, antiphospholipid syndrome, refractory Celiac disease, pancreatitis, autoimmune pancreatitis, mucocutaneous lymph node syndrome, lung cancer metastasis, pancreatic cancer, gastric cancer, myelodysplastic syndrome, leukemia; polymyositis, colitis, helminthic infection, bacterial infection, abdominal aortic aneurysm, wound healing, migraine, depression, psychological stress, pain, neuropathic pain, periodontitis, pericarditis including Dressler syndrome, ischemia-reperfusion injury, frontotemporal dementia, HIV-related neurocognitive disorder, traumatic brain injury, traumatic spinal cord injury, ankylosing spondylitis, cytokine release syndrome.

[0869] Preferably, the disease, disorder or abnormality is selected from the group consisting of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, demyelination, multiple sclerosis, encephalomyelitis, leukoencephalopathy, viral encephalitis, epilepsy, stroke, traumatic brain and spinal cord injury, atherosclerosis, asthma and allergic inflammation, cryptopyrin-associated periodic syndrome (CAPS), gout, inflammatory bowel disease (IBD), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), hypertension, myocardial infarction, oxalate-induced nephropathy, transplantation, These diseases include: drug-versus-host disease, type 1 diabetes mellitus, type 2 diabetes mellitus, rheumatoid arthritis, acute kidney disease, chronic kidney disease, 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 relapsing fever (HRF), acne, atopic dermatitis, and hidradenitis suppurativa (HS).

[0870] More preferably, the disease, disorder or abnormality is selected from Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, demyelination, multiple sclerosis, viral encephalitis, epilepsy, stroke, atherosclerosis, asthma and allergic inflammation, cryptopyrin-associated periodic syndrome (CAPS), gout, inflammatory bowel disease (IBD), 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, hidradenitis suppurativa (HS), gout, rheumatoid arthritis, acute kidney disease, chronic kidney disease and myelodysplastic syndrome.

[0871] 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), chronic kidney disease, inflammatory bowel disease (IBD), hidradenitis suppurativa (HS), 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), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), hidradenitis suppurativa (HS), chronic kidney disease and gout.

[0872] In one embodiment, the disease, disorder or abnormality responsive to modulation of a component of the NLRP3 inflammasome pathway, particularly 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, inflammatory bowel syndrome (SAPHO), multiple sclerosis (MS), psoriasis, Behçet's disease, Sjögren's syndrome, Schnitzler syndrome, chronic obstructive pulmonary disease (COPD), steroid-resistant asthma, asbestosis, silicosis, cystic fibrosis, motor neuron disease, Huntington's disease, cerebral malaria, brain damage due to pneumococcal meningitis, obesity, age-related macular degeneration (AMD), corneal infection, eye color Laminitis, dry eye, chronic kidney disease, diabetic nephropathy, alcoholic liver disease, contact allergy, sunburn, osteoarthritis, systemic juvenile idiopathic arthritis, adult-onset Still's disease, relapsing polychondritis, Chikungunya virus, Ross River virus, influenza, HIV, coronavirus, dengue fever, Zika virus, hidradenitis suppurativa (HS), lung cancer metastasis, pancreatic cancer, gastric cancer, myelodysplastic syndrome, leukemia; polymyositis, colitis, helminthic infection, bacterial infection, abdominal aortic aneurysm, wound healing, depression, psychological stress, pericarditis including Dressler syndrome, ischemia-reperfusion injury, frontotemporal dementia, HIV-related neurocognitive disorders, coronavirus-related inflammatory lesions, and traumatic brain injury.

[0873] 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 relapsing fever (HRF).

[0874] 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.

[0875] 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. Even more preferably, the disease, disorder or abnormality is selected from Alzheimer's disease, Parkinson's disease, cryptopyrin-associated periodic syndrome (CAPS), rheumatoid arthritis and gout.

[0876] In one embodiment, the disease, disorder or abnormality is selected from Alzheimer's disease and Parkinson's disease. In another embodiment, the disease, disorder or abnormality is selected from cryopyrin-associated periodic syndrome (CAPS), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH) and gout.

[0877] In one embodiment, the present invention relates to a compound of formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV) or (V) as defined herein, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, for use in treating, alleviating or preventing IL-18 and / or IL-1β related diseases by modulating NLRP3 inflammasome pathway components, in particular by modulating NLRP3 inflammasome pathway. IL-18 and / or IL-1β levels in a subject are reduced as a result of administering a compound of formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV) or (V) as defined herein, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof.

[0878] IL-18 and / or IL-1β related diseases, disorders or abnormalities are selected from chronic obstructive pulmonary disease (COPD), transfusion-related lung injury, bronchopulmonary dysplasia (BPD), acute respiratory distress syndrome (ARDS), coronavirus-associated respiratory distress syndrome (CARDS), 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 (FHLH) associated with genetic defects in perforin, munc 13-4 and 18-2, synthaxin 11. Immunodeficiency such as Cheyenne-Higashi 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, hidradenitis suppurativa (HS), septic arthritis, pyoderma gangrenosum and acne (PAPA), pulmonary sarcoidosis, edema (DME), geographic atrophy (GA), heart failure, ischemic heart disease, dry eye disease (DED), keratitis, corneal ulcers and abrasions, iris The following conditions are listed in Table 1: Inflammation, glaucoma, Sjögren's syndrome, autoimmune 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-IgD syndrome (mevalonate kinase gene mutation), gout, Schnitzler syndrome, Wegener's granulomatosis also known as granulomatosis with polyangiitis (GPA), Hashimoto's thyroiditis, Crohn's disease, early-onset inflammatory bowel disease (EOIBD), very advanced EOIBD (VEOIBD), infantile IBD, neonatal IBD, ulcerative colitis, and Blau syndrome (NOD-2 mutation).

[0879] Modulation of the NLRP3 inflammasome pathway has been shown to be beneficial in diseases or disorders or abnormalities with altered IL-18 levels and / or IL-1β levels, which lead to pathological inflammation.

[0880] The present invention relates to compounds of formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV) or (V) as defined herein, which are modulators of NLRP3 inflammasome activity and / or modulators of IL-18 and / or IL-1b levels in an individual.

[0881] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV) or (V) 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.

[0882] In another embodiment, the present invention relates to a pharmaceutical composition comprising a compound of formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV) or (V) 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 a compound of formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV) or (V), and optionally comprising at least one pharmaceutically acceptable carrier, diluent, adjuvant or excipient.

[0883] In another embodiment, the present invention relates to a pharmaceutical composition comprising a compound of formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV) or (V) 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 a compound of formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV) or (V), and optionally comprising at least one pharmaceutically acceptable carrier, diluent, adjuvant or excipient.

[0884] In particular, other bioactive 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 other bioactive compounds, the dosage of each compound may be different from the dosage when the compound is used as a monotherapy. These bioactive compounds are well known in the literature. Such bioactive compounds are, for example, compounds, peptides, antibody fragments or nucleic acids, which, when applied to an individual (e.g., a patient) in combination with the compounds of the present invention, have therapeutic activity or enhance therapeutic activity.

[0885] In another embodiment, the invention relates to a pharmaceutical composition for use as a medicament, comprising a compound of formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV) or (V) 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 a compound of formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV) or (V), and optionally comprising at least one pharmaceutically acceptable carrier, diluent, adjuvant or excipient.

[0886] The term "combination" refers to a fixed combination in the form of one dosage unit, or to a combined administration wherein the 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 are administered independently simultaneously or separately within time intervals.

[0887] In another embodiment, the present invention relates to a combination, in particular a pharmaceutical combination, comprising a therapeutically effective amount of a compound of formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV) or (V) as defined herein, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, and at least one further biologically active compound, and optionally at least one pharmaceutically acceptable carrier, diluent, adjuvant or excipient. In particular, the at least one further biologically active compound is a compound different from formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV) or (V).

[0888] 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), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV) or (V) as defined herein, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, and at least one additional biologically active compound different from a compound of formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV) or (V), and optionally comprising at least one pharmaceutically acceptable carrier, diluent, adjuvant or excipient.

[0889] The present invention relates to the use of compounds of formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV) or (V) as defined herein, or stereoisomers, racemic mixtures, tautomers, polymorphs, pharmaceutically acceptable salts, prodrugs, hydrates or solvates thereof as analytical references or in vitro screening tools. The compounds of the present invention, or stereoisomers, racemic mixtures, tautomers, polymorphs, pharmaceutically acceptable salts, prodrugs, hydrates or solvates thereof, 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.

[0890] Accordingly, the present invention provides a compound of formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV) or (V) as defined herein, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, for use in treating, alleviating or preventing disorders or abnormalities 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 medicament is prepared for administration with another biologically active agent. The present invention also provides the use of another bioactive agent for treating, alleviating or preventing a disorder or abnormality that responds to the modulation of a component of the NLRP3 inflammasome pathway or to the modulation, particularly the reduction, of IL-1β and / or IL-18 levels, wherein the other bioactive agent is administered together with a compound of the present invention or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof.

[0891] In another embodiment, the present invention provides a compound of formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV) or (V) as defined herein, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, for use in treating, alleviating or preventing a 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 levels, wherein the modulation is reduction and / or inhibition of IL-1β and / or IL-1β levels. Preferably, the modulation is reduction and / or inhibition of IL-1β. Preferably, the modulation is inhibition of IL-1β. In another embodiment, the present invention provides a compound of formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV) or (V) as defined herein, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, for use as a medicament, in particular for inhibiting IL-1β.

[0892] In another embodiment, the present invention also provides a compound of formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV) or (V) as defined herein, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, for use in treating, alleviating or preventing a 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), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV) or (V) is prepared for administration with an additional biologically active compound (as defined herein).

[0893] In another embodiment, the present invention also provides a method for treating, alleviating 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, 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 (including Crohn's disease, ulcers), inflammatory bowel disease (including Crohn's disease, ulcers), inflammatory bowel disease (including inflammatory bowel disease ... colitis), nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, hypertension, myocardial infarction, heart failure, coronary artery disease, oxalate-induced nephropathy, graft-versus-host disease, type 1 diabetes mellitus, type 2 diabetes mellitus, edema (DME), geographic atrophy (GA), 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, septic 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, skin contact allergy, sunburn, psoriasis, hidradenitis suppurativa (HS), epidermolysis bullosa, acne, eczema, alopecia areata, actinic keratosis, hyperostosis, osteitis syndrome (SAPHO), vitiligo, atopic dermatitis, cutaneous lupus, multiple sclerosis (MS), shellfish Hecht's disease, Sjögren's syndrome, Schnitzler's syndrome, chronic obstructive pulmonary disorder (COPD), coronavirus-associated inflammatory disease, coronavirus-associated respiratory distress syndrome (CARDS), steroid-resistant asthma, asbestosis, silicosis, cystic fibrosis, motor neuron disease, Huntington's disease, cerebral malaria, brain damage due to pneumococcal meningitis, obesity, age-related macular degeneration (AMD), corneal infection, uveitis, dry eye, acute kidney disease, chronic kidney disease, diabetic nephropathy, alcoholic liver disease, 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, migraine, depression, psychological stress, pain, neuropathic pain, periodontitis, pericarditis including Dressler syndrome, ischemia-reperfusion injury, frontotemporal dementia, HIV-related neurocognitive disorders, traumatic brain injury, traumatic spinal cord injury, ankylosing spondylitis and cytokine release syndrome; preferably, the disorder is selected from Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, demyelination, multiple sclerosis, viral encephalitis, epilepsy, stroke, traumatic brain injury, spinal cord injury, atherosclerosis, asthma, allergic inflammation, 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, acute kidney disease, chronic kidney disease, 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), hidradenitis suppurativa (HS), psoriatic arthritis and hereditary relapsing fever (HRF), the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I), (II'), (II), (II'a), (IIa), (II'b), (IIb), (III), (IV) or (V) as defined herein, or a stereoisomer, or racemic mixture, or tautomer, or polymorph, or pharmaceutically acceptable salt, or hydrate, or solvate thereof.

[0894] In one embodiment, the disease, disorder or abnormality that is responsive to modulation of NLRP3 inflammasome pathway components or to modulation, in particular reduction, of IL-1β and / or IL-18 levels 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 Kidney disease, 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, pyogenic arthritis, pyoderma gangrenosum and acne (PAPA), A20 haploinsufficiency (HA20), PLCG2-related antibody deficiency and immune dysregulation (PLAID), pediatric granulomatous arthritis (PGA), PLCG2-related autoinflammatory, antibody deficiency and immune dysregulation (AP LAID), 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, Behçet's disease, Sjögren's syndrome, Schnitzler syndrome, chronic obstructive pulmonary disease (COPD), steroid-resistant asthma, asbestosis, silicosis, cystic fibrosis, motor neuron disease, Huntington's disease, cerebral malaria, brain damage due to pneumococcal meningitis, obesity, age-related macular degeneration (AMD), corneal Infections, uveitis, dry eye, chronic kidney disease, diabetic nephropathy, alcoholic liver disease, contact allergies, sunburn, osteoarthritis, systemic juvenile idiopathic arthritis, adult-onset Still's disease, relapsing polychondritis, Chikungunya virus, Ross River virus, influenza, HIV, coronavirus, dengue fever, Zika virus, hidradenitis suppurativa (HS), lung cancer metastasis, pancreatic cancer, gastric cancer, myelodysplastic syndrome, leukemia; polymyositis, colitis, helminthic infections, bacterial infections, abdominal aortic aneurysm, wound healing, depression, psychological stress, pericarditis including Dressler syndrome, ischemia-reperfusion injury, frontotemporal dementia, HIV-associated neurocognitive disorders, coronavirus-associated inflammatory disorders, 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 relapsing fever (HRF), which comprises administering to the individual a therapeutically effective amount of a compound of (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV) or (V) as defined herein, or a stereoisomer, or racemic mixture, or tautomer, or polymorph, or pharmaceutically acceptable salt, or hydrate, or solvate thereof. ;

[0895] In another embodiment, the present invention also provides a method of inhibiting IL-1β in a subject in need thereof, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV) or (V) as defined herein, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof.

[0896] 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, for example, but not limited to, IL-1β or IL-18, for example, the disease, disorder or abnormality responds to modulation of one or more of IL-1β, IL-17, IL-18, IL-1a, IL-37, IL-33 and Th17 cells, preferably the disease, disorder or abnormality responds to modulation of IL-1β and / or IL-18.

[0897] Also contemplated in the present invention are any combinations of the embodiments, preferred embodiments and more preferred embodiments disclosed herein.

[0898] Pharmaceutical composition

[0899] Although the compounds of the present invention, or their stereoisomers, racemic mixtures, tautomers, polymorphs, pharmaceutically acceptable salts, prodrugs, hydrates or solvates, can be administered alone, it is preferred 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), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV) or (V), or their stereoisomers, racemic mixtures, tautomers, polymorphs, pharmaceutically acceptable salts, prodrugs, hydrates or solvates, optionally in admixture with a pharmaceutically acceptable carrier, diluent, adjuvant or excipient.

[0900] The term "therapeutically effective amount" of a compound of the invention refers to an amount of a compound of the invention (i.e., a compound of (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV) or (V), 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 amelioration of symptoms, alleviation of symptoms, slowing or delaying disease progression, or prevention of a disease, disorder or abnormality. In one embodiment, the term "therapeutically effective amount" refers to an amount of a compound of the invention that, when administered to a subject in need thereof (e.g., a patient), is effective in at least partially alleviating, preventing and / or ameliorating 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.

[0901] Pharmaceutically acceptable carriers, diluents, adjuvants, and excipients are well known in the pharmaceutical art and are described, for example, in Remington's Pharmaceutical Sciences, 18th ed. (Alfonso R. Gennaro, ed.; Mack Publishing Company, Easton, PA, 1990); Remington: the Science and Practice of Pharmacy, 19th ed. (Lippincott, Williams & Wilkins, 1995); Handbook of Pharmaceutical Excipients, 3rd ed. (Arthur H. Kibbe, ed.; Amer. Pharmaceutical Assoc, 1999); Pharmaceutical Codex: Principles and Practice of Pharmaceutics, 12th ed. (Walter Lund ed.; Pharmaceutical Press, London, 1994); 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.

[0902] 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.

[0903] Pharmaceutically useful excipients that can be used to formulate the pharmaceutical compositions of the present invention may include, for example, vehicles, solvents (e.g., monohydric alcohols such as ethanol, isopropyl alcohol, and polyhydric alcohols such as ethylene glycol), edible oils (e.g., soybean oil, coconut oil, olive oil, safflower oil, and cottonseed oil), oily esters (e.g., ethyl oleate and isopropyl myristate), binders (e.g., hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), pregelatinized starch, and combinations thereof), solubilizers, thickeners, stabilizers, disintegrants (e.g., carboxymethylcellulose calcium (CMC-Ca), carboxymethylcellulose sodium (CMC-Na), cross-linked PVP (e.g., crospovidone, or XL), alginic acid, sodium alginate, guar gum, cross-linked CMC (cross-linked sodium carboxymethylcellulose, such as Ac-Di- ), carboxymethyl starch-Na (sodium starch glycolate) (e.g. or ), preferably cross-linked PVP and / or cross-linked sodium carboxymethylcellulose), glidants (e.g. colloidal SiO2 (e.g. 200), magnesium trisilicate, powdered cellulose, talc, and combinations thereof), lubricants (e.g., magnesium stearate, aluminum or calcium silicate, stearic acid, hydrogenated castor oil, talc, glyceryl behenate, sodium stearyl fumarate, and combinations thereof), buffers, emulsifiers, wetting agents, suspending agents, sweeteners, colorants, flavorings, coating agents, preservatives, antioxidants, processing aids, drug delivery modifiers and enhancers (e.g., calcium phosphate), magnesium stearate, talc, monosaccharides, disaccharides, starch, gelatin, cellulose, methylcellulose, sodium carboxymethylcellulose, dextrose, hydroxypropyl-β-cyclodextrin, polyvinylpyrrolidone, a low melting point wax, and ion exchange resins.

[0904] There is no particular limitation on the carrier and it will depend on the route of administration and the form of the pharmaceutical composition (i.e., solid, liquid, etc.). Suitable carriers include, but are not limited to, polyols such as mannitol, sorbitol, xylitol; disaccharides such as lactose, sucrose, dextrose, and maltose; polysaccharides such as maltodextrin and dextran; starches such as corn starch; cellulose such as microcrystalline cellulose, sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, or mixtures thereof; cyclodextrins and inorganic 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 target.

[0905] There is no particular limitation 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.

[0906] Adjuvants are additives which themselves have little or no pharmacological effect, but which, if administered together with the compounds of the present invention, increase the efficacy or effectiveness of the compounds of the present invention.

[0907] 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.

[0908] For example, the compounds can be administered orally in the form of tablets, capsules, ovules, elixirs, solutions or suspensions, which may contain flavorings or colorings for immediate, delayed, modified, sustained, pulsed or controlled-release applications.

[0909] Tablets can 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 carboxymethyl cellulose, 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 can be included. Similar types of solid compositions can also be used as fillers in gelatin capsules. Preferred excipients in this regard include starch, cellulose, milk sugars, such as lactose or high molecular weight polyethylene glycols. For aqueous suspensions and / or elixirs, the active agent can be combined with a variety of sweeteners or flavorings, coloring matter, or dyes, with emulsifiers and / or suspending agents, and with diluents such as water, ethanol, propylene glycol, and glycerol, and combinations thereof.

[0910] If the compounds of the present invention as disclosed herein are administered parenterally, examples of such administration include one or more of the following: intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​intrasternal, intracranial, intramuscular or subcutaneous administration of the compound; and / or using infusion techniques. For parenteral administration, the compound can be used in the form of a sterile aqueous solution that may contain other substances, such as sufficient salts or glucose to make the solution isotonic with the blood. If necessary, the aqueous solution should be appropriately buffered (preferably at a pH of 3-9). The preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.

[0911] As indicated, the compounds of the invention can be administered intranasally or by inhalation and are conveniently delivered in the form of a dry powder inhaler or aerosol spray from a pressurized container, pump, sprayer or nebulizer using a suitable propellant, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, a hydrofluoroalkane such as 1,1,1,2-tetrafluoroethane (HFA134AT) or 1,1,1,2,3,3,3-heptafluoropropane (HFA 227EA), carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount. The pressurized container, pump, sprayer or nebulizer can contain a solution or suspension of the active compound, for example, using a mixture of ethanol and the propellant as a solvent, which may additionally contain a lubricant, for example, sorbitan trioleate. Capsules and cartridges for use in an inhaler or insufflator (e.g., made of gelatin) can be formulated to contain a powder mix of the compound and a suitable powder base (e.g., lactose or starch).

[0912] Alternatively, the compounds of the invention as defined herein may be administered in the form of a suppository or pessary, 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.

[0913] They can also be administered via the pulmonary or rectal routes. They can also be administered via the ophthalmic route. For ophthalmic use, the compounds can be formulated as micronized suspensions in isotonic, pH-adjusted sterile saline, or preferably as solutions in isotonic, pH-adjusted sterile saline, optionally in combination with a preservative such as benzalkonium chloride. Alternatively, they can be formulated in an ointment, such as petrolatum.

[0914] For topical application to the skin, the compounds of the invention can 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 can 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 esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0915] Generally, the clinician will determine the actual dosage that will be most suitable for an individual. 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, route and time of administration, rate of excretion, drug combination, severity of the particular condition, and the individual being treated.

[0916] The claimed compounds as defined herein may 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 may be compounds for treating, alleviating or preventing the diseases.

[0917] The above-mentioned combination can be conveniently used in the form of a pharmaceutical preparation. The individual components of such a combination can be administered sequentially or simultaneously in a separate or combined pharmaceutical preparation by any convenient route. When administered sequentially, the compound of the invention or another biologically active compound can be administered first. When administered simultaneously, the combination can be administered in the form of the same or different pharmaceutical compositions. When combined in the same formulation, it will be understood that the two compounds must be stable and compatible with each other and with the other components of the formulation. When formulated separately, they can be provided in any convenient formulation, conveniently providing in a manner known to the art for such compounds.

[0918] The pharmaceutical compositions of the present 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).

[0919] The compounds of the present invention as disclosed herein may also be provided in admixture with at least one additional biologically active compound and / or a pharmaceutically acceptable carrier, diluent, adjuvant or excipient. The compounds and / or additional biologically active compounds are preferably present in a therapeutically effective amount.

[0920] The nature of the additional biologically active compound will depend on the intended use of the mixture. The additional biologically active substance or compound may exert its biological effect by the same or similar mechanism as the compounds of the present invention or by an unrelated mechanism of action or by multiple related and / or unrelated mechanisms of action.

[0921] 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 present invention are those 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 thus may be preferred in some circumstances. Isotopic variations of the compounds of the invention can generally be prepared by conventional methods, for example, by the illustrative methods or by the preparative methods described in the Examples and Preparations below, using appropriate isotopic variations of suitable reagents.

[0922] Invention application method

[0923] There is evidence for a role for NLRP3-induced IL-1 and IL-18 in inflammatory responses that are associated with or occur as a result of a variety of different diseases, disorders, or abnormalities that respond to modulation of 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).

[0924] The present invention provides compounds of formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV) or (V) 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 are useful for treating, alleviating or preventing diseases, or disorders or abnormalities that are responsive to modulation of components of the NLRP3 inflammasome pathway and / or responsive to modulation of IL-1β and / or IL-18 levels. NLRP3 has been implicated in a number of diseases, disorders or abnormalities, including, for example, one of the following:

[0925] A. Central nervous system (CNS) diseases, disorders, or abnormalities, 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, spinal cord injury, neuropathic pain, migraine, amyotrophic lateral sclerosis, or multiple sclerosis (MS);

[0926] 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, antiphospholipid syndrome, refractory celiac disease, autoimmune pancreatitis, or relapsing-remitting multiple sclerosis (RRMS);

[0927] C. Inflammatory diseases, including autoinflammation and inflammation that occurs due to an inflammatory disease, disorder, or abnormality, 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, or developmental delay (SIFD);

[0928] D. Skin diseases, disorders, or abnormalities, including inflammatory conditions of the skin such as hidradenitis suppurativa (HS), dermatitis, psoriasis, contact allergies, acne, periodic fever syndrome (HIDS), Sweet syndrome, eczema, skin lesions, burns, wounds, wound healing, trauma, sunburn, actinic keratosis, interleukin 1 receptor antagonist deficiency (DIRA), epidermolysis bullosa, vitiligo, atopic dermatitis, cutaneous lupus, or alopecia areata;

[0929] E. Eye diseases, disorders, or abnormalities, such as age-related macular degeneration (AMD), corneal infection, uveitis, glaucoma, dry eye, geographic atrophy (GA), or demyelination;

[0930] 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, heart failure, coronary artery disease or stroke;

[0931] G. Metabolic diseases, disorders or abnormalities, such as type 2 diabetes, obesity, edema (DME), atherosclerosis, gout or pseudogout;

[0932] 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), coronavirus-associated respiratory distress syndrome (CARDS), steroid-resistant asthma, or asthma;

[0933] I. Liver diseases, disorders, or abnormalities (e.g., liver diseases, disorders, or abnormalities), such as hepatitis, primary biliary cholangitis, cytokine release syndrome, 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;

[0934] J. renal diseases, disorders or abnormalities (e.g., diseases, disorders or abnormalities of the renal system), such as oxalate-induced nephropathy, diabetic nephropathy, lupus nephritis, chronic kidney disease or acute kidney disease;

[0935] K. a cancer disease, disorder or abnormality (e.g., cancer, tumor or malignancy), such as lung cancer (e.g., lung cancer metastasis), pancreatic cancer, gastric cancer, leukemia, myelodysplastic syndrome (MOS), skin cancer, a tumor of the endocrine system or thyroid cancer;

[0936] L. Infections, including viral infections, such as helminthic infections (e.g., from schistosomes, roundworms, tapeworms, or flukes), viral encephalitis, bacterial infections, periodontitis, human immunodeficiency virus (HIV), HIV-associated neurocognitive disorders, chronic nonbacterial osteomyelitis (CNO), chronic bacterial osteomyelitis, interleukin-1 receptor antagonist deficiency (DIRA), or epilepsy; alphaviruses (e.g., Chikungunya virus and Ross River virus), arboviruses (e.g., dengue and Zika virus), coronavirus-associated inflammatory disorders, coronavirus, or influenza virus;

[0937] M. Mental illness, disorder or abnormality, such as depression and psychological stress;

[0938] 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 that occurs secondary to trauma, injury, or autoimmunity. Examples of inflammation include inflammatory reactions associated with or occurring as a result of:

[0939] i. a joint disease, disorder or abnormality 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, ankylosing spondylitis or adult-onset Still's disease;

[0940] ii. Gastrointestinal diseases, disorders or abnormalities (e.g., diseases, disorders or abnormalities of the gastrointestinal tract), such as colitis, ulcerative colitis or inflammatory bowel disease;

[0941] iii. Muscle diseases, disorders or abnormalities, such as polymyositis or myasthenia gravis;

[0942] 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

[0943] v. Vascular diseases, disorders or abnormalities, such as Behçet's disease or mucocutaneous lymphadenopathy syndrome.

[0944] In one embodiment, the disease, disorder or abnormality is selected from Alzheimer's disease, Parkinson's disease, cryopyrin-associated periodic syndrome (CAPS), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH) and hidradenitis suppurativa (HS).

[0945] 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, 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 (IBD) (including Crohn's disease, ulcerative colitis), hepatitis, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, hyperlipidemia, leukemia, leukemia, schizoaffective disorder (SMD), leukemia, schizoaffective disorder (LSMD), leukemia, schizoaffective disorder (LSMD), leukemia, schizoaffective disorder (S ... Blood pressure, myocardial infarction, heart failure, coronary artery disease, oxalate-induced nephropathy, graft-versus-host disease, type 1 diabetes mellitus, type 2 diabetes mellitus, edema (DME), geographic atrophy (GA), 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, septic 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 recurrent multifocal osteomyelitis (CRMO), synovitis, impetigo, skin contact allergy, sunburn, psoriasis, hidradenitis suppurativa ( HS), epidermolysis bullosa, acne, eczema, alopecia areata, actinic keratosis, hyperostosis, inflammatory bone syndrome (SAPHO), vitiligo, atopic dermatitis, cutaneous lupus, multiple sclerosis (MS), Behçet's disease, Sjögren's syndrome, Schnitzler syndrome, chronic obstructive pulmonary disorder (COPD), asthma, steroid-resistant asthma, coronavirus-associated inflammatory diseases, including coronavirus-associated respiratory distress syndrome (CARDS), asbestosis, silicosis, cystic fibrosis, motor neuron disease, Huntington's disease, cerebral malaria, brain ulcers due to pneumococcal meningitis Injury, obesity, age-related macular degeneration (AMD), corneal infection, uveitis, dry eye, acute kidney injury, chronic kidney disease, lupus nephritis, diabetic nephropathy, alcoholic liver disease, osteoarthritis, systemic juvenile idiopathic arthritis, adult-onset Still's disease, relapsing polychondritis, Chikungunya virus, Ross River virus, influenza, HIV, coronavirus, dengue fever, Zika virus, primary biliary cholangitis, antiphospholipid syndrome, refractory celiac disease, pancreatitis, autoimmune pancreatitis, mucocutaneous lymph node syndrome, lung cancer metastasis, pancreas cancer, gastric cancer, myelodysplastic syndrome, leukemia; polymyositis, colitis, helminth infection, bacterial infection, abdominal aortic aneurysm, wound healing, migraine, depression, psychological stress, pain, neuropathic pain, periodontitis, pericarditis including Dressler syndrome, ischemia-reperfusion injury, frontotemporal dementia, HIV-related neurocognitive disorder, traumatic brain injury, traumatic spinal cord injury, inflammatory pain, chronic pain, neuropathic pain, metastatic cancer-induced bone pain, chemotherapy-induced peripheral neuropathy and migraine; ankylosing spondylitis, cytokine release syndrome. Preferably,The disease, disorder or abnormality is selected from the group consisting of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, demyelination, multiple sclerosis, encephalomyelitis, leukoencephalopathy, viral encephalitis, epilepsy, stroke, traumatic brain and spinal cord injury, atherosclerosis, asthma and allergic inflammation, cryptopyrin-associated periodic syndrome (CAPS), gout, inflammatory bowel disease (IBD), 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, hidradenitis suppurativa (HS), rheumatoid arthritis, acute kidney disease, chronic kidney disease, 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 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).

[0946] In one embodiment, the disease, disorder or abnormality responsive to modulation of a component of the NLRP3 inflammasome pathway, particularly inhibition of activation, can be selected from Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, demyelination, viral encephalitis, epilepsy, stroke, atherosclerosis, 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 (IBD) (including Crohn's disease, ulcerative colitis), hepatitis, non-alcoholic fatty liver disease disease, nonalcoholic steatohepatitis, hypertension, myocardial infarction, heart failure, coronary artery disease, oxalate-induced nephropathy, graft-versus-host disease, type 1 diabetes mellitus, type 2 diabetes mellitus, edema (DME), geographic atrophy (GA), 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, septic arthritis, pyoderma gangrenosum, and acne vulgaris (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 recurrent multifocal osteomyelitis (CRMO), synovitis, impetigo, skin contact allergy, sunburn, Psoriasis, hidradenitis suppurativa (HS), epidermolysis bullosa, acne, eczema, alopecia areata, actinic keratosis, hyperostosis, inflammatory bone disease syndrome (SAPHO), vitiligo, atopic dermatitis, cutaneous lupus, multiple sclerosis (MS), Behçet's disease, Sjögren's syndrome, Schnitzler syndrome, chronic obstructive pulmonary disease (COPD), asthma, steroid-resistant asthma, coronavirus-associated inflammatory diseases, including coronavirus-associated respiratory distress syndrome (CARDS), asbestosis, silicosis, cystic fibrosis, motor neurone disease Huntington's disease, cerebral malaria, brain damage due to pneumococcal meningitis, obesity, age-related macular degeneration (AMD), corneal infection, uveitis, dry eye, acute kidney injury, chronic kidney disease, lupus nephritis, diabetic nephropathy, alcoholic liver disease, osteoarthritis, systemic juvenile idiopathic arthritis, adult-onset Still's disease, relapsing polychondritis, Chikungunya virus, Ross River virus, influenza, HIV, coronavirus, dengue fever, Zika virus, primary biliary cholangitis, antiphospholipid syndrome, refractory Celiac disease, pancreatitis, autoimmune pancreatitis, mucocutaneous lymph node syndrome, lung cancer metastasis, pancreatic cancer, gastric cancer, myelodysplastic syndrome, leukemia; polymyositis, colitis, helminth infection, bacterial infection, abdominal aortic aneurysm, wound healing, migraine, depression, psychological stress, pain, neuropathic pain, periodontitis, pericarditis including Dressler syndrome, ischemia-reperfusion injury, frontotemporal dementia, HIV-related neurocognitive disorder, traumatic brain injury, traumatic spinal cord injury, ankylosing spondylitis, cytokine release syndrome. Preferably,The disease, disorder or abnormality is selected from Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, demyelination, multiple sclerosis, encephalomyelitis, leukoencephalopathy, viral encephalitis, epilepsy, stroke, traumatic brain and spinal cord injury, atherosclerosis, asthma and allergic inflammation, cryptopyrin-associated periodic syndrome (CAPS), gout, inflammatory bowel disease (IBD), 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, hidradenitis suppurativa (HS), rheumatoid arthritis, acute kidney disease, chronic kidney disease, 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 relapsing fever (HRF).

[0947] definition

[0948] Within the meaning of this application, the following definitions apply unless otherwise indicated and, where appropriate, terms used in the singular will also include the plural and vice versa:

[0949] "Alkyl" refers to a saturated straight or branched chain organic group composed 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 "C1-C6 alkyl" refers to an alkyl group having 1 to 6 carbon atoms. The terms "C1-C4 alkyl," "C1-C3 alkyl," or "C1 alkyl" should be interpreted accordingly.

[0950] "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.

[0951] "-O-C1-C6 alkyl", wherein "C1-C6 alkyl" is as generally defined above. Examples of "-O-C1-C6 alkyl" include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, pentyloxy, and hexyloxy.

[0952] The term "C3-C6 cycloalkyl" refers to a saturated monocyclic hydrocarbon group having 3-6 carbon atoms. The term "C5-C6 cycloalkyl" should be interpreted accordingly. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0953] "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 heteroatoms are independently selected from nitrogen and oxygen. Examples include azetidine, oxetane, pyrrolidine, tetrahydrofuran, oxazolidine, isoxazolidine, piperidine, and morpholine, with pyrrolidine and piperidine being preferred.

[0954] "8-, 9- or 10-membered bicyclic heterocycloalkyl" refers to a stable 8-, 9- or 10-membered non-aromatic fused bicyclic ring radical containing 1, 2 or 3 heteroatoms. The heteroatoms are preferably independently selected from nitrogen and oxygen. Examples of 8-, 9- or 10-membered bicyclic heterocycloalkyls include 6-methyloctahydro-pyrrolo[2,3-c]pyridine, such as Re is selected from C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxy C1-C6 alkyl or -OH, preferably

[0955] The dotted circle in the five-membered ring indicates that double bonds can be optionally present at any available position. According to chemical rules, C as one of the options Z, E and Q has four bonds to adjacent atoms, and N as one of the options Z, E and Q has three bonds to adjacent atoms. The bonds can be single or double. Examples of five-membered rings include: pyrazolo[iota] ... imidazolyl

[0956] Used to indicate the connection point. For example, for the compound of formula (I') the wavy line Represents R A and R B an atom on which R A and R B Connected to the core structure of the compound of formula (I').

[0957] : Circles (dashed or solid) indicate that the double bond can be present at any available position in the ring.

[0958] 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).

[0959] Unless otherwise indicated, the term "compound of the present invention" refers to a compound of Formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV) or (V) 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. 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, and conformer mixtures and single conformers), tautomers, atropisomers, and rotamers. All isomeric forms are encompassed by the present invention. Compounds containing olefinic double bonds described herein include both E and Z geometric isomers. Also included in the present invention are all pharmaceutically acceptable salts, prodrugs, polymorphs, hydrates and solvates of compounds of Formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV) or (V).

[0960] Tautomers are isomers of a compound that differ only in the position of their protons and electrons. The skeleton of the compound remains unchanged. Common tautomeric pairs include: keto-enol

[0961] 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 (such as methanol or ethanol).

[0962] "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, for example, the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like; and salts prepared from organic acids such as, but not limited to, acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, and the like. The pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing alkaline or acidic moieties. Typically, such salts can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture thereof. Organic solvents include, but are not limited to, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile. Lists of suitable salts can be found in Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, PA, 1990, p. 1445, the disclosure of which is incorporated herein by reference.

[0963] 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 herein below in the specification and claims of the present invention, the term "prodrug" refers to any covalently bonded compound that releases the active parent drug due to in vivo biotransformation. The reference Goodman and Gilman (The Pharmacological Basis of Therapeutics, 8th edition, McGraw-Hill, Int. Ed. 1992, "Biotransformation of Drugs", pages 13-15) generally describing prodrugs is incorporated herein by reference.

[0964] "Pharmaceutically acceptable" is defined as those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in 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.

[0965] 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.

[0966] As used herein, "NLRP3" refers to the NOD-like receptor (NLR) family of inflammasomes, protein 3 components containing a pyrin domain. Inflammasomes are intracellular supramolecular complexes that contain sensor molecules, apoptosis-associated speckle-like proteins (ASC) whose connectors contain CARDs, 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. The proinflammatory mediators released upon NLRP3 activation are IL-1β (β), IL-18, high mobility group protein B1 (HMGB1), leukotrienes, and prostaglandins.

[0967] Activation of the NLRP3 inflammasome pathway is an important driver of inflammation, interacting with various cytokine pathways to form immune responses to infection and injury. The production of several proinflammatory cytokines is triggered by activation of the NLRP3 inflammasome pathway.

[0968] 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.

[0969] The term "treating" or "treating" of any disease, disorder or abnormality refers to alleviating or ameliorating or modulating the disease or 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 or disorder or abnormality, including those that may not be discernible by an individual (e.g., a patient).

[0970] The term "preventing" any disease, disorder or abnormality responsive to modulation of a component of the NLRP3 inflammasome pathway refers to prophylactic treatment of the disease, disorder or abnormality; or delaying the onset or progression of the disease or disorder.

[0971] The term "in need of" treatment means that an individual would benefit biologically, medically, or in quality of life from such treatment.

[0972] As used herein, "modulate" refers to alteration, such as upregulation, downregulation, increase or decrease, preferably decrease.

[0973]

[0974]

[0975] Unless stated otherwise, the definitions and preferred definitions given in the "Definitions" section apply to all embodiments described below.

[0976] General synthetic scheme for the preparation of the compounds of the present invention :

[0977] The compounds of the present invention can be synthesized by one skilled in the art using well-known preparative procedures, for example, those in the general methods shown in the following schemes. These methods are given for illustrative purposes only and should not be considered limiting.

[0978] 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 standard method (TW Green and PGM Wuts (2014) Protective Groups in Organic Synthesis, the 5th edition, John Wiley & Sons) of organic synthesis. These groups are removed using the obvious method of those skilled in the art at the convenient stage of compound synthesis.

[0979] In the following general method, R0, R1, R2, R3, R a、 X' and Y are as defined in the previous embodiments.

[0980] Process 1a:

[0981]

[0982] "Lg" means a leaving group. Examples of suitable leaving groups include -Cl, -Br or -I.

[0983] "Pg" means a protecting group. Examples of suitable protecting groups include -CH3, -MOM or -MEM.

[0984] Commercially available diaminopyridines can be functionalized. a In the case where R is methyl, a two-step strategy can be applied. First, selective carbamate formation using CbzCl followed by reduction using, for example, LAH can provide the desired intermediate. Alternatively, commercially available diaminopyridines can be selectively functionalized with ethyl iodide or 2-bromopropane to provide R aThe desired intermediate of ethyl or isopropyl. Then, in the presence of sodium bisulfite, commercial aldehydes are used to carry out cyclization using appropriate solvents, and bicyclic intermediates can be provided after purification. In the case where aromatic aldehydes are not commercially available, they can be prepared from commercially available starting materials by multi-step reactions, including Suzuki coupling reaction, nucleophilic substitution, halogen-lithium exchange reaction using BuLi and DMF, or palladium-mediated introduction of OCH3 with potassium persulfate and 3-(trifluoromethyl) aniline. Finally, the bicyclic intermediate can be further functionalized using suitable amines and alcohols or by nucleophilic substitution using palladium-catalyzed Buchwald reaction, to obtain compounds of formula (IIa) after purification. In the case where R2 has a protecting group, the protecting group can be cleaved under acidic conditions (boron tribromide, TFA) to obtain compounds of formula (IIb) after purification. In the case where compounds of formula (IIa) contain secondary amines, reductive amination conditions are adopted to obtain compounds of formula (IIa) containing tertiary amines. In case racemic mixtures are obtained, these can be separated by SFC to give compounds of formula (IIa).

[0985] Process 1a:

[0986]

[0987] "Pg" means a protecting group. Examples of suitable protecting groups include -CH3, -MOM or -MEM.

[0988] In the case that the diaminopyridine without the required substitution pattern can not be commercially available, the aminopyridine derivative containing bromine atoms can be processed with a suitable amine to provide a diaminopyridine derivative. Then, in the presence of sodium bisulfite, commercial aldehydes are used to use a suitable solvent to carry out cyclization, and a dicyclic intermediate can be provided after purification. The dicyclic intermediate can be oxidized (3-chloroperoxybenzoic acid), followed by phosphorus oxychloride treatment, to obtain the dicyclic intermediate containing the chlorine leaving group. Finally, after the protecting group (BBr ) cleavage, the dicyclic intermediate can use the Buchwald reaction catalyzed by palladium or further functionalized by nucleophilic substitution to obtain a compound of formula (IIa). In the case of obtaining a racemic mixture, they can be separated and obtain the compound of formula (II'a) by SFC.

[0989] Process 1b:

[0990]

[0991] "Lg" means a leaving group. Examples of suitable leaving groups include -Cl, -Br or -I.

[0992] "Pg" means a protecting group. Examples of suitable protecting groups include -CH3, -MOM or -MEM.

[0993] Commercially available bicyclic skeletons can be made from S N Ar is functionalized using a suitable amine or alcohol or sodium 2-chloro-2,2-difluoro-acetate. The pyrazole ring is then reacted with a suitable boronic acid or boronic ester using a suitable copper catalyst to give intermediate B. If a protecting group is present at R2, the protecting group can be cleaved under acidic conditions (boron tribromide) to give the compound of formula (IIb) after purification.

[0994] Process 1c:

[0995]

[0996] "Lg" means a leaving group. Examples of suitable leaving groups include -Cl, -Br or -I.

[0997] "Pg" means a protecting group. Examples of suitable protecting groups include -CH3, -MOM or -MEM.

[0998] Commercially available bicyclic skeletons can be functionalized with suitable thiols by SNAr. If intermediate B contains a thioether structure at the -Y-R3 position, the thioether can be converted into a leaving group by oxidation (3-chloroperoxybenzoic acid), and then the leaving group can be replaced with a suitable amine by nucleophilic substitution to obtain intermediate B. If a protecting group is present at R2, the protecting group can be cleaved under acidic conditions (boron tribromide) and purified to obtain the compound of formula (IIb).

[0999] Process 1d:

[1000]

[1001] "Lg" means a leaving group. Examples of suitable leaving groups include -Cl, -Br or -I.

[1002] "Pg" means a protecting group. Examples of suitable protecting groups include -CH3, -MOM or -MEM.

[1003] Commercially available bicyclic skeletons can be functionalized with suitable thiols by SNAr. Then, the pyrazole ring is reacted with a suitable boronic acid or ester using a suitable copper catalyst to obtain intermediate B. In the case where intermediate B contains a thioether structure, the thioether can be converted into a leaving group by oxidation (3-chloroperoxybenzoic acid), which can then be replaced by a suitable amine by nucleophilic substitution to obtain intermediate C. In the case where R2 has a protecting group, the protecting group can be cleaved under acidic conditions (boron tribromide) and purified to obtain a compound of formula (IIb).

[1004] Process 1e:

[1005]

[1006] "Lg" means a leaving group. Examples of suitable leaving groups include -Cl, -Br or -I.

[1007] "Pg" means a protecting group. Examples of suitable protecting groups include -CH3, -MOM or -MEM.

[1008] Commercially available amino-nitropyridines can be functionalized to diaminopyridines by bromination (NBS) and subsequent reduction of the nitro group (Fe, acid). a In the case of methyl, a two-step strategy can be applied. First, CbzCl is used to selectively form a carbamate, followed by reduction using, for example, LAH, to obtain the desired intermediate. Then, in the presence of sodium bisulfite, commercial aldehydes are used to perform cyclization using an appropriate solvent, and a bicyclic intermediate can be obtained after purification. Finally, the bicyclic intermediate can be further functionalized by nucleophilic substitution. Palladium-mediated exchange of bromine structures by nitrile gives a nitrile-containing bicyclic intermediate. The nitrile structure is saponified to an acid, and then reduced with borane to give a compound of formula (II'a) containing a primary alcohol structure. Alternatively, in the presence of sodium bisulfite, an aldehyde containing a protecting group is used to perform cyclization using an appropriate solvent, which can provide a bicyclic intermediate after purification. Acid-mediated (boron tribromide) protecting group cleavage provides a bicyclic intermediate after purification. Nucleophilic substitution, followed by Stille coupling using an appropriate tin reagent, gives a compound containing a methyl ketone structure. Methyl ketone derivatives are treated with a Grignard reagent (CH3MgBr) to give a compound of formula (II'a) containing a tertiary alcohol structure.

[1009] Process 1f:

[1010]

[1011] "Pg" means a protecting group. Examples of suitable protecting groups include -CH3, -MOM or -MEM.

[1012] Commercially available 3-bromo-6-chloropyrazine-2-amine can be functionalized to diaminopyrazine by carrying out amination reaction with suitable amine. Then, in the presence of sodium bisulfite, using the aldehyde containing alcohol protecting group (such as MOM or MEM), using suitable solvent to carry out cyclization, can obtain bicyclic intermediate after purification. Acid-mediated protecting group (TFA) cracking obtains bicyclic intermediate after purification. Finally, bicyclic intermediate can be further functionalized by using suitable alcohol and amine nucleophilic substitution to obtain the compound of formula (II'a). In the case where the nucleophilic substitution product contains acetal structure, after acetal cleavage and subsequent Grignard reaction, the compound of formula (II'a) containing tertiary alcohol can be obtained. In the case of obtaining a racemic mixture, they can be separated and obtained by SFC to obtain the compound of formula (II'a). Alternatively, in the presence of sodium bisulfite, using the aldehyde containing alcohol protecting group such as methyl, using suitable solvent to carry out cyclization, can obtain bicyclic intermediate after purification. The bicyclic intermediate can be further functionalized by using the Buchwald conditions with suitable alcohol and amine or palladium catalysis, using suitable amine to carry out nucleophilic substitution. Finally, the methyl protecting group can be cracked under Lewis acid conditions (boron tribromide) to obtain a compound of formula (II'a). Alternatively, in the presence of sodium bisulfite, an aldehyde containing an alcohol protecting group such as methyl is used, and a suitable solvent is used to carry out cyclization, which can provide the bicyclic intermediate after purification. The methyl protecting group can be cracked under Lewis acid conditions (boron tribromide) to obtain a bicyclic intermediate containing a chlorine leaving group. Finally, the bicyclic intermediate can be further functionalized by using the Buchwald conditions with suitable alcohol and amine or palladium catalysis, using suitable amine to carry out nucleophilic substitution and obtain a compound of formula (II'a). In the case where the compound of formula (II'a) contains a secondary amine, reductive amination conditions are used to obtain a compound of formula (II'a) containing a tertiary amine.

[1013] Process 1g:

[1014]

[1015] "Pg" means a protecting group. Examples of suitable protecting groups include -CH3, -MOM or -MEM.

[1016] The bicyclic intermediate containing a methyl protecting group can be brominated (NBS) to obtain a bromine-containing bicyclic intermediate. Stille coupling conditions are used to exchange bromine for -CH2OH, and after acid-mediated (boron tribromide) cleavage of the methyl protecting group, a compound of formula (II'a) is obtained. Alternatively, the bromine-containing bicyclic intermediate can be treated with methanol under alkaline conditions, and after acid-mediated (boron tribromide) cleavage of the methyl protecting group, a -CH2OCH3 compound of formula (II'a) is obtained. In the case where the compound of formula (II'a) contains a secondary amine, reductive amination conditions can be used to obtain a compound of formula (II'a) containing a tertiary amine.

[1017] Process 1h:

[1018]

[1019] "Pg" means a protecting group. Examples of suitable protecting groups include -CH3, -MOM or -MEM.

[1020] Suitable diaminopyrazines can be cyclized with orthoesters to give bicyclic intermediates. Bicyclic intermediates can be further functionalized by nucleophilic substitution with suitable amino alcohols containing amine protecting groups. Iodination reaction with 1,2,3,4,5-pentafluoro-6-iodo-benzene under alkaline conditions gives bicyclic intermediates containing iodinated structures. Suzuki coupling using suitable borate esters gives the corresponding coupling products, which can be converted to compounds of formula (II'a) after acid (boron tribromide)-mediated deprotection. In the case where the compound of formula (II'a) contains a secondary amine, reductive amination conditions can be used to obtain compounds of formula (II'a) containing tertiary amines.

[1021] Process 1i:

[1022]

[1023] "Lg" means a leaving group. Examples of suitable leaving groups include -Cl, -Br or -I.

[1024] "Pg" means a protecting group. Examples of suitable protecting groups include -CH3, -MOM or -MEM.

[1025] Commercially available 2-chloropyrimidine-4,5-diamine can be selectively functionalized with methyl iodide to afford R a The desired intermediate of methyl. Then, in the presence of sodium bisulfite, commercial aldehydes are used to carry out cyclization using appropriate solvents, which can provide a bicyclic intermediate after purification. In the case where aromatic aldehydes are not commercially available, they can be prepared from commercially available starting materials by a multi-step reaction comprising Suzuki coupling reaction, nucleophilic substitution, halogen-lithium exchange reaction using BuLi and DMF, or palladium-mediated introduction of -OCH3 using potassium persulfate and 3-(trifluoromethyl)aniline. The protecting group present on R2 can be cleaved under acidic conditions (TFA) to obtain a deprotected bicyclic intermediate after purification. Finally, the bicyclic intermediate can be further functionalized by nucleophilic substitution to obtain a compound of formula (II'a) after purification.

[1026] Process 2:

[1027]

[1028] "Lg" means a leaving group. Examples of suitable leaving groups include -Cl, -Br or -I.

[1029] "Pg" means a protecting group. Examples of suitable protecting groups include -CH3, -MOM or -MEM.

[1030] Diaminopyridines containing a leaving group can be cyclized with suitable reagents such as 1,1′-carbonyldiimidazole to afford the cyclized product after purification. A palladium-mediated Suzuki coupling reaction of the appropriate boronic acid using an appropriate base and solvent can then provide the coupled product after purification. Treatment of the coupled product with phosphoryl chloride followed by nucleophilic substitution of the chloro derivative with an appropriate amine, alcohol, or amino alcohol affords the coupled product with a -Y-R3 substituent after purification. Finally, acid-mediated cleavage of the protecting group under microwave conditions (p-toluenesulfonic acid, lithium chloride) affords the compound of formula (III) after purification. Example

[1031] 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 are not intended to limit the scope of the present disclosure.

[1032]

[1033]

[1034]

[1035] 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 stated, all evaporations were performed 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 spectroscopic characteristics, such as MS, IR, NMR. 1H-NMR spectra were recorded on a Bruker 400 MHz-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 a 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 appropriate solvents, as described in the specific examples. Rapid purification was performed using a CombiFlash system, and the solvent gradients are given in the specific examples. Thin layer chromatography (TLC) was performed on silica gel plates with UV detection.

[1036] Synthesis of intermediates

[1037] Intermediate 1: 6-Chloro-N3-methylpyridine-2,3-diamine

[1038]

[1039] Step A:

[1040] To a stirred solution of 6-chloropyridine-2,3-diamine (5 g, 34.83 mmol) in DCM (50 mL) was added Et3N (14.56 mL, 104.48 mmol) at 0 ° C., followed by benzyl chloroformate (4.91 mL, 34.83 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC. After the starting material was consumed, the reaction mixture was diluted with DCM (100 mL) and washed with brine (2 x 100 mL). The organic phase was dried over Na2SO4 and concentrated under reduced pressure to obtain a crude compound. The crude compound was purified by flash chromatography (silica gel 100-200 mesh; eluted with ethyl acetate (40 to 50%) in hexane). The collected pure fractions were concentrated under reduced pressure to obtain benzyl (2-amino-6-chloropyridin-3-yl)carbamate (5 g, 52%) as an off-white solid.

[1041] MS(ESI):278.24[M+H] + .

[1042] 1 H NMR (400MHz, CDCl3): δ = 7.51-7.35 (m, 6H), 6.72-6.70 (d, 1H), 6.17 (brs, 1H), 5.22 (s, 2H), 4.68 (brs, 2H).

[1043] Step B:

[1044] To a stirred solution of (2-amino-6-chloropyridin-3-yl)benzyl carbamate (obtained from step A) (5 g, 18.01 mmol) in dry THF (100 mL) was added dropwise 1.0 M LAH (72.02 mL, 72.02 mmol) at 0° C. for 20 minutes. The mixture was stirred at 70° C. for 15 min under an N atmosphere. After the starting material was consumed, the reaction mixture was cooled to room temperature, quenched with a saturated NH Cl solution (100 mL), and extracted with EtOAC (2x100 mL). The organic phase was dried over Na SO and concentrated under reduced pressure to give a crude compound. The crude compound was purified by flash chromatography (silica gel 100-200 mesh; eluted with ethyl acetate (45 to 50%) in hexane). The collected pure fractions were concentrated under reduced pressure to afford 6-chloro-N3-methylpyridine-2,3-diamine (1.5 g, 53%) as a brown solid.

[1045] MS(ESI):158.16[M+H] + .

[1046] 1 H NMR (400MHz, DMSO-d6): δ = 6.52 (d, 1H), 6.45 (d, 1H), 5.86 (s, 2H), 4.95-4.96 (m, 1H), 2.68 (d, 3H).

[1047] Intermediate 2: 6-Chloro-N3-ethylpyridine 2,3-diamine

[1048]

[1049] Step A:

[1050] To a stirred solution of 6-chloropyridine-2,3-diamine (5.0g, 34.3mmol) in N,N-dimethylformamide (100mL) was added potassium carbonate (14.44g, 104.48mmol) and ethyl iodide (8.400mL, 104.48mmol) at room temperature and stirred for 16 hours. The reaction process was monitored by TLC. TLC showed that SM was complete. The reaction mixture was diluted with water (300mL) and extracted with EtOAC (2x400mL). The combined organic layer was washed with saline solution (100mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product as a black oil. The crude product was purified by silica gel column chromatography and eluted with EtOAc / hexane gradient. The product was eluted with 30% EtOAc in hexane. The pure fractions were collected and concentrated under reduced pressure to afford 6-chloro-N3-ethylpyridine 2,3-diamine (2.0 g, 33%) as a light pink solid.

[1051] MS(ESI):172.02[M+H] + .

[1052] Intermediate 3: 6-Chloro-N3-isopropylpyridine-2,3-diamine

[1053]

[1054] Step A:

[1055] To a stirred solution of 6-chloropyridine-2,3-diamine (5.0 g, 34.83 mmol) in N, N-dimethylacetamide (100 mL) was added potassium carbonate (14.44 g, 104.479 mmol) and 2-bromopropane (9.8 mL, 104.48 mmol) at room temperature and stirred at 100 ° C for 8 hours. The reaction was monitored by TLC. TLC showed that SM was complete. The reaction mixture was diluted with water (300 mL) and extracted with EtOAC (2x400 mL). The combined organic layer was washed with saline solution (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product as a black oil. The crude product was purified by silica gel column (100-200) chromatography and eluted with 0-50% EtOAC / hexane gradient. The product was eluted in 20% EtOAc / hexane. The pure fractions were collected and concentrated under reduced pressure to afford 6-chloro-N3-isopropylpyridine-2,3-diamine (2.5 g, 39%) as an off-white solid.

[1056] MS(ESI):185.81[M+H] + .

[1057] Intermediate 4: 2-(Methoxymethoxy)-6-methyl-4-(trifluoromethyl)benzaldehyde

[1058]

[1059] Step-A:

[1060] To a stirred solution of 3-bromo-5-(trifluoromethyl)phenol (30 g, 124.48 mmol) in 1,4-dioxane (300 mL) and water (30 mL) were added methylboric acid (14.9 g, 248.95 mmol) and cesium carbonate (121.670 g, 373.43 mmol). The mixture was degassed with N₂ for 20 minutes, and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (4.55 g, 6.22 mmol) was added at room temperature. The mixture was heated to 90°C for 12 hours. The progress of the reaction was monitored by TLC. After the starting material was consumed, the reaction mixture was filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure to provide the crude compound. The crude compound was purified by chromatography on a silica gel column (100-200 mesh) eluting with a gradient of 0-50% EtOAc in hexanes. The product was eluted in 15% EtOAc in hexanes. The pure fractions were collected and concentrated under reduced pressure to afford 3-methyl-5-(trifluoromethyl)phenol (21 g, 96%) as a light yellow liquid.

[1061] MS(ESI):175.05[MH] - .

[1062] 1 H NMR (400MHz, CDCl3): δ = 7.00 (s, 1H), 6.88 (s, 1H), 6.82 (s, 1H), 5.00 (s, 1H), 2.36 (s, 3H).

[1063] Step-B:

[1064] At 0 ℃, sodium hydride 57-63% oil dispersion (6.86g, 204.39mmol) was added to a stirred solution of 3-methyl-5-(trifluoromethyl)phenol (obtained from step A) (12g, 68.13mmol) in toluene (420mL). The reaction mixture was stirred at 0 ℃ for 30 minutes. Iodine (19g, 74.94mmol) was then added in batches at 0 ℃, and stirring continued for 3 hours. After the raw material was consumed, the reaction mixture was quenched with ice-cold water (80mL), acidified with 1N HCl solution, and extracted with EtOAC (2x200mL). The combined organic layer was washed with saline solution (80mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column (100-200 mesh) chromatography and eluted with 0-50% EtOAC gradient in hexane. The product was eluted in 15% EtOAc in hexanes. The pure fractions were collected and concentrated under reduced pressure to afford 2-iodo-3-methyl-5-(trifluoromethyl)phenol (13.5 g, 65%) as a yellow oil.

[1065] MS(ESI):301.17[MH] - .

[1066] Step-C:

[1067] To a stirred solution of 2-iodo-3-methyl-5-(trifluoromethyl)phenol (obtained from step B) (13.5 g, 44.70 mmol) in THF (135 mL) was added dropwise N,N-diisopropylethylamine (31 mL, 178.79 mmol) and methoxymethyl chloride (8.49 mL, 111.74 mmol) at 0°C under an argon atmosphere. The reaction mixture was stirred at room temperature for 16 hours. After the starting material was consumed, the reaction mixture was concentrated under reduced pressure to obtain a crude product. The crude product was chromatographed on a silica gel column (100-200 mesh) and purified by eluting with a hexane gradient. The pure fractions were collected and concentrated under reduced pressure to give 2-iodo-1-(methoxymethoxy)-3-methyl-5-(trifluoromethyl)benzene (12 g, 78%) as a colorless oil.

[1068] MS(ESI):346.0[M+H] + .

[1069] 1 H NMR (400MHz, CDCl3): δ = 7.17 (s, 1H), 7.08 (s, 1H), 5.27 (s, 2H), 3.52 (s, 3H), 2.53 (s, 3H).

[1070] Step-D:

[1071] To a stirred solution of 2-iodo-1-(methoxymethoxy)-3-methyl-5-(trifluoromethyl)benzene (obtained from step C) (12.0 g, 31.08 mmol) in THF (120 mL) was added n-butyllithium (1.6 M) in hexane (25 mL, 40.34 mmol) at -78 ° C, and the mixture was stirred for 5 minutes. N, N-dimethylformamide (2.9 mL, 37.29 mmol) was added, and the mixture was stirred at the same temperature for 10 minutes. After the starting material was consumed, the reaction mixture was quenched with a saturated NH4Cl solution and extracted with EtOAC (2x40 mL). The combined organic layers were washed with brine solution (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude 2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)benzaldehyde (6.5 g, 84%) as an oil.

[1072] 1 H NMR (400MHz, DMSO-d6): δ = 10.55 (s, 1H), 7.43 (s, 1H), 7.32 (s, 1H), 5.43 (s, 2H), 3.38 (s, 3H), 2.36 (s, 3H).

[1073] Intermediate 5: 4-Chloro-2-methoxy-6-methylbenzaldehyde

[1074]

[1075] Step-A:

[1076] To a stirred solution of 2-bromo-4-chloro-6-methylaniline (20g, 90.71mmol) in methanol (100mL) was added approximately 30% w / w sodium methoxide and copper (I) iodide (19g, 99.78mmol) in methanol (60mL) at room temperature and heated to 100°C for 18 hours. The reaction was monitored by TLC. TLC showed that SM was complete. The reaction mixture was diluted with water (500mL) and extracted with DCM (2x 500mL). The combined organic layer was washed with saline solution (100mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was a liquid. The crude product was purified by silica gel column chromatography and eluted with an EtOAc gradient in hexane. The product was eluted with 5% EtOAc in hexane. Pure fractions were collected and concentrated under reduced pressure to obtain a pure compound (5.9g, 38%).

[1077] MS(ESI):172.27[M+H] + .

[1078] Step-B:

[1079] 97% stable isoamyl nitrite (7.06mL, 52.44mmol) was added to a stirred solution of 4-chloro-2-methoxy-6-methylaniline (6.0g, 34.96mmol) in acetonitrile (150mL) at 0°C. The reaction mixture was stirred for 30 minutes. CuBr2 (8.43g, 37.78mmol) was then added at 0°C. The reaction mixture was stirred at room temperature for 16 hours. The reaction process was monitored by TLC. TLC showed that SM was complete. The reaction mixture was diluted with water (250mL) and extracted with EtOAC (2x 250mL). The combined organic layer was washed with saline solution (100mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was a liquid. The crude product was purified by silica gel (100-200) column chromatography and eluted with an EtOAc gradient in hexane. The product was eluted at 2% EtOAc in hexane. The pure fractions were collected and concentrated under reduced pressure to afford the pure compound (4.47 g, 55%).

[1080] MS(ESI):233.94[M+H] + .

[1081] Step-C:

[1082] To a stirred solution of 2-bromo-5-chloro-1-methoxy-3-methylbenzene (4.2 g, 17.83 mmol) in THF (50 mL) was added n-BuLi (1.6 M in hexane) (16.71 mL, 26.75 mmol) at -78 ° C, and the reaction mixture was stirred for 10 minutes. Then N, N-dimethylformamide (4.11 mL, 53.502 mmol) was added at -78 ° C, and the reaction mixture was stirred for 30 minutes. The reaction process was monitored by TLC. TLC showed completion. The reaction mixture was quenched with a saturated NH4Cl solution and extracted with EtOAC (2x250 mL). The combined organic layers were washed with saline solution (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product as a solid. The crude product was purified by silica gel (100-200) column chromatography and gradient elution with EtOAc in hexane. The product was eluted in 5% EtOAc in hexanes. The pure fractions were collected and concentrated under reduced pressure to afford the pure compound (2.87 g, 88%).

[1083] MS(ESI):183.9[M+H] + .

[1084] Intermediate 6: 2-(5-chloro-1-methyl-1H-imidazo[4,5-b]pyridin-2-yl)-3-methyl-5-(trifluoromethyl) phenol

[1085]

[1086] Step A:

[1087] To a stirred solution of 6-chloro-N3-methylpyridine-2,3-diamine (Int 1) (1.8 g, 11.42 mmol) and 2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)benzaldehyde (Int 2) (6.52 g, 26.27 mmol) in DMA (10 mL) was added sodium bisulfite (1.43 g, 13.71 mmol) at room temperature, and the reaction mixture was stirred at 100 ° C for 16 hours. After the starting material was consumed, the reaction mixture was quenched with ice-cold water (30 mL) and extracted with EtOAC (2x100 mL). The combined organic layers were washed with brine solution (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by chromatography on a silica gel column (100-200 mesh) using a gradient of EtOAC in hexane. The product was eluted in 30% EtOAc in hexanes. The pure fractions were collected and concentrated under reduced pressure to give 5-chloro-2-(2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl)-1-methyl-1H-imidazo[4,5-b]pyridine (4.2 g, 95%) as an oil.

[1088] MS (ESI): 386.29 [M+H] +.

[1089] 1 H NMR (400MHz, DMSO-d6): δ=8.23-8.21(d,1H),7.49-7.42(d,3H),5.32-5.31(d,1H),5.23-5.21(d,1H),3.63(s,3H),3.24(s,3H),2.15(s,3H).

[1090] Step B:

[1091] To a stirred solution of 5-chloro-2-(2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl)-1-methyl-1H-imidazo[4,5-b]pyridine (obtained from step A) (4.2g, 10.89mmol) in DCM (84mL) was added trifluoroacetic acid (63mL) at 0°C, and the reaction mixture was stirred at room temperature for 2 hours. After the raw material was consumed, the reaction mixture was quenched with ice-cold water (50mL) and stirred for 10 minutes. The precipitated solid was filtered, washed with water (100mL), and dried in vacuo to give 2-(5-chloro-1-methyl-1H-imidazo[4,5-b]pyridin-2-yl)-3-methyl-5-(trifluoromethyl)phenol (3.5g, 94%) as an off-white solid.

[1092] MS(ESI):342.25[M+H] + .

[1093] 1 H NMR (400MHz, DMSO-d6): δ=10.79(s,1H)8.22-8.20(d,1H),7.44-7.424(d,1H),7.25(s,1H),7.15(s,1H),3.64(s,3H),2.16(s,3H).

[1094] Intermediate 7: 2-(5-chloro-1-methyl-1H-imidazo[4,5-b]pyridin-2-yl)-5-(trifluoromethyl)phenol

[1095]

[1096] Step A:

[1097] To a stirred solution of 6-chloro-N3-methylpyridine-2,3-diamine (Int 1) (0.2 g, 1.27 mmol) and 2-hydroxy-4-(trifluoromethyl)benzaldehyde (0.241 g, 1.27 mmol) in DMA (5 mL) was added sodium bisulfite (0.158 g, 1.52 mmol) at room temperature, and the reaction mixture was stirred at 100 ° C for 16 hours. After the raw material was consumed, the reaction mixture was diluted with ice water (50 mL) and stirred for 10 minutes. The precipitate was collected by filtration and dried to give 2-(5-chloro-1-methyl-1H-imidazo[4,5-b]pyridin-2-yl)-5-(trifluoromethyl)phenol (0.2 g, 48%) as a light yellow solid.

[1098] MS(ESI):328.22[M+H] + .

[1099] 1 H NMR (400MHz, DMSO-d6): δ = 11.24 (brs, 1H), 8.21-8.19 (d, 1H), 7.75-7.73 (d, 1H), 7.43-7.41 (d, 1H), 7.36-7.34 (m, 2H), 3.77 (s, 3H).

[1100] Analogously to the above method, the following intermediates were prepared using the corresponding amine and the appropriate aldehyde, optionally followed by a deprotection step, as shown in Table 1:

[1101] Table 1

[1102]

[1103]

[1104] Intermediate 16: 2-methoxy-6-methyl-4-(trifluoromethyl)benzaldehyde

[1105]

[1106] Step A:

[1107] To a solution of 1-bromo-3-methyl-5-(trifluoromethyl)benzene (45 g, 188.26 mmol, 1.0 equiv) in a mixed solvent of dioxane (450 mL) and H₂O (45 mL) were added LiOH.H₂O (13.53 g, 564.78 mmol, 3.0 equiv), Pd₂(dba)₃ (3.45 g, 3.77 mmol, 0.02 equiv), and di-tert-butyl-[2-(1,3,5-triphenylpyrazol-4-yl)pyrazol-3-yl]phosphane (3.82 g, 7.53 mmol, 0.04 equiv), followed by degassing with N₂ three times. The resulting reaction mixture was heated to 100°C and stirred at 100°C under N₂ for 12 hours. TLC (PE / EA = 10 / 1, product Rf = 0.50, developer: UV 254 nm) indicated the reaction was complete. The reaction mixture is poured into 500mL H o, 50mL EA subsequently.Then with 2M HCl, pH is adjusted to 4.Afterwards, water is separated, and with EA extraction (80mL*3).The organic layer that merges is washed with water (20mL*2) and salt solution (20ml*1) continuously, through anhydrous Na sO dry, filter, and concentrate to obtain resistates.With resistates through column chromatography purification (SiO , petroleum ether / ethyl acetate=100 / 1 to 10 / 1).Obtain 3-methyl-5-(trifluoromethyl)phenol (44g, 249.81mmol, 66.35% yield, N / A purity), be yellow oil.

[1108] 1 H NMR (400 MHz, chloroform-d) δ=7.01 (s, 1H), 6.89 (s, 1H), 6.82 (s, 1H), 5.04 (s, 1H), 2.37 (s, 3H)

[1109] Step B:

[1110] To a solution of 3-methyl-5-(trifluoromethyl)phenol (39 g, 221.42 mmol, 1.0 eq) in Tol. (800 mL) was added NaH (17.71 g, 442.84 mmol, 60% purity, 2.0 eq) at 0°C, and the reaction mixture was stirred at 0°C for 30 minutes, followed by the addition of I (39.34 g, 154.99 mmol, 31.22 mL, 0.7 eq). The resulting reaction mixture was stirred at 0°C for 1.5 hours. TLC (PE / EA = 10 / 1, product Rf = 0.45, developer: UV 254 nm) indicated the reaction was complete. The reaction mixture was poured into 200 mL of saturated NH4Cl. The pH was then adjusted to 4 with 2M HCl. The resulting solution was then extracted with EA (100 mL * 3). The combined organic layers were washed successively with water (200 mL*2) and brine (200 mL*1), dried over anhydrous Na2SO4, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 10 / 1). 2-iodo-3-methyl-5-(trifluoromethyl)phenol (38.6 g, 127.80 mmol, 57.72% yield, N / A purity) was obtained as a yellow solid.

[1111] 1 H NMR (400 MHz, chloroform-d) δ=7.07 (s, 2H), 5.62 (s, 1H), 2.52 (s, 3H)

[1112] Step C:

[1113] To a solution of 2-iodo-3-methyl-5-(trifluoromethyl)phenol (5.6 g, 18.54 mmol, 1.0 equiv) in acetone (60 mL) was added KCO (5.12 g, 37.08 mmol, 2.0 equiv) and CHI (5.26 g, 37.08 mmol, 2.31 mL, 2.0 equiv). The resulting reaction mixture was stirred at 20° C. for 12 hours. TLC (PE / EA=10 / 1, product Rf=0.70, developer: UV 254 nm) showed that the reaction was complete. The reaction solution was filtered to remove KCO and then concentrated to obtain a residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate=100 / 0 to 98 / 2). 2-Iodo-1-methoxy-3-methyl-5-(trifluoromethyl)benzene (5.3 g, 16.77 mmol, 90.44% yield, N / A purity) was obtained as a white solid.

[1114] 1H NMR (400 MHz, chloroform-d) δ=7.14 (s, 1H), 6.82 (s, 1H), 3.94 (s, 3H), 2.54 (s, 3H)

[1115] Step D:

[1116] To a solution of 2-iodo-1-methoxy-3-methyl-5-(trifluoromethyl)benzene (8 g, 25.31 mmol, 1.0 equiv) in THF (80 mL) was added n-BuLi (2.5 M, 25.31 mL, 2.5 equiv), and the reaction mixture was stirred at -70°C for 30 minutes, followed by the addition of DMF (18.50 g, 253.12 mmol, 19.48 mL, 10 equiv). The resulting reaction mixture was stirred at -70°C for 6 hours. TLC (PE / EA=4 / 1, product Rf=0.60, developer: UV 254 nm) indicated the reaction was complete. The reaction mixture was quenched at 0°C with 100 mL of H2O, followed by 30 mL of DCM. The aqueous phase was then separated and extracted with DCM (30 mL*3). The combined organic layers were washed successively with water (20 mL*2) and brine (20 mL*1), dried over anhydrous Na2SO4, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 10 / 1). 2-methoxy-6-methyl-4-(trifluoromethyl)benzaldehyde (4 g, 18.33 mmol, 72.43% yield) was obtained as a yellow oil.

[1117] 1 H NMR (400 MHz, chloroform-d) δ = 10.65 (s, 1H), 7.07 (d, J = 8.8 Hz, 2H), 3.97 (s, 3H), 2.62 (s, 3H)

[1118] Intermediate 18: 4-chloro-2-methoxy-6-methylbenzaldehyde

[1119]

[1120] Step A:

[1121] To a solution of 4-chloro-2-methyl-benzaldehyde (2 g, 12.94 mmol, 1.0 eq) in DCE (70 mL) was added MeOH (8.29 g, 258.74 mmol, 10.47 mL, 20.0 eq), Pd(OAc)2 (435.67 mg, 1.94 mmol, 0.15 eq), potassium persulfate (6.99 g, 25.87 mmol, 5.18 mL, 2.0 eq), 3-(trifluoromethyl)aniline (2.08 g, 12.94 mmol, 1.62 mL, 1.0 eq), and the resulting reaction mixture was stirred at 95°C in a sealed tube for 48 hours. LCMS showed 29% starting material remaining and 46% of the desired product. The reaction mixture was poured into 300 mL of H2O, followed by 100 mL of DCM. Afterwards, the aqueous phase was separated and extracted with DCM (100 mL*2). The combined organic layers were washed successively with water (20 mL x 2) and brine (20 mL x 1), dried over anhydrous Na2SO4, filtered, and concentrated to yield a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 20 / 1) and then triturated with 20 mL of PE to yield the pure product. The residue was purified by preparative HPLC (column: Waters Xbridge C18 150*50 mm*10 μm; mobile phase: [H2O(10 mM NH4HCO3)-ACN]; gradient: 35%-65% B over 8.0 minutes) to yield the title product. The residue was purified by preparative HPLC (column: Waters Xbridge C18 150*50 mm*10 μm; mobile phase: [H2O(10 mM NH4HCO3)-ACN]; gradient: 35%-65% B over 8.0 minutes) to yield the title product. 4-Chloro-2-methoxy-6-methyl-benzaldehyde (1.5 g, 8.12 mmol, 20.93% yield, N / A purity) was obtained as a white solid.

[1122] LC-MS (ES+, m / z): 185.1 [(M+H) + ].

[1123] 1 H NMR (400MHz, DMSO-d6) δ = 10.43 (s, 1H), 7.18 (s, 1H), 6.99 (s, 1H), 3.91 (s, 3H), 2.46 (s, 3H)

[1124] Intermediate 19:

[1125]

[1126] Step A:

[1127] To a solution of 4-fluoro-2-methyl-benzaldehyde (500 mg, 3.62 mmol, 1.0 eq) in DCE (15 mL) was added Pd(OAc) (81.26 mg, 361.96 μmol, 0.1 eq), potassium persulfate (1.96 g, 7.24 mmol, 1.45 mL, 2.0 eq), MeOH (2.32 g, 72.39 mmol, 2.93 mL, 20.0 eq), 3-(trifluoromethyl)aniline (233.28 mg, 1.45 mmol, 180.84 μL, 0.4 eq), and the reaction mixture was stirred in a sealed tube at 80° C. for 48 hours. The reaction mixture was poured into 20 mL of H O, followed by 10 mL of EtOAc. Afterwards, the aqueous phase was separated and extracted with EtOAc (20 mL×2). The combined organic layers were washed sequentially with water (20 mL x 2) and brine (20 mL x 1), dried over anhydrous NaSO, filtered, and concentrated to yield a residue. The residue was purified by preparative TLC (SiO, PE:EtOAc = 10:1). 4-Fluoro-2-methoxy-6-methyl-benzaldehyde (0.5 g, 2.97 mmol, 82.14% yield, N / A purity) was obtained as a white solid.

[1128] 1 H NMR (400MHz, CDCl3) δ = 10.54 (s, 1H), 6.58-6.50 (m, 2H), 3.90 (s, 3H), 2.59 (s, 3H).

[1129] MS:168.7[(M+H) + ].

[1130] Synthesis of Inventive Examples

[1131] Embodiment 1: 2-(5-((2-hydroxyethyl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-2-yl)-5- (Trifluoromethyl)phenol

[1132]

[1133] Step A:

[1134] A stirred solution of 2-(5-chloro-1-methyl-1H-imidazo[4,5-b]pyridin-2-yl)-5-(trifluoromethyl)phenol (Int 7) (0.2 g, 0.61 mmol) and 2-aminoethan-1-ol (0.075 g, 1.22 mmol) in THF (10 mL) was degassed with nitrogen for 10 minutes. BrettPhos Pd G3 (0.028 g, 0.031 mmol) was then added at room temperature, followed by LiHMDS (1.0 M in THF) (1.83 mL, 1.83 mmol). The reaction mixture was stirred at 70 ° C for 24 hours. After the starting material was consumed, the reaction mixture was diluted with ice-cold water (50 mL) and extracted with ethyl acetate (2x50 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give a crude compound. The crude compound was purified by preparative HPLC (column XBridge C18 (150 mm x 19 mm, 5 μm), buffer: 10 mM ammonium bicarbonate, mobile phase: acetonitrile, flow rate: 14 mL / min), and the product-containing fractions were collected and freeze-dried to give 2-(5-((2-hydroxyethyl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-2-yl)-5-(trifluoromethyl)phenol (22 mg, 6%) as an off-white solid.

[1135] MS(ESI):353.27[M+H] + .

[1136] 1 H NMR (400MHz, DMSO-d6): δ=12.40(brs,1H),7.91-7.89(d,1H),7.77-7.75(d,1H),7.36-7.29( m,2H),6.59-6.48(m,2H),4.76(brs,1H),3.83(s,3H),3.57-3.56(m,2H),3.40-3.36(q,2H).

[1137] The following examples were prepared according to the method of Example 1 using halogenated aromatic intermediates and the corresponding commercially available amines, as shown in Table 2:

[1138] Table 2

[1139]

[1140]

[1141]

[1142]

[1143]

[1144]

[1145] Examples 18-18A and 18B: Enantiopure 3-methyl-2-(1-methyl-5-((1-methylpyrrolidin-3-yl)amino)- 1H-imidazo[4,5-b]pyridin-2-yl)-5-(trifluoromethyl)phenol

[1146]

[1147] The racemate product (prepared as described in Example 1, starting from Int 6 and the commercially available racemate amine, 1-methylpyrrolidin-3-amine) was obtained in 78% yield and separated by chiral SFC (column: Chiralpak IK, 250 mm x 30 mm, 5 μm, 30° C., eluent B: MeOH 15% + 0.5% diethylamine, flow rate: 90 g / min, pressure: 100 bar, cycle time: 18 min) to give two enantiomers Ex 18A (first eluting) and Ex 18B (second eluting).

[1148] Ex18A 1 H NMR (400MHz, DMSO-d6): δ=10.53(brs,1H),7.70-7.68(d,1H),7.19(s,1H),7.11(s,1H),6.57-6.55(d,1H),6.51-6.49(d,1H),4.41-4.38(m ,1H),3.47(s,3H),3.00-2.98(m,1H),2.92-2.88(m,1H),2.67-2.66(m ,2H),2.43(s,3H),2.33-2.26(m,1H),2.14(s,3H),1.76-1.73(m,1H).

[1149] MS(ESI):406.34[M+H] + .

[1150] Ex 18B 1 H NMR (400MHz, DMSO-d6): δ = 10.62 (brs, 1H), 7.66-7.64 (d, 1H), 7.15 (s, 1H), 7.08 (s, 1H), 6.49-6.44 (m, 2H), 4.36-4.35 (m, 1H) ),3.46(s,3H),2.75-2.74(m,1H),2.66-2.58(m,1H),2.38-2.35(m,2H),2.30-2.29(m,4H),2.13(s,3H),1.60-1.63(m,1H).

[1151] MS(ESI):406.34[M+H] + .

[1152] Example 19: Enantiopure 2-(1-methyl-5-((1-methylpyrrolidin-3-yl)amino)-1H-imidazo[4,5-b] Pyridin-2-yl)-5-(trifluoromethyl)phenol

[1153]

[1154] The racemate product (prepared as described in Example 1, starting from Int 7 and commercially available racemate 1-methylpyrrolidin-3-amine) was separated by chiral SFC (column: Chiralpak IE, 250 mm x 10 mm, 5 μm, 30° C., eluent B: MeOH 15% + 0.2% diethylamine, flow rate: 2 mL / min, cycle time: 18 min) to give enantiomerically pure Ex 19 (second eluting).

[1155] 1 H NMR (400MHz, DMSO-d6): δ=12.40(brs,1H),7.89-7.87(d,1H),7.75-7.73(d,1H),7.30-7.27(m,2H),6.67-6.65(d,1H),6.56-6.54(d ,1H),4.39-4.34(m,1H),3.82(s,3H),2.76-2.72(m,1H),2.67-2.57(m,1H),2.40-2.32(m,2H),2.27-2.19(m,4H),1.65-1.57(m,1H).

[1156] MS(ESI):392.41[M+H] + .

[1157] Example 20: (trans) enantiopure 2-(5-((2-hydroxycyclohexyl)amino)-1-methyl-1H-imidazo[4,5- b]pyridin-2-yl)-3-methyl-5-(trifluoromethyl)phenol

[1158]

[1159] The racemate product (prepared as described in Example 1, starting from Int 6 and commercially available trans racemate 2-aminocyclyl-1-ol) was separated by chiral SFC (column: Chiralpak IC, 150 mm x 4.6 mm, 5 μm, 30° C., eluent B: MeOH 20%, flow rate: 100 g / min, cycle time: 18 min, pressure: 100 bar) to give the pure enantiomer Ex 20 (eluting first).

[1160] 1H NMR (400MHz, DMSO-d6): δ=10.50(s,1H),7.68-7.66(d,1H),7.10(s,1H),7.10(s,1H),6.54-6.52(d,1H),6.19-6.14(m,1H),5.09-4.94(d,1H) ,3.64-3.60(m,1H),3.47(s,3H),3.36-3.34(m,1H),2.14(s,3H),2.07 -2.05(m,1H),1.91-1.89(m,1H),1.67-1.63(m,2H),1.32-1.12(m,4H).

[1161] MS(ESI):421.14[M+H] + .

[1162] Example 21: (trans) enantiopure 2-(5-((3-hydroxycyclohexyl)amino)-1-methyl-1H-imidazo[4,5- b]pyridin-2-yl)-3-methyl-5-(trifluoromethyl)phenol

[1163]

[1164] The racemate product (prepared as described in Example 1, starting from Int 6 and commercially available trans racemate 3-aminocyclohexan-1-ol) was obtained in 93% yield and separated by chiral SFC (column: Chiralpak IK, 250 mm x 30 mm, 5 μm, 30° C., eluent B: MeOH 20% + 0.5% IPA, flow rate: 90 g / min, cycle time: 18 min, pressure: 100 bar) to give the pure enantiomer Ex 21 (eluting first).

[1165] 1 H NMR (400MHz, DMSO-d6): δ=10.37(brs,1H),7.64-7.62(d,1H),7.17(s,1H),7.09(s,1H),6.48-6.46(d,1H),6.09-6.07(d ,1H),4.40(s,1H),4.21-4.18(m,1H),3.93-3.89(m,1H),3.46(s,3H),2.14(s,3H),1.80-1.47(m,7H),1.35-1.28(m,1H).

[1166] MS(ESI):421.67[M+H] + .

[1167] Examples 22A and 22B: ( trans) enantiopure 2-(5-((3-hydroxycyclohexyl)amino)-1-methyl-1H-imidazo [4,5-b]pyridin-2-yl)-5-(trifluoromethyl)phenol

[1168]

[1169] The racemate product (prepared as described in Example 1, starting from Int 7 and commercially available trans racemate 3-aminocyclohexan-1-ol) was obtained in 38% yield and separated by chiral SFC (column: Chiralpak IK, 250 mm x 4.6 mm, 5 μm, 30° C., eluent B: MeOH 25% + 0.5% IPA, flow rate: 3 mL / min, pressure: 1500 psi, cycle time: 26 min) to give two enantiomers Ex 22A (first eluting) and Ex 22B (second eluting).

[1170] Ex 22A 1 H NMR(400MHz,DMSO-d6)δ12.48(s,1H),7.91(d,1H),7.74(d,1H),7.35-7.28(m,2H),6.55(d,1H),6.32(d,1H),4.4 3(d,1H),4.21(td,1H),4.01-3.90(m,1H),3.84(s,3H),1.89-1.64(m,3H),1.63-1.40(m,4H),1.37-1.25(m,1H).

[1171] MS(ESI):407.38[M+H] + .

[1172] Ex 22B 1 H NMR (400MHz, DMSO-d6) δ12.42(s,1H),7.90(d,1H),7.73(d,1H),7.32(s,1H),7.29(dd,1H),6.55(d,1H),6.31(d,1H),4. 52-4.34(m,1H),4.21(tt,1H),3.98-3.90(m,1H),3.84(s,3H),1.88-1.63(m,3H),1.62-1.40(m,4H),1.35-1.25(m,1H).

[1173] MS(ESI):407.38[M+H] + .

[1174] Example 23: (2-(5-methoxy-1-methyl-1H-imidazo[4,5-b]pyridin-2-yl)-3-methyl-5-(trimethoxy) ... (fluoromethyl)phenol

[1175]

[1176] Step A:

[1177] To a stirred solution of 2-(5-chloro-1-methyl-1H-imidazo[4,5-b]pyridin-2-yl)-3-methyl-5-(trifluoromethyl)phenol (Int 6) (0.200 g, 0.59 mmol) and methanol (0.038 g, 1.17 mmol) in THF (10 mL) was added a 60% dispersion of sodium hydride in mineral oil (0.4 g, 3.51 mmol) at room temperature, and the reaction mixture was heated to 70 ° C for 96 hours. After the starting material was consumed, the reaction mixture was diluted with water (10 mL) and extracted with EtOAC (2x20 mL). The combined organic layers were washed with brine solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product as a yellow solid. The crude compound was purified by preparative HPLC (mobile phase A: 10 mM ammonium bicarbonate (aq), mobile phase B: acetonitrile:MeOH (60:40), column: INERTSIL ODS, flow rate: 19 ml / min, method: (t / % B): 0 / 40, 1 / 40, 11 / 60, 15 / 20, 15.1 / 100, 17 / 100, 17.1 / 40, 19 / 40, solubility: ACN + THF + water, temperature: ambient temperature). Pure fractions were freeze-dried to give (2-(5-methoxy-1-methyl-1H-imidazo[4,5-b]pyridin-2-yl)-3-methyl-5-(trifluoromethyl)phenol (78 mg, 39%) as an off-white solid.

[1178] MS(ESI):338.13[M+H] + .

[1179] 1 H NMR (400MHz, DMSO-d6): δ=10.65(brs,1H),8.02-7.99(d,1H),7.21(s,1H),7.12(s,1H),6.77-6.75(d,1H),3.90(s,3H),3.57(s,3H),2.14(s,3H).

[1180] The following examples were prepared using the halogenated aromatic intermediates and alcohols according to the method of Example 23, as shown in Table 3:

[1181] Table 3

[1182]

[1183]

[1184]

[1185]

[1186] Example 36: Cis-enantiopure 2-(5-(hydroxycyclopentyl)amino)-1-methyl-1H-imidazo[4,5-b]pyrrolidone pyridin-2-yl)-3-methyl-5-(trifluoromethyl)phenol

[1187]

[1188] The racemate product (prepared as described in Example 1, starting from Int 6 and commercially available cis racemate 2-aminocyclopentan-1-ol) was obtained in 50% yield and separated by chiral SFC (column: Lux-cellulose-5C, 150 mm x 4.6 mm, 3 μm, 30° C., eluent B: MeOH 25% + 0.5% IPA, flow rate: 3 mL / min, pressure: 1500 psi, run time: 14 min) to give the pure cis enantiomer Example 25 (second eluting).

[1189] 1 H NMR (400MHz, DMSO-d6) δ10.63(s,1H),7.70(d,1H),7.15(s,1H),7.08(d,1H),6.53(d,1H),6.43(dd,1H),5.57( d,1H),3.93-3.77(m,2H),3.48(s,3H),2.19-2.05(m,4H),1.89(ddt,1H),1.77-1.60(m,2H),1.59-1.44(m,2H).

[1190] MS(ESI):407.3[M+H] + .

[1191] Examples 37A and 37B: trans-2-(5-((3-hydroxycyclopentyl)oxy)-1-methyl-1H-imidazo[4,5-b] Pyridin-2-yl)-5-(trifluoromethyl)phenol

[1192]

[1193] The racemate product (prepared as described in Example 1, starting from Int 7 and commercially available trans racemate cyclopentane-1,3-diol) was obtained in 13% yield and separated by chiral SFC (column: Chiralpak IG, 250 mm x 4.6 mm, 5 μm, 30° C., eluent B: MeOH 40% + 0.5% IPA, flow rate: 3 mL / min, pressure: 1500 psi, run time: 18 min) to give the pure trans enantiomers.

[1194] Ex 37A (eluted first).

[1195] 1H NMR(400MHz,DMSO-d6)δ11.58(s,1H),8.01(d,1H),7.79(d,1H),7.31(d,2H),6.72(d,1H),5.51(tt,1H),4.60(d,1H),4 .35-4.21(m,1H),3.78(s,3H),2.23(dtd,1H),2.04(dddd,1H),1.99-1.82(m,2H),1.74-1.63(m,1H),1.61-1.47(m,1H).

[1196] MS(ESI):394.22[M+H] + .

[1197] Ex 37B (second elution).

[1198] 1 H NMR(400MHz,DMSO-d6)δ11.58(s,1H),8.01(d,1H),7.79(d,1H),7.34-7.28(m,2H),6.72(d,1H),5.51(tt,1H),4.60(d,1H) ,4.34-4.25(m,1H),3.78(s,3H),2.23(dtd,1H),2.04(dddd,1H),1.99-1.83(m,2H),1.74-1.62(m,1H),1.60-1.48(m,1H).

[1199] MS(ESI):394.23[M+H] + .

[1200] Example 38: 5-chloro-3-methyl-2-(1-methyl-5-(2,2,2-trifluoroethoxy)-1H-imidazo[4,5-b] Pyridin-2-yl)phenol

[1201]

[1202] Step A:

[1203] To a stirred solution of 5-chloro-2-(5-chloro-1-methyl-1H-imidazo[4,5-b]pyridin-2-yl)-3-methylphenol (200 mg, 0.649 mmol) (Int 13) and 2,2,2-trifluoroethane-1-ol (325 mg, 3.245 mmol) in toluene (10 mL) was added potassium tert-butoxide (218 mg, 1.947 mmol) at room temperature, and the mixture was purged with nitrogen for 5 minutes. BrettPhos-Pd G3 (59 mg, 0.065 mmol) was added to the above mixture, and the mixture was irradiated at 100 ° C under microwave for 1 hour. The reaction progress was monitored by TLC. The reaction mixture was cooled to room temperature, filtered on a Celite bed, and washed with EtOAc (50 mL). The resulting filtrate was concentrated under reduced pressure to give a crude product. The crude compound was purified by preparative HPLC. Conditions: Mobile phase A: 10 mM aqueous ammonium bicarbonate, mobile phase B: acetonitrile, column: UNISIL, flow rate: 19 mL / min. Method: (T / % of B): 0 / 45, 3 / 50, 1 / 3 / 60, 15 / 60, 15.1 / 99, 20 / 99, 20.1 / 45, 24 / 45. Solubility: ACN + THF + water, temperature: ambient temperature.

[1204] The pure fractions were collected and freeze-dried to give pure 5-chloro-3-methyl-2-(1-methyl-5-(2,2,2-trifluoroethoxy)-1H-imidazo[4,5-b]pyridin-2-yl)phenol (38 mg, 156%) as an off-white solid.

[1205] MS(ESI):372.17[M+H] + .

[1206] 1 H NMR (400MHz, DMSO-d6) δ10.64(s,1H),8.09(d,1H),6.91-6.83(m,3H),5.04(q,2H),3.58(s,3H),2.05(s,3H).

[1207] Example 39: 5-chloro-2-(5-(3,3-difluorocyclobutyloxy)-1-methyl-1H-imidazo[4,5-b]pyridine-2- methyl)-3-methylphenol

[1208]

[1209] Step A:

[1210] To a stirred solution of 5-chloro-2-(5-chloro-1-methyl-1H-imidazo[4,5-b]pyridin-2-yl)-3-methylphenol (800 mg, 2.596 mmol) (Int 13) in THF (8 mL) was added dropwise N,N-diisopropylethylamine (1.8 mL, 10.384 mmol) and methoxymethyl chloride (0.59 mL, 7.79 mmol) at 0 ° C under an argon atmosphere. The reaction mixture was stirred at room temperature for 16 hours. The reaction process was monitored by TLC. TLC showed that the starting material was consumed. The reaction mixture was diluted with ice water (100 mL) and extracted with EtOAC (2x100 mL). The combined organic layer was washed with brine solution (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product as a liquid. The crude product was purified by silica gel column chromatography. The product was eluted in 40% EtOAc in hexane. The pure fractions were collected and concentrated under reduced pressure to afford pure 5-chloro-2-(4-chloro-2-(methoxymethoxy)-6-methylphenyl)-1-methyl-1H-imidazo[4,5-b]pyridine (501 mg, 55%).

[1211] MS(ESI):352.14[M+H] + .

[1212] Step B:

[1213] To a stirred solution of 5-chloro-2-(4-chloro-2-(methoxymethoxy)-6-methylphenyl)-1-methyl-1H-imidazo[4,5-b]pyridine (400 mg, 1.136 mmol) and 3,3-difluorocyclobutan-1-ol (613.76 mg, 5.678 mmol) in toluene (10 mL) was added potassium tert-butoxide (382.30 mg, 3.407 mmol) at room temperature. The mixture was purged with nitrogen for 5 minutes, then BrettPhos Pd G3 (103 mg, 0.114 mmol) was added, and the mixture was heated to 100° C. for 16 hours under sealed conditions. The reaction progress was monitored by TLC. TLC indicated the reaction was complete. The reaction mixture was cooled to room temperature, filtered over a bed of Celite, washed with EtOAc (250 mL), and concentrated under reduced pressure to give the crude product 2-(4-chloro-2-(methoxymethoxy)-6-methylphenyl)-5-(3,3-difluorocyclobutyloxy)-1-methyl-1H-imidazo[4,5-b]pyridine (400 mg, 15%).

[1214] MS(ESI):424.24[M+H] + .

[1215] Step C:

[1216] To a stirred solution of 2-(4-chloro-2-(methoxymethoxy)-6-methylphenyl)-5-(3,3-difluorocyclobutyloxy)-1-methyl-1H-imidazo[4,5-b]pyridine (400 mg, 0.944 mmol) in trifluoroethanol (12.5 mL) was added trimethylchlorosilane (5.0 mL) at 0 ° C, and the reaction mixture was stirred at room temperature for 1 hour. The reaction process was monitored by TLC. TLC showed that the reaction was complete. The reaction mixture was evaporated under reduced pressure, then diluted with ice / water (100 mL) and extracted with DCM (2x100 mL). The combined organic layers were washed with saline solution (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product as a solid. The crude compound was purified by preparative HPLC. Preparative HPLC conditions: Mobile phase A: ammonium bicarbonate, Mobile phase B: acetonitrile, Column: HYPERSIL BDS (20 mm x 250 mm) 5 μM, Flow rate: 19 mL / min. Method: (T / % of B): -0 / 45, 2 / 45, 6 / 65, 10.50 / 65, 10.51 / 100, 16 / 100, 16.01 / 45, 20 / 45. Solubility: ACN + THF + water. Pure fractions were collected and lyophilized to yield pure 5-chloro-2-(5-(3,3-difluorocyclobutyloxy)-1-methyl-1H-imidazo[4,5-b]pyridin-2-yl)-3-methylphenol (6.5 mg, 11%) as a yellow solid.

[1217] MS(ESI):378.19[M+H] + .

[1218] 1 H NMR (400MHz, DMSO-d6) δ7.99(d,1H),6.80-6.69(m,3H),5.18(qd,1H),3.55(s,3H),3.23-3.12(m,2H),2.82-2.64(m,2H),2.03(s,3H).

[1219] Example 40: (R)-2-(6-((1-methylpiperidin-3-yl)amino)-2H-pyrazolo[3,4-b]pyridin-2-yl)- 5-(Trifluoromethyl)phenol formate

[1220]

[1221] Step A:

[1222] To a solution of 6-chloro-2H-pyrazolo[3,4-b]pyridine (600 mg, 3.91 mmol, 1.0 equiv) in NMP (6 mL) was added (3R)-1-methylpiperidin-3-amine (1.34 g, 11.72 mmol, 3.0 equiv) and DIEA (1.51 g, 11.72 mmol, 2.04 mL, 3.0 equiv). The resulting reaction mixture was stirred at 180°C under microwave irradiation for 16 hours. LC-MS indicated the reaction was complete. The residue was purified by preparative HPLC (column: Waters Xbridge BEH C18, 100 x 30 mm, 10 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 10%-40%, 8 min) to afford the title product. (R)-N-(1-methylpiperidin-3-yl)-2H-pyrazolo[3,4-b]pyridin-6-amine (400 mg, 1.73 mmol, 44% yield) was obtained as a yellow solid.

[1223] MS(ESI):232.4[M+H] + .

[1224] 1 H NMR (400MHz, DMSO-d6)δ=12.71(br s,1H),7.-0-7.62(m,2H),6.80(br d,1H),6.37(d,1H),4.-4-3.93(m,1H),2.85(br d,1H),2.-8-2.52(m,1H),2.15(s,3H),1.95(br t,1H),1.-4-1.65(m,3H),1.-2-1.42(m,1H),1.33-1.15(m,1H).

[1225] Step B:

[1226] To a solution of [2-methoxy-4-(trifluoromethyl)phenyl]boronic acid (172 mg, 778.22 μmol, 1.2 eq) in a mixed solvent of pyridine (0.1 mL) and THF (0.4 mL) were successively added N-[(3R)-1-methyl-3-piperidinyl]-2H-pyrazolo[3,4-b]pyridin-6-amine (150 mg, 648.52 μmol, 1 eq), Cu(OAc)2 (235.58 mg, 1.30 mmol, 2 eq) and molecular sieves. (140 mg), and then the mixture was degassed with N2 three times. The resulting reaction mixture was heated to 80 ° C and stirred at 80 ° C under N2 for 6 hours. LCMS showed that the reaction was complete. The reaction solution was filtered to remove the molecular sieve The residue was then concentrated to afford the crude product. The residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 100 mm x 30 mm, 10 μm; mobile phase: [water(NH4HCO3)-ACN]; B%: 35%-55%, 8 min) to afford the title product. This yielded 2-[2-methoxy-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methyl-3-piperidinyl]pyrazolo[3,4-b]pyridin-6-amine (42 mg, 104 μmol, 16% yield) as a pale yellow solid.

[1227] MS(ESI):406.3[M+H] + .

[1228] Step C:

[1229] A solution of 2-[2-methoxy-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methyl-3-piperidinyl]pyrazolo[3,4-b]pyridin-6-amine (40 mg, 98.66 μmol, 1.0 equiv) in DCM (4 mL) was cooled to 0°C, and then BBr3 (74.15 mg, 295.99 μmol, 28.52 μL, 3 equiv) was added dropwise at 0°C. After the addition was complete, the reaction mixture was stirred at 20°C for 0.5 hours. LCMS showed that the reaction was complete. The reaction solution was concentrated to give the crude product. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 100 mm x 30 mm, 5 μm; mobile phase: [water (FA)-ACN]; B%: 1%-35%, 8 min) to give the title product. 2-[6-[[(3R)-1-methyl-3-piperidinyl]amino]pyrazolo[3,4-b]pyridin-2-yl]-5-(trifluoromethyl)phenol (10 mg, 25 μmol, 25% yield, 98% purity) was obtained as a white solid. LC-MS (ESI): 392.3 [M+H] + .

[1230] 1H NMR (400MHz, DMSO-d6)δ=11.92(br s,1H),8.84(s,1H),8.18(s,1H),8.09(d,1H),7.77(d,1H),7.36(s,1H),7.32(br d,1H),7.14(d,1H),6.54(d,1H),4.21-4.00(m,1H),2.90(br d,1H),2.65-2.56(m,1H),2.21(s,3H),2.04(br s,1H),1.92(br s,1H),1.84(br dd,12.1Hz,1H),1.73(br dd,1H),1.56(br dd,1H),1.30(br d,1H).

[1231] The following examples were prepared according to the method of Example 40 using the corresponding commercially available amines, as shown in Table 4:

[1232] Table 4

[1233]

[1234] Example 42: 2-(6-methoxypyrazolo[3,4-b]pyridin-2-yl)-5-(trifluoromethyl)cyclohexane-2,4-diol En-1-ol

[1235]

[1236] Step A:

[1237] 6-chloro-2H-pyrazolo[3,4-b]pyridine (1 g, 6.51 mmol, 1 equivalent) was added to a solution of 30% NaOMe in MeOH (19.54 mL, 6.51 mmol, 1 equivalent), and the resulting reaction mixture was stirred at 80 ° C for 24 hours. LC-MS showed that the reaction was complete. The reaction mixture was poured into 30 mL H2O, followed by 30 mL EtOAc. Afterwards, the aqueous phase was separated and extracted with EtOAC (2x30 mL). The combined organic layer was washed continuously with water (2x20 mL) and brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 10 / 1) to give the desired product 6-methoxy-2H-pyrazolo[3,4-b]pyridine (0.7 g, 4.69 mmol, 72%) as a yellow solid. MS (ESI): 150.0 [M+H] + .

[1238] Step B:-

[1239] According to Example 43, Step B, 2-(6-methoxypyrazolo[3,4-b]pyridin-2-yl)-5-(trifluoromethyl)-cyclohexa-2,4-dien-1-ol (5.5 mg, 17.67 μmol, 14%) was obtained as a white solid.

[1240] MS(ESI):309.8[M+H] + .

[1241] 1 H NMR (400MHz, DMSO-d6) δ = 11.61 (br s, 1H), 9.04 (s, 1H), 8.15 (d, J = 8.9Hz, 1H), 8.10 (d, J = 8.4Hz, 1H), 7.38 (s, 1H), 7.33 (br d,J=8.5Hz,1H),6.69(d,J=8.9Hz,1H),3.95(s,3H)

[1242] Example 43: (R)-5-chloro-2-(6-((1-methylpiperidin-3-yl)amino)-2H-pyrazolo[3,4-b]pyridine- 2-aminophenol

[1243]

[1244] Step A:

[1245] To a solution of 6-chloro-2H-pyrazolo[3,4-b]pyridine (8g, 52.09mmol, 1.0 equivalent) in dioxane (20mL) was added NaSMe (365g, 1.04mol, 332mL, 20 equivalents), and the resulting reaction mixture was stirred at 130°C for 24 hours. LCMS showed that 34% of the raw materials remained, and 64% of the desired product was obtained. The reaction mixture was poured into 500mL H2O, followed by 120mL EtOAc. Afterwards, the aqueous phase was separated and extracted with EtOAC (2x 120mL). The combined organic layer was washed continuously with water (2x200mL) and brine (120mL), dried over anhydrous Na2SO4, filtered, and concentrated to give residue. The residue was purified by preparative HPLC (column: Agela DuraShell C18, 250 mm x 70 mm, 10 μm; mobile phase: [H2O(10 mM NH4HCO3)-ACN]; gradient: 12%-42% B over 17 min) to afford the title product. 6-Methylsulfanyl-2H-pyrazolo[3,4-b]pyridine (3 g, 18.16 mmol, 35%) was obtained as a white solid.

[1246] MS(ESI):166.1[M+H] + .

[1247] 1 H NMR (400MHz, DMSO-d6) δ = 13.53 (br s, 1H), 8.02 (t, 2H), 7.05 (d, 1H), 2.58 (s, 3H).

[1248] Step B:

[1249] To a solution of 6-methylsulfanyl-2H-pyrazolo[3,4-b]pyridine (700 mg, 4.24 mmol, 1.0 equiv) in pyridine (8 mL) was added (4-chloro-2-methoxy-phenyl)boronic acid (1.03 g, 5.51 mmol, 1.3 equiv), Cu(OAc)2 (769.55 mg, 4.24 mmol, 1.0 equiv), and 4A MS (700 mg, 4.24 mmol, 1.0 equiv), and the resulting reaction mixture was stirred at 100°C under an O2 atmosphere for 72 hours. LC-MS showed the reaction was complete. The reaction mixture was poured into 20 mL of H2O, followed by 10 mL of EtOAc. The aqueous phase was then separated and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed successively with water (2 x 20 mL) and brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated to yield a residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1). 2-(4-chloro-2-methoxy-phenyl)-6-methylsulfanyl-pyrazolo[3,4-b]pyridine (150 mg, 491 μmol, 12%) was obtained as a yellow oil.

[1250] MS(ESI):306.0[M+H] + .

[1251] 1 H NMR (400MHz, DMSO-d6)δ=8.75(s,1H),8.25(s,1H),8.10(d,1H),8.04(d,1H),7.84(d,1H),7.48(d,1H),7.44(d,1H),7.39(d ,1H),7.23-7.23(m,1H),7.23(dd,1H),7.21-7.14(m,2H),7.01(d,1H),3.94(s,2H),3.77(s,3H),2.59(s,2H),2.45(s,3H).

[1252] Step C:

[1253] To a solution of 2-(4-chloro-2-methoxy-phenyl)-6-methylsulfanyl-pyrazolo[3,4-b]pyridine (350 mg, 1.14 mmol, 1 equivalent) in DCM (8 mL) was added m-CPBA (465 mg, 2.29 mmol, 85% purity, 2 equivalents) at 0 ° C, and the resulting reaction mixture was stirred at 20 ° C for 2 hours. LC-MS showed that the reaction was complete. The reaction mixture was poured into 20 mL of H2O, followed by 10 mL of DCM. Afterwards, the aqueous phase was separated and extracted with DCM (2 x 10 mL). The combined organic layers were washed continuously with water (2 x 20 mL) and brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated to obtain a residue. The residue was purified by preparative TLC (SiO2, petroleum ether / ethyl acetate = 1:1). 2-(4-Chloro-2-methoxy-phenyl)-6-methylsulfonyl-pyrazolo[3,4-b]pyridine (90 mg, 266 μmol, 23%) was obtained as a yellow solid. MS (ESI): 338.0 [M+H] + .

[1254] Step D:

[1255] To a solution of 2-(4-chloro-2-methoxy-phenyl)-6-methylsulfonyl-pyrazolo[3,4-b]pyridine (10 mg, 29.60 μmol, 1 equivalent) in DMF (1 mL) was added (3R)-1-methylpiperidin-3-amine (17 mg, 148 μmol, 5 equivalents), Pd2(dba)3 (27 mg, 30 μmol, 1 equivalent), Cs2CO3 (19 mg, 59 μmol, 2 equivalents) and XPhos (28 mg, 59 μmol, 2 equivalents), and the resulting reaction mixture was stirred at 120 ° C for 12 hours. LC-MS showed that the reaction was complete. The reaction mixture was poured into 15 mL of H2O, followed by 10 mL of EtOAc. Afterwards, the aqueous phase was separated and extracted with EtOAC (2 x 10 mL). The combined organic layers were washed successively with water (2 x 15 mL) and brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give a residue. The residue was purified by preparative TLC (SiO2, DCM:MeOH = 5:1). 2-(4-chloro-2-methoxy-phenyl)-N-[(3R)-1-methyl-3-piperidinyl]pyrazolo[3,4-b]pyridin-6-amine (15 mg, 40.34 μmol, 23%) was obtained as a yellow oil.

[1256] MS(ESI):372.2[M+H] + .

[1257] Step E:

[1258] According to Example 46, Step F, (R)-5-chloro-2-(6-((1-methylpiperidin-3-yl)amino)-2H-pyrazolo[3,4-b]pyridin-2-yl)phenol (3 mg, 9 μmol, 23%) was obtained as a white solid.

[1259] MS(ESI):358.2[M+H] + .

[1260] 1 H NMR (400MHz, DMSO-d6) δ = 12.22-11.49 (m, 1H), 8.70 (s, 1H), 7.85 (d, 1H), 7.75 (d, 1H), 7.11 (d,1H),7.07(d,1H),7.03(dd,1H),6.52(d,1H),4.17-4.03(m,1H),2.90(brd,1H),2.60(br d,J=10.3Hz,1H),2.21(s,3H),2.04(br s,1H),1.97-1.79(m,2H),1.78-1.66(m,1H),1.56(br dd,1H),1.29(br d,1H).

[1261] Example 44: 2-[6-(Difluoromethoxy)pyrazolo[3,4-b]pyridin-2-yl]-5-(trifluoromethyl)phenol

[1262]

[1263] Step A:

[1264] To a solution of 2,7-dihydropyrazolo[3,4-b]pyridin-6-one (330 mg, 2.44 mmol, 1 eq) and sodium 2-chloro-2,2-difluoro-acetate (559 mg, 3.66 mmol, 1.5 eq) in DMF (5 mL) was added KCO (169 mg, 1.22 mmol, 0.5 eq). The mixture was stirred at 90 ° C for 3 hours. LC-MS showed that the reaction was complete. After completion, the precipitate was collected by filtration to obtain the crude product. The residue was purified by preparative HPLC (column: Waters Xbridge C18, 150 mm x 50 mm, 10 μm; mobile phase: [H2O(10 mM NH4HCO3)-ACN]; gradient: 1-55% B over 8 min) to give compound 6-(difluoromethoxy)-2H-pyrazolo[3,4-b]pyridine (140 mg, 756 μmol, 31%) as a white solid.

[1265] MS(ESI):184.7[MH] - .

[1266] 1 H NMR (400MHz, DMSO-d6)δ=13.77-13.65(m,1H),8.33(d,1H),8.16-8.10(m,1H),7.94 -7.58(m,1H),6.86(d,1H)

[1267] Step B:

[1268] According to Example 43, step B, using [2-benzyloxy-4-(trifluoromethyl)phenyl], 2-[2-benzyloxy-4-(trifluoromethyl)phenyl]-6-(difluoromethoxy)pyrazolo[3,4-b]pyridine boronic acid (45 mg, 104 μmol, 14%) was obtained as a white solid. MS (ESI): 436.1 [M+H] + .

[1269] Step C:

[1270] To a mixture of 2-[2-benzyloxy-4-(trifluoromethyl)phenyl]-6-(difluoromethoxy)pyrazolo[3,4-b]pyridine (30 mg, 68.9 μmol, 1 eq) in MeOH (5 mL) was added Pd / C (73 mg, 69 μmol, 10% purity, 1 eq) and the mixture was stirred at 25° C. under H 2 atmosphere for 1 hour. LCMS showed the reaction was complete. After completion, the reaction mixture was filtered and the filtrate was collected to give the crude product. The crude product was purified by preparative HPLC (Waters Xbridge BEH C18 100 x 30 mm, 10 μm; mobile phase: [H2O (10 mM NH4HCO3)-ACN]; gradient: 40-70% B over 8 min) to give the title compound 2-[6-(difluoromethoxy)pyrazolo[3,4-b]pyridin-2-yl]-5-(trifluoromethyl)phenol (4.5 mg, 13 μmol, 19%) as a white solid.

[1271] MS(ESI):346.0[M+H] + .

[1272] 1 H NMR (400MHz, DMSO-d6)δ=11.66(br s,1H),9.18(s,1H),8.41(d,1H),8.09(d,1H),8.10 -7.70(m,1H),7.39(s,1H),7.33(br d,1H),6.88(d,1H)

[1273] Example 45: 2-[6-(Trifluoromethoxy)pyrazolo[3,4-b]pyridin-2-yl]-5-(trifluoromethyl)phenol

[1274]

[1275] Step A:

[1276] According to Ex 47, step B, 2-[2-methoxy-4-(trifluoromethyl)phenyl]pyrazolo[3,4-b]pyridine (450 mg, 1.53 mmol, 4%) was obtained as a white solid.

[1277] MS(ESI):294.2[M+H] + .

[1278] 1 H NMR (400MHz, DMSO-d6) δ = 8.97 (s, 1H), 8.70 (dd, 1H), 8.30 (dd, J = 1.6, 8.4Hz, 1H), 8.10 (d, 1H), 7.66 (s, 1H), 7.56 (d, 1H), 7.17 (dd, 1H), 4.02 (s, 3H).

[1279] Step B:

[1280] To a solution of 2-[2-methoxy-4-(trifluoromethyl)phenyl]pyrazolo[3,4-b]pyridine (450 mg, 1.53 mmol, 1 eq) in EtOAc (20 mL) was added m-CPBA (779 mg, 3.84 mmol, 85% purity, 2.5 eq) at 0°C. The mixture was stirred at 50°C for 6 hours. LC-MS showed that the reaction was complete. The reaction mixture was diluted with 30 mL of H2O and extracted with EtOAC (3 x 20 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative TLC (SiO2, DCM:MeOH=10:1) to give 2-[2-methoxy-4-(trifluoromethyl)phenyl]-7-oxido-pyrazolo[3,4-b]pyridin-7-ium (200 mg, 647 μmol, 42%) as a light yellow solid.

[1281] MS(ESI):310.2[M+H] + .

[1282] Step C:

[1283] To a solution of 2-[2-methoxy-4-(trifluoromethyl)phenyl]-7-oxido-pyrazolo[3,4-b]pyridin-7-ium (150 mg, 485 μmol, 1 eq) in DME (15 mL) was added trifluoromethyl triflate (212 mg, 970 μmol, 2 eq), and the mixture was stirred at 20 ° C for 2 hours. The mixture was stirred at 60 ° C for 10 hours. LC-MS showed that the reaction was complete. The reaction mixture was concentrated in vacuo. The residue was purified by preparative TLC (SiO2, DCM:MeOH=20:1) to give the product. 2-[2-methoxy-4-(trifluoromethyl)phenyl]-6-(trifluoromethoxy)pyrazolo[3,4-b]pyridine (20 mg, 53.02 μmol, 11%) was obtained as a light yellow solid. MS (ESI): 378.1 [M+H] + .

[1284] Step D:

[1285] According to Example 46, Step F, 2-[6-(trifluoromethoxy)pyrazolo[3,4-b]pyridin-2-yl]-5-(trifluoromethyl)phenol (6 mg, 16 μmol, 30%) was obtained as a white solid.

[1286] MS(ESI):363.9[M+H] + .

[1287] 1 H NMR (400MHz, DMSO-d6) δ = 11.57 (br s, 1H), 9.17 (s, 1H), 8.53 (d, 1H), 8.11 (d, 1H), 7.43 (s, 1H), 7.39 (br d, 1H), 7.02 (d, 1H).

[1288] Example 46 (R)-2-(6-fluoro-1-methyl-5-((1-methylpyrrolidin-3-yl)amino)-1H-imidazo[4,5- b]pyridin-2-yl)-3-methyl-5-(trifluoromethyl)phenol

[1289]

[1290] Step A:

[1291] To 3-bromo-5-fluoro-pyridin-2-amine (3 g, 15.71 mmol, 1.0 eq) in 40% MeNH2 (9.32 g, 120.00 mmol, 20 mL, 40% purity, 7.64 eq) was added copper sulfate pentahydrate (250.69 mg, 1.57 mmol, 241.05 μL, 0.1 eq) and the reaction mixture was stirred at 100 ° C for 12 hours. The reaction mixture was filtered through Celite. The Celite pad was rinsed with DCE: MeOH = 9: 1 (3 x 50 mL) and concentrated under vacuum to give a crude product. The crude product was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1. The crude product was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1) to give 5-fluoro-N3-methyl-pyridine-2,3-diamine (2 g, 14.17 mmol, 90.21% yield) as a dark brown solid.

[1292] LC-MS(ES + ,m / z):142.7[(M+H) + ].

[1293] Step B:

[1294] To a solution of 5-fluoro-N3-methyl-pyridine-2,3-diamine (1.5g, 10.63mmol, 1.0 equivalent) in DMA (15mL) was added NaHSO (1.33g, 12.75mmol, 896.66μL, 1.2 equivalents) and 2-methoxy-6-methyl-4-(trifluoromethyl)benzaldehyde (2.32g, 10.63mmol, 1 equivalent). The resulting reaction mixture was stirred at 100°C for 12 hours. LCMS showed that the reaction was complete. The reaction mixture was poured into 50mL H2O, followed by 20mL DCM. Afterwards, the aqueous phase was separated and extracted with DCM (20mLx3). The combined organic layer was washed continuously with water (20mL x2) and brine (20mLx1), dried over anhydrous Na2SO4, filtered, and concentrated to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 1 / 1) to afford 6-fluoro-2-[2-methoxy-6-methyl-4-(trifluoromethyl)phenyl]-1-methyl-imidazo[4,5-b]pyridine (2.6 g, 7.66 mmol, 72.11% yield, N / A purity) as a yellow solid.

[1295] LC-MS(ES + ,m / z):340.4[(M+H) + ].

[1296] 1 H NMR (400MHz, DMSO-d6) δ = 8.45 (s, 1H), 8.16 (dd, J = 2.8, 8.9Hz, 1H), 7.43 (s, 1H), 7.36 (s, 1H), 3.84 (s, 3H), 3.56 (s, 3H), 2.17 (s, 3H)

[1297] Step C:

[1298] To a solution of 6-fluoro-2-[2-methoxy-6-methyl-4-(trifluoromethyl)phenyl]-1-methyl-imidazo[4,5-b]pyridine (2.6 g, 7.66 mmol, 1.0 equiv) in DCM (30 mL) was added m-CPBA (3.11 g, 15.33 mmol, 85% purity, 2.0 equiv) at 0 ° C. The resulting reaction mixture was stirred at 20 ° C for 12 hours. LCMS showed that the reaction was complete. The reaction mixture was poured into 50 mL of H2O, followed by 20 mL of DCM. Afterwards, the aqueous phase was separated and extracted with DCM (20 mL x3). The combined organic layers were washed continuously with water (20 mL x2) and brine (20 mL x1), dried over anhydrous Na2SO4, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO2, DCM / MeOH=100 / 1 to 15 / 1). 6-Fluoro-2-[2-methoxy-6-methyl-4-(trifluoromethyl)phenyl]-1-methyl-4-oxido-imidazo[4,5-b]pyridin-4-ium (2.4 g, 6.08 mmol, 79.34% yield, 90% purity) was obtained as a yellow solid.

[1299] LC-MS(ES + ,m / z):356.2[(M+H) + ].

[1300] 1 H NMR (400MHz, DMSO-d6) δ = 8.54 (dd, J = 1.8, 5.8Hz, 1H), 7.97-7.82 (m, 1H), 7.44 (s, 1H), 7.37 (s, 1H), 3.85 (s, 3H), 3.56 (s, 3H), 2.18 (s, 3H)

[1301] Step D:

[1302] To a solution of 6-fluoro-2-[2-methoxy-6-methyl-4-(trifluoromethyl)phenyl]-1-methyl-4-oxido-imidazo[4,5-b]pyridin-4-ium (2.4 g, 6.08 mmol, 1.0 equivalent) in toluene (25 mL) was added POCl (2.80 g, 18.24 mmol, 1.70 mL, 3.0 equivalents). The resulting reaction mixture was stirred at 110 ° C for 1 hour. LCMS showed that the reaction was complete. The reaction mixture was poured into 50 mL of H2O, followed by 20 mL of DCM. Afterwards, the aqueous phase was separated and extracted with DCM (20 mL x 3). The combined organic layer was washed continuously with water (20 mL x 2) and brine (20 mL x 1), dried over anhydrous Na2SO4, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 4 / 1). 5-Chloro-6-fluoro-2-[2-methoxy-6-methyl-4-(trifluoromethyl)phenyl]-1-methyl-imidazo[4,5-b]pyridine (1.8 g, 1.20 mmol, 19.81% yield, 25% purity) was obtained as a white solid.

[1303] LC-MS(ES + ,m / z):374.4[(M+H) + ].

[1304] 1 H NMR (400MHz, DMSO-d6) δ = 8.59 (d, J = 2.0Hz, 1H), 7.44 (s, 1H), 7.37 (s, 1H), 3.85 (s, 3H), 3.77 (s, 3H), 2.18 (s, 3H)

[1305] Step E:

[1306] To a solution of 5-chloro-6-fluoro-2-[2-methoxy-6-methyl-4-(trifluoromethyl)phenyl]-1-methyl-imidazo[4,5-b]pyridine (100.00 mg, 66.89 μmol, 25% purity, 1.0 eq) in THF (2 mL) was added (3R)-1-methylpyrrolidin-3-amine (40.20 mg, 401.36 μmol, 2.0 eq), BINAP (24.99 mg, 40.14 μmol, 0.2 eq), t-BuONa (57.86 mg, 602.04 μmol, 3.0 eq), and Pd(OAc)2 (9.01 mg, 40.14 μmol, 0.2 eq). The resulting reaction mixture was stirred at 100°C for 12 hours. LCMS indicated the reaction was complete. The reaction mixture was poured into 20 mL of saturated NH4Cl at 0°C, followed by 10 mL of DCM. Afterwards, the aqueous phase was separated and extracted with DCM (20 mL x 2). The combined organic layers were washed continuously with water (20 mL x 2) and brine (20 mL x 1), dried over anhydrous Na2SO4, filtered, and concentrated to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 100 mm x 30 mm x 5 μm; mobile phase: [H2O(0.2% FA)-ACN]; gradient: 10%-40% B over 8.0 minutes) to give the title product. 6-Fluoro-2-[2-methoxy-6-methyl-4-(trifluoromethyl)phenyl]-1-methyl-N-[(3R)-1-methylpyrrolidin-3-yl]imidazo[4,5-b]pyridin-5-amine (batch × 2 total, 40 mg, 91.44 μmol, 68.4% yield, N / A purity) as a white solid.

[1307] LC-MS(ES + ,m / z):438.2[(M+H) + ].

[1308] 1 H NMR (400MHz, DMSO-d6) δ = 7.86 (d, J = 11.0Hz, 1H), 7.39 (s, 1H), 7.31 (s, 1H), 6.30 (br s, 1H), 4.45 (br s, 1H), 3.81 (s, 3H), 3.44 (s, 3H), 2.90 (br t,J=6.6Hz,1H),2.68(br s,1H),2.56(br s,2H),2.35-2.29(m,3H),2.24(br d,J=5.3Hz,1H),2.15(s,3H),1.88-1.75(m,1H)

[1309] Step F:

[1310] To a solution of 6-fluoro-2-[2-methoxy-6-methyl-4-(trifluoromethyl)phenyl]-1-methyl-N-[(3R)-1-methylpyrrolidin-3-yl]imidazo[4,5-b]pyridin-5-amine (40 mg, 91.44 μmol, 1.0 equiv) in DCM (1 mL) was added BBr3 (114.54 mg, 457.21 μmol, 44.05 μL, 5.0 equiv) at 0 ° C. The resulting reaction mixture was stirred at 20 ° C for 0.5 hours. LCMS showed that the reaction was complete. After completion, the solvent was removed by concentration to give a residue. The residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 100 mm x 30 mm x 10 μm; mobile phase: [H2O(10 mM NH4HCO3)-ACN]; gradient: 20% to 50% B over 8.0 minutes) to afford the title product. 2-[6-Fluoro-1-methyl-5-[[(3R)-1-methylpyrrolidin-3-yl]amino]imidazo[4,5-b]pyridin-2-yl]-3-methyl-5-(trifluoromethyl)phenol (17.0 mg, 39.70 μmol, 43.42% yield, 98.88% purity) was obtained as a white solid.

[1311] LC-MS(ES + ,m / z):424.2[(M+H) + ].

[1312] 1 H NMR (400MHz, DMSO-d6) δ = 10.76-10.43 (m, 1H), 7.84 (d, J = 11.0Hz, 1H), 7.18 (s, 1H), 7.10 (s, 1H), 6.22 (br d,J=6.5Hz,1H),4.50-4.38(m,1H),3.48(s,3H),2.84-2.79(m,1H),2.62-2.54(m,1H),2. 45-2.38(m,2H),2.26(d,J=3.9Hz,3H),2.24-2.18(m,1H),2.14(s,3H),1.83-1.71(m,1H)

[1313] Example 47 (R)-5-chloro-2-(6-fluoro-1-methyl-5-((1-methylpyrrolidin-3-yl)amino)-1H-imidazo [4,5-b]pyridin-2-yl)-3-methylphenol formate

[1314]

[1315] Step A:

[1316] To at MeNH H o solution (3.00g, 28.98mmol, 30% purity, 1.85 equivalents) in 3-bromo-5-fluoro-pyridine-2-amine (3g, 15.71mmol, 1.0 equivalents) add CuSO .5H o (392.17mg, 1.57mmol, 0.1 equivalents), and the reaction mixture obtained was stirred at 100 ℃ for 12 hours. LCMS shows that the reaction is complete. The reaction mixture is tilted to 100mLH o, followed by 60mL EA. Afterwards, the aqueous phase is separated, and extracted with EA (60mL x2). The organic layer merged is washed with water (50mL x2) and salt solution (50mL x1) continuously, through anhydrous Na sO dried, filtered, and concentrated to obtain residue. By residue through column chromatography purification (SiO , petroleum ether / ethyl acetate=100 / 1 to 0 / 1). 5-Fluoro-N3-methyl-pyridine-2,3-diamine (2.9 g, 20.55 mmol, 65.41% yield, N / A purity) was obtained as a grey solid.

[1317] LC-MS(ES + ,m / z):142.1[(M+H) + ].

[1318] 1 H NMR (400MHz, DMSO-d6) δ = 7.15 (d, J = 2.6Hz, 1H), 6.42 (dd, J = 2.5, 11.0Hz, 1H), 5.33 (s, 2H), 5.26 (br d, J = 3.1Hz, 1H), 2.69 (d, J = 4.9Hz, 3H)

[1319] Step B:

[1320] To a solution of 5-fluoro-N3-methyl-pyridine-2,3-diamine (600mg, 4.25mmol, 1.0 equivalent) in DMA (6mL) was added 4-chloro-2-methoxy-6-methyl-benzaldehyde (784.80mg, 4.25mmol, 1.0 equivalent) and NaHSO3 (884.71mg, 8.50mmol, 597.78μL, 2.0 equivalents), and the resulting reaction mixture was stirred at 100°C for 12 hours. LCMS showed that the reaction was complete. The reaction mixture was poured into 20mL H2O, followed by 10mL EA. Afterwards, the aqueous phase was separated and extracted with EA (10mL x2). The combined organic layer was washed continuously with water (20mL x2) and brine (20mL x1), dried over anhydrous Na2SO4, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1) to afford 2-(4-chloro-2-methoxy-6-methyl-phenyl)-6-fluoro-1-methyl-imidazo[4,5-b]pyridine (1 g, 3.27 mmol, 76.94% yield, N / A purity) as a white solid.

[1321] LC-MS(ES + ,m / z):306.1[(M+H) + ].

[1322] 1 H NMR (400MHz, DMSO-d6) δ=8.43-8.43(m,1H),8.43(dd,J=2.0,2.6Hz,1H),7.16(dd,J=1.4,12.2Hz,2H),3.77(s,3H),3.54(s,3H),2.08(s,3H)

[1323] Step C:

[1324] 2-(4-chloro-2-methoxy-6-methyl-phenyl)-6-fluoro-1-methyl-imidazo[4,5-b]pyridine (1 g, 3.27 mmol, 1.0 equiv) was added to a DCM solution (9 mL) at 0 ° C, followed by m-CPBA (1.33 g, 6.54 mmol, 85% purity, 2.0 equiv), and the resulting reaction mixture was stirred at 25 ° C for 24 hours. LCMS showed that the reaction was complete. The reaction mixture was poured into 20 mL of H2O, followed by 10 mL of DCM. Afterwards, the aqueous phase was separated and extracted with DCM (10 mL x2). The combined organic layers were washed continuously with water (20 mL x2) and brine (20 mL x1), dried over anhydrous Na2SO4, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO2, DCM / MeOH=100 / 1 to 1 / 1). 2-(4-Chloro-2-methoxy-6-methyl-phenyl)-6-fluoro-1-methyl-4-oxido-imidazo[4,5-b]pyridin-4-ium (950 mg, 2.95 mmol, 90.28% yield, N / A purity) was obtained as a white solid.

[1325] LC-MS(ES + ,m / z):322.0[(M+H) + ].

[1326] 1 H NMR (400MHz, DMSO-d6) δ = 8.52 (dd, J = 2.1, 5.9Hz, 1H), 7.87 (dd, J = 2.1, 7.8Hz, 1H), 7.21-7.12 (m, 2H), 3.78 (s, 3H), 3.54 (s, 3H), 2.09 (s, 3H)

[1327] Step D:

[1328] To a solution of 2-(4-chloro-2-methoxy-6-methyl-phenyl)-6-fluoro-1-methyl-4-oxidation-imidazo[4,5-b]pyridin-4-ium (950 mg, 2.95 mmol, 1.0 equivalent) in toluene (10 mL) was added POCl (905.50 mg, 5.91 mmol, 550.46 μL, 2.0 equivalents), and the resulting reaction mixture was stirred at 110 ° C for 1 hour. LCMS showed that the reaction was complete. The reaction mixture was poured into 20 mL of H2O, followed by 10 mL of EA. Afterwards, the aqueous phase was separated and extracted with EA (10 mL x 2). The combined organic layer was washed continuously with water (20 mL x 2) and brine (20 mL x 1), dried over anhydrous Na2SO4, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1). 5-Chloro-2-(4-chloro-2-methoxy-6-methyl-phenyl)-6-fluoro-1-methyl-imidazo[4,5-b]pyridine (760 mg, 558.53 μιηοΐ, 18.92% yield, 25% purity) was obtained as a white solid.

[1329] LC-MS(ES + ,m / z):340.1[(M+H) + ].

[1330] 1 H NMR (400 MHz, chloroform-d) δ = 7.53 (d, J = 7.6 Hz, 1H), 7.00 (s, 1H), 6.87 (d, J = 1.4 Hz, 1H), 3.84 (s, 3H), 3.79-3.74 (m, 3H), 2.18-2.17 (m, 3H)

[1331] Step E:

[1332] To a solution of 5-chloro-2-(4-chloro-2-methoxy-6-methyl-phenyl)-6-fluoro-1-methyl-imidazo[4,5-b]pyridine (200 mg, 146.98 μmol, 1.0 eq) in THF (2 mL) was added (3R)-1-methylpyrrolidin-3-amine (29.44 mg, 293.96 μmol, 2.0 eq), BINAP (18.30 mg, 29.40 μmol, 0.2 eq), t-BuONa (28.25 mg, 293.96 μmol, 2 eq) and Pd(OAc) (3.30 mg, 14.70 μmol, 0.1 eq) and the resulting reaction mixture was stirred at 100 ° C for 24 hours. LCMS showed that the reaction was complete. The reaction mixture was poured into 20 mL of H2O, followed by 10 mL of EA. Afterwards, the aqueous phase was separated and extracted with EA (10 mL x 2). The combined organic layers were washed successively with water (20 mL x 2) and brine (20 mL x 1), dried over anhydrous Na2SO4, filtered, and concentrated to give a residue. The residue was purified by preparative TLC (SiO2, DCM:MeOH = 10:1). The residue was purified by preparative HPLC (column: Phenomenex Luna C18 100 mm x 30 mm x 5 μm; mobile phase: [H2O (0.2% FA)-ACN]; gradient: 1%-35% B over 8.0 minutes) to give the title product. 2-(4-Chloro-2-methoxy-6-methyl-phenyl)-6-fluoro-1-methyl-N-[(3R)-1-methylpyrrolidin-3-yl]imidazo[4,5-b]pyridin-5-amine (10 mg, 24.76 μmol, 16.85% yield, N / A purity) was obtained as a yellow gum.

[1333] LC-MS(ES + ,m / z):404.2[(M+H) + ].

[1334] 1 H NMR (400MHz, DMSO-d6) δ = 7.82 (d, J = 11.0Hz, 1H), 7.11 (d, J = 6.8Hz, 2H), 6.24 (br d,J=4.4Hz,1H),4.51-4.37(m,1H),3.75(s,3H),3.42(s,3H),2.86(ddd,J=2.6,6.8,9.3Hz,1H),2.69-2 .58(m,2H),2.48-2.42(m,1H),2.29(d,J=3.9Hz,3H),2.26-2.18(m,1H),2.06(s,3H),1.86-1.71(m,1H)

[1335] Step F:

[1336] To a solution of 2-(4-chloro-2-methoxy-6-methyl-phenyl)-6-fluoro-1-methyl-N-[(3R)-1-methylpyrrolidin-3-yl]imidazo[4,5-b]pyridin-5-amine (8 mg, 19.81 μmol, 1 eq) in DCM (0.5 mL) was added BBr (24.81 mg, 99.04 μmol, 9.54 μL, 5.0 eq) at 0 ° C, and the resulting reaction mixture was stirred at 20 ° C for 1 hour. LCMS showed that the reaction was complete. After completion, the solvent was removed by concentration to obtain a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 100 mm x 30 mm x 5 μm; mobile phase: [H2O(0.2% FA)-ACN]; gradient: 1%-20% B over 8.0 minutes) to give the title product. 5-Chloro-2-[6-fluoro-1-methyl-5-[[(3R)-1-methylpyrrolidin-3-yl]amino]imidazo[4,5-b]pyridin-2-yl]-3-methylphenol (4.65 mg, 11.91 μmol, 60.14% yield, 99.87% purity) was obtained as a white solid.

[1337] LC-MS(ES + ,m / z):390.3[(M+H) + ].

[1338] 1 H NMR (400MHz, DMSO-d6) δ = 10.39 (br s, 1H), 7.82 (d, J = 11.0Hz, 1H), 6.89 (brd, J = 19.1Hz, 2H), 6.24 (br d,J=6.4Hz,1H),4.53-4.39(m,1H),3.46(s,3H),2.91(br t,J=8.3Hz,2H),2.67(br s,2H),2.33(br s,3H),2.24(br dd,J=6.2,13.2Hz,1H),2.05(s,3H),1.81(br d,J=6.9Hz,1H).

[1339] Example 49: 5-Chloro-2-(1-methyl-5-(trifluoromethyl)-1H-imidazo[4,5-b]pyridin-2-yl)phenol

[1340]

[1341] Step A:

[1342] To a stirred solution of 2-chloro-6-(trifluoromethyl)pyridin-3-amine (4.0 g, 20.35 mmol) and NEt (5.67 ml, 40.70 mmol) in chloroform (30 mL) was added pivaloyl chloride (2.70 g, 22.39 mmol) at 0°C, and the mixture was stirred at 0°C for 30 minutes. The reaction mixture was heated to 60°C for 2 hours. The reaction process was monitored by TLC. TLC showed that the reaction was complete. The reaction mixture was cooled to room temperature, diluted with DCM (100 mL), washed with water (100 mL), and concentrated to give a crude product. The crude product was purified by Combi flash chromatography. The product was eluted in 10% EtOAc in hexane. The pure fractions were collected and concentrated under reduced pressure to give N-(2-chloro-6-(trifluoromethyl)pyridin-3-yl)pivalamide (5.6 g, 98%) as an oil.

[1343] MS(ESI):281.31[M+H] + .

[1344] Step B:

[1345] To a stirred solution of N-(2-chloro-6-trifluoromethylpyridin-3-yl)-2,2-dimethylpropionamide (4.5 g, 16.03 mmol) in THF (45 mL) was added sodium hydride 57-63% oil dispersion (1.54 g, 32.07 mmol) at 0 ° C, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was cooled, and then methyl iodide (6.83 g, 48.10 mmol) was added, and the mixture was stirred at room temperature for 5 hours. The reaction process was monitored by TLC. TLC showed that the reaction was complete. The reaction mixture was poured into ice / water (200 ml) and extracted with ethyl acetate (2x100 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give N-(2-chloro-6-(trifluoromethyl)pyridin-3-yl)-N-methylpivalamide (4.2 g, 88%) as a light yellow solid.

[1346] MS(ESI):295.08[M+H] + .

[1347] Step C:

[1348] By N-(2-chloro-6-(trifluoromethyl)pyridin-3-yl)-N-methylpivalamide (4.2g, 14.252mmol) in IPA (21mL): acetonitrile (42mL): concentrated HCl (21mL) solution was stirred at room temperature for 2h, and heated to 80 ℃ for 18 hours. The reaction process was monitored by TLC. TLC showed that the reaction was complete. The reaction mixture was cooled to room temperature. The reaction mixture was quenched with saturated sodium bicarbonate aqueous solution (200mL) and extracted with ethyl acetate (2x200 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain a crude product. The crude product was purified by combi flash chromatography. The product was eluted in 10% EtOAc in hexane. Pure fractions were collected and concentrated under reduced pressure to obtain 2-chloro-N-methyl-6-(trifluoromethyl)pyridin-3-amine (2.1g, 70%) as an oil.

[1349] MS(ESI):211.03[M+H] + .

[1350] Step D:

[1351] To a stirred solution of 2-chloro-N-methyl-6-(trifluoromethyl)pyridin-3-amine (500mg, 2.374mmol) and benzophenone imine (860mg, 4.75mmol) in toluene (15mL) was added potassium tert-butoxide (800mg, 7.123mmol), and the mixture was degassed with N2 for 5 minutes. BrettPhos Pd G3 (215mg, 0.24mmol) was added, and the mixture was heated to 100°C for 3 hours. The reaction process was monitored by TLC. TLC showed that the reaction was complete. The reaction mixture was diluted with DCM (30mL) and washed with water (30mL). The organic layer was concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography. The product was eluted in 10% EtOAc in hexane. Pure fractions were collected and concentrated under reduced pressure to obtain the desired compound as an oil (500mg).

[1352] MS(ESI):356.34[M+H] + .

[1353] Step E:

[1354] To the stirring solution of 2-((diphenylmethylene)amino)-N-methyl-6-(trifluoromethyl)pyridine-3-amine (500mg, 1.407mmol) in 1,4-dioxane (10mL) was added 4.0M HCl (3.0ml) in dioxane, and the mixed solution was stirred at room temperature for 18 hours. The reaction process was monitored by TLC. The reaction mixture was diluted with EtOAc (10ml), washed with water, and concentrated to give a crude compound (200mg).

[1355] MS(ESI):192.22[M+H] + .

[1356] Step F:

[1357] To a stirred solution of N3-methyl-6-(trifluoromethyl)pyridine-2,3-diamine (200 mg, 1.046 mmol) and 4-chloro-2-hydroxybenzaldehyde (164 mg, 1.046 mmol) in DMA (5 mL) was added sodium bisulfite (130 mg, 1.256 mmol) at room temperature, and the reaction mixture was stirred at 100 ° C for 16 hours. The reaction process was monitored by TLC. TLC showed that the starting material was consumed. The reaction mixture was diluted with water (10 mL) and extracted with EtOAC (2x10 mL). The combined organic layers were washed with brine solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product as an oil. The crude product was purified by preparative HPLC. Conditions: mobile phase A: 10 mM ammonium bicarbonate aqueous solution, mobile phase B: acetonitrile. Column: INERTIAL, Flow rate: 20 mL / min Method: (T / % of B): -0 / 10, 2 / 10, 11 / 60, 15 / 60, 15.1 / 100, 17 / 100, 17.1 / 10. Solubility: ACN + THF + HO. Temperature: Ambient. Pure fractions were evaporated and freeze-dried to afford 5-chloro-2-(1-methyl-5-(trifluoromethyl)-1H-imidazo[4,5-b]pyridin-2-yl)phenol (22 mg, 6% over 3 steps) as an off-white solid.

[1358] MS(ESI):328.27[M+H] + .

[1359] 1 H NMR (400MHz, DMSO-d6) δ8.32(d,1H),7.81(d,1H),7.53(d,1H),7.05(d,1H),7.01(dd,1H),3.80(s,3H).

[1360] The following examples were prepared according to the preparation of Example 49, Step F using the appropriate aldehyde followed by a deprotection step, as shown in Table 5:

[1361] Table 5

[1362]

[1363] Example 51: 2-(6-(Hydroxymethyl)-5-methoxy-1-methyl-1H-imidazo[4,5-b]pyridin-2-yl)- 5-(Trifluoromethyl)phenol

[1364]

[1365] Step A:

[1366] To the stirring solution of 6-chloro-3-nitropyridine-2-amine (15g, 86.427mmol) in DMF (300mL) in room temperature, add N-bromosuccinimide (16.921g, 95.070mmol), and the mixed solution was stirred at room temperature for 3 hours. Monitor the reaction process by TLC. TLC shows that the reaction is complete. The reaction mixture is quenched with ice-cold water (300mL), and stirred for 30 minutes. Solid is filtered off, washed with water (300mL), and vacuum dried to obtain the desired product (20.0g, 92%), which is a yellow solid.

[1367] MS(ESI):252.1[M+H] + .

[1368] Step B:

[1369] To a stirred solution of 5-bromo-6-chloro-3-nitropyridine-2-amine (20g, 79.224mmol) in ethanol (400mL) and water (100mL) was added iron powder (13.27g, 237.67mmol), followed by an aqueous HCl solution (10mL). The reaction mixture was stirred at 100°C for 2 hours. The reaction process was monitored by LCMS. LC-MS showed that the reaction was complete. The reaction mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure to obtain a crude product. It was purified by silica gel column chromatography. The product was eluted in 15% EtOAc in petroleum ether. Pure fractions were collected and concentrated under reduced pressure to give 5-bromo-6-chloropyridine-2,3-diamine (11.0g, 62%) as a brown solid.

[1370] MS(ESI):222.20[M+H] + .

[1371] Step C:

[1372] Pyridine (12 mL, 148.34 mmol) and benzyl chloroformate (7.02 mL, 49.45 mmol) were added to a stirred solution of 5-bromo-6-chloropyridine-2,3-diamine (11 g, 49.445 mmol) in THF (220 mL) at 0 ° C, and the mixture was stirred at room temperature for 2 hours. The reaction process was monitored by TLC. TLC showed that the reaction was complete. The reaction mixture was diluted with ice / water (200 mL). The pH was adjusted with glacial acetic acid and extracted with EtOAC (2x100 mL). The combined organic layers were washed with saline solution (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product as a brown solid. The crude product was purified by silica gel column chromatography. The product was eluted in 10% EtOAc in hexane. The pure fractions were collected and concentrated under reduced pressure to afford benzyl (2-amino-6-chloropyridin-3-yl)carbamate (16 g, 94%) as a brown solid.

[1373] 1 H NMR (400MHz, CDCl3) δ7.39 (s, 6H), 6.18 (s, 1H), 5.21 (s, 2H), 4.64 (s, 2H).

[1374] Step D:

[1375] 2M LAH (28.04mL, 56.085mmol) was added to the stirred solution of (2-amino-5-bromo-6-chloropyridin-3-yl) benzyl carbamate (5.0g, 14.021mmol) in THF (100mL) at 0°C, and the mixed solution was stirred at room temperature for 60 minutes. The reaction process was monitored by TLC. TLC showed that the starting material was consumed. The reaction mixture was quenched with saturated ammonium chloride (200mL), adjusted to pH 4 with glacial acetic acid, and extracted with EtOAC (2x250 mL). The organic layer merged was washed with saline solution (100mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was a liquid. It was purified by silica gel column chromatography. The product was eluted in 50% EtOAc in hexane. The pure fractions were collected and concentrated under reduced pressure to afford 5-bromo-6-chloro-N3-methylpyridine-2,3-diamine (2 g, 60%) as an off-white solid.

[1376] MS(ESI):236.01[M+H] + .

[1377] Step E:

[1378] To a stirred solution of 5-bromo-6-chloro-N3-methylpyridine-2,3-diamine (2 g, 8.512 mmol) and 2-hydroxy-4-(trifluoromethyl)benzaldehyde (1.78 g, 9.36 mmol) in DMA (30 mL) was added sodium bisulfite (1.33 g, 12.77 mmol) at room temperature, and the reaction mixture was stirred at 100 ° C for 16 hours. The reaction process was monitored by TLC. TLC showed that the reaction was complete. The reaction mixture was cooled to room temperature, diluted with water (100 mL), and stirred for 10 minutes. The solid was filtered off, washed with water (100 mL), and dried in vacuo to give 2-(6-bromo-5-chloro-1-methyl-1H-imidazo[4,5-b]pyridin-2-yl)-5-(trifluoromethyl)phenol (1.9 g, 54.9%) as an off-white solid.

[1379] MS(ESI):406.08[M+H] + .

[1380] Step F:

[1381] To a stirred solution of 2-(6-bromo-5-chloro-1-methyl-1H-imidazo[4,5-b]pyridin-2-yl)-5-(trifluoromethyl)phenol (500 mg, 1.23 mmol) in methanol (10 mL) was added approximately 30% w / w sodium methoxide in methanol (10 mL) at room temperature, and the mixture was stirred at 90 ° C for 48 hours. The reaction process was monitored by LCMS. The reaction mixture was cooled to room temperature, diluted with water (100 mL), and extracted with EtOAC (2x300 mL). The combined organic layers were separated, washed with NaCl solution (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was washed with pentane (10 mL) followed by diethyl ether (10 mL) to give 2-(6-bromo-5-methoxy-1-methyl-1H-imidazo[4,5-b]pyridin-2-yl)-5-(trifluoromethyl)phenol (270 mg, 55%) as an off-white solid.

[1382] MS(ESI):402.20[M+H] + .

[1383] Step G:

[1384] A stirred solution of 2-(6-bromo-5-methoxy-1-methyl-1H-imidazo[4,5-b]pyridin-2-yl)-5-(trifluoromethyl)phenol (500 mg, 1.243 mmol) in N,N-dimethylformamide (10 mL) was purged with nitrogen for 5 minutes. Tetrakis(triphenylphosphine)palladium(0) (287 mg, 0.249 mmol) and zinc cyanide (145 mg, 1.243 mmol) in a sealed tube were added at room temperature, and the mixture was stirred at 110°C for 12 hours. The reaction progress was monitored by LCMS. The reaction mixture was cooled to room temperature, diluted with water (100 mL), and extracted with EtOAC (2x300 mL). The combined organic layers were separated, washed with NaCl solution (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was washed with pentane (20 mL) followed by diethyl ether (15 mL) to give 2-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methoxy-1-methyl-1H-imidazo[4,5-b]pyridine-6-carbonitrile (270 mg, 62%) as an off-white solid.

[1385] MS(ESI):349.25[M+H] + .

[1386] Step H:

[1387] A stirred solution of 2-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methoxy-1-methyl-1H-imidazo[4,5-b]pyridine-6-carbonitrile (270 mg, 0.775 mmol) in a 4N KOH aqueous solution (10 mL) was heated to 100 ° C for 12 hours. The reaction process was monitored by LCMS. The reaction mixture was cooled to room temperature, diluted with water (50 mL), and extracted with EtOAC (2x30 mL). The aqueous layer was acidified with 2N HCl and extracted with EtOAC (2x200 mL). The organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was washed with pentane (25 mL) followed by diethyl ether (15 mL) to give 2-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methoxy-1-methyl-1H-imidazo[4,5-b]pyridine-6-carboxylic acid (250 mg, 88%) as an off-white solid.

[1388] MS(ESI):368.20[M+H] + .

[1389] Step I:

[1390] To a cooled solution of 2-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methoxy-1-methyl-1H-imidazo[4,5-b]pyridine-6-carboxylic acid (250 mg, 0.136 mmol) in THF (10 mL) at 0°C was added borane-tetrahydrofuran complex (10 mL). The reaction mixture was allowed to gradually reach room temperature and stirred at room temperature for 12 hours. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 300 mL). The combined organic layers were separated, washed with NaCl solution (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the crude compound, which was purified by preparative HPLC. Conditions: Mobile phase A: 10 mM aqueous ammonium bicarbonate, mobile phase B: acetonitrile. Column: YMC C18 (25 mm x 150 mm, 10 μm), flow rate: 20 mL / min. Method: (T / % of B): 0 / 20, 2 / 30, 8 / 60. Solvent: acetonitrile + water + THF. Temperature: ambient temperature. Pure fractions were collected, concentrated under reduced pressure, and freeze-dried to yield 2-(6-(hydroxymethyl)-5-methoxy-1-methyl-1H-imidazo[4,5-b]pyridin-2-yl)-5-(trifluoromethyl)phenol (48 mg, 20%).

[1391] MS(ESI):354.21[M+H] + .

[1392] 1 H NMR (400MHz, DMSO-d6) δ11.78(s,...

Claims

1. Compounds of formula (I') or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof; in X' is selected from CH or N; W is selected from N, CH or CR c ; Q is selected from N and C; E is selected from NR a and CR a ; Z is selected from N and C; Where at least one of Q and Z is C, and / or E is CR a ; R c Selected from -C1-C4 alkyl, -O-C1-C4 alkyl, -C1-C4 alkyl-OH, -halo or -C1-C4 alkyl-Hal; R a Selected from -H and -C1-C3 alkyl; R A and R B Each selected from Where R A and R B One of them is And R A and R B The other one is 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, NR d , O, or a key; R d Selected from -C1-C4 alkyl, -C1-C4 alkyl-OH or -C1-C4 alkyl-Hal; R3 is selected from A 4-, 5- or 6-membered heterocycloalkyl group comprising one or two heteroatoms, wherein the heteroatoms are independently selected from N and O, which is 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, -NR5R6 and halo; or An 8-, 9- or 10-membered bicyclic fused heterocycloalkyl containing 1 to 3 heteroatoms, wherein the heteroatoms are independently selected from N and O, which is optionally substituted at any available position with one or two substituents independently selected from the group consisting of C1-C4 alkyl, halo C1-C4 alkyl, hydroxy C1-C4 alkyl, -OH, -NR5R6 and halo; or C3-C6 cycloalkyl, which is optionally substituted by 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; or C1-C6 alkyl, optionally substituted by one or two substituents independently selected from the group consisting of -OH, halo, halo-substituted C1-C4 alkyl, C1-C4 alkoxy, and -NR5R6; R5 and R6 are independently selected from H and C1-C3 alkyl; and m is 0, 1 or 2.

2. The compound according to claim 1, which has the structure of formula (II') or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof; in X' is selected from CH or N; W is selected from N, CH or CR c ; Q is selected from N and C; E is selected from NR a and CR a ; Z is selected from N and C; Where at least one of Q and Z is C, and / or E is CR a ; R c Selected from C1-C4 alkyl, -O-C1-C4 alkyl, C1-C4 alkyl-OH, halo or halogenated C1-C4 alkyl; R d Selected from -C1-C4 alkyl, -C1-C4 alkyl-OH or -C1-C4 alkyl-Hal; R a Selected from -H and -C1-C3 alkyl; 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; R A yes Y is selected from NH, NR d , O, or a key; R3 is selected from A 4-, 5- or 6-membered heterocycloalkyl group comprising one or two heteroatoms, preferably one heteroatom, wherein the heteroatoms are independently selected from N and O, which is 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, -NR5R6 and halo; or An 8-, 9- or 10-membered bicyclic fused heterocycloalkyl containing 1 to 3 heteroatoms, wherein the heteroatoms are independently selected from N and O, which is optionally substituted at any available position with one or two substituents independently selected from the group consisting of C1-C4 alkyl, halo C1-C4 alkyl, hydroxy C1-C4 alkyl, -OH, -NR5R6 and halo; or C3-C6 cycloalkyl, which is optionally substituted by 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; or C1-C6 alkyl, optionally substituted by one or two substituents independently selected from the group consisting of -OH, halo, halo-substituted C1-C4 alkyl, C1-C4 alkoxy, and -NR5R6; R5 and R6 are independently selected from H and C1-C3 alkyl; and m is 0, 1 or 2.

3. The compound according to claim 1, which has the structure of formula (I) or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof; in Q is selected from N and C; E is selected from NR a and CR a ; Z is selected from N and C; Where at least one of Q and Z is C, and / or E is CR a ;and R a Selected from -H and -C1-C3 alkyl; R A and R B Each selected from Where R A and R B One of them is And R A and R B The other one is 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 heteroatoms are independently selected from N and O, which is optionally substituted with one or two substituents independently selected from the following: C1-C4 alkyl, halo-C1-C4 alkyl, hydroxy-C1-C4 alkyl, -OH 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 optionally substituted with one or two substituents independently selected from the group consisting of -OH, halo, halo C1-C4 alkyl, C1-C4 alkoxy, and -NR5R6, wherein R5 and R6 are independently selected from the group consisting of H and C1-C3 alkyl.

4. A compound according to any one of claims 1 to 3, having the structure of formula (II) or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof; in Q is selected from N and C; E is selected from NR a and CR a ; Z is selected from N and C; Where at least one of Q and Z is C, and / or E is CR a ; R a Selected from -H and -C1-C3 alkyl; 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 heteroatoms are independently selected from N and O, which is optionally substituted with one or two substituents independently selected from the following: C1-C4 alkyl, halo-C1-C4 alkyl, hydroxy-C1-C4 alkyl, -OH 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 optionally substituted with one or two substituents independently selected from the group consisting of -OH, halo, halo C1-C4 alkyl, C1-C4 alkoxy, and -NR5R6, wherein R5 and R6 are independently selected from the group consisting of H and C1-C3 alkyl.

5. A compound according to claim 1 or 3, which has the structure of formula (III) or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof; wherein Q, E, Z, R0, R1, R2, R3 and Y are as defined in claim 1 or 3.

6. The compound according to claim 2, which has the structure of formula (II'a) or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof; Where X', W, R0, R1, R2, R3, R a , m and Y are as defined in claim 1.

7. The compound according to claim 2, which has the structure of formula (II'b) or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof; Where X', W, R0, R1, R2, R3, R a , m and Y are as defined in claim 1.

8. A compound according to any one of claims 2 to 4 having the structure of formula (IIa) or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof; Among them, R0, R1, R2, R3, R a and Y is as defined in any one of claims 2 to 4.

9. A compound according to any one of claims 2 to 4 having the structure of formula (IIb) or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof; Among them, R0, R1, R2, R3, R a and Y is as defined in any one of claims 2 to 4.

10. The compound according to claim 2, which has the structure of formula (IV) or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof; Among them, R0, R1, R2, R3, R a、 m and Y are as defined in claim 2.

11. The compound according to claim 2, which has the structure of formula (V) or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof; Among them, R0, R1, R2, R3, R a、 m and Y are as defined in claim 2.

12. A compound according to any one of the preceding claims, wherein R3 is selected from 4-, 5- or 6-membered heterocycloalkyl containing one heteroatom, wherein the heteroatom is N or O, which is optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl; C3-C6 cycloalkyl, optionally substituted by one or two substituents independently selected from the group consisting of C1-C4 alkyl, -OH and halo; Hydroxy C1-C6 alkyl; and C1-C6 alkyl optionally substituted with -NR5R6, wherein R5 and R6 are independently selected from H and C1-C3 alkyl.

13. A compound according to any one of the preceding claims, wherein R3 is selected from Me and CF3; in X is selected from O and NR4; R4 is independently selected from H, halo or C1-C3 alkyl; R5 is independently selected from H or C1-C3 alkyl, preferably H or Me; R6 is selected from C1-C4 alkyl; and n is selected from 0, 1 or 2.

14. A compound according to any one of claims 1 to 10, wherein R3 is selected from Me and CF3; X is selected from O and NR4; R4 is independently selected from H, halo or C1-C3 alkyl; R5 is independently selected from -H or -Me; R6 is selected from C1-C4 alkyl; and n is selected from 0, 1 or 2.

15. A compound according to claim 11, wherein R3 is selected from Me and CF3; in R4 is independently selected from H, F or C1-C3 alkyl; and R5 is methyl; and n is selected from 0, 1 or 2.

16. A compound according to any one of claims 1 to 10, wherein R3 is selected from in X is selected from O and NR4; R4 is independently selected from -H or -C1-C3 alkyl; a is selected from 0 and 1; and n is selected from 0, 1 or 2.

17. A compound according to claim 16, wherein R3 is selected from wherein R4 is independently selected from -H or -C1-C3 alkyl; and n is selected from 0, 1 or 2.

18. A compound according to any one of the preceding claims, wherein R0 is -H or -CH3; R1 is -CF3 or -halo, preferably -Cl; and R2 is -OH.

19. A compound 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.

20. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 19 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.

21. A compound according to any one of claims 1 to 19, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, for use as a medicament.

22. A compound according to any one of claims 1 to 19, 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.

23. The compound for use according to claim 22, wherein the modulation is a reduction and / or inhibition of IL-1[beta].

24. The compound for use according to claim 22, wherein the inflammasome pathway component is the NLRP3 inflammasome.

25. The compound for use according to claim 22 or 24, wherein activation of the NLRP3 inflammasome pathway is inhibited.

26. A compound for use according to any one of claims 22 to 25, wherein the disease, disorder or abnormality is selected from Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, demyelination, viral encephalitis, epilepsy, stroke, atherosclerosis, 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 (IBD) (including Crohn's disease, ulcerative colitis), hepatitis, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, hypertension, myocardial infarction, heart failure, coronary artery disease, oxalate-induced Nephropathy, graft-versus-host disease, type 1 diabetes, type 2 diabetes, edema (DME), geographic atrophy (GA), rheumatoid arthritis, myelodysplastic syndrome, familial Mediterranean fever (FMF), TNF receptor-associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD), hyperimmunoglobulinemia D, periodic fever syndrome (HIDS), interleukin-1 receptor antagonist deficiency (DIRA), Majeed syndrome, pyogenic arthritis pyoderma gangrenosum and acne (PAPA), A20 haploinsufficiency (HA20), PLCG2-related antibody deficiency and immune dysregulation (PLAID), pediatric granulomatous arthritis (PGA), PLCG2-related autoinflammatory disease , 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, skin contact allergy, sunburn, psoriasis, hidradenitis suppurativa (HS), epidermolysis bullosa, acne, eczema, alopecia areata, actinic keratosis, hyperostosis, osteoarthritis syndrome (SAPHO), vitiligo, atopic dermatitis, cutaneous lupus, multiple sclerosis (MS), psoriasis, Behcet's disease, Sjögren's syndrome, Schnitzler syndrome, chronic obstructive pulmonary disorder (COPD), asthma, steroid-resistant asthma, coronary Virus-related inflammatory diseases, including coronavirus-associated respiratory distress syndrome (CARDS), 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, acute kidney disease, chronic kidney disease, lupus nephritis, 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, primary biliary cholangitis, antiphospholipid syndrome, refractory celiac disease, pancreatitis,Autoimmune pancreatitis, mucocutaneous lymph node syndrome, lung cancer metastasis, pancreatic cancer, gastric cancer, myelodysplastic syndrome, leukemia; polymyositis, colitis, helminthic infection, bacterial infection, abdominal aortic aneurysm, wound healing, migraine, depression, psychological stress, pain, neuropathic pain, pericarditis including Dressler syndrome, ischemia-reperfusion injury, frontotemporal dementia, HIV-related neurocognitive disorders, traumatic spinal cord injury, traumatic brain injury, inflammatory pain, chronic pain, neuropathic pain, metastatic cancer-induced bone pain, chemotherapy-induced peripheral neuropathy and migraine; ankylosing spondylitis and cytokine release syndrome; preferably the disorder is selected from Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, demyelination, multiple sclerosis, encephalomyelitis, leukoencephalopathy, viral encephalitis, epilepsy, stroke, traumatic brain injury, spinal cord injury, atherosclerosis, asthma, allergic inflammation, cryptopyrin-associated periodic syndrome (CAPS), gout, inflammatory bowel disease (IBD), non-alcoholic fatty liver disease (NAFLD), Nonalcoholic steatohepatitis (NASH), hypertension, myocardial infarction, oxalate-induced nephropathy, graft-versus-host disease, type 1 diabetes, type 2 diabetes, rheumatoid arthritis, myelodysplastic syndrome, anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV), acute kidney disease, chronic kidney disease, lupus nephritis, anti-glomerular basement membrane (GMB) disease, IgA nephropathy, glomerulonephritis (GN), systemic lupus erythematosus (SLE), focal segmental glomerulosclerosis, minimal change disease (MCD), psoriasis Arthritis, hereditary relapsing fever (HRF), acne, atopic dermatitis, hidradenitis suppurativa (HS) 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).

27. A compound for use according to claim 26, wherein the disease, disorder or abnormality is selected from Alzheimer's disease, Parkinson's disease and multiple sclerosis.

28. A compound for use according to claim 26, 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), chronic kidney disease and gout.

29. A compound for use according to claim 26, wherein the disease, disorder or abnormality is a skin disease, disorder and abnormality selected from the group consisting of hidradenitis suppurativa (HS), dermatitis, psoriasis, skin contact allergies, acne, periodic fever syndrome (HIDS), Sweet syndrome, eczema, skin lesions, burns, wounds, wound healing, trauma, sunburn, actinic keratosis, interleukin 1 receptor antagonist deficiency (DIRA), epidermolysis bullosa, vitiligo, atopic dermatitis, cutaneous lupus and alopecia areata.

30. The compound for use according to claim 29, wherein the disease, disorder or abnormality is hidradenitis suppurativa (HS).

31. Use of a compound according to any one of claims 1 to 19 or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof as an analytical reference or in vitro screening tool.

Images