Pyrolotriazine and imidazotriazine derivatives as regulators of the NLRP3 inflammasome pathway

Abstract

This application relates to pyrrolotriazine and imidazotriazine derivatives of general formula (I) for the treatment, alleviation, or prevention of a group of diseases, disorders, and abnormalities that respond to the modulation or inhibition of the activation of components of the NLRP3 inflammasome pathway. In particular, the components of the inflammasome pathway are the NOD-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3) inflammasome. More specifically, the compounds have the ability to modulate the NLRP3 inflammasome pathway and are suitable for the treatment, alleviation, or prevention of a group of diseases, disorders, and abnormalities that respond to the modulation, particularly the reduction, of IL-I beta and / or IL-I8 levels, such as Alzheimer's disease, Parkinson's disease, non-alcoholic fatty liver disease, and gout. JPEG2025524640000115.jpg56170

Description

Technical Field

[0001] The present invention relates to novel compounds useful for the treatment, alleviation, or prevention of diseases, disorders, or abnormalities responsive to the modulation of components of the NLRP3 inflammasome pathway, particularly the inhibition of its activation. In particular, the components of the inflammasome pathway are the NOD-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3) inflammasome. More specifically, the compounds of the present invention have the ability to modulate the NLRP3 inflammasome pathway, for example, inhibit the activation of the NLRP3 inflammasome pathway. Further, the compounds of the present invention have the ability to modulate, particularly reduce, IL-1 beta and / or IL-18 levels. The present invention relates to novel compounds for the treatment, alleviation, or prevention of diseases, disorders, or abnormalities responsive to the inhibition of the activation of the NLRP3 inflammasome pathway. The present invention relates to novel compounds for the treatment, alleviation, or prevention of diseases, disorders, or abnormalities responsive to the modulation of IL-1 beta and / or IL-18 levels. The present invention relates to pharmaceutical compositions containing said compounds, methods of using said compounds in the treatment of various diseases, disorders, or abnormalities responsive to the above modulation, medicaments containing them, and their use.

Background Art

[0002] The inflammasome protein complex is an important component of inflammatory signaling. These complexes are assembled in response to various danger signals such as molecules derived from infectious pathogens (pathogen-associated molecular patterns, PAMPs), as well as altered host molecules, products of sterile tissue damage and environmental factors (damage-associated molecular patterns, DAMPs). The inflammasome family consists of NALP1-14, IPAF, and NAIP 1-6, and each family member confers specificity for different PAMPs / DAMPs, including nucleic acids, bacterial proteins, metabolites, protein aggregates, and the activity of toxins (Sharma, D. & Kanneganti, T.D. The cell biology of inflammasomes: mechanisms of inflammasome activation and regulation. J. Cell Biol. 213, 617-629 (2016)). The inflammasome typically consists of a sensor (cytosolic pattern recognition receptor, PRR), an adaptor protein called apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and an effector such as the protease caspase-1 (Broz, P.; Dixit, V. M. Inflammasomes: Mechanism of Assembly, Regulation and Signalling. Nat. Rev. Immunol. 2016, 16, 407-420).

[0003] The NLRP3 (NOD-like receptor (NLR) family, pyrin domain-containing protein 3) inflammasome is one of the most well-reported family members. It is a trimeric protein of the NLR family and contains an amino-terminal PYRIN (PYD) domain, a nucleotide-binding NACHT domain, and a carboxy-terminal leucine-rich repeat (LRR) domain. In response to various agents, 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) adapter protein. Polymerization of ASC proteins into large complexes (ASC specks) leads to the activation of caspase-1 effector proteins and their subsequent cleavage of pro-IL-1 beta (β) and pro-IL18 into their active secreted forms, mediating pyroptosis (Heneka et al., 2018 Nat Rev Neurosci). IL-1 beta (β) acts through the IL-1 beta (β) receptor, inducing secondary pro-inflammatory signals, including IL-6 and TNF alpha secretion, attracting and activating 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.

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

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

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

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

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

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

[0010] WO 2016 / 131098, WO 2017 / 140778 and WO 2018 / 215818 relate to sulfonylureas and related compounds, and their use in treating or identifying diseases or conditions responsive to inhibition of NLRP3 or activation of NLRP3 or related components of the inflammatory process.

[0011] WO 2019 / 008025, WO 2019 / 008029, WO 2019 / 034686, WO 2019 / 034688, WO 2019 / 034690, WO 2019 / 034692, WO 2019 / 034693, WO 2019 / 034696, WO 2019 / 034697, WO 2019 / 068772, WO 2019 / 092170, WO 2019 / 092171, and WO 2019 / 092172 relate to novel compounds (e.g., sulfonylureas, sulfonylthioureas, sulfoximine ureas, and sulfoximine thioureas) that are useful in the treatment and prevention of medical disorders and diseases, especially by inhibition of NLRP3.

[0012] WO 2017 / 184604, WO 2017 / 184623, WO 2017 / 184624, WO 2019 / 023145, WO 2019 / 023147, and WO 2019 / 079119 relate to chemical entities useful for treating a condition, disease, or disorder in which a decrease or increase in NLRP3 activity contributes to the pathology and / or symptoms and / or progression of the condition, disease, or disorder in a subject.

[0013] WO 2019 / 211463, WO 2020 / 021447, WO 2021 / 043966, WO 2021 / 239885, WO 2021 / 219784, WO 2021 / 214284, WO 2021 / 209552, and WO 2021 / 209539 disclose compounds for inhibiting NLRP3 and / or the NLRP3 inflammasome pathway.

[0014] WO 2018 / 136890 relates to sulfonylurea and sulfonylthiourea compounds and their use in treating diseases or conditions responsive to modulation of cytokines such as IL-1 beta (β) and IL-18, modulation of NLRP3, or inhibition of activation of NLRP3 or related components of the inflammatory process.

[0015] International Publication Nos. 2018 / 225018 and 2019 / 043610 refer to NLRP3 regulators, and further to the use of novel inhibitor compounds in the treatment of diseases or conditions, and in the treatment of NLRP3-mediated pathologies, and in the treatment of diseases or conditions in which interleukin-1 beta (β) activity and interleukin-18 (IL-18) are involved.

[0016] International Publication No. 2018 / 015445 relates to sulfonylurea compounds having inflammasome inhibitory activity and thus useful in methods for treating a human or animal body.

[0017] International Publication No. 2020 / 018975 discloses sulfonimide amide derivatives defined as inhibitors of interleukin-1 activity and as NLRP3 regulators associated with the inflammatory process.

[0018] International Publication No. 98 / 32733 relates to aryl and heteroaryl substituted sulfonylureas which are inhibitors of interleukin-1 alpha (α) and interleukin-1 beta (β) processing and release.

[0019] International Publication No. 2020 / 018970 discloses sulfonylureas defined as inhibitors of interleukin-1 activity.

[0020] International Publication No. 2020 / 234715 discloses pyridazin-3-ylphenol compounds defined as inhibitors of NOD-like receptor protein 3 (NLRP3) inflammasome activity.

[0021] International Publication No. 2021 / 193897 relates to substituted pyridazine compounds described as having an inhibitory effect on NLRP3 inflammasome activity.

[0022] The crosstalk between the NLRP3 inflammasome pathway and tauopathy has recently been elucidated. Ising et al. (Nature 2019 Nov; 575(7784):669-673) investigated the important role of microglia and NLRP3 inflammasome pathway activation in the development of tauopathy in a tau22 mouse model of frontotemporal dementia (FTD). Genetic ablation of components of the NLRP3 inflammasome pathway in tau22 mice reduced tau aggregation / phosphorylation and improved cognition. Stancu et al. (Acta Neuropathol. 2019; 137(4): 599-617) investigated the role of inflammasome activation in prion-like or templated seeding of tauopathy. Marked inhibition of externally seeded tauopathy was seen in ASC-deficient PS19 tau transgenic mice. Furthermore, chronic intracerebral administration of the NLRP3 inhibitor, MCC950, demonstrated inhibition of externally seeded tauopathy. Finally, ASC deficiency also decreased non-externally seeded tauopathy in PS19 mice.

[0023] There is a need to identify and develop specific NLRP3 inflammasome pathway inhibitors and / or regulators of interleukin activity having beneficial pharmacological and / or physiological and / or physicochemical properties.

[0024] The present invention surprisingly provides compounds of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie) which have been found to be capable of modulating components of the NLRP3 inflammasome pathway, in particular of inhibiting the activation of components of the NLRP3 inflammasome pathway such as the NLRP3 inflammasome. Thus, such compounds are useful in the treatment of diseases, disorders or abnormalities which respond to modulation of components of the NLRP3 inflammasome pathway and / or to modulation of IL-1 beta and / or IL-18 levels which normally result in pathological inflammation.

Prior Art Documents

Patent Documents

[0025] [Patent Document 1] International Publication No. 2016 / 131098 [Patent Document 2] International Publication No. 2017 / 140778 [Patent Document 3] International Publication No. 2018 / 215818 [Patent Document 4] International Publication No. 2019 / 008025 [Patent Document 5] International Publication No. 2019 / 008029 [Patent Document 6] International Publication No. 2019 / 034686 [Patent Document 7] International Publication No. 2019 / 034688 [Patent Document 8] International Publication No. 2019 / 034690 [Patent Document 9] International Publication No. 2019 / 034692 [Patent Document 10] International Publication No. 2019 / 034693 [Patent Document 11] International Publication No. 2019 / 034696 [Patent Document 12] International Publication No. 2019 / 034697 [Patent Document 13] International Publication No. 2019 / 068772 [Patent Document 14] International Publication No. 2019 / 092170 [Patent Document 15] International Publication No. 2019 / 092171 [Patent Document 16] International Publication No. 2019 / 092172 [Patent Document 17] International Publication No. 2017 / 184604 [Patent Document 18] International Publication No. 2017 / 184623 [Patent Document 19] International Publication No. 2017 / 184624 [Patent Document 20] International Publication No. 2019 / 023145

Patent Document 21

Patent Document 22

Patent Document 23

Patent Document 24

Patent Document 25

Patent Document 26

Patent Document 27

Patent Document 28

Patent Document 29

Patent Document 30

Patent Document 31

Patent Document 32

Patent Document 33

Patent Document 34

Patent Document 35

Patent Document 36

Patent Document 37

Patent Document 38

Patent Document 39

Non-Patent Document

[0026] [Non-Patent Document 1] Sharma, D. & Kanneganti, T.D. The cell biology of inflammasomes: mechanisms of inflammasome activation and regulation. J. Cell Biol. 213, 617-629 (2016) [Non-Patent Document 2] Broz, P.; Dixit, V. M. Inflammasomes: Mechanism of Assembly, Regulation and Signalling. Nat. Rev. Immunol. 2016, 16, 407-420 [Non-Patent Document 3] Heneka et al., 2018 Nat Rev Neurosci. [Non-Patent Document 4] Heneka et al., Nat. Rev. Neurosci. 2018 Oct;19(10):610-621 [Non-Patent Document 5] Mangan et al., Nat. Rev. Drug Discov. 2018 Aug; 17(8):588-606 [Non-Patent Document 6] Baldwin, A. G., Brough, D. & Freeman, S. Inhibiting the NLRP3 inflammasome pathway: a chemical perspective. J. Med. Chem. 59, 1691-1710 (2016) [Non-Patent Document 7] Ising et al., Nature 2019 Nov; 575(7784):669-673 [Non-Patent Document 8] Remington's Pharmaceutical Sciences, 18th Edition (edited by Alfonso R. Gennaro; Mack Publishing Company, Easton, PA, 1990) [Non-Patent Document 9] Remington: the Science and Practice of Pharmacy, 19th Edition (Lippincott, Williams & Wilkins, 1995)

Non-Patent Document 10

Non-Patent Document 11

Non-Patent Document 12

Non-Patent Document 13

Non-Patent Document 14

Non-Patent Document 15

Non-Patent Document 16

Non-Patent Document 17

Non-Patent Document 18

Non-Patent Document 19

Non-Patent Document 20

Non-Patent Document 21

Non-Patent Document 22

Summary of the Invention

Means for Solving the Problems

[0027] In view of the above, the present invention provides a compound that can be used in the treatment, alleviation, or prevention of diseases, disorders, or abnormalities that respond to the regulation, particularly inhibition, of components of the NLRP3 inflammasome pathway, or that respond to the regulation, particularly reduction, of IL-1 beta and / or IL-18 levels.

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

[0029] Within the scope of one aspect, a compound of formula (I),

[0030]

Chemical formula

[0031] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof is provided herein [wherein, Z1 and Z2 are each independently selected from N and C, when Z1 is N, Z2 is C, and when Z1 is C, Z2 is N, V, X, and E are each independently selected from N and CR a and at least one of V, X, and E is CR a ; R a is independently selected from the group consisting of -H, -C1-C3 alkyl, -CF₃, and halo, R0 is selected from the group consisting of -H, C1-C3 alkyl, and halo, R1 is selected from the group consisting of -CF₃, -OCF₃, -OCHF₂, and halo, R2 is selected from the group consisting of -OH, -H, and -CF₃, Y is selected from NH and O, R3 is a 4-, 5-, or 6-membered heterocycloalkyl containing one or two heteroatoms, preferably one heteroatom, which is N, and 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, and halo; A 5- or 6-membered aryl or heteroaryl containing one or two heteroatoms which are N, the 5- or 6-membered aryl or heteroaryl being optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, hydroxy C1-C4 alkyl, halo C1-C4 alkyl, -CN, and halo; C3-C6 cycloalkyl optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, halo C1-C4 alkyl, hydroxy C1-C4 alkyl, -OH, and halo; and C1-C6 alkyl substituted with one or two substituents independently selected from the group consisting of -OH, halo, halo C1-C4 alkyl, and C1-C4 alkoxy selected from the group consisting of.

[0032] Within the scope of the preferred embodiments, compounds of formula (I'),

[0033]

Chemical formula

[0034] or stereoisomers, racemic mixtures, tautomers, polymorphs, pharmaceutically acceptable salts, prodrugs, hydrates, or solvates thereof are provided herein [wherein, Z1 is N, Z2 is C, V, X, and E are each independently selected from N and CR a and at least one of V, X, and E is CR a such that, R a is independently selected from the group consisting of -H, -C1-C3 alkyl, -CF3, and halo, R0 is selected from the group consisting of -H, C1-C3 alkyl, and halo, R1 is selected from the group consisting of -CF3, -OCF3, -OCHF2, and halo, R2 is selected from the group consisting of -OH, -H, and -CF3, Y is selected from NH and O, R3 is a 4-, 5-, or 6-membered heterocycloalkyl containing one or two heteroatoms which is N, preferably a 4-, 5-, or 6-membered heterocycloalkyl containing one heteroatom, 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; a 5- or 6-membered aryl or heteroaryl containing one or two heteroatoms which is N, optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, hydroxy C1-C4 alkyl, halo C1-C4 alkyl, -CN, and halo; a C3-C6 cycloalkyl 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 a C1-C6 alkyl substituted with one or two substituents independently selected from the group consisting of -OH, halo, halo C1-C4 alkyl, and C1-C4 alkoxy selected from the group consisting of].

[0035] In one aspect, there is provided a compound of formula (Ib),

[0036]

Chemical formula

[0037] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof [wherein, E is selected from N and CR a and R ais selected from the group consisting of -H, -C1-C3 alkyl, -CF3, and halo; R0 is selected from the group consisting of -H, C1-C3 alkyl, and halo; R1 is selected from the group consisting of -CF3, -OCF3, -OCHF2, and halo; R2 is selected from the group consisting of -OH, -H, and -CF3; Y is selected from NH and O; R3 is a 4-, 5-, or 6-membered heterocycloalkyl containing one or two heteroatoms which are N, preferably a 4-, 5-, or 6-membered heterocycloalkyl containing one heteroatom, 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; a 5- or 6-membered aryl or heteroaryl containing one or two heteroatoms which are N, optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, hydroxy C1-C4 alkyl, halo C1-C4 alkyl, -CN, and halo; a 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 a C1-C6 alkyl substituted with one or two substituents independently selected from the group consisting of -OH, halo, halo C1-C4 alkyl, and C1-C4 alkoxy selected from the group consisting of].

[0038] In another aspect, a compound of formula (Ic),

[0039]

Chemical formula

[0040] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof is provided [wherein, E is selected from N and CR a and is selected from R a is selected from the group consisting of -H, -C1-C3 alkyl, -CF3, and halo R0 is selected from the group consisting of -H, C1-C3 alkyl, and halo R1 is selected from the group consisting of -CF3, -OCF3, -OCHF2, and halo R2 is selected from the group consisting of -OH, -H, and -CF3 Y is selected from NH and O R3 is a 4-, 5-, or 6-membered heterocycloalkyl containing one or two heteroatoms which is N, preferably a 4-, 5-, or 6-membered heterocycloalkyl containing one heteroatom, 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, and halo; a 5- or 6-membered aryl or heteroaryl containing one or two heteroatoms which is N, which is optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, hydroxy C1-C4 alkyl, halo C1-C4 alkyl, -CN, and halo; a 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 a C1-C6 alkyl substituted with one or two substituents independently selected from the group consisting of -OH, halo, halo C1-C4 alkyl, and C1-C4 alkoxy selected from the group consisting of].

[0041] In another aspect, a compound of formula (Ie),

[0042]

Chem.

[0043] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof is provided [wherein, X is selected from N and CR a and is selected from R a is selected from the group consisting of -C1-C3 alkyl, -CF3, and halo, R0 is selected from the group consisting of -H, C1-C3 alkyl, and halo, R1 is selected from the group consisting of -CF3, -OCF3, -OCHF2, and halo, R2 is selected from the group consisting of -OH, -H, and -CF3, Y is selected from NH and O, R3 is a 4-, 5-, or 6-membered heterocycloalkyl containing one or two heteroatoms which are N, preferably a 4-, 5-, or 6-membered heterocycloalkyl containing one heteroatom, 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, and halo; a 5- or 6-membered aryl or heteroaryl containing one or two heteroatoms which are N, which is optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, hydroxy C1-C4 alkyl, halo C1-C4 alkyl, -CN, and halo; a 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 substituted with one or two substituents independently selected from the group consisting of -OH, halo, halo C1-C4 alkyl, and C1-C4 alkoxy selected from the group consisting of].

[0044] Within the scope of one aspect, a compound of formula (Ia),

[0045]

Chemical formula

[0046] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof is provided [wherein, E is selected from N and CR a selected, R a is selected from the group consisting of -H, -C1-C3 alkyl, and -CF3, R0 is selected from the group consisting of -H, C1-C3 alkyl, and halo, R1 is selected from the group consisting of -CF3, -OCF3, -OCHF2, and halo, R2 is selected from the group consisting of -OH, -H, and -CF3, Y is selected from NH and O, R3 is, a 4-membered, 5-membered, or 6-membered heterocycloalkyl containing one or two heteroatoms which are N, preferably a 4-membered, 5-membered, or 6-membered heterocycloalkyl containing one heteroatom, 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; a 5-membered or 6-membered aryl or heteroaryl containing one or two heteroatoms which are N, optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, hydroxy C1-C4 alkyl, halo C1-C4 alkyl, -CN, and halo; C3-C6 cycloalkyl optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, halo C1-C4 alkyl, hydroxy C1-C4 alkyl, -OH, and halo; and C1-C6 alkyl substituted with one or two substituents independently selected from the group consisting of -OH, halo, halo C1-C4 alkyl, and C1-C4 alkoxy selected from the group consisting of].

[0047] In another aspect, there is provided a compound of formula (Id),

[0048]

Chemical formula

[0049] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof [wherein, X is selected from N and CR a selected from, R a is selected from the group consisting of -H, -C1-C3 alkyl, -CF3, and halo, R0 is selected from the group consisting of -H, C1-C3 alkyl, and halo, R1 is selected from the group consisting of -CF3, -OCF3, -OCHF2, and halo, R2 is selected from the group consisting of -OH, -H, and -CF3, Y is selected from NH and O, R3 is a 4-, 5-, or 6-membered heterocycloalkyl containing one or two heteroatoms, preferably one heteroatom, which is N, and 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, and halo; A 5- or 6-membered aryl or heteroaryl containing one or two heteroatoms which are N, optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, hydroxy C1-C4 alkyl, halo C1-C4 alkyl, -CN, and halo; C3-C6 cycloalkyl optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, halo C1-C4 alkyl, hydroxy C1-C4 alkyl, -OH, and halo; and C1-C6 alkyl substituted with one or two substituents independently selected from the group consisting of -OH, halo, halo C1-C4 alkyl, and C1-C4 alkoxy selected from the group consisting of.

[0050] Within the scope of the present invention, any reference to a compound of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie), or to any of their preferred embodiments, is also intended to refer to their stereoisomers, or racemic mixtures, or tautomers, or polymorphs, or pharmaceutically acceptable salts, or prodrugs, or hydrates, or solvates.

[0051] Compounds of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie), or their stereoisomers, racemic mixtures, tautomers, polymorphs, pharmaceutically acceptable salts, prodrugs, hydrates, or solvates are suitable for the treatment, alleviation, or prevention of diseases, disorders, or abnormalities that respond to the modulation, particularly inhibition, of components of the NLRP3 inflammasome pathway, or that respond to the modulation, particularly reduction, of IL-1 beta and / or IL-18 levels. In particular, the components of the inflammasome pathway are the NLRP3 inflammasome. Activation of the NLRP3 inflammasome pathway can lead to the formation of ASC specks, cleavage and activation of caspase-1 and caspase-8 and subsequent activation and release of IL-1 beta, IL-18, gasdermin D cleavage and pore formation, pyroptosis, and release of IL-1 alpha, IL-33, IL-17, and high mobility group box (HMGB) proteins. Compounds of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie), or their stereoisomers, racemic mixtures, tautomers, polymorphs, pharmaceutically acceptable salts, prodrugs, hydrates, or solvates have the ability to modulate, particularly reduce, IL-1 beta and / or IL-18 levels.

[0052] Compounds of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie), or their stereoisomers, racemic mixtures, tautomers, polymorphs, pharmaceutically acceptable salts, prodrugs, hydrates, or solvates modulate components of the NLRP3 inflammasome pathway, particularly when the components of the inflammasome pathway are the NLRP3 inflammasome, and particularly show high ability in inhibiting the activation of such components. Due to such unique design features, these compounds exhibit properties such as modulation or inhibition of the activation of the NLRP3 inflammasome pathway, and may be successful medicaments for the treatment, alleviation, or prevention of diseases, disorders, and abnormalities that respond to the modulation or inhibition of components of the NLRP3 inflammasome pathway, such as Alzheimer's disease, Parkinson's disease, CAPS, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and gout.

[0053] In another embodiment, the present invention relates to a pharmaceutical composition comprising a compound of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie), or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof, optionally comprising at least one pharmaceutically acceptable carrier, diluent, adjuvant, or excipient.

[0054] In another embodiment, the present invention relates to a compound of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie), or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof, for use as a medicament.

[0055] In yet another embodiment, the present invention relates to a compound of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie), or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof, for use in the treatment, alleviation, or prevention of a disease, disorder, or abnormality responsive to modulation of a component of the NLRP3 inflammasome pathway, particularly inhibition of activation of said component, and / or responsive to modulation of IL-1 beta and / or IL-18 levels, particularly reduction thereof.

[0056] Another embodiment relates to the use of a compound of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie), or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof, for the manufacture of a medicament for treating, alleviating, or preventing a disease, disorder, or abnormality responsive to modulation of a component of the NLRP3 inflammasome pathway, particularly inhibition of activation of said component, and / or responsive to modulation of IL-1 beta and / or IL-18 levels, particularly reduction thereof.

[0057] In yet another embodiment, the present invention is directed to a method of treating, alleviating, or preventing a disease, disorder, or abnormality that responds to modulation of components of the NLRP3 inflammasome pathway, particularly inhibition of activation of its components, or to modulation of IL-1 beta and / or IL-18 levels, particularly a decrease, the method comprising administering to a subject (e.g., a patient) in need thereof a therapeutically effective amount of a compound of formula (I'), (I), (Ia), (Ib), (Ic), (Id), or (Ie), or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof.

[0058] Also subject to the present invention is a pharmaceutical composition comprising a combination of a compound of formula (I'), (I), (Ia), (Ib), (Ic), (Id), or (Ie), or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof, and at least one other bioactive compound different from the compound of formula (I'), (I), (Ia), (Ib), (Ic), (Id), or (Ie), or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof, optionally comprising at least one pharmaceutically acceptable carrier, diluent, adjuvant, or excipient.

[0059] In particular, the at least one other bioactive compound can be a compound used in the treatment of a disease, disorder, or abnormality associated with a disease targeting different pathophysiological mechanisms, such as, but not limited to, an anti-amyloid beta antibody, an anti-tau antibody, a small molecule amyloid beta inhibitor, a small molecule tau aggregation inhibitor, an anti-alpha-synuclein antibody or a small molecule alpha-synuclein aggregation inhibitor, an anti-TDP-43 antibody or a small molecule anti-TDP-43 aggregation inhibitor. When the compounds of the present invention are used in combination with at least one other bioactive compound, the dosage of each compound may be different from the dosage when the compound is used as monotherapy.

[0060] Additional embodiments relate to the use of a compound of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie), or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof as an analytical standard or an in vitro screening tool.

[0061] The present invention is described below.

Brief Description of the Drawings

[0062]

Figure 1

Modes for Carrying Out the Invention

[0063] The present invention relates to a compound of formula (I'), and compounds of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie) (including their stereoisomers, racemic mixtures, tautomers, polymorphs, pharmaceutically acceptable salts, prodrugs, hydrates, or solvates).

[0064] For the compound of formula (I), any of the definitions of R0, R1, R2, R3, R a , E, V, X and Y, whenever R0, R1, R 2、 R3, R a , E, V, X, and / or Y are used, apply equally to the compounds of formula (I'), (Ia), (Ib), (Ic), (Id) and (Ie).

[0065] The present invention relates to a compound of formula (I') as defined below,

[0066]

Chemical Formula

[0067] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof [wherein, Z1 is N, Z2 is C, V, X, and E are each independently selected from N and CR a and at least one of V, X, and E is CR a and R a is independently selected from the group consisting of -H, -C1-C3 alkyl, -CF3, and halo, R0 is selected from the group consisting of -H, C1-C3 alkyl, and halo, R1 is selected from the group consisting of -CF3, -OCF3, -OCHF2, and halo, R2 is selected from the group consisting of -OH, -H, and -CF3, Y is selected from NH and O, R3 is a 4-, 5-, or 6-membered heterocycloalkyl having one or two heteroatoms which are N, preferably a 4-, 5-, or 6-membered heterocycloalkyl having one heteroatom which is N, 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; a 5- or 6-membered aryl or a heteroaryl having one or two heteroatoms which are N, optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, hydroxy C1-C4 alkyl, halo C1-C4 alkyl, -CN, and halo; a 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 substituted with one or two substituents independently selected from the group consisting of -OH, halo, halo C1-C4 alkyl, and C1-C4 alkoxy selected from the group consisting of].

[0068] The present invention relates to a compound of formula (I) as defined below,

[0069]

Chemical formula

[0070] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof [wherein, Z1 and Z2 are each independently selected from N and C, when Z1 is N, Z2 is C, and when Z1 is C, Z2 is N, V, X, and E are each independently selected from N and CR a and at least one of V, X, and E is CR a wherein R a is selected from the group consisting of -H, -C1-C3 alkyl, -CF3, and halo, R0 is selected from the group consisting of -H, C1-C3 alkyl, and halo, R1 is selected from the group consisting of -CF3, -OCF3, -OCHF2, and halo, R2 is selected from the group consisting of -OH, -H, and -CF3, Y is selected from NH and O, R3 is a 4-membered, 5-membered, or 6-membered heterocycloalkyl containing one or two heteroatoms, preferably one heteroatom, 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, and halo; A 5- or 6-membered aryl or heteroaryl containing one or two heteroatoms which are N, optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, hydroxy C1-C4 alkyl, halo C1-C4 alkyl, -CN, and halo; C3-C6 cycloalkyl optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, halo C1-C4 alkyl, hydroxy C1-C4 alkyl, -OH, and halo; and C1-C6 alkyl substituted with one or two substituents independently selected from the group consisting of -OH, halo, halo C1-C4 alkyl, and C1-C4 alkoxy selected from the group consisting of.

[0071] In a preferred embodiment, R0 is selected from -H and C1-C3 alkyl. In a preferred embodiment, R0 is -H. In another preferred embodiment, R0 is C1-C3 alkyl, preferably methyl or ethyl, more preferably methyl.

[0072] 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.

[0073] In another embodiment, R1 is halo. When R1 is halo, the halogen (halo) is preferably chloro.

[0074] In a preferred embodiment, R2 is -OH or H, more preferably -OH. In another embodiment, R2 is -H. In another embodiment, R2 is -CF3.

[0075] In a preferred embodiment, R0 is -H, R1 is selected from -CF3, -OCF3, and -OCHF2, and R2 is -OH or -H. In a preferred embodiment, R0 is -H, R1 is -CF3, and R2 is -OH.

[0076] In a preferred embodiment, R3 is a 4-, 5-, or 6-membered heterocycloalkyl containing one or two heteroatoms which is N, preferably a 4-, 5-, or 6-membered heterocycloalkyl containing one heteroatom, 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; a 6-membered aryl or heteroaryl containing one or two heteroatoms which is N, optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, hydroxy C1-C4 alkyl, halo C1-C4 alkyl, -CN, and halo, a 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 a C1-C6 alkyl substituted with one or two substituents independently selected from the group consisting of -OH, halo, halo C1-C4 alkyl, and C1-C4 alkoxy selected from the group consisting of.

[0077] R3 is

[0078]

Chemical formula

[0079] selected from the group consisting of [wherein R4 is independently selected from -H or -C1-C3 alkyl, and n is selected from 0, 1, or 2].

[0080] Preferably, R3 is

[0081]

Chemical formula

[0082] selected from the group consisting of [wherein, R4 is independently selected from -H or -C1-C3 alkyl, n is selected from 0, 1, or 2].

[0083] In a preferred embodiment, R3 is selected from a 5-membered or 6-membered heterocycloalkyl containing 1 or 2 heteroatoms, preferably 1 heteroatom, which is N. In a preferred embodiment, R3 is a 6-membered heterocycloalkyl containing 1 heteroatom which is N. The 5-membered or 6-membered heterocycloalkyl may be substituted with 1 or 2 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 at any position available in the heterocyclic group.

[0084] In a preferred embodiment, R3 is

[0085]

Chemical formula

[0086] [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.

[0087] In a preferred embodiment, R3 is

[0088]

Chemical formula

[0089] 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.

[0090] In another preferred embodiment, R3 is

[0091] [ka]

[0092] 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, whereby R3 is

[0093] [ka]

[0094] is.

[0095] In another preferred embodiment, R3 is

[0096] [ka]

[0097] is.

[0098] In another embodiment, R3 is selected from 6-membered aryl or heteroaryl containing one or two heteroatoms which are N. The 6-membered aryl or heteroaryl may be substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, hydroxy C1-C4 alkyl, halo C1-C4 alkyl, -CN, and halo. The substituents may be at any available position on the aryl or heteroaryl group.

[0099] In one embodiment, R3 is 6-membered heteroaryl containing two heteroatoms N. The 6-membered heteroaryl may be substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, hydroxy C1-C4 alkyl, halo C1-C4 alkyl, -CN, and halo. In one embodiment, R3 is

[0100]

Chemical formula

[0101] selected from the group consisting of.

[0102] In another embodiment, R3 is C3-C6 cycloalkyl, preferably cyclopropyl or cyclobutyl. The C3-C6 cycloalkyl 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. The substituents may be at any available position on the cycloalkyl group.

[0103] In a preferred embodiment, R3 is

[0104]

Chemical formula

[0105] 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

[0106]

Chemical formula

[0107] is. In another preferred embodiment, R3 is

[0108]

Chemical formula

[0109] is.

[0110] In another preferred embodiment, R3 is C1-C6 alkyl, preferably C1-C3 alkyl, such as methyl, ethyl, or propyl. The alkyl may be substituted with one or two substituents independently selected from the group consisting of -OH, halo, halo C1-C4 alkyl, and C1-C4 alkoxy. In a preferred embodiment, R3 is hydroxy C1-C6 alkyl (i.e., C1-C6 alkyl substituted with -OH), more preferably hydroxy C1-C3 alkyl, and hydroxyethyl is preferred.

[0111] In a preferred embodiment, R3 is

[0112]

Chemical formula

[0113] is [wherein, n is 0, 1, or 2]. In another preferred embodiment, R3 is

[0114]

Chemical formula

[0115] wherein, n is 0, 1, or 2.

[0116] In some embodiments, one of V, X, and E is CR a wherein, R a is as defined above. In a preferred embodiment, two of V, X, and E are CR a wherein, R a is as defined above. In another preferred embodiment, V, X, and E are each CR a wherein, R a is as defined above.

[0117] In a preferred embodiment, X is CR a wherein, R a is selected from H and -C1-C3 alkyl. In a preferred embodiment, X is CH.

[0118] In a preferred embodiment, Z1 is N. In a preferred embodiment, Z1 is N, V is CH, and X and E are independently selected from N and CR a wherein, R a is as defined above.

[0119] In another preferred embodiment, Z1 is N, and V, X, and E are all CR a wherein, R a is as defined above. In some preferred embodiments, Z1 is N, and at least two of V, X, and E are CR a wherein, R a is as defined above. In a preferred embodiment, Z1 is N, and V, X, and E are all CH.

[0120] In another preferred embodiment, Z1 is N, E is N, and V and X are each CR a wherein, Ra is as defined above. In one embodiment, Z1 is N, E is N, and both V and X are CH. In another preferred embodiment, Z1 is N, V is N, and E and X are each CR a where R a is as defined above. In one embodiment, Z1 is N, V is N, and both E and X are CH. In another embodiment, Z1 is N, X is N, and V and E are each CR a where R a is as defined above. In another embodiment, Z1 is N, X is N, and both V and E are CH.

[0121] In a preferred embodiment, Z1 is N and Z2 is C.

[0122] In a more preferred embodiment: Z1 is N, V is N, X and E are CR a where Z2 is C, or Z1 is N, V, X, E are CR a where Z2 is C, or Z1 is N, E is N, X and V are CR a where Z2 is C.

[0123] In other aspects, Z2 is N. In one embodiment, Z2 is N, E is CH, and V and X are each independently selected from N and CR a where R a is as defined above. In one embodiment, Z2 is N and V, X, and E are all CR a where R a is as defined above. In some embodiments, Z2 is N and at least two of V, X, and E are CR a where R a is as defined above. In one embodiment, Z2 is N and V, X, and E are all CH. In another embodiment, Z2 is N, E is N, and V and X are each CRa wherein R a is as defined above]. In one embodiment, Z2 is N, E is N, and both V and X are CH. In another embodiment, Z2 is N, V is N, and E and X are each CR a wherein R a is as defined above]. In one embodiment, Z2 is N, V is N, and both E and X are CH. In another embodiment, Z2 is N, X is N, and V and E are each CR a wherein R a is as defined above]. In another embodiment, Z2 is N, X is N, and both V and E are CH.

[0124] In an embodiment, a compound of formula (I) having formula (Ia),

[0125]

Chemical formula

[0126] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof is provided [wherein, E is selected from N and CR a , R a is selected from the group consisting of -H, -C1-C3 alkyl, and -CF3, and R0, R1, R2, R3, and Y are as defined in any of the above embodiments].

[0127] In a preferred embodiment of the compound of formula (Ia), E is N. In another preferred embodiment of the compound of formula (Ia), E is CR a wherein R a is as defined above]. In a preferred embodiment of the compound of formula (Ia), E is CH.

[0128] In a preferred embodiment, R0 is selected from -H and C1-C3 alkyl. In a preferred embodiment, R0 is -H. In another preferred embodiment, R0 is C1-C3 alkyl, preferably methyl or ethyl, more preferably methyl.

[0129] 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.

[0130] In another embodiment, R1 is halo. When R1 is halo, the halogen (halo) is preferably chloro.

[0131] In a preferred embodiment, R2 is -OH. In another embodiment, R2 is -H. In another embodiment, R2 is -CF3.

[0132] In a preferred embodiment, R0 is -H, R1 is selected from -CF3, -OCF3, and -OCHF2, and R2 is -OH or -H. In a preferred embodiment, R0 is -H, R1 is -CF3, and R2 is -OH.

[0133] In a preferred embodiment, R3 is a 4-, 5-, or 6-membered heterocycloalkyl containing one or two heteroatoms which are N, preferably a 4-, 5-, or 6-membered heterocycloalkyl containing one heteroatom, 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; a 6-membered aryl or heteroaryl containing one or two heteroatoms which are N, optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, hydroxy C1-C4 alkyl, halo C1-C4 alkyl, -CN, and halo, C3-C6 cycloalkyl optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, halo C1-C4 alkyl, hydroxy C1-C4 alkyl, -OH, and halo; and C1-C6 alkyl substituted with one or two substituents independently selected from the group consisting of -OH, halo, halo C1-C4 alkyl and C1-C4 alkoxy is independently selected from the group consisting of.

[0134] In a preferred embodiment, R3 is selected from 5- or 6-membered heterocycloalkyl containing one or two heteroatoms which are N, preferably one heteroatom. In a preferred embodiment, R3 is 6-membered heterocycloalkyl containing one heteroatom which is N. The 5- or 6-membered heterocycloalkyl 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. The substituents may be at any position available in the heterocyclic group.

[0135] In a preferred embodiment, R3 is

[0136]

Chemical formula

[0137] wherein [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.

[0138] In a preferred embodiment, R3 is

[0139]

Chemical formula

[0140] 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.

[0141] In another preferred embodiment, R3 is

[0142]

Chemical formula

[0143] as follows.

[0144] In another preferred embodiment, R3 is

[0145]

Chemical formula

[0146] 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, whereby R3 is

[0147]

Chemical formula

[0148] as follows.

[0149] In another embodiment, R3 is selected from heteroaryl containing one or two heteroatoms which are 6-membered aryl or N. The 6-membered aryl or heteroaryl may be substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, hydroxy C1-C4 alkyl, halo C1-C4 alkyl, -CN, and halo. The substituents may be at any available position on the aryl or heteroaryl group.

[0150] In one embodiment, R3 is a 6-membered heteroaryl containing two heteroatoms N. The 6-membered heteroaryl may be substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, hydroxy C1-C4 alkyl, halo C1-C4 alkyl, -CN, and halo. In one embodiment, R3 is

[0151]

Chemical formula

[0152] selected from the group consisting of.

[0153] In another embodiment, R3 is C3-C6 cycloalkyl, preferably cyclopropyl or cyclobutyl. The C3-C6 cycloalkyl 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. The substituents may be at any available position on the cycloalkyl group.

[0154] In a preferred embodiment, R3 is

[0155]

Chemical formula

[0156] 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

[0157]

Chemical formula

[0158] is. In another preferred embodiment, R3 is

[0159]

Chemical formula

[0160] is.

[0161] In another preferred embodiment, R3 is C1-C6 alkyl, preferably C1-C3 alkyl, such as methyl, ethyl, or propyl. The alkyl may be substituted with one or two substituents independently selected from the group consisting of -OH, halo, halo C1-C4 alkyl, and C1-C4 alkoxy. In a preferred embodiment, R3 is hydroxy C1-C6 alkyl (i.e., C1-C6 alkyl substituted with -OH), more preferably hydroxy C1-C3 alkyl, preferably hydroxyethyl.

[0162] In a preferred embodiment, R3 is

[0163]

Chemical formula

[0164] is [wherein, n is 0, 1, or 2]. In another preferred embodiment, R3 is

[0165]

Chemical formula

[0166] wherein n is 0, 1, or 2.

[0167] In a preferred embodiment, a compound of formula (I) or (I') having formula (Ib),

[0168]

Chemical formula

[0169] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof is provided [wherein Ra, R0, R1, R2, R3, E and Y are as defined in any of the above embodiments].

[0170] In a preferred embodiment of the compound of formula (Ib), E is N. In another preferred embodiment of the compound of formula (Ib), E is CR a wherein R a is as defined above. In a preferred embodiment of the compound of formula (Ib), E is CH.

[0171] In a preferred embodiment, R0 is selected from -H and C1-C3 alkyl. In a preferred embodiment, R0 is -H. In another preferred embodiment, R0 is C1-C3 alkyl, preferably methyl or ethyl, more preferably methyl.

[0172] 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.

[0173] In another embodiment, R1 is halo. When R1 is halo, the halogen (halo) is preferably chloro.

[0174] In a preferred embodiment, R2 is -OH. In another embodiment, R2 is -H. In another embodiment, R2 is -CF3.

[0175] In a preferred embodiment, R0 is -H, R1 is selected from -CF3, -OCF3, and -OCHF2, and R2 is -OH or -H. In a preferred embodiment, R0 is -H, R1 is -CF3, and R2 is -OH.

[0176] In a preferred embodiment, R3 is a 4-, 5-, or 6-membered heterocycloalkyl containing one or two heteroatoms which are N, preferably one heteroatom, and being 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; a 6-membered aryl or heteroaryl containing one or two heteroatoms which are N, and being optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, hydroxy C1-C4 alkyl, halo C1-C4 alkyl, -CN, and halo; a 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 a C1-C6 alkyl substituted with one or two substituents independently selected from the group consisting of -OH, halo, halo C1-C4 alkyl, and C1-C4 alkoxy independently selected from the group consisting of.

[0177] In a preferred embodiment, R3 is selected from 5- or 6-membered heterocycloalkyl containing one or two heteroatoms which are N, preferably 5- or 6-membered heterocycloalkyl containing one heteroatom which is N. In a preferred embodiment, R3 is 6-membered heterocycloalkyl containing one heteroatom which is N. The 5- or 6-membered heterocycloalkyl 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. The substituents may be at any available position on the heterocyclic group.

[0178] In a preferred embodiment, R3 is

[0179]

Chemical formula

[0180] wherein [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.

[0181] In a preferred embodiment, R3 is

[0182]

Chemical formula

[0183] wherein [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.

[0184] In another preferred embodiment, R3 is

[0185]

Chemical formula

[0186] is.

[0187] In another preferred embodiment, R3 is

[0188]

Chemical formula

[0189] 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, whereby R3 is

[0190]

Chemical formula

[0191] is.

[0192] In another embodiment, R3 is selected from 6-membered aryl or heteroaryl containing one or two heteroatoms which is N. The 6-membered aryl or heteroaryl may be substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, hydroxy C1-C4 alkyl, halo C1-C4 alkyl, -CN, and halo. The substituents may be at any position available on the aryl or heteroaryl group.

[0193] In one embodiment, R3 is 6-membered heteroaryl containing two heteroatoms N. The 6-membered heteroaryl may be substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, hydroxy C1-C4 alkyl, halo C1-C4 alkyl, -CN, and halo. In one embodiment, R3 is

[0194]

Chemical formula

[0195] is selected from the group consisting of.

[0196] In another embodiment, R3 is C3-C6 cycloalkyl, preferably cyclopropyl or cyclobutyl. C3-C6 cycloalkyl 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. The substituents may be at any available position on the cycloalkyl group.

[0197] In a preferred embodiment, R3 is

[0198]

Chemical formula

[0199] wherein [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

[0200]

Chemical formula

[0201] is. In another preferred embodiment, R3 is

[0202]

Chemical formula

[0203] is.

[0204] In another preferred embodiment, R3 is selected from C1-C6 alkyl, preferably C1-C3 alkyl, such as methyl, ethyl, or propyl. The alkyl may be substituted with one or two substituents independently selected from the group consisting of -OH, halo, halo C1-C4 alkyl, and C1-C4 alkoxy. In a preferred embodiment, R3 is hydroxy C1-C6 alkyl (i.e., C1-C6 alkyl substituted with -OH), more preferably hydroxy C1-C3 alkyl, preferably hydroxyethyl.

[0205] In a preferred embodiment, R3 is

[0206]

Chemical formula

[0207] wherein n is 0, 1, or 2. In another preferred embodiment, R3 is

[0208]

Chemical formula

[0209] wherein n is 0, 1, or 2.

[0210] In another preferred embodiment, a compound of formula (I) or (I') having formula (Ic),

[0211]

Chemical formula

[0212] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof is provided [wherein, E is selected from N and CR a and R ais selected from the group consisting of -H, -C1-C3 alkyl, -CF3, and halo; R0 is selected from the group consisting of -H, C1-C3 alkyl, and halo; R1 is selected from the group consisting of -CF3, -OCF3, -OCHF2, and halo; R2 is selected from the group consisting of -OH, -H, and -CF3; Y is selected from NH and O; R3 is a 4-, 5-, or 6-membered heterocycloalkyl having one or two heteroatoms which are N, preferably a 4-, 5-, or 6-membered heterocycloalkyl having one heteroatom, 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, and halo; a 5- or 6-membered aryl or heteroaryl having one or two heteroatoms which are N, which is optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, hydroxy C1-C4 alkyl, halo C1-C4 alkyl, -CN, and halo; a 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 a C1-C6 alkyl substituted with one or two substituents independently selected from the group consisting of -OH, halo, halo C1-C4 alkyl, and C1-C4 alkoxy selected from the group consisting of].

[0213] In a preferred embodiment of the compound of formula (Ic), E is CR a wherein R a is as defined above]. In a preferred embodiment of the compound of formula (Ic), E is CH. In another embodiment of the compound of formula (Ic), E is N.

[0214] In a preferred embodiment, R0 is selected from -H and C1-C3 alkyl. In a preferred embodiment, R0 is -H. In another preferred embodiment, R0 is C1-C3 alkyl, preferably methyl or ethyl, more preferably methyl.

[0215] 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.

[0216] In another embodiment, R1 is halo. When R1 is halo, the halogen (halo) is preferably chloro.

[0217] In a preferred embodiment, R2 is -OH. In another embodiment, R2 is -H. In another embodiment, R2 is -CF3.

[0218] In a preferred embodiment, R0 is -H, R1 is selected from -CF3, -OCF3, and -OCHF2, and R2 is -OH or -H. In a preferred embodiment, R0 is -H, R1 is -CF3, and R2 is -OH.

[0219] In a preferred embodiment, R3 is a 4-membered, 5-membered, or 6-membered heterocycloalkyl containing one or two heteroatoms which are N, preferably a 4-membered, 5-membered, or 6-membered heterocycloalkyl containing one heteroatom, 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, and halo; a 6-membered aryl or heteroaryl containing one or two heteroatoms which are N, which is optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, hydroxy C1-C4 alkyl, halo C1-C4 alkyl, -CN, and halo; C3-C6 cycloalkyl optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, halo C1-C4 alkyl, hydroxy C1-C4 alkyl, -OH, and halo; and C1-C6 alkyl substituted with one or two substituents independently selected from the group consisting of -OH, halo, halo C1-C4 alkyl and C1-C4 alkoxy is independently selected from the group consisting of.

[0220] In a preferred embodiment, R3 is selected from 5- or 6-membered heterocycloalkyl containing one or two heteroatoms, preferably one heteroatom, which is N. In a preferred embodiment, R3 is 6-membered heterocycloalkyl containing one heteroatom which is N. The 5- or 6-membered heterocycloalkyl 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. The substituents may be at any available position on the heterocyclic group.

[0221] In a preferred embodiment, R3 is

[0222]

Chemical formula

[0223] wherein [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.

[0224] In a preferred embodiment, R3 is

[0225]

Chemical formula

[0226] 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.

[0227] In another preferred embodiment, R3 is

[0228]

Chemical formula

[0229] as follows.

[0230] In another preferred embodiment, R3 is

[0231]

Chemical formula

[0232] 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, whereby R3 is

[0233]

Chemical formula

[0234] as follows.

[0235] In another embodiment, R3 is selected from 6-membered aryl or heteroaryl containing one or two heteroatoms which are N. The 6-membered aryl or heteroaryl may be substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, hydroxy C1-C4 alkyl, halo C1-C4 alkyl, -CN, and halo. The substituents may be at any available position on the aryl or heteroaryl group.

[0236] In one embodiment, R3 is a 6-membered heteroaryl containing two heteroatoms N. The 6-membered heteroaryl may be substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, hydroxy C1-C4 alkyl, halo C1-C4 alkyl, -CN, and halo. In one embodiment, R3 is

[0237]

Chemical formula

[0238] selected from the group consisting of.

[0239] In another embodiment, R3 is C3-C6 cycloalkyl, preferably cyclopropyl or cyclobutyl. The C3-C6 cycloalkyl 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. The substituents may be at any available position on the cycloalkyl group.

[0240] In a preferred embodiment, R3 is

[0241]

Chemical formula

[0242] 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

[0243]

Chemical formula

[0244] is. In another preferred embodiment, R3 is

[0245]

Chemical formula

[0246] is.

[0247] In another preferred embodiment, R3 is selected from C1-C6 alkyl, preferably C1-C3 alkyl, such as methyl, ethyl, or propyl. The alkyl may be substituted with one or two substituents independently selected from the group consisting of -OH, halo, halo C1-C4 alkyl, and C1-C4 alkoxy. In a preferred embodiment, R3 is hydroxy C1-C6 alkyl (i.e., C1-C6 alkyl substituted with -OH), more preferably hydroxy C1-C3 alkyl, preferably hydroxyethyl.

[0248] In a preferred embodiment, R3 is

[0249]

Chemical formula

[0250] is [wherein, n is 0, 1, or 2]. In another preferred embodiment, R3 is

[0251]

Chemical formula

[0252] wherein n is 0, 1, or 2.

[0253] In another embodiment, a compound of formula (I) having formula (Id),

[0254]

Chemical formula

[0255] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof is provided [wherein Ra, R0, R1, R2, R3, X, and Y are as defined in any of the above embodiments].

[0256] In a preferred embodiment of the compound of formula (Id), X is CR a wherein R a is as defined above. In a preferred embodiment of the compound of formula (Ic), X is CH. In another embodiment of the compound of formula (Ic), X is N.

[0257] In a preferred embodiment, R0 is selected from -H and C1-C3 alkyl. In a preferred embodiment, R0 is -H. In another preferred embodiment, R0 is C1-C3 alkyl, preferably methyl or ethyl, more preferably methyl.

[0258] 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.

[0259] In another embodiment, R1 is halo. When R1 is halo, the halogen (halo) is preferably chloro.

[0260] In a preferred embodiment, R2 is -OH. In another embodiment, R2 is -H. In another embodiment, R2 is -CF3.

[0261] In a preferred embodiment, R0 is -H, R1 is selected from -CF3, -OCF3, and -OCHF2, and R2 is -OH or -H. In a preferred embodiment, R0 is -H, R1 is -CF3, and R2 is -OH.

[0262] In a preferred embodiment, R3 is a 4-membered, 5-membered, or 6-membered heterocycloalkyl containing one or two heteroatoms that are N, preferably one heteroatom, and being 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; a 6-membered aryl or heteroaryl containing one or two heteroatoms that are N, and being optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, hydroxy C1-C4 alkyl, halo C1-C4 alkyl, -CN, and halo; a 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 a C1-C6 alkyl substituted with one or two substituents independently selected from the group consisting of -OH, halo, halo C1-C4 alkyl, and C1-C4 alkoxy is independently selected from the group consisting of.

[0263] In a preferred embodiment, R3 is selected from a 5- or 6-membered heterocycloalkyl containing one or two heteroatoms which are N, preferably one heteroatom. In a preferred embodiment, R3 is a 6-membered heterocycloalkyl containing one heteroatom which is N. The 5- or 6-membered heterocycloalkyl 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. The substituents may be at any available position in the heterocyclic group.

[0264] In a preferred embodiment, R3 is

[0265]

Chemical formula

[0266] wherein [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.

[0267] In a preferred embodiment, R3 is

[0268]

Chemical formula

[0269] wherein [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.

[0270] In another preferred embodiment, R3 is

[0271]

Chemical formula

[0272] is.

[0273] In another preferred embodiment, R3 is

[0274]

Chemical formula

[0275] 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, whereby R3 is

[0276]

Chemical formula

[0277] is.

[0278] In another embodiment, R3 is selected from 6-membered aryl or heteroaryl containing one or two heteroatoms which is N. The 6-membered aryl or heteroaryl may be substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, hydroxy C1-C4 alkyl, halo C1-C4 alkyl, -CN, and halo. The substituents may be at any position available in the aryl or heteroaryl group.

[0279] In one embodiment, R3 is 6-membered heteroaryl containing two heteroatoms N. The 6-membered heteroaryl may be substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, hydroxy C1-C4 alkyl, halo C1-C4 alkyl, -CN, and halo. In one embodiment, R3 is

[0280]

Chemical formula

[0281] is selected from the group consisting of.

[0282] In another embodiment, R3 is C3-C6 cycloalkyl, preferably cyclopropyl, or cyclobutyl. C3-C6 cycloalkyl 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. The substituents may be at any available position on the cycloalkyl group.

[0283] In a preferred embodiment, R3 is

[0284]

Chemical formula

[0285] wherein [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

[0286]

Chemical formula

[0287] is. In another preferred embodiment, R3 is

[0288]

Chemical formula

[0289] is.

[0290] In another preferred embodiment, R3 is selected from C1-C6 alkyl, preferably C1-C3 alkyl, such as methyl, ethyl, or propyl. The alkyl may be substituted with one or two substituents independently selected from the group consisting of -OH, halo, halo C1-C4 alkyl, and C1-C4 alkoxy. In a preferred embodiment, R3 is hydroxy C1-C6 alkyl (i.e., C1-C6 alkyl substituted with -OH), more preferably hydroxy C1-C3 alkyl, preferably hydroxyethyl.

[0291] In a preferred embodiment, R3 is

[0292]

Chemical formula

[0293] wherein n is 0, 1, or 2. In another preferred embodiment, R3 is

[0294]

Chemical formula

[0295] wherein n is 0, 1, or 2.

[0296] In another preferred embodiment, a compound of formula (I) or (I') having formula (Ie),

[0297]

Chemical formula

[0298] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof is provided [wherein, X is selected from N and CR a and R ais selected from the group consisting of -C1-C3 alkyl, -CF3, and halo; R0 is selected from the group consisting of -H, C1-C3 alkyl, and halo; R1 is selected from the group consisting of -CF3, -OCF3, -OCHF2, and halo; R2 is selected from the group consisting of -OH, -H, and -CF3; Y is selected from NH and O; R3 is a 4-, 5-, or 6-membered heterocycloalkyl containing one or two heteroatoms which is N, preferably a 4-, 5-, or 6-membered heterocycloalkyl containing one heteroatom which is N, 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; a 5- or 6-membered aryl or heteroaryl containing one or two heteroatoms which is N, optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, hydroxy C1-C4 alkyl, halo C1-C4 alkyl, -CN, and halo; a 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 a C1-C6 alkyl substituted with one or two substituents independently selected from the group consisting of -OH, halo, halo C1-C4 alkyl, and C1-C4 alkoxy selected from the group consisting of].

[0299] In a preferred embodiment of the compound of formula (Ie), X is N. In another preferred embodiment of the compound of formula (Ie), X is CR a is.

[0300] In a preferred embodiment, R0 is selected from -H and C1-C3 alkyl. In a preferred embodiment, R0 is -H. In another preferred embodiment, R0 is C1-C3 alkyl, preferably methyl or ethyl, more preferably methyl.

[0301] 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.

[0302] In another embodiment, R1 is halo. When R1 is halo, the halogen (halo) is preferably chloro.

[0303] In a preferred embodiment, R2 is -OH. In another embodiment, R2 is -H. In another embodiment, R2 is -CF3.

[0304] In a preferred embodiment, R0 is -H, R1 is selected from -CF3, -OCF3, and -OCHF2, and R2 is -OH or -H. In a preferred embodiment, R0 is -H, R1 is -CF3, and R2 is -OH.

[0305] In a preferred embodiment, R3 is a 4-membered, 5-membered, or 6-membered heterocycloalkyl containing one or two heteroatoms which are N, preferably a 4-membered, 5-membered, or 6-membered heterocycloalkyl containing one heteroatom, 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; a 6-membered aryl or heteroaryl containing one or two heteroatoms which are N, optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, hydroxy C1-C4 alkyl, halo C1-C4 alkyl, -CN, and halo; C3-C6 cycloalkyl optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, halo C1-C4 alkyl, hydroxy C1-C4 alkyl, -OH, and halo; and C1-C6 alkyl substituted with one or two substituents independently selected from the group consisting of -OH, halo, halo C1-C4 alkyl and C1-C4 alkoxy is independently selected from the group consisting of.

[0306] In a preferred embodiment, R3 is selected from 5- or 6-membered heterocycloalkyl containing one or two, preferably one, heteroatom which is N. In a preferred embodiment, R3 is 6-membered heterocycloalkyl containing one heteroatom which is N. The 5- or 6-membered heterocycloalkyl 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. The substituents may be at any available position on the heterocyclic group.

[0307] In a preferred embodiment, R3 is

[0308]

Chemical formula

[0309] wherein [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.

[0310] In a preferred embodiment, R3 is

[0311]

Chemical formula

[0312] 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.

[0313] In another preferred embodiment, R3 is

[0314]

Chemical formula

[0315] as follows.

[0316] In another embodiment, R3 is

[0317]

Chemical formula

[0318] 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, whereby R3 is

[0319]

Chemical formula

[0320] as follows.

[0321] In another embodiment, R3 is selected from 6-membered aryl or heteroaryl containing one or two heteroatoms which are N. The 6-membered aryl or heteroaryl may be substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, hydroxy C1-C4 alkyl, halo C1-C4 alkyl, -CN, and halo. The substituents may be at any available position on the aryl or heteroaryl group.

[0322] In one embodiment, R3 is 6-membered heteroaryl containing two heteroatoms N. The 6-membered heteroaryl may be substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, hydroxy C1-C4 alkyl, halo C1-C4 alkyl, -CN, and halo. In one embodiment, R3 is

[0323]

Chemical formula

[0324] selected from the group consisting of.

[0325] In another embodiment, R3 is C3-C6 cycloalkyl, preferably cyclopropyl or cyclobutyl. The C3-C6 cycloalkyl 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. The substituents may be at any available position on the cycloalkyl group.

[0326] In a preferred embodiment, R3 is

[0327]

Chemical formula

[0328] 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

[0329]

Chemical formula

[0330] is. In another preferred embodiment, R3 is

[0331]

Chemical formula

[0332] is.

[0333] In another preferred embodiment, R3 is selected from C1-C6 alkyl, preferably C1-C3 alkyl, such as methyl, ethyl, or propyl. The alkyl may be substituted with one or two substituents independently selected from the group consisting of -OH, halo, halo C1-C4 alkyl, and C1-C4 alkoxy. In a preferred embodiment, R3 is hydroxy C1-C6 alkyl (i.e., C1-C6 alkyl substituted with -OH), more preferably hydroxy C1-C3 alkyl, preferably hydroxyethyl.

[0334] In a preferred embodiment, R3 is

[0335]

Chemical formula

[0336] is [wherein, n is 0, 1, or 2]. In another preferred embodiment, R3 is

[0337]

Chemical formula

[0338] wherein n is 0, 1, or 2.

[0339] In another embodiment, the present invention relates to the following compounds of formula (I') or (I),

[0340]

Chemical formula

[0341] or their stereoisomers, racemic mixtures, tautomers, polymorphs, pharmaceutically acceptable salts, prodrugs, hydrates, or solvates.

[0342] The present invention further relates to a pharmaceutical composition comprising a compound of formula (I'), (I), (Ia), (Ib), (Ic), (Id), or (Ie) as defined in the present invention, or its stereoisomers, racemic mixtures, tautomers, polymorphs, pharmaceutically acceptable salts, prodrugs, hydrates, or solvates, optionally containing at least one pharmaceutically acceptable carrier, diluent, adjuvant, or excipient.

[0343] In one embodiment, the pharmaceutical composition comprises a compound of formula (I'), (I), (Ia), (Ib), (Ic), (Id), or (Ie) as defined in the present invention, or its stereoisomers, racemic mixtures, tautomers, polymorphs, pharmaceutically acceptable salts, prodrugs, hydrates, or solvates, optionally containing at least one pharmaceutically acceptable carrier, diluent, adjuvant, or excipient.

[0344] It is recognized that various embodiments of the present invention are described herein, and that the features specified in each embodiment may be combined with other specified features to provide another embodiment of the present invention.

[0345] The present invention relates to a compound of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie) as defined herein, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, for use as a medicament.

[0346] The present invention relates to a compound of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie) as defined herein, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, for use in the treatment, alleviation or prevention of a disease, disorder or abnormality responsive to modulation of a component of the NLRP3 inflammasome pathway, particularly inhibition of activation of said component, and / or responsive to modulation of IL-1 beta and / or IL-18 levels, particularly reduction thereof. In one embodiment, the modulation is reduction and / or inhibition of IL-1 beta and / or IL-1 beta levels. In particular, the modulation is reduction and / or inhibition of IL-1 beta.

[0347] In another embodiment, the present invention relates to a compound of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie) as defined herein, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, for use in a method of reducing and / or inhibiting IL-1 beta, particularly inhibiting IL-1 beta.

[0348] The present invention relates to a compound of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie) as defined herein, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, for use in the treatment, alleviation or prevention of a disease, disorder or abnormality responsive to modulation of a component of the NLRP3 inflammasome pathway, particularly inhibition of activation of said component.

[0349] The present invention relates to the use of a compound of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie) as defined herein, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, for the treatment, alleviation or prevention of diseases, disorders or abnormalities responsive to the modulation of the NLRP3 inflammasome pathway, in particular the inhibition of its activation.

[0350] The present invention relates to the use of a compound of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie) as defined herein, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, for the treatment, alleviation or prevention of diseases, disorders or abnormalities responsive to the modulation of IL-1 beta and / or IL-18 levels, in particular the reduction thereof.

[0351] In other words, the present invention is a method for treating, alleviating or preventing a disease, disorder or abnormality responsive to the modulation of components of the NLRP3 inflammasome pathway, in particular the inhibition of the activation of its components, and / or responsive to the modulation of IL-1 beta and / or IL-18 levels, in particular the reduction thereof, the method comprising administering to a subject (e.g., a patient) in need thereof a therapeutically effective amount of a compound of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie) as defined herein, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof.

[0352] In one embodiment, the present invention is a method for treating, preventing or alleviating a disease, disorder or abnormality responsive to the modulation of components of the NLRP3 inflammasome pathway, in particular the inhibition of the activation of its components, the method comprising administering to a subject (e.g., a patient) in need thereof a therapeutically effective amount of a compound of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie) as defined herein, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof.

[0353] The present invention further relates to a method of treating, preventing, or alleviating a disease, disorder, or abnormality that responds to modulation of the NLRP3 inflammasome pathway, particularly inhibition of its activation, comprising administering to a subject (e.g., a patient) in need thereof a therapeutically effective amount of a compound of formula (I'), (I), (Ia), (Ib), (Ic), (Id), or (Ie) as defined in the present invention, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof.

[0354] In one embodiment, the present invention relates to a method of treating, preventing, or alleviating a disease, disorder, or abnormality that responds to modulation of IL-1 beta and / or IL-18 levels, particularly a decrease, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I'), (I), (Ia), (Ib), (Ic), (Id), or (Ie) as defined in the present invention, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof.

[0355] The present invention relates to the use of a compound of formula (I'), (I), (Ia), (Ib), (Ic), (Id), or (Ie) as defined in the present invention, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof, for the manufacture of a medicament. In another embodiment, the present invention relates to the use of a compound of formula (I'), (I), (Ia), (Ib), (Ic), (Id), or (Ie) as defined in the present invention, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof, for the manufacture of a medicament for treating, alleviating, or preventing a disease, disorder, or abnormality that responds to modulation of a component of the NLRP3 inflammasome pathway, particularly inhibition of the activation of the component, and / or responds to modulation of IL-1 beta and / or IL-18 levels, particularly a decrease. In one embodiment, the disease, disorder, or abnormality is selected from the list disclosed herein.

[0356] The present invention relates to the use of a compound of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie) as defined herein, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, for the manufacture of a medicament for treating, alleviating or preventing a disease, disorder or abnormality responsive to the modulation of components of the NLRP3 inflammasome pathway, particularly inhibition of the activation of such components.

[0357] The present invention relates to the use of a compound of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie) as defined herein, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, for the manufacture of a medicament for treating, alleviating or preventing a disease, disorder or abnormality responsive to the modulation of the NLRP3 inflammasome pathway, particularly inhibition of the activation of such components.

[0358] The present invention relates to the use of a compound of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie) as defined herein, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, for the manufacture of a medicament for treating, alleviating or preventing a disease, disorder or abnormality responsive to the modulation of IL-1 beta and / or IL-18 levels, particularly a decrease.

[0359] The present invention relates to the use of a compound of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie) as defined in the present invention, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, for the manufacture of a medicament for reducing and / or inhibiting IL-1 beta and / or IL-1 beta levels. In one embodiment, the present invention relates to the use of a compound of the present invention as defined herein for the manufacture of a medicament for reducing and / or inhibiting IL-1 beta. In another embodiment, the present invention relates to the use of a compound of the present invention as defined herein for the manufacture of a medicament for reducing IL-1 beta. <>

[0360] In one embodiment, the present invention relates to the use of a compound of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie) as defined in the present invention, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, for the treatment, alleviation or prevention of tauopathy by modulating components of the inflammasome pathway, particularly by modulating the NLRP3 inflammasome pathway.

[0361] In another embodiment, the disease, disorder or abnormality responds to the modulation of one or more of IL-1β, IL-17, IL-18, IL-1α, IL-37, IL-33, and Th17 cells, preferably IL-1β and IL-18.

[0362] 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, such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, cryopyrin-associated periodic syndrome (CAPS), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and gout.

[0363] In another embodiment, the disease, disorder, or abnormality is a disease, disorder, or abnormality of the immune system. In an 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 can be a disease, disorder, or condition of the skin. The disease, disorder, or abnormality can be a disease, disorder, or condition of the cardiovascular system. The disease, disorder, or abnormality or condition can be cancer, a tumor, or other malignancy. The disease, disorder, or abnormality or condition can be a disease, disorder, or abnormality of the renal system. The disease, disorder, or abnormality or condition can be a disease, disorder, or abnormality of the gastrointestinal tract. The disease, disorder, or abnormality or condition can be a disease, disorder, or abnormality of the respiratory system. The disease, disorder, or abnormality or condition can be a disease, disorder, or abnormality of the endocrine system. The disease, disorder, or abnormality or condition can be a disease, disorder, or abnormality associated with the liver.

[0364] In one embodiment, diseases, disorders, or abnormalities that respond to the modulation of components of the NLRP3 inflammasome pathway, particularly the inhibition of the activation of its components, include Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, demyelination, viral encephalitis, epilepsy, stroke, cerebral hemorrhage, atherosclerosis, asthma, allergic inflammation, cryopyrin-associated periodic syndrome (CAPS), Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), neonatal-onset multisystem inflammatory disease (NOMID), gout, pseudogout, inflammatory bowel disease, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, hypertension, myocardial infarction, oxalate-induced nephropathy, graft-versus-host disease, type 1 diabetes, type 2 diabetes, rheumatoid arthritis, myelodysplastic syndrome, familial Mediterranean fever (FMF), TNF receptor-associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD), hyperimmunoglobulin D syndrome, periodic fever syndrome (HIDS), interleukin 1 receptor antagonist deficiency (DIRA), Magid syndrome, acne, pyogenic arthritis - pyoderma gangrenosum - acne (PAPA), A20 haploinsufficiency (HA20), PLCG2-related antibody deficiency and immune dysregulation (PLAID), pediatric granulomatous arthritis (PGA), PLCG2-related autoinflammation, antibody deficiency and immune dysregulation (APLAID), B cell immunodeficiency, periodic fever, sideroblastic anemia with developmental delay (SIFD), chronic non-bacterial osteomyelitis (CNO), Sweet syndrome, chronic recurrent multifocal osteomyelitis (CRMO), synovitis, pustulosis, acne, eczema, alopecia areata, actinic keratosis, hyperostosis, synovitis, acne, pustulosis, hyperostosis, osteitis syndrome (SAPHO), multiple sclerosis (MS), psoriasis, Behçet's disease, Sjögren's syndrome, Schnitzler's syndrome, chronic obstructive pulmonary disease (COPD), steroid-resistant asthma, asbestosis, silicosis, cystic fibrosis, motor neuron disease, Huntington's disease, cerebral malaria, brain injury from pneumococcal meningitis, obesity, age-related macular degeneration (AMD), corneal infection, uveitis, dry eye, chronic kidney disease, diabetic nephropathy, alcoholic liver disease, skin contact hypersensitivity, sunburn, osteoarthritis, systemic juvenile idiopathic arthritis, adult-onset Still's disease, relapsing polychondritis, chikungunya virus, Ross River virus, influenza, HIV, coronavirus, dengue fever, Zika virus, hidradenitis suppurativa (HS), lung cancer metastasis, pancreatic cancer, gastric cancer, myelodysplastic syndrome, leukemia;It can be selected from polymyositis, colitis, helminth infection, bacterial infection, abdominal aortic aneurysm, wound healing, depression, psychological stress, pericarditis including Dressler syndrome, ischemia-reperfusion injury, frontotemporal dementia, HIV-related neurocognitive disorder, coronavirus-related inflammatory disease, traumatic brain and spinal cord injury, inflammatory pain, chronic pain, neuropathic pain, metastatic cancer-induced bone pain, chemotherapy-induced peripheral neuropathy, migraine, and amyloidosis (including AL amyloidosis, AA amyloidosis, ATTR amyloidosis, hereditary amyloidosis (including apolipoprotein A-I (AApoAI), apolipoprotein A-II (AApoAII), gelsolin (AGel), fibrinogen (AFib), and lysozyme (ALys)), beta-2 microglobulin amyloidosis, and iAPP amyloidosis).;

[0365] In one embodiment, diseases, disorders, or abnormalities that respond to the regulation of components of the NLRP3 inflammasome pathway, particularly inhibition of the activation of those components, include Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, demyelination, viral encephalitis, epilepsy, stroke, atherosclerosis, asthma, allergic inflammation, cryopyrin-associated periodic syndrome (CAPS), Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), neonatal-onset multisystem inflammatory disease (NOMID), gout, pseudogout, inflammatory bowel disease, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, hypertension, myocardial infarction, oxalate-induced nephropathy, graft-versus-host disease, type 1 diabetes, type 2 diabetes, rheumatoid arthritis, myelodysplastic syndrome, familial Mediterranean fever (FMF), TNF receptor-associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD), hyperimmunoglobulin D syndrome, periodic fever syndrome (HIDS), interleukin 1 receptor antagonist deficiency (DIRA), Majid syndrome, acne, pyogenic arthritis, pyoderma gangrenosum, acne (PAPA), A20 haploinsufficiency (HA20), PLCG2-related antibody deficiency and immune dysregulation (PLAID), pediatric granulomatous arthritis (PGA), PLCG2-related autoinflammation, antibody deficiency and immune dysregulation (APLAID), B cell immunodeficiency, periodic fever, sideroblastic anemia with developmental delay (SIFD), chronic non-bacterial osteomyelitis (CNO), Sweet's syndrome, chronic recurrent multifocal osteomyelitis (CRMO), synovitis, pustulosis, acne, eczema, alopecia areata, actinic keratosis, hyperostosis, synovitis, acne, pustulosis, hyperostosis, osteitis syndrome (SAPHO), multiple sclerosis (MS), psoriasis, Behçet's disease, Sjögren's syndrome, Schnitzler's syndrome, chronic obstructive pulmonary disease (COPD), steroid-resistant asthma, asbestosis, silicosis, cystic fibrosis, motor neuron disease, Huntington's disease, cerebral malaria, brain injury from pneumococcal meningitis, obesity, age-related macular degeneration (AMD), corneal infection, uveitis, dry eye, chronic kidney disease, diabetic nephropathy, alcoholic liver disease, skin contact hypersensitivity, sunburn, osteoarthritis, systemic juvenile idiopathic arthritis, adult-onset Still's disease, relapsing polychondritis, chikungunya virus, Ross River virus, influenza, HIV, coronavirus, dengue fever, Zika virus, hidradenitis suppurativa (HS), lung cancer metastasis, pancreatic cancer, gastric cancer, myelodysplastic syndrome, leukemia;It can be selected from polymyositis, colitis, helminth infection, bacterial infection, abdominal aortic aneurysm, wound healing, depression, psychological stress, pericarditis including Dressler syndrome, ischemia-reperfusion injury, frontotemporal dementia, HIV-associated neurocognitive disorder, coronavirus-associated inflammatory disease states, and traumatic brain injury.;

[0366] Preferably, the disease, disorder, or abnormality is selected from Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, demyelination, viral encephalitis, epilepsy, stroke, chronic pain, atherosclerosis, asthma and allergic inflammation, cryopyrin-associated periodic syndrome (CAPS), gout, inflammatory bowel disease, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), hypertension, myocardial infarction, oxalate-induced nephropathy, graft-versus-host disease, type 1 diabetes, type 2 diabetes, rheumatoid arthritis, myelodysplastic syndrome, antineutrophil cytoplasmic antibody-associated vasculitis (AAV), lupus nephritis, anti-glomerular basement membrane (GMB) disease, IgA nephropathy, glomerulonephritis (GN), systemic lupus erythematosus (SLE), focal segmental glomerulosclerosis, minimal change disease (MCD), psoriatic arthritis, and hereditary recurrent fever (HRF).

[0367] 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, cryopyrin-associated periodic syndrome (CAPS), gout, inflammatory bowel disease, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), hypertension, myocardial infarction, oxalate-induced nephropathy, graft-versus-host disease, type 1 diabetes, type 2 diabetes, rheumatoid arthritis, myelodysplastic syndrome, antineutrophil cytoplasmic antibody-associated vasculitis (AAV), lupus nephritis, anti-glomerular basement membrane (GMB) disease, IgA nephropathy, glomerulonephritis (GN), systemic lupus erythematosus (SLE), focal segmental glomerulosclerosis, minimal change disease (MCD), psoriatic arthritis, and hereditary recurrent fever (HRF).

[0368] More preferably, the disease, disorder, or abnormality is selected from Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, demyelination, viral encephalitis, epilepsy, stroke, atherosclerosis, asthma and allergic inflammation, cryopyrin-associated periodic syndrome (CAPS), gout, inflammatory bowel disease, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), hypertension, myocardial infarction, oxalate-induced nephropathy, graft-versus-host disease, type 1 and type 2 diabetes, rheumatoid arthritis, and myelodysplastic syndrome.

[0369] 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, cryopyrin-associated periodic syndrome (CAPS), gout, inflammatory bowel disease, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), hypertension, myocardial infarction, oxalate-induced nephropathy, graft-versus-host disease, type 1 and type 2 diabetes, rheumatoid arthritis, and myelodysplastic syndrome.

[0370] Even more preferably, the disease, disorder, or abnormality is selected from Alzheimer's disease, Parkinson's disease, multiple sclerosis, cryopyrin-associated periodic syndrome (CAPS), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), rheumatoid arthritis, and gout. Even more preferably, the disease, disorder, or abnormality is selected from Alzheimer's disease, Parkinson's disease, multiple sclerosis, cryopyrin-associated periodic syndrome (CAPS), rheumatoid arthritis, and gout.

[0371] In one embodiment, the disease, disorder, or abnormality is selected from Alzheimer's disease, Parkinson's disease, cryopyrin-associated periodic syndrome (CAPS), rheumatoid arthritis, and gout, such as Alzheimer's disease, Parkinson's disease, cryopyrin-associated periodic syndrome (CAPS), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), rheumatoid arthritis, and gout.

[0372] In one embodiment, the invention relates to the use of a compound of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie) as defined in the present invention, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, for the treatment, alleviation or prevention of diseases associated with IL-18 and / or IL-1 beta, in particular by modulating the components of the NLRP3 inflammasome pathway, especially by modulating the NLRP3 inflammasome pathway. The levels of IL-18 and / or IL-1 beta in a subject are reduced as a result of the administration of a compound of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie) as defined in the present invention, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof.

[0373] Diseases, disorders, or abnormalities associated with IL-18 and / or IL-1 beta include chronic obstructive pulmonary disease (COPD), transfusion-related acute lung injury, bronchopulmonary dysplasia (BPD), acute respiratory distress syndrome (ARDS), pediatric autoinflammatory diseases or conditions, Still's disease, particularly adult Still's disease or juvenile Still's disease, juvenile rheumatoid arthritis (JRA), juvenile idiopathic arthritis (JIA), systemic-onset juvenile idiopathic arthritis (SoJIA), systemic juvenile idiopathic arthritis (sJIA), interstitial lung disease (ILD), macrophage activation syndrome (MAS) including primary, secondary, and recurrent MAS, hemophagocytic lymphohistiocytosis (HLH), familial (hereditary) hemophagocytic lymphohistiocytosis (FHLH) associated with gene deficiencies in perforin, munc 13-4, and 18-2, syntaxin 11, immunodeficiencies such as Chediak-Higashi syndrome (CHS), Griscelli syndrome (GS), X-linked lymphoproliferative syndrome (XLP2), X-linked inhibitor of apoptosis protein deficiency (XIAP), acquired hemophagocytic lymphohistiocytosis associated with infectious states, particularly herpesviruses such as EBV and other pathogens, autoinflammatory syndromes associated with NLRC4 mutations, giant cell arteritis (GCA), acne, pyogenic arthritis- pyoderma gangrenosum-acne (PAPA), pulmonary sarcoidosis, heart failure, ischemic heart disease, dry eye disease (DED), keratitis, corneal ulcers and abrasions, iritis, glaucoma, Sjogren's syndrome, autoimmune uveitis, Behcet's disease, conjunctivitis, allergic conjunctivitis, type 2 diabetes, organ and hematopoietic stem cell transplantation, ischemia-reperfusion injury, familial Mediterranean fever (FMF), tumor necrosis factor receptor 1-associated periodic syndrome (TRAPS), hyper IgD syndrome (mutation in the mevalonate kinase gene), 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), ultra-EOIBD (VEOIBD), infantile IBD, neonatal IBD, ulcerative colitis, and Blau syndrome (NOD-2 mutation).

[0374] Modulation of the NLRP3 inflammasome pathway appears to be beneficial in diseases or disorders or abnormalities associated with altered IL-18 levels and / or IL-1 beta that result in pathological inflammation.

[0375] The present invention relates to a compound of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie) as defined in the present invention, which is an agent for regulating NLRP3 inflammasome activity and / or an agent for regulating IL-18 and / or IL-1β levels in a subject.

[0376] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie) as defined in the present invention, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, and at least one other bioactive compound. Optionally, the combination pharmaceutical can comprise a pharmaceutically acceptable carrier, diluent, adjuvant or excipient described herein.

[0377] In another embodiment, the present invention relates to a pharmaceutical composition comprising a compound of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie) as defined in the present invention, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, and a combination of at least one other bioactive compound different from the compound of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie), optionally comprising at least one pharmaceutically acceptable carrier, diluent, adjuvant or excipient.

[0378] In another embodiment, the present invention relates to a pharmaceutical composition comprising a compound of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie) as defined in the present invention, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, and a combination of at least one other bioactive compound different from the compound of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie), optionally comprising at least one pharmaceutically acceptable carrier, diluent, adjuvant or excipient.

[0379] In particular, another bioactive compound can be a compound used for the treatment of a disease, disorder, or abnormality targeting different pathological mechanisms, such as, inter alia, an anti-amyloid beta antibody, an anti-tau antibody, a low molecular weight amyloid beta inhibitor, a low molecular weight tau aggregation inhibitor, an anti-alpha synuclein antibody or a low molecular weight alpha synuclein aggregation inhibitor, an anti-TDP-43 antibody or a low molecular weight anti-TDP-43 aggregation inhibitor. When the compound of the present invention is used in combination with another bioactive compound, the dosage of each compound may be different from the dosage when the compound is used as monotherapy. Such bioactive compounds are well known from the literature. Such bioactive compounds are chemical compounds, peptides, antibodies, antibody fragments, or nucleic acids that exhibit therapeutic activity or improve therapeutic activity when administered to a subject (e.g., a patient) in combination with the compound of the present invention.

[0380] In another embodiment, the present invention relates to a pharmaceutical composition for use as a medicament, comprising a compound of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie) as defined in the present invention, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof, in combination with at least one other bioactive compound different from the compound of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie), optionally comprising at least one pharmaceutically acceptable carrier, diluent, adjuvant, or excipient.

[0381] The term "combination" refers to a fixed combination in one dosage unit form, or a combined administration in which the compound of the present invention and the combination partner (e.g., another drug as described above, also known as a "therapeutic agent" or "another bioactive compound") can be administered independently simultaneously or within a time interval individually.

[0382] In another embodiment, the present invention relates to a combination, particularly a combination medicament, comprising a therapeutically effective amount of a compound of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie) as defined in the present invention, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, and at least one other bioactive compound, optionally comprising at least one pharmaceutically acceptable carrier, diluent, adjuvant or excipient. In particular, at least one other bioactive compound is a compound different from the compound of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie).

[0383] In another embodiment, the present invention relates to a combination for use as a medicament, comprising a therapeutically effective amount of a compound of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie) as defined in the present invention, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, and at least one other bioactive compound different from the compound of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie), optionally comprising at least one pharmaceutically acceptable carrier, diluent, adjuvant or excipient.

[0384] The present invention relates to the use of a compound of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie) as defined in the present invention, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, as an analytical standard or an in vitro screening tool. The compounds of the present invention, or stereoisomers, racemic mixtures, tautomers, polymorphs, pharmaceutically acceptable salts, prodrugs, hydrates or solvates thereof, can be used as an analytical standard or an in vitro screening tool for the characterization of cells in which the NLRP3 inflammasome pathway is activated and for the testing of compounds targeting the NLRP3 inflammasome pathway.

[0385] Accordingly, the present invention provides the use of a compound of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie) as defined herein, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, for treating, alleviating or preventing a disorder or abnormality which responds to modulation of a component of the NLRP3 inflammasome pathway or to modulation, particularly reduction, of IL-1 beta and / or IL-18 levels, wherein the medicament is formulated for administration with another bioactive substance. The present invention also provides the use of another bioactive substance for treating, alleviating or preventing a disorder or abnormality which responds to modulation of a component of the NLRP3 inflammasome pathway or to modulation, particularly reduction, of IL-1 beta and / or IL-18 levels, wherein the other bioactive substance is administered with a compound of the invention, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof.

[0386] In another embodiment, the present invention provides the use of a compound of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie) as defined herein, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, for treating, alleviating or preventing a disorder or abnormality which responds to modulation of a component of the NLRP3 inflammasome pathway or to modulation, particularly reduction, of IL-1 beta and / or IL-18 levels, wherein the modulation is a reduction and / or inhibition of IL-1 beta and / or IL-18 levels. Preferably, the modulation is a reduction and / or inhibition of IL-1 beta. Preferably, the modulation is an inhibition of IL-1 beta. In another embodiment, the present invention provides a compound of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie) as defined herein, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, for use as a medicament, particularly for use as a medicament for inhibiting IL-1 beta.

[0387] In another embodiment, the invention provides a compound of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie) as defined herein, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, for use in a method of treating, alleviating or preventing a disease, disorder or abnormality that responds to modulation of a component of the NLRP3 inflammasome pathway or to modulation, particularly reduction, of IL-1 beta and / or IL-18 levels, wherein said compound of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie) is prepared for administration with another bioactive compound (as defined herein), or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof.

[0388] In another embodiment, the present invention is a method for treating, alleviating, or preventing a disease, disorder, or abnormality that responds to the regulation of components of the NLRP3 inflammasome pathway or to the regulation, particularly the reduction, of IL-1 beta and / or IL-18 levels, wherein the disease, disorder, or abnormality is Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, demyelination, viral encephalitis, epilepsy, stroke, atherosclerosis, asthma, allergic inflammation, cryopyrin-associated periodic syndrome (CAPS), Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), neonatal-onset multisystem inflammatory disease (NOMID), gout, pseudogout, inflammatory bowel disease, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, hypertension, myocardial infarction, oxalate-induced nephropathy, graft-versus-host disease, type 1 diabetes, type 2 diabetes, rheumatoid arthritis, myelodysplastic syndrome, familial Mediterranean fever (FMF), TNF receptor-associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD), hyperimmunoglobulin D syndrome, periodic fever syndrome (HIDS), interleukin 1 receptor antagonist deficiency (DIRA), Magid syndrome, acne, pyogenic arthritis, pyoderma gangrenosum, acne (PAPA), A20 haploinsufficiency (HA20), PLCG2-related antibody deficiency and immune dysregulation (PLAID), pediatric granulomatous arthritis (PGA), PLCG2-related autoinflammation, antibody deficiency and immune dysregulation (APLAID), B cell immunodeficiency, periodic fever, sideroblastic anemia with developmental delay (SIFD), chronic non-bacterial osteomyelitis (CNO), Sweet's syndrome, chronic recurrent multifocal osteomyelitis (CRMO), synovitis, pustulosis, acne, eczema, alopecia areata, actinic keratosis, hyperostosis, synovitis, acne, pustulosis, hyperostosis, osteitis syndrome (SAPHO), multiple sclerosis (MS), psoriasis, Behçet's disease, Sjögren's syndrome, Schnitzler's syndrome, chronic obstructive pulmonary disease (COPD), steroid-resistant asthma, asbestosis, silicosis, cystic fibrosis, motor neuron disease, Huntington's disease, cerebral malaria, brain injury from pneumococcal meningitis, obesity, age-related macular degeneration (AMD), corneal infection, uveitis, dry eye, chronic kidney disease, diabetic nephropathy, alcoholic liver disease, skin contact allergy, sunburn, osteoarthritis, systemic juvenile idiopathic arthritis, adult-onset Still's disease, relapsing polychondritis, chikungunya virus, Ross River virus, influenza, HIV, coronavirus, dengue fever, Zika virus,Hidradenitis suppurativa (HS), lung cancer metastasis, pancreatic cancer, gastric cancer, myelodysplastic syndrome, leukemia; polymyositis, colitis, helminth infection, bacterial infection, abdominal aortic aneurysm, wound healing, depression, psychological stress, pericarditis including Dressler syndrome, ischemia-reperfusion injury, frontotemporal dementia, HIV-associated neurocognitive disorder, coronavirus-associated inflammatory disorders, and traumatic brain injury, preferably the disorder is Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, demyelination, viral encephalitis, epilepsy, stroke, atherosclerosis, asthma, allergic inflammation, cryopyrin-associated periodic syndrome (CAPS), gout, inflammatory bowel disease, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), hypertension, myocardial infarction, oxalate-induced nephropathy, graft-versus-host disease, type 1 diabetes, type 2 diabetes, rheumatoid arthritis, myelodysplastic syndrome, antineutrophil cytoplasmic antibody-associated vasculitis (AAV), lupus nephritis, anti-glomerular basement membrane (GMB) disease, IgA nephropathy, glomerulonephritis (GN), systemic lupus erythematosus (SLE), focal segmental glomerulosclerosis, minimal change disease (MCD), psoriatic arthritis, hereditary recurrent fever (HRF), and amyloidosis (including AL amyloidosis, AA amyloidosis, ATTR amyloidosis, hereditary amyloidosis (including apolipoprotein A-I (AApoAI), apolipoprotein A-II (AApoAII), gelsolin (AGel), fibrinogen (AFib), and lysozyme (ALys)), beta-2 microglobulin amyloidosis, iAPP amyloidosis), the method comprising administering to a subject a therapeutically effective amount of a compound of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie) as defined herein, or a stereoisomer thereof, or a racemic mixture, or a tautomer, or a polymorph, or a pharmaceutically acceptable salt, or a hydrate, or a solvate.

[0389] In another embodiment, the present invention provides a method of inhibiting IL-1 beta in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie), or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof.

[0390] In particular, the disease, disorder, or abnormality is a disease, disorder, or abnormality responsive to inhibition of activation of the NLRP3 inflammasome pathway. More particularly, the disease, disorder, or abnormality responds to modulation of one or more of, but not limited to, for example, 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-1α, IL-37, IL-33, and Th17 cells, and preferably the disease, disorder, or abnormality responds to modulation of IL-1β and / or IL-18.

[0391] Any combination of the embodiments, preferred embodiments, and more preferred embodiments disclosed herein is contemplated in the present invention.

[0392] Pharmaceutical Composition The compounds of the present invention, or their stereoisomers, racemic mixtures, tautomers, polymorphs, pharmaceutically acceptable salts, prodrugs, hydrates, or solvates can be administered alone, and it is preferred to formulate them into pharmaceutical compositions according to standard pharmaceutical practice. Accordingly, the present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie), or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof, optionally admixed with a pharmaceutically acceptable carrier, diluent, adjuvant or excipient.

[0393] The term "therapeutically effective amount" of a compound of the present invention refers to an amount of the compound of the present invention (i.e., a compound of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie), or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof) that induces a biological or medical response in a subject, such as a reduction or inhibition of enzyme or protein activity, or an improvement of symptoms, a reduction of a condition, a deceleration or delay of disease progression, or a prevention of a disease, disorder, or abnormality. In one embodiment, the term "therapeutically effective amount" refers to an amount of a compound of the present invention that, when administered to a subject (e.g., a patient) in need thereof, is effective to at least partially reduce, prevent, and / or improve a disease, disorder, or abnormality that responds to modulation of a component of the NLRP3 inflammasome pathway or to modulation, particularly reduction, of IL-1 beta and / or IL-18.

[0394] 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 Edition (ed. Alfonso R. Gennaro; Mack Publishing Company, Easton, PA, 1990); Remington: the Science and Practice of Pharmacy, 19th Edition (Lippincott, Williams & Wilkins, 1995); Handbook of Pharmaceutical Excipients, 3rd Edition (ed. Arthur H. Kibbe; Amer. Pharmaceutical Assoc, 1999); Pharmaceutical Codex: Principles and Practice of Pharmaceutics, 12th Edition (ed. Walter Lund; Pharmaceutical Press, London, 1994); The United States Pharmacopeia: The National Formulary (United States Pharmacopeial Convention); Fiedler's "Lexikon der Hilfsstoffe", 5th Edition, 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 (ed. Louis S. Goodman and Lee E. Limbird; McGraw Hill, 1992), the disclosures of which are hereby incorporated by reference herein.

[0395] The carrier, diluent, adjuvant, and pharmaceutical excipient can be selected in relation to the intended route of administration and standard pharmaceutical practice. These compounds must be acceptable compounds in the sense that they are not harmful to their recipients.

[0396] Pharmaceutically useful excipients that can be used in the formulation of the pharmaceutical composition of the present invention include, for example, vehicles, solvents (monohydric alcohols such as ethanol and isopropanol, and polyhydric alcohols such as glycols, etc.), edible oils (soybean oil, coconut oil, olive oil, safflower oil, and cottonseed oil, etc.), oily esters (ethyl oleate, isopropyl myristate, etc.), binders (hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), pregelatinized starch, and combinations thereof, etc.), solubilizers, thickening agents, stabilizers, disintegrants (calcium carboxymethylcellulose (CMC-Ca), sodium carboxymethylcellulose (CMC-Na), crosslinked PVP (e.g., crospovidone, Polyplasdone® or Kollidon® XL), alginic acid, sodium alginate, guar gum, crosslinked CMC (sodium croscarmellose, e.g., Ac-Di-Sol®), sodium carboxymethyl starch (sodium starch glycolate) (e.g., Primojel® or Explotab®), preferably crosslinked PVP and / or sodium croscarmellose, etc.), fluidizing agents (colloidal SiO2 (e.g., Aerosil® 200), magnesium trisilicate, powdered cellulose, talc, and combinations thereof, etc.), lubricants (magnesium stearate, aluminum or calcium silicate, stearic acid, hydrogenated castor oil, talc, glyceryl behenate, sodium fumarate stearate, and combinations thereof, etc.), buffering agents, emulsifying agents, wetting agents, suspending agents, sweetening agents, coloring agents, flavoring agents, coating agents, preservatives, antioxidants, processing agents, drug delivery modifiers and enhancers (calcium phosphate, etc.), magnesium stearate, talc, monosaccharides, disaccharides, starch, gelatin, cellulose, methylcellulose, sodium carboxymethylcellulose, dextrose, hydroxypropyl-β-cyclodextrin, polyvinylpyrrolidone, low melting point wax, and ion exchange resins can be included.

[0397] The carrier is not particularly limited and is determined by the administration route and the form of the pharmaceutical composition (i.e., solid, liquid, etc.). Suitable carriers include polyols such as mannitol, sorbitol, and xylitol; disaccharides such as lactose, sucrose, dextrose, and maltose; polysaccharides such as maltodextrin and dextran; starches such as corn starch; celluloses such as crystalline cellulose, sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, or mixtures thereof; cyclodextrin, and inorganic substances such as dicalcium phosphate, calcium hydrogen phosphate; hydroxyapatite, tricalcium phosphate, talc, and silica, but are not limited thereto. Crystalline cellulose, sucrose, and / or lactose are preferred as carriers. Combinations thereof can also be used. Carriers can also include proteins and cell-penetrating peptides, but should be selected according to the administration route and target.

[0398] The diluent is not particularly limited and is determined by the administration route and the form of the pharmaceutical composition (i.e., solid, liquid, etc.). Examples of diluents include water, ethanol, propylene glycol, and glycerin, and combinations thereof.

[0399] An adjuvant is an additive that has little or no pharmacological effect by itself but increases their effectiveness or potency when the compounds of the present invention are administered together.

[0400] Examples of the administration (delivery) route of the compound of the present invention include, but are not limited to, one or more of the following administration routes: oral (e.g., as tablets, capsules, or ingestible solutions), topical, mucosal (e.g., as nasal sprays or aerosols for inhalation), nasal, parenteral (e.g., in injectable form), gastrointestinal tract, intraspinal, intraperitoneal, intramuscular, intravenous, intraarterial, intrathecal, intrauterine, intraocular, intradermal, intracranial, intratracheal, intravaginal, intraventricular, intracerebral, subcutaneous, transocular (including intravitreal or in the anterior chamber), transdermal, rectal, buccal, epidural, and sublingual.

[0401] For example, the compound can be orally administered in the form of tablets, capsules, suppositories, elixirs, solutions or suspensions that can contain a perfume or a colorant for immediate, delayed, modified, sustained, pulsed or controlled release applications.

[0402] Tablets can contain excipients such as crystalline cellulose, lactose, sodium citrate, calcium carbonate, calcium hydrogen phosphate and glycine, disintegrants such as starch (preferably corn, potato, or tapioca starch), sodium starch glycolate, croscarmellose sodium, and some complex silicates, and granulating binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin, and acacia. Further, lubricants such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included. Solid compositions of the same type can also be used as fillers in gelatin capsules. Preferred excipients in this regard include starch, cellulose, lactose, such as lactose or high molecular weight polyethylene glycol. In aqueous suspensions and / or elixirs, the active agent can be combined with various sweetening or flavoring agents, coloring substances or dyes, emulsifying and / or suspending agents, diluents such as water, ethanol, propylene glycol, and glycerin, and combinations thereof.

[0403] When the compounds of the invention disclosed herein are administered parenterally, examples of such administration include administering the compound intravenously, intraarterially, intraperitoneally, intrathecally, intracerebroventricularly, intraurethrally, intrasternal, intracranial, intramuscularly, or subcutaneously; and / or using one or more of infusion techniques. For parenteral administration, the compound can be used in the form of a sterile aqueous solution that can contain other substances, such as salts or glucose sufficient to render the solution isotonic with blood. The aqueous solution should preferably be buffered (preferably to pH 3 - 9) if necessary. Preparation of suitable parenteral formulations under aseptic conditions is readily achieved by standard formulation techniques well known to those skilled in the art.

[0404] As indicated, the compounds of the present invention can be administered intranasally or by inhalation, and advantageously are delivered in the form of a dry powder inhaler or aerosol spray presentation from a pressurized container, pump, nebulizer, or atomizer using a suitable propellant such as 1,1,1,2 - tetrafluoroethane (HFA134A T) or 1,1,1,2,3,3,3 - heptafluoropropane (HFA 227EA), carbon dioxide, or other suitable gas, for example dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, hydrofluoroalkane. 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, spray, or nebulizer can contain a solution or suspension of the active compound using, for example, a mixture of ethanol and a propellant as a solvent, and can further contain a lubricant such as sorbitan trioleate. Capsules and cartridges (e.g., made of gelatin) for use in inhalers or insufflators can be formulated to contain a powder mixture of the compound and a suitable powder base such as lactose or starch.

[0405] Alternatively, the compounds of the present invention as defined herein can be administered in the form of suppositories or vaginal suppositories, or can be topically applied in the form of gels, hydrogels, lotions, solutions, creams, ointments, or powders. The compounds of the present invention as defined herein can also be administered dermally or transdermally, for example by use of a skin patch.

[0406] They can also be administered by the pulmonary or rectal routes. They can also be administered by the ocular route. For ocular use, the compounds can be formulated as a micronized suspension in pH - adjusted isotonic sterile saline or, preferably, as a solution in pH - adjusted isotonic sterile saline optionally in combination with a preservative such as benzalkonium chloride. Alternatively, they can be formulated as an ointment such as petrolatum.

[0407] For topical application to the skin, the compounds of the present invention can be formulated as suitable ointments containing the active compound suspended or dissolved in a mixture of one or more of, for example, the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, emulsifying wax, and water. Alternatively, they can be formulated as suitable lotions or creams suspended or dissolved in a mixture of one or more of, for example, the following: mineral oil, sorbitan monostearate, polyethylene glycol, liquid paraffin, polysorbate 60, cetyl palmitate, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0408] Typically, a physician will determine the actual dosage most suitable for an individual subject. The specific dosage level and frequency of administration for any particular individual may vary and will depend on a variety of factors including the activity of the specific compound utilized, the metabolic stability and duration of action of that compound, age, body weight, general health status, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the individual being treated.

[0409] The claimed compounds as defined herein can be used alone or in combination with one or more other bioactive compounds as defined herein for the treatment, alleviation, or prevention of the described conditions. In particular, the other bioactive compounds can be compounds used for the treatment, alleviation, or prevention of the described diseases.

[0410] The combinations referred to above can conveniently be presented for use in the form of pharmaceutical formulations. The individual components of such combinations can be administered simultaneously, either continuously or in separate or combined pharmaceutical formulations, by any convenient route. When the administration is a continuous administration, the compound of the present invention or another bioactive compound can be administered first. When the administration is a simultaneous administration, the combination can be administered in the same or different pharmaceutical compositions. When combined in the same formulation, it is recognized that the two compounds must be stable and mutually compatible and compatible with the other components of the formulation. When formulated separately, they can be provided in any convenient formulation, and conveniently in a form known for such compounds in the art.

[0411] The pharmaceutical compositions of the present invention can be produced in a form known per se to those skilled in the art, for example, as described in Remington's Pharmaceutical Sciences, 15th Edition, Mack Publishing Co., New Jersey (1975).

[0412] The compounds according to the present invention disclosed herein can also be provided in the form of a mixture with at least one other bioactive compound and / or a pharmaceutically acceptable carrier, diluent, adjuvant, or excipient. The compound and / or the other bioactive compound are preferably present in a therapeutically effective amount.

[0413] The nature of the other bioactive compound depends on the intended use of the mixture. The other bioactive substance or compound can exert its biological effect by the same or similar mechanism as the compound according to the present invention, or by an unrelated mechanism of action, or by a number of related and / or unrelated mechanisms of action.

[0414] The present invention also includes all suitable isotope variants of the compounds of the present invention. Isotope variants of the compounds of the present invention are defined as those in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass than that 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, such as 2 H, 3 H, 13 C, 14 C, 15 N, 17 O, 18 O, 35 S, 18 F and 36 CI. Some isotope variants of the present invention, such as those incorporated with radioactive isotopes such as 3 H or 14 C, etc., are useful in drug and / or substrate tissue distribution studies. Tritium, i.e., 3 H and carbon-14, i.e., 14 C isotopes are particularly preferred because of their ease of preparation and detectability. 18 F-labeled compounds are particularly suitable for imaging applications such as PET. Furthermore, substitution with isotopes such as deuterium, i.e., 2 H, etc., can result in several therapeutic advantages due to improved metabolic stability, such as an increase in in vivo half-life or a reduction in required dosage, and may therefore be preferred depending on the situation. Isotope variants of the compounds of the present invention can generally be prepared by ordinary procedures such as exemplary methods, or by the preparations described in the following examples and preparations using appropriate isotope variants of suitable reagents.

[0415] Methods of Use of the Present Invention There is evidence for the role of NLRP3-induced IL-1 and IL-18 in inflammatory responses associated with or resulting from a number of different diseases, disorders, or abnormalities that respond to modulation of components of the NLRP3 inflammasome pathway and / or to modulation of IL-1 beta and / or IL-18 levels (Menu et al., Clinical and Experimental Immunology, 2011, 166, 1-15; Strowig et al., Nature, 2012, 481, 278-286).

[0416] The present invention provides compounds of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie) as defined herein, or stereoisomers, racemic mixtures, tautomers, polymorphs, pharmaceutically acceptable salts, prodrugs, hydrates, or solvates thereof, which exhibit useful pharmacological properties, such as NLRP3 inhibitory properties against the NLRP3 inflammasome pathway. The said compounds of the present invention may be useful in the treatment, alleviation, or prevention of diseases or disorders or abnormalities that respond to modulation of components of the NLRP3 inflammasome pathway and / or to modulation of IL-1 beta and / or IL-18 levels. A plurality of diseases, disorders, or abnormalities have been shown to be involved in NLRP3, including, for example, one of the following. 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 injury from pneumococcal meningitis, motor neuron disease, traumatic brain injury, amyotrophic lateral sclerosis, or multiple sclerosis (MS); B. Immune diseases, disorders, or abnormalities (e.g., autoimmune diseases, disorders, or abnormalities, and diseases, disorders, or abnormalities involving the immune system), such as multiple sclerosis (MS) including type 1 diabetes, hidradenitis suppurativa (HS), Schnitzler syndrome, primary progressive multiple sclerosis (PPMS), Sjögren's syndrome, secondary progressive multiple sclerosis (SPMS), TNF receptor-associated periodic syndrome (TRAPS), graft-versus-host disease, or relapsing-remitting multiple sclerosis (RRMS); C. Mevalonate kinase deficiency (MKD), hyperimmunoglobulin D syndrome, cryopyrin-associated periodic syndromes (CAPS), Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), neonatal-onset multisystem inflammatory disease (NOMID), familial Mediterranean fever (FMF), acne, pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA), adult-onset Still's disease (AOSD), Magid syndrome, PLCG2-related antibody deficiency and immune dysregulation (PLAID), PLCG2-related autoinflammation, antibody deficiency and immune dysregulation (APLAID), pyogenic arthritis, A20 haploinsufficiency (HA20), pediatric granulomatous arthritis (PGA), or B cell immunodeficiency, periodic fever, sideroblastic anemia with developmental delay (SIFD), etc., including inflammation resulting from autoinflammatory and inflammatory diseases, disorders, or abnormalities, inflammatory diseases; D. Hidradenitis suppurativa (HS), dermatitis, psoriasis, cutaneous contact hypersensitivity, acne, periodic fever syndrome (HIDS), Sweet syndrome, eczema, skin lesions, burns, wounds, wound healing, trauma, sunburn, actinic keratosis, interleukin 1 receptor antagonist deficiency (DIRA), or alopecia areata, etc., skin diseases, disorders, or abnormalities; E. Age-related macular degeneration (AMD), corneal infections, uveitis, glaucoma, dry eye, or demyelination, etc., eye diseases, disorders, or abnormalities; F. Myocardial infarction, hypertension, ischemia-reperfusion injury, pericarditis including Dressler syndrome, aneurysms including abdominal aortic aneurysm, or stroke, etc., cardiovascular diseases, disorders, or abnormalities (e.g., diseases, disorders, or abnormalities of the cardiovascular system); G. Type 2 diabetes, obesity, atherosclerosis, gout, or pseudogout, etc., metabolic diseases, disorders, or abnormalities; H. Asbestosis, silicosis, cystic fibrosis, allergic inflammation, chronic obstructive pulmonary disease (COPD), steroid-resistant asthma, or asthma, etc., respiratory diseases, disorders, or abnormalities (e.g., diseases, disorders, or abnormalities of the respiratory system); I. Alcoholic liver disease, alcoholic fatty liver disease (AFLD), alcoholic steatohepatitis (ASH), non-alcoholic fatty liver disease (NAFLD) including advanced fibrosis stages F3 and F4, or non-alcoholic steatohepatitis (NASH), etc., liver diseases, disorders, or abnormalities (e.g., diseases, disorders, or abnormalities of the liver); J. Renal diseases, disorders, or abnormalities such as oxalate-induced nephropathy, diabetic nephropathy, chronic kidney disease, or kidney diseases, disorders, or abnormalities (e.g., diseases, disorders, or abnormalities of the renal system); K. Cancer diseases, disorders, or abnormalities such as lung cancer (e.g., lung cancer metastasis), pancreatic cancer, gastric cancer, leukemia, myelodysplastic syndrome (MOS), skin cancer, endocrine tumors, or thyroid cancer (e.g., cancer, tumor, or malignant tumor); L. Infectious diseases including helminth infections (e.g., from Schistosoma mansoni, Ascaris lumbricoides, tapeworms, or flukes), viral encephalitis, bacterial infections, human immunodeficiency virus (HIV), HIV-related neurocognitive disorders, chronic non-bacterial osteomyelitis (CNO), chronic bacterial osteomyelitis, interleukin 1 receptor antagonist deficiency (DIRA), or epilepsy; viral infections such as alphaviruses (e.g., chikungunya virus and Ross River virus), flaviviruses (e.g., dengue fever and Zika virus), coronavirus-related inflammatory pathologies, coronaviruses, or influenza viruses; M. Psychological diseases, disorders, or abnormalities such as depression and psychological stress; N. Inflammation including inflammation resulting from inflammatory diseases, disorders, or abnormalities such as autoinflammatory diseases, inflammation occurring as a symptom of non-inflammatory disorders, inflammation resulting from infections, or inflammation associated with trauma, injury, or autoimmunity. Examples of inflammation include: i. Joint diseases, disorders, or abnormalities such as periodic fever syndrome (HIDS), rheumatoid arthritis, pustulosis, synovitis, osteoarthritis, chronic recurrent multifocal osteomyelitis (CRMO), systemic juvenile idiopathic arthritis, synovitis, acne, pustulosis, hyperostosis, osteitis syndrome (SAPHO), hyperostosis, relapsing polychondritis, or adult-onset Still's disease; ii. Gastrointestinal diseases, disorders, or abnormalities such as colitis, ulcerative colitis, or inflammatory bowel disease (e.g., diseases, disorders, or abnormalities of the gastrointestinal tract); iii. Muscle diseases, disorders, or abnormalities such as polymyositis or myasthenia gravis; iv. Endocrine system diseases, disorders, or abnormalities such as diabetes, parathyroid diseases (e.g., hypothyroidism), endocrine tumors, thyroid cancer, or hypoglycemia; and / or v. Vascular diseases, disorders, or abnormalities such as Behçet's disease Inflammatory reactions associated with or resulting from them may be mentioned.

[0417] In one embodiment, the disease, disorder, or abnormality is selected from Alzheimer's disease, Parkinson's disease, cryopyrin-associated periodic syndrome (CAPS), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and gout.

[0418] In particular, the disease, disorder, or abnormality is Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, demyelination, viral encephalitis, epilepsy, stroke, cerebral hemorrhage, atherosclerosis, asthma, allergic inflammation, cryopyrin-associated periodic syndrome (CAPS), Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), neonatal-onset multisystem inflammatory disease (NOMID), gout, pseudogout, inflammatory bowel disease, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, hypertension, myocardial infarction, oxalate-induced nephropathy, graft-versus-host disease, type 1 diabetes, type 2 diabetes, rheumatoid arthritis, myelodysplastic syndrome, familial Mediterranean fever (FMF), TNF receptor-associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD), hyperimmunoglobulin D syndrome, periodic fever syndrome (HIDS), interleukin 1 receptor antagonist deficiency (DIRA), Majid syndrome, pyogenic arthritis, pyoderma gangrenosum, acne (PAPA), A20 haploinsufficiency (HA20), PLCG2-related antibody deficiency and immune dysregulation (PLAID), pediatric granulomatous arthritis (PGA), PLCG2-related autoinflammation, antibody deficiency and immune dysregulation (APLAID), B cell immunodeficiency, periodic fever, sideroblastic anemia with developmental delay (SIFD), chronic non-bacterial osteomyelitis (CNO), Sweet's syndrome, chronic recurrent multifocal osteomyelitis (CRMO), synovitis, pustulosis, acne, eczema, alopecia areata, actinic keratosis, hyperostosis, synovitis, acne, pustulosis, hyperostosis, osteitis syndrome (SAPHO), multiple sclerosis (MS), psoriasis, Behçet's disease, Sjögren's syndrome, Schnitzler's syndrome, chronic obstructive pulmonary disease (COPD), steroid-resistant asthma, asbestosis, silicosis, cystic fibrosis, motor neuron disease, Huntington's disease, cerebral malaria, brain injury from pneumococcal meningitis, obesity, age-related macular degeneration (AMD), corneal infection, uveitis, dry eye, chronic kidney disease, diabetic nephropathy, alcoholic liver disease, skin contact hypersensitivity, sunburn, osteoarthritis, systemic juvenile idiopathic arthritis, adult-onset Still's disease, relapsing polychondritis, chikungunya virus, Ross River virus, influenza, HIV, coronavirus, dengue fever, Zika virus, hidradenitis suppurativa (HS), lung cancer metastasis, pancreatic cancer, gastric cancer, myelodysplastic syndrome, leukemia;Selected from polymyositis, colitis, helminth infection, bacterial infection, abdominal aortic aneurysm, wound healing, depression, psychological stress, pericarditis including Dressler syndrome, ischemia-reperfusion injury, frontotemporal dementia, HIV-associated neurocognitive disorder, coronavirus-associated inflammatory disease states, and traumatic brain and spinal cord injury, inflammatory pain, chronic pain, neuropathic pain, metastatic cancer-induced bone pain, chemotherapy-induced peripheral neuropathy, and migraine; preferably, the disorder is Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, demyelination, viral encephalitis, epilepsy, stroke, atherosclerosis, asthma, allergic inflammation, cryopyrin-associated periodic syndrome (CAPS), gout, inflammatory bowel disease, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), hypertension, myocardial infarction, oxalate-induced nephropathy, graft-versus-host disease, type 1 diabetes, type 2 diabetes, rheumatoid arthritis, 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 recurrent fever (HRF), and amyloidosis (including AL amyloidosis, AA amyloidosis, ATTR amyloidosis, hereditary amyloidosis (including apolipoprotein A-I (AApoAI), apolipoprotein A-II (AApoAII), gelsolin (AGel), fibrinogen (AFib), and lysozyme (ALys)), beta2-microglobulin amyloidosis, iAPP amyloidosis);

[0419] In one embodiment, the disease, disorder, or abnormality is Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, demyelination, viral encephalitis, epilepsy, stroke, atherosclerosis, asthma, allergic inflammation, cryopyrin-associated periodic syndrome (CAPS), Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), neonatal-onset multisystem inflammatory disease (NOMID), gout, pseudogout, inflammatory bowel disease, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, hypertension, myocardial infarction, oxalate-induced nephropathy, graft-versus-host disease, type 1 diabetes, type 2 diabetes, rheumatoid arthritis, myelodysplastic syndrome, familial Mediterranean fever (FMF), TNF receptor-associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD), hyperimmunoglobulin D syndrome, periodic fever syndrome (HIDS), interleukin 1 receptor antagonist deficiency (DIRA), Majid syndrome, acne, pyogenic arthritis - pyoderma gangrenosum - acne (PAPA), A20 haploinsufficiency (HA20), PLCG2-related antibody deficiency and immune dysregulation (PLAID), pediatric granulomatous arthritis (PGA), PLCG2-related autoinflammation, antibody deficiency and immune dysregulation (APLAID), B cell immunodeficiency, periodic fever, sideroblastic anemia with developmental delay (SIFD), chronic non-bacterial osteomyelitis (CNO), Sweet's syndrome, chronic recurrent multifocal osteomyelitis (CRMO), synovitis, pustulosis, acne, eczema, alopecia areata, actinic keratosis, hyperostosis, synovitis, acne, pustulosis, hyperostosis, osteitis syndrome (SAPHO), multiple sclerosis (MS), psoriasis, Behçet's disease, Sjögren's syndrome, Schnitzler's syndrome, chronic obstructive pulmonary disorder (COPD), steroid-resistant asthma, asbestosis, silicosis, cystic fibrosis, motor neuron disease, Huntington's disease, cerebral malaria, brain injury from pneumococcal meningitis, obesity, age-related macular degeneration (AMD), corneal infection, uveitis, dry eye, chronic kidney disease, diabetic nephropathy, alcoholic liver disease, skin contact hypersensitivity, sunburn, osteoarthritis, systemic juvenile idiopathic arthritis, adult-onset Still's disease, relapsing polychondritis, chikungunya virus, Ross River virus, influenza, HIV, coronavirus, dengue fever, Zika virus, hidradenitis suppurativa (HS), lung cancer metastasis, pancreatic cancer, gastric cancer, myelodysplastic syndrome, leukemia;It may be selected from polymyositis, colitis, helminth infection, bacterial infection, abdominal aortic aneurysm, wound healing, depression, psychological stress, periodontitis, pericarditis including Dressler syndrome, ischemia-reperfusion injury, frontotemporal dementia, HIV-associated neurocognitive disorder, coronavirus-associated inflammatory disease states, and traumatic brain injury. Preferably, the disorder is selected from Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, demyelination, viral encephalitis, epilepsy, stroke, atherosclerosis, asthma, allergic inflammation, cryopyrin-associated periodic syndrome (CAPS), gout, inflammatory bowel disease, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), hypertension, myocardial infarction, oxalate-induced nephropathy, graft-versus-host disease, type 1 diabetes, type 2 diabetes, rheumatoid arthritis, myelodysplastic syndrome, antineutrophil cytoplasmic antibody-associated vasculitis (AAV), lupus nephritis, anti-glomerular basement membrane (GMB) disease, IgA nephropathy, glomerulonephritis (GN), systemic lupus erythematosus (SLE), focal segmental glomerulosclerosis, minimal change disease (MCD), psoriatic arthritis, and hereditary recurrent fever (HRF).;

[0420] In yet another embodiment, the disease, disorder, or abnormality is preferably an inflammatory disease, disorder, or abnormality; or an autoimmune disease, disorder, or abnormality; or a skin disease, disorder, or abnormality (such as, but not limited to, psoriasis, acne, eczema, alopecia areata, or actinic keratosis, etc.); or a cardiovascular disease, disorder, or abnormality; or a disease, disorder, or abnormality such as cancer, tumor, or malignant tumor; or a kidney disease, disorder, or abnormality; a gastrointestinal disease, disorder, or abnormality; a respiratory disease, disorder, or abnormality; or an endocrine disease, disorder, or abnormality; or a central nervous system (CNS) disease, disorder, or abnormality; or a liver disease, disorder, or abnormality.

[0421] Definitions Within the scope of meaning of this application, the following definitions apply unless otherwise specified, and when appropriate, terms used in the singular form also include the plural form, and vice versa.

[0422] "Alkyl" refers to a saturated straight-chain or branched organic moiety consisting of carbon and hydrogen atoms. Examples of suitable alkyl groups include those having 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, and (optionally) methyl, ethyl, propyl, isopropyl, n-butyl, t-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.

[0423] "Hal", "halo", or "halogen" refers to F, Cl, Br, and I. Preferably, the halogen is F or Cl. More preferably, the halogen is Cl. Even more preferably, the halogen is F.

[0424] "-O-C1-C6 alkyl" as "C1-C6 alkyl" is defined above in a broad sense. Examples of "-O-C1-C6 alkyl" include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, pentoxy, and hexyloxy.

[0425] The term "C3-C6 cycloalkyl" refers to a saturated monocyclic hydrocarbyl group having 3 to 6 carbon atoms. The term "C5-C6 cycloalkyl" should be interpreted accordingly. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0426] "4-membered, 5-membered, or 6-membered heterocycloalkyl" refers to a stable 4-membered, 5-membered, or 6-membered non-aromatic monocyclic ring group containing one or two heteroatoms. The heteroatom is nitrogen. An example is piperidine.

[0427] "Aryl" refers to an aromatic hydrocarbon group having 5 or 6 carbon atoms in the ring moiety. Preferably, "aryl" is phenyl.

[0428] "Heteroaryl" refers to an aromatic "5-membered or 6-membered ring" in which one or two of the ring carbon atoms are replaced by heteroatoms. In the context of the present invention, the heteroatom is N. The heteroaryl group can be bonded via a carbon atom or a heteroatom. Examples of heteroaryl include, but are not limited to, pyridine and pyrimidine.

[0429] With respect to a group, "optionally substituted" means that the group is optionally substituted with one or more substituents (i.e., the substituents may or may not be present).

[0430] Unless otherwise specified, the term "compound of the present invention" refers to a compound of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie) disclosed herein, or a partial formula thereof 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 can exist as racemates and racemic mixtures (including mixtures in all ratios), stereoisomers (including mixtures of diastereomers and individual diastereomers, mixtures of enantiomers and single enantiomers, mixtures of conformational isomers and single conformational isomers), tautomers, atropisomers, and rotamers. All isomeric forms are included in the present invention. Compounds described in the present invention containing an olefinic double bond include E and Z geometric isomers. Pharmaceutically acceptable salts, prodrugs, hydrates, and solvates of the compounds of formula (I'), (I), (Ia), (Ib), (Ic), (Id) or (Ie) are also all included in the present invention.

[0431] Tautomers are isomers of a compound that differ only in the position of protons and electrons. The skeleton of the compound remains unchanged. Commonly seen tautomer pairs include keto-enol (H-O-C=CH⇔O=C-CH2), enamine-imine (H2N-C=N⇔HN=C-NH).

[0432] Salt solvates, hydrates, and anhydrous forms are also encompassed by the present invention. The solvent contained in the solvate is not particularly limited and can be any pharmaceutically acceptable solvent. Examples include water and C 1~4 alcohol (such as methanol or ethanol).

[0433] "Pharmaceutically acceptable salts" are defined as derivatives of the disclosed compounds in which the parent compound is modified by making its acid or base salts. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids, etc. Pharmaceutically acceptable salts include, for example, the normal non-toxic salts or quaternary ammonium salts of the parent compound formed from non-toxic inorganic or organic acids. For example, such normal non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid (not limited to these); and acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid (not limited to these), etc. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compounds containing basic or acidic moieties by ordinary chemical methods. Generally, such salts can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of an appropriate base or acid in water or an organic solvent, or a mixture of both. Examples of organic solvents include, but are not limited to, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile. A list of suitable salts can be found in Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing Company, Easton, PA, 1990, page 1445, the disclosure of which is incorporated herein by reference.

[0434] The compounds of the invention as defined herein may also be provided in the form of prodrugs, i.e., compounds that are metabolized in vivo to the active metabolite. As used hereinafter in the specification and claims of the invention, the term "prodrug" means any covalent compound that releases an active parent drug for in vivo bioconversion. The reference by Goodman and Gilman that reviews prodrugs (The Pharmacological Basis of Therapeutics, 8th Edition, McGraw-Hill, Int. Ed. 1992, "Biotransformation of Drugs", pages 13-15) is incorporated herein by reference.

[0435] "Pharmaceutically acceptable" is defined as a compound, material, composition, and / or dosage form suitable for use in contact with the tissues of humans and animals within the scope of sound medical judgment, without excessive toxicity, irritation, allergic response, or other problems or complications and commensurate with a reasonable benefit / risk ratio.

[0436] As used herein, the terms "patient" or "subject" described in the present invention typically refer to animals, particularly mammals (e.g., rabbits, rats, dogs, mice, guinea pigs, pigs), and more particularly primates (e.g., humans, male or female). In some embodiments, the subject is a human.

[0437] As used herein, "NLRP3" refers to the NLR family pyrin domain-containing protein 3 component of the inflammasome. The inflammasome is an intracellular supramolecular complex that includes a sensor molecule, the CARD-containing adaptor apoptosis-associated speck-like protein (ASC), and the effector protease caspase 1. Upon activation of the inflammasome sensor molecule, ASC self-associates into helical filament assemblies, resulting in the formation of so-called ASC specks or pyroptosomes, which act as a molecular platform for the activation of procaspase 1 via proximity-induced autocatalytic activation. Active caspase 1 triggers the activation and release of interleukin-1 (IL-1) family proteins and enables the unconventional secretion of numerous cytoplasmic proteins. Among the pro-inflammatory mediators released upon NLRP3 activation are IL-1 beta (β), IL-18, high-mobility group protein B1 (HMGB1), leukotrienes, and prostaglandins.

[0438] Activation of the NLRP3 inflammasome pathway is an important driver of inflammation that interacts with various cytokine pathways that shape the immune response to infection and injury. The formation of some pro-inflammatory cytokines is caused by activation of the NLRP3 inflammasome pathway.

[0439] The terms "inhibit", "inhibiting", or "inhibition" refer to the reduction or suppression of a given condition, symptom, or disorder, or disease, or abnormality in response to modulation of a component of the NLRP3 inflammasome pathway, or a marked decrease in the baseline activity of a biological activity or process.

[0440] The terms "treating," "treatment," or "treat" with respect to any disease, disorder, or abnormality refer to reducing, ameliorating, or modulating a disease or disorder or abnormality (i.e., slowing or halting the occurrence of at least one of the disease, disorder, or abnormality, or their clinical symptoms); or reducing, ameliorating, or modulating at least one physical parameter or biomarker associated with a disease or disorder or abnormality, including those that may not be distinguishable to a subject (e.g., a patient).

[0441] The terms "preventing," "prevention," or "prevent" with respect to any disease, disorder, or abnormality that responds to modulation of a component of the NLRP3 inflammasome pathway refer to a prophylactic treatment for the disease or disorder or abnormality; or a delay in the onset or progression of a disease or disorder.

[0442] The term "in need of treatment" means a subject in need of treatment when such subject would benefit biologically, medically, or in terms of quality of life from such treatment.

[0443] As used herein, "modulate" refers to a change, e.g., upregulation, downregulation, increase, or decrease, preferably decrease.

[0444] [Table 1]

[0445] The definitions and preferred definitions set forth in the "Definitions" section apply to all of the embodiments described herein unless otherwise stated.

[0446] General synthetic scheme for the preparation of the compounds of the present invention: The compounds of the present invention can be synthesized by using preparation processes generally known to those skilled in the art, e.g., the preparation processes of the general methods shown in the following schemes. These methods are described for illustrative purposes only and should not be construed as limiting.

[0447] In all methods, it is well understood that protecting groups can be utilized for sensitive or reactive groups if necessary, in accordance with the general principles of chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Green and P. G. M. Wuts (2014) Protective Groups in Organic Synthesis, 5th Edition, John Wiley & Sons). These groups are removed at convenient stages of compound synthesis using methods that are readily apparent to those skilled in the art.

[0448] In the following general methods, R0, R1, R2, R3, Z1, Z2, E, V, X, and Y are as previously defined in the above embodiments.

[0449] [Table 2]

[0450] [Chemical Formula]

[0451] Commercially available 5-membered heterocyclic esters can be condensed with hydrazine and then carbamates can be formed, enabling the synthesis of intermediate B. Cyclization can be carried out under basic conditions such as KOH in a suitable solvent to obtain bicyclic intermediate C. Subsequently, halogenation using POCl3 or any halogenating reagent can result in intermediate D. Introduction of the YR3 substituent can be carried out by palladium-catalyzed amination using a standard palladium catalyst, base, and solvent. Intermediate E can be subjected to halogenation using POCl3 or any halogenating reagent. Finally, intermediate F can be further functionalized by a palladium-catalyzed Suzuki reaction to obtain a compound of formula (I'), (I), (Ia), (Ib), (Ic), (Id), or (Ie).

[0452] [Chemical Formula]

[0453] Starting from intermediate B, intermediate G can be obtained by cyclization using CS2 in the presence of a base. Intermediate J can be obtained by performing selective alkylation using standard conditions followed by chlorination. Finally, the compound of formula (I) can be obtained by performing SNAr followed by metal coupling, for example using boronic acid and a palladium catalyst.

[0454]

Chemical formula

[0455] As another approach, an approach can be mentioned in which intermediate A is cyclized with an orthoformate reagent to obtain intermediate L. The benzylation of the scaffold using standard conditions can result in intermediate M. Subsequently, the alkyl ether can be converted within the leaving group by a two-step method. Starting from intermediate N, intermediate O can be obtained by metal coupling. Finally, pyridone is converted to a leaving group in a one-pot reaction to obtain intermediate P. Finally, the compound of formula (I) can be obtained by an SNAr reaction using standard conditions.

Examples

[0456] The present disclosure is further illustrated by the following examples and synthetic schemes, but they should not be construed as limiting the scope of the specific procedures described herein. It should be understood that the examples are described to illustrate some embodiments and are not intended to limit the scope of the present disclosure.

[0457] Unless otherwise noted, all reagents and solvents were obtained from commercial sources and used without further purification. Chemical names were generated using ChemDraw from CambridgeSoft. Temperatures are reported in degrees Celsius. Unless otherwise stated, all evaporations were carried out under reduced pressure, typically at about 15 mmHg to 100 mmHg (= 20 to 133 mbar). The structures of the final products, intermediates, and starting materials were confirmed by standard analytical methods, such as microanalysis and spectroscopic properties, e.g., MS, IR, NMR. 1 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 in Hertz. Spin multiplicities are indicated by the symbols shown below: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), bs (broad singlet). Mass spectra (MS) were obtained using a Waters Alliance HPLC (Waters e2695 separation module), Waters Arc HPLC, or Waters Acquity UPLC. Chromatography was performed using silica gel (SRL: silica gel 100 - 200 mesh) and suitable solvents as indicated in the specific examples. Flash purification was carried out using a CombiFlash system and solvent gradients as indicated in the specific examples. Thin-layer chromatography (TLC) was performed on silica gel plates with UV detection.

[0458] Intermediate 1

[0459] [Chemical formula]

[0460] Step 1: To a mixture of ethyl 1H-imidazole-2-carboxylate (100 g, 713.57 mmol, 1 eq) in EtOH (1 L) was slowly added N2H4·H2O (225.41 mL, 3.72 mol, 5.21 eq). The mixture was stirred at 25 °C for 4 h. The reaction mixture was filtered. The filter cake was washed with H2O (300 mL × 3) and dried to give 1H-imidazole-2-carbohydrazide (70 g, 77%) as a white solid. 1 H NMR: (400 MHz, DMSO-d6) δ = 12.64 (br s, 1H), 9.66 (s, 1H), 7.14 (s, 2H), 4.60 (s, 2H). MS: 127.3 [M+H] + .

[0461] Step 2: To a mixture of 1H-imidazole-2-carbohydrazide (60 g, 475.75 mmol, 1 eq) in pyridine (1.6 L) was added CS2 (573.60 mL, 8.52 mol, 20.0 eq). The mixture was stirred at 100 °C for 16 h. The reaction mixture was concentrated under vacuum, and the residue was diluted with H2O (500 mL), then the pH was adjusted to pH = 2 with 1M HCl. The resulting yellow solid was filtered and dried. The crude product was triturated with MeOH (200 mL) at 25 °C for 16 h. The mixture was filtered, the filter cake was washed with MeOH (20 mL × 3), and lyophilized to give 5-mercaptoimidazo[1,2-d][1,2,4]triazin-8-ol (25.5 g, 31%) as a yellow solid. 1 H NMR: (400 MHz, DMSO-d6) δ = 8.21 (d, 1H), 7.72 (d, 1H). MS: 169.0 [M+H] + .

[0462] (Example 1) (R)-2-(1-((1-Methylpiperidin-3-yl)amino)pyrrolo[1,2-d][1,2,4]triazin-4-yl)-5-(trifluoromethyl)phenol

[0463]

Chem.

[0464] Step A: A solution of methyl 1H-pyrrole-2-carboxylate (10 g, 79.92 mmol) in hydrazine hydrate (76.86 mL, 2397.51 mmol) was stirred at room temperature for 1 hour and then heated to 100 °C for 2 hours. After the starting material was consumed, the reaction mixture was diluted with H2O (50 mL), and upon cooling, a solid precipitated. The solid was filtered through a Buchner funnel, washed with H2O (20 mL), and dried to give 1H-pyrrole-2-carbohydrazide (8.0 g, 80%) as an off-white solid. 1 H NMR (400 MHz, CDCl3): δ = 11.42 (brs, 1H), 9.22 (brs, 1H), 6.83 - 6.82 (m, 1H), 6.73 (brs, 1H), 6.05 - 6.03 (m, 1H), 4.28 - 4.27 (brs, 2H). MS: 125.98 [M+H] +.

[0465] Step B: To a stirred solution of 1H-pyrrole-2-carbohydrazide (obtained from Step A) (8.0 g, 63.93 mmol) and N,N-diisopropylethylamine (33.41 ml, 191.80 mmol) in DCM (350 mL) was added dropwise methyl chloroformate (7.428 ml, 95.90 mmol) over 15 minutes at room temperature. The mixture was stirred at room temperature for 2 hours. After the starting material was consumed, the reaction mixture was evaporated under reduced pressure to give a crude compound. The crude compound was co-distilled with DCM (50 mL) and dried thoroughly under vacuum to give crude product methyl 2-(1H-pyrrole-2-carbonyl)hydrazine-1-carboxylate (8.0 g, 68%) as an oil. MS:184.07[M+H] + 。

[0466] Step C: A stirred solution of methyl 2-(1H-pyrrole-2-carbonyl)hydrazine-1-carboxylate (obtained from Step B) (8.0 g, 43.68 mmol) in EtOH (800 mL) was added with KOH (8.58 g, 152.87 mmol), and the mixture was heated to reflux for 2 hours. The reaction was monitored by TLC. After the starting material was consumed, the reaction mixture was cooled to room temperature. The resulting precipitate was filtered, and the solid was dissolved in H2O (50 mL), then acidified to pH - 4 with 1.0 N HCl (aqueous solution) and extracted with EtOAc (2 × 300 mL). The combined organic layers were evaporated under reduced pressure to obtain 2,3-dihydropyrrolo[1,2-d][1,2,4]triazine-1,4-dione (6.3 g, 95%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6): δ = 11.42 (s, 2H), 7.67 -7.66 (s, 1H), 6.81 - 6.80 (m, 1H), 6.73 - 6.71 (m, 1H). MS: 152.04 [M+H] + .

[0467] Step D: To a stirred solution of 2,3-dihydropyrrolo[1,2-d][1,2,4]triazine-1,4-dione (obtained from Step C) (2.5 g, 16.54 mmol) in POCl3 (15.56 mL, 165.42 mmol), DIPEA (2.3 mL, 13.23 mmol) was added dropwise at room temperature, and the mixture was stirred at 120 °C for 16 hours. The progress of the reaction was monitored by TLC. After the starting material was consumed, the reaction mixture was added dropwise to ice with stirring, and then stirred for 15 minutes. The off-white solid was filtered off through a Buchner funnel and dried to obtain the desired product 1-chloropyrrolo[1,2-d][1,2,4]triazin-4(3H)-one (1.8 g, 64%) as an off-white solid. 1 H NMR (400 MHz DMSO-d6): δ = 12.53 (s, 1H), 7.88 -7.86 (m, 1H), 6.92 - 6.87 (m, 2H). MS: 168.01 [M-H]- .

[0468] Step E: To a stirred solution of degassed 1-chloropyrrolo[1,2-d][1,2,4]triazin-4(3H)-one (1.0 g, 5.93 mmol, obtained from Step D) and (R)-1-methylpiperidin-3-amine (1.36 g, 11.86 mmol) in tetrahydrofuran (10 mL) at room temperature were added BrettPhos Pd G3 (0.54 g, 0.59 mmol) and BrettPhos (0.318 g, 0.59 mmol), followed by a one-time addition of 1 M lithium bis(trimethylsilyl)amide solution in THF (17.80 ml, 17.80 mmol). The mixture was stirred at 65 °C for 16 h. The reaction was monitored by TLC. After the starting material was consumed, the reaction mixture was quenched with saturated NH4Cl solution (70 mL) and extracted with ethyl acetate (2 × 200 mL). The combined organic layers were dried over Na2SO4, filtered, and evaporated under reduced pressure to give the crude compound as a light brown solid. The crude compound was triturated with diethyl ether (2 × 20 mL) to give a brown solid. The obtained solid was filtered through a Buchner funnel and dried to give (R)-1-((1-methylpiperidin-3-yl)amino)pyrrolo[1,2-d][1,2,4]triazin-4(3H)-one (1.2 g, 82%) as a light brown solid. 1 H NMR (400 MHz, DMSO-d6): δ =11.20 (s, 1H), 7.60 - 7.59 (q, 1H), 6.99 - 6.98 (dd, 1H), 6.67 - 6.65 (t, 1H), 6.28 - 6.26 (d, 1H), 5.75 (s, 1H), 3.78 - 3.71 (m, 1H), 2.96 - 2.94 (m, 1H), 2.65 - 2.62 (m, 1H), 2.15 (s, 3H), 1.91 - 1.66 (m, 4H), 1.55 - 1.45 (m, 1H),1.30 - 1.20 (m, 1H). MS: 248.11 [M+H] + .

[0469] Step F: (R)-1-((1-Methylpiperidin-3-yl)amino)pyrrolo[1,2-d][1,2,4]triazin-4(3H)-one (obtained from Step E) (500 mg, 2.02 mmol) was added dropwise to a stirred solution in POCl3 (3 mL) with N,N-diisopropylethylamine (0.28 mL, 1.62 mmol) at room temperature, and the mixture was stirred at 120 °C for 6 hours. The reaction was monitored by TLC. After the starting material was consumed, the reaction mixture was evaporated, quenched with ice, basified with saturated sodium bicarbonate solution (50 ml), and extracted with EtOAc (2 × 150 mL). The combined organic layers were washed with brine solution (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product (R)-4-chloro-N-(1-methylpiperidin-3-yl)pyrrolo[1,2-d][1,2,4]triazin-1-amine (380 mg, 70%) as an off-white rubbery solid. MS: 266.06 [M+H] + 。

[0470] Step G: To a stirred solution of degassed (R)-4-chloro-N-(1-methylpiperidin-3-yl)pyrrolo[1,2-d][1,2,4]triazin-1-amine (obtained from Step F) (250 mg, 0.94 mmol) and (2-hydroxy-4-(trifluoromethyl)phenyl)boronic acid (232.47 mg, 1.13 mmol) in 1,4-dioxane (3 mL) and water (3 mL), potassium carbonate (390.18 mg, 2.82 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane adduct (76.78 mg, 0.27 mmol) were added at room temperature, and the mixture was heated to 100 °C for 16 hours. The reaction was monitored by TLC. After the starting material was consumed, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 × 30 mL). The combined organic layers were separated, washed with brine solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude compound. The crude compound was purified by preparative HPLC.

[0471] Fractional HPLC Purification Conditions Mobile Phase: 10 mM ammonium bicarbonate in water / acetonitrile Column: Mobile Phase - Inertsil ODS-3V (25×150) mm 10 μm Flow Rate: 18 mL / min Gradient Method: T / %B - 0 / 30, 4 / 55, 12 / 55, 12.05 / 99, 14.05 / 99, 14.10 / 30, 18.10 / 30. Collect pure fractions, lyophilize to obtain (R)-2-(1-((1-methylpiperidin-3-yl)amino)pyrrolo[1,2-d][1,2,4]triazin-4-yl)-5-(trifluoromethyl)phenol (22 mg, 6%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6): δ = 10.81 (brs, 1H), 7.65 - 7.63 (d, 1H), 7.32 - 7.29 (m, 2H), 7.08 - 7.04 (dd, 2H), 6.99 - 6.97 (d, 1H), 6.72 - 6.70 (t, 1H), 4.25 (brs, 1H), 3.04 - 3.02 (d, 1H), 2.71 - 2.67 (brs, 1H), 2.21 (s, 3H), 1.92 - 1.90 (m, 3H), 1.76 - 1.72 (m, 1H), 1.62 - 1.56 (m, 1H), 1.41 - 1.36 (m, 1H), MS: 392.26 [M+H] + .

[0472] (Examples 2 to 5) In the same manner as the procedure of Example 1 above, the following examples were synthesized:

[0473]

Table 3

[0474] (Example 6) 5-(4-Chlorophenyl)-N-[(3R)-1-methyl-3-piperidyl]imidazo[1,2-d][1,2,4]triazin-8-amine

[0475]

Chemical formula

[0476] Step 1: To a solution of 5-sulfanylimidazo[1,2-d][1,2,4]triazin-8-ol (Intermediate 1) (15 g, 89.19 mmol, 1.0 equivalent) in acetone (150 mL) were added K2CO3 (24.65 g, 178.38 mmol, 2 equivalents) and MeI (15.19 g, 107.03 mmol, 6.66 mL, 1.2 equivalents). The resulting reaction mixture was stirred at 20 °C for 3 hours. The reaction solution was filtered to remove K2CO3 and then concentrated to obtain a crude product. The crude product was triturated with DCE (1000 mL) at 80 °C for 30 minutes. 5-Methylsulfanyl-imidazo[1,2-d][1,2,4]triazin-8-ol (12 g, crude) was obtained as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ = 12.62 (br s, 1H), 7.88 (d, 1H), 7.62 (d, 1H), 2.63 (s, 3H). MS: 183.1 [M+H] + .

[0477] Step 2: A solution of 5-methylsulfanylimidazo[1,2-d][1,2,4]triazin-8-ol (4 g, 21.95 mmol, 1 equiv) in POCl3 (58.49 g, 381.46 mmol, 35.56 mL, 17.38 equiv) was heated at 100 °C for 5 h. The reaction mixture was poured onto saturated NaHCO3 (100 mL) followed by DCM (20 mL). Thereafter, the aqueous phase was separated and extracted with DCM (30 mL × 3). The combined organic layers were successively washed 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, DCM:MeOH = 100 / 1 to 10 / 1). 8-Chloro-5-methylsulfanyl-imidazo[1,2-d][1,2,4]triazine (4.4 g, 50% yield) was obtained as a yellow solid. 1 1H NMR (400 MHz, DMSO-d6) δ = 8.22 (d, 1H), 7.97 (d, 1H), 2.84 (s, 3H). MS: 200.09 [M+H] + .

[0478] Step 3: A solution of 8-chloro-5-methylsulfanyl-imidazo[1,2-d][1,2,4]triazine (2 g, 9.97 mmol, 1.0 equiv) in DMSO (10 mL) was added to (3R)-1-methylpiperidin-3-amine (1.37 g, 11.96 mmol, 1.2 equiv) and KF (1.16 g, 19.94 mmol, 467.01 μL, 2 equiv). The resulting reaction mixture was stirred at 100 °C for 12 h. The reaction mixture was poured onto saturated Na2CO3 (30 mL). The resulting solution was then extracted with EtOAc (20 mL × 6) (while maintaining the aqueous phase at pH = 12). The combined organic layers were successively washed with saturated Na2CO3 (20 mL × 3) and brine (20 mL × 3) (while maintaining the aqueous phase at pH = 12), dried over anhydrous Na2SO4, filtered, and concentrated to give a residue. The residue was purified by flash silica gel chromatography (SiO2, DCM / MeOH = 100 / 1 to 5 / 1), and then further purified by preparative HPLC (column: Waters Xbridge BEH C18 250×70 mm×10 μm; mobile phase: [H2O(0.05% NH3H2O)-ACN]; gradient: 15% - 45% B over 20.0 min) to give the title product. N-[(3R)-1-Methyl-3-piperidyl]-5-methylsulfanyl-imidazo[1,2-d][1,2,4]triazin-8-amine (2.34 g, 42% yield) was obtained as a yellow oil. 1 H NMR (400 MHz, DMSO-d6) δ = 7.88 (d, 1H), 7.67 (d, 1H), 7.02 (br d, 1H), 4.24 - 4.13 (m, 1H), 2.84 - 2.76 (m, 1H), 2.71 (s, 3H), 2.55 - 2.53 (m, 1H), 2.21 - 2.16 (s, 3H), 2.11 - 1.99 (m, 2H), 1.80 - 1.74 (m, 1H), 1.67 (br dd, 1H), 1.58 - 1.47 (m, 2H). MS: 279.2 [M+H] + .

[0479] Step 4: A solution of N-[(3R)-1-methyl-3-piperidyl]-5-methylsulfanyl-imidazo[1,2-d][1,2,4]triazin-8-amine (0.3 g, 1.08 mmol, 1.0 equiv) in THF (5 mL) was added with (4-chlorophenyl)boronic acid (252.78 mg, 1.62 mmol, 1.5 equiv), cuprous iodide; 2-hydroxy-3-methyl-benzoate (578.40 mg, 2.69 mmol, 2.5 equiv), and Pd(PPh3)4 (373.60 mg, 323.30 μmol, 0.3 equiv). The resulting reaction mixture was stirred at 100 °C for 1 h. The reaction mixture was poured onto saturated EDTA (20 mL) followed by EtOAc (10 mL). The solution was stirred at 20 °C for 0.5 h. Thereafter, the aqueous phase was separated and extracted with EtOAc (20 mL × 5). The combined organic layers were successively washed with saturated Na2CO3 (20 mL × 1), dried over anhydrous Na2SO4, filtered, and concentrated to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 3 / 1 to DCM / MeOH = 10 / 1) to obtain 0.5 g of a product with a purity of 20%. Further purification by preparative HPLC (column: Phenomenex Luna C18 100×30 mm×5 μm; mobile phase: [H2O(0.2% FA)-ACN]; gradient: 5% - 30% B over 8.0 min) gave a pure product. 5-(4-Chlorophenyl)-N-[(3R)-1-methyl-3-piperidyl]imidazo[1,2-d][1,2,4]triazin-8-amine (45 mg, yield 12%) was obtained as an off-white solid. 1H NMR (400 MHz, DMSO) δ 7.92 (s, 1H), 7.87 (d, 2H), 7.71 - 7.63 (m, 3H), 7.31 (d, 1H), 4.41 - 4.23 (m, 1H), 2.84 (d, 1H), 2.60 - 2.51 (m, 1H), 2.22 (s, 3H), 2.11 (d, 2H), 1.79 (s, 1H), 1.74 - 1.66 (m, 1H), 1.66 - 1.49 (m, 2H). MS: 343.1 [M+H] + .

[0480] (Example 7) 5-chloro-2-[8-[[(3R)-1-methyl-3-piperidyl]amino]imidazo[1,2-d][1,2,4]triazin-5-yl]phenol formate

[0481] [Chemical formula]

[0482] To a solution of N-[(3R)-1-methyl-3-piperidyl]-5-methylsulfanyl-imidazo[1,2-d][1,2,4]triazin-8-amine (0.3 g, 1.08 mmol, 1.0 eq) in THF (5 mL) were added (4-chloro-2-hydroxy-phenyl)boronic acid (278.65 mg, 1.62 mmol, 1.5 eq), cuprous(I) 2-hydroxy-3-methyl-benzoate (578.40 mg, 2.69 mmol, 2.5 eq) and Pd(PPh3)4 (373.60 mg, 323.30 μmol, 0.3 eq). The resulting reaction mixture was stirred at 100 °C for 1 h in a sealed tube. The reaction mixture was poured onto saturated EDTA (20 mL) followed by EtOAc (10 mL). The solution was stirred at 20 °C for 0.5 h. Thereafter, the aqueous phase was separated and extracted with EtOAc (20 mL × 5). The combined organic layers were successively washed with saturated Na2CO3 (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 = 3 / 1 to DCM / MeOH = 10 / 1) to give 0.25 g of a product with a purity of 30%. Further purification by preparative HPLC (column: Phenomenex luna C18 100×40 mm×3 μm; mobile phase: [H2O(0.2% FA)-ACN]; gradient: 2% - 25% B over 8.0 min) gave 5-chloro-2-[8-[[(3R)-1-methyl-3-piperidyl]amino]imidazo[1,2-d][1,2,4]triazin-5-yl]phenol (42 mg, 11%) as a white solid. 1H NMR (400 MHz, DMSO) δ 10.88 (s, 1H), 8.19 (s, 1H), 7.59 (d, 1H), 7.49 (dd, 2H), 7.25 (d, 1H), 7.14 - 6.97 (m, 2H), 4.32 (s, 1H), 2.87 (d, 1H), 2.57 (s, 1H), 2.24 (s, 3H), 2.21 - 2.04 (m, 2H), 1.87 - 1.68 (m, 2H), 1.58 (q, 2H). MS: 359.1 [M+H] + .

[0483] (Example 8) 2-(1-((1s,3s)-3-Hydroxy-3-methylcyclobutoxy)pyrrolo[1,2-d][1,2,4]triazin-4-yl)-5-(trifluoromethyl)phenol

[0484] [Chemical Structure]

[0485] Step 1: To a stirred solution of 1-chloropyrrolo[1,2-d][1,2,4]triazin-4(3H)-one (1.0 g, 5.897 mmol) in toluene (20 mL) was added Lawesson's reagent (3.578 g, 8.846 mmol) at room temperature, and the reaction mixture was stirred at 120 °C for 3 h. The progress of the reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure to give the crude compound as a brown rubbery solid. The crude product was purified by column chromatography using silica gel (100 - 200) and eluting with 0 - 30% EtOAc in petroleum ether as a gradient. The product was eluted with 8% EtOAc in petroleum ether. The pure compound fractions were collected and concentrated under reduced pressure to give 1-chloropyrrolo[1,2-d][1,2,4]triazine-4(3H)-thione (0.66 g, 60%) as a white solid. MS:186.06[M+H] + 。

[0486] Step 2: To a stirred solution of degassed 1-chloropyrrolo[1,2-d][1,2,4]triazine-4(3H)-thione (600 mg, 3.232 mmol) in THF (10.0 mL) and water (5.0 mL) at room temperature, ethyl 2-bromoacetate (0.429 mL, 3.879 mmol) and potassium carbonate (670.073 mg, 4.848 mmol) were added, and the reaction mixture was stirred at room temperature for 3 h. The progress of the reaction was monitored by TLC. The reaction mixture was diluted with ice-cold water (30 mL), the solid was filtered off, and dried in vacuo to give ethyl 2-((1-chloropyrrolo[1,2-d][1,2,4]triazin-4-yl)thio)acetate (660 mg, 75%) as an off-white solid. MS: 272.39 [M+H] + 。

[0487] Step 3: To a stirred solution of degassed ethyl 2-((1-chloropyrrolo[1,2-d][1,2,4]triazin-4-yl)thio)acetate (660 mg, 2.429 mmol), (2-methoxy-4-(trifluoromethyl)phenyl)boronic acid (1175.359 mg, 5.344 mmol) and copper(I) 3-methylsalicylate (1147.251 mg, 5.344 mmol) in THF (8 mL) at room temperature, tetrakis(triphenylphosphine)palladium(0) (140.344 mg, 0.121 mmol) was added, and the reaction mixture was stirred at 70 °C for 3 h. The progress of the reaction was monitored by TLC. The crude material was filtered through a Celite bed and washed with THF (10 mL). The filtrate was evaporated and dried in vacuo to give a brown rubbery material. The crude product was purified by column chromatography using silica gel (100 - 200) and eluting with 0 - 50% EtOAc in petroleum ether as a gradient. The product was eluted with 25% EtOAc in petroleum ether. The pure fractions were collected and concentrated under reduced pressure to give 1-chloro-4-(2-methoxy-4-(trifluoromethyl)phenyl)pyrrolo[1,2-d][1,2,4]triazine (600 mg, 75.38%) as a yellow solid. MS: 328.43 [M+H] + 。

[0488] Step 4: To a stirred solution of 1-chloro-4-(2-methoxy-4-(trifluoromethyl)phenyl)pyrrolo[1,2-d][1,2,4]triazine (600 mg, 1.831 mmol) in DCM (12 mL) was added a 1 M solution of boron tribromide in DCM (6 mL) at -10 °C, and the reaction mixture was stirred at 0 °C for 1 hour. The progress of the reaction was monitored by TLC. The crude material was evaporated under reduced pressure and co-distilled with DCM (5 mL) to give the crude residue as a brown rubbery solid. This was triturated further with DCM (5 mL), and the resulting solid was filtered and dried thoroughly under vacuum to give 2-(1-chloropyrrolo[1,2-d][1,2,4]triazin-4-yl)-5-(trifluoromethyl)phenol (480 mg, 83.58%) as an off-white solid. MS: 314.08 [M+H] + 。

[0489] Step 5: To a stirred solution of degassed 1-methylcyclobutane-1,3-diol (374.010 mg, 3.662 mmol) in THF (6 mL) was added a 1 M solution of LiHMDS in THF (4.577 mL, 4.577 mmol) at 60 °C. The reaction mixture was stirred at 60 °C for 30 minutes and then cooled to room temperature. 1-Chloro-4-(2-methoxy-4-(trifluoromethyl)phenyl)pyrrolo[1,2-d][1,2,4]triazine (300 mg, 0.915 mmol) was added and the reaction mixture was stirred at 60 °C for 16 hours. The progress of the reaction was monitored by LCMS. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 × 80 mL). The combined organic layers were separated, washed with brine solution (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product as a brownish oil. The crude product was purified by column chromatography using silica gel (100 - 200) and eluting with a gradient of 0 - 10% MeOH in DCM. The product was eluted with 7% MeOH in DCM. The pure fractions were collected and concentrated under reduced pressure. The resulting residue was triturated with diethyl ether (5 mL), the precipitated solid was filtered off, and dried in vacuo to give 2-(1-((1s,3s)-3-hydroxy-3-methylcyclobutoxy)pyrrolo[1,2-d][1,2,4]triazin-4-yl)-5-(trifluoromethyl)phenol (25 mg, 7%) as an off-white solid. 1H NMR (400 MHz, DMSO) δ 10.94 (s, 1H), 7.70 (d, 1H), 7.38 - 7.29 (m, 2H), 7.22 (dd, 1H), 6.91 (dd, 1H), 6.87 (dd, 1H), 5.21 (s, 1H), 5.09 (p, 1H), 2.61 (ddd, 2H), 2.31 - 2.22 (m, 2H), 1.30 (s, 3H). MS: 380.24 [M+H] + .

[0490] (Example 9) 5-Chloro-2-[8-[[(3R)-1-methylpyrrolidin-3-yl]amino]imidazo[1,2-d][1,2,4]triazin-5-yl]phenol

[0491]

Chem.

[0492] Step 1: KF (463.27 mg, 7.97 mmol, 186.80 μL, 2 equiv) was added to a solution of 8-chloro-5-methylsulfanyl-imidazo[1,2-d][1,2,4]triazine (800 mg, 3.99 mmol, 1 equiv) and (3R)-1-methylpyrrolidin-3-amine (798.70 mg, 7.97 mmol, 2 equiv) in DMSO (8 mL). The mixture was stirred at 100 °C for 1 h. The reaction mixture was adjusted to pH 12 with saturated Na2CO3 (20 mL), and then extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine 20 mL, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, DCM:MeOH = 1 / 0 to 90 / 10) to afford N-[(3R)-1-methylpyrrolidin-3-yl]-5-methylsulfanyl-imidazo[1,2-d][1,2,4]triazin-8-amine (700 mg, 2.65 mmol, 66.41%) as a yellow oil. 1 H NMR (400 MHz, DMSO-d6) δ = 7.87 (d, 1H), 7.67 (d, 1H), 7.33 (br d, 1H), 4.56 - 4.46 (m, 1H), 2.82 (dd, 1H), 2.71 (s, 3H), 2.63 - 2.58 (m, 1H), 2.54 - 2.53 (m, 1H), 2.46 - 2.41 (m, 1H), 2.26 (s, 3H), 2.24 - 2.16 (m, 1H), 1.89 (tdd, 1H) MS: 265.5 [M+H] + .

[0493] Step 2: To a solution of N-[(3R)-1-methylpyrrolidin-3-yl]-5-methylsulfanyl-imidazo[1,2-d][1,2,4]triazin-8-amine (300 mg, 1.13 mmol, 1 equiv) and (4-chloro-2-hydroxy-phenyl)boronic acid (293.43 mg, 1.70 mmol, 1.5 equiv) in THF (5 mL) were added Pd(PPh3)4 (393.42 mg, 340.46 μmol, 0.3 equiv) and CuMeSal (609.09 mg, 2.84 mmol, 2.5 equiv). The mixture was stirred in a sealed tube at 100 °C for 8 h. The reaction mixture was quenched by the addition of EDTA (10 mL), and then extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, DCM / MeOH = 1 / 0 to 5 / 1), and then further purified by preparative HPLC (column: Phenomenex Luna C18 100×30 mm×5 μm; mobile phase: [H2O(0.2%FA)-ACN]; gradient: 1% - 25% B over 8.0 min) to afford 5-chloro-2-[8-[[(3R)-1-methylpyrrolidin-3-yl]amino]imidazo[1,2-d][1,2,4]triazin-5-yl]phenol (20.8 mg, 5%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ = 11.51 - 10.30 (m, 1H), 7.60 (s, 2H), 7.49 (t, 2H), 7.11 - 7.01 (m, 2H), 4.66 (br d, 1H), 2.93 (br d, 1H), 2.73 - 2.61 (m, 2H), 2.55 (br d, 1H), 2.34 (br d, 3H), 2.30 - 2.21 (m, 1H), 2.03 - 1.91 (m, 1H). 11H NMR (400 MHz, CDCl3) δ = 8.55 (broad singlet, 1H), 7.96 (singlet, 1H), 7.74 - 7.69 (multiplet, 2H), 7.53 (broad singlet, 1H), 7.20 (doublet, 1H), 7.05 - 7.00 (multiplet, 1H), 5.08 (broad singlet, 1H), 3.53 - 3.47 (multiplet, 2H), 3.10 - 3.05 (multiplet, 1H), 2.74 (broad doublet, 1H), 2.68 (singlet, 3H), 2.65 (broad doublet, 1H), 2.32 - 2.22 (multiplet, 1H). MS: 345.1 [M+H] + .

[0494] (Example 10) 2-(8-Fluoro-1-(((1s,3s)-3-hydroxy-3-methylcyclobutyl)amino)pyrrolo[1,2-d][1,2,4]triazin-4-yl)-5-(trifluoromethyl)phenol In the same procedure as in Example 8 above, the following examples were synthesized:

[0495]

Chemical Structure

[0496]

Table 4

[0497] (Example 11) 2-(4-(((1s,3s)-3-hydroxy-3-methylcyclobutyl)amino)pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol

[0498]

Chemical Structure

[0499] Step 1: A stirred solution of degassed 1-chloropyrrolo[1,2-d][1,2,4]triazin-4(3H)-one (0.60 g, 3.538 mmol) in 1,4-dioxane (12 mL) and water (1.2 mL) was added with (2-methoxy-4-(trifluoromethyl)phenyl)boronic acid (0.778 g, 3.538 mmol), potassium phosphate (0.751 g, 3.538 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), dichloromethane complex (0.144 g, 0.177 mmol) at room temperature, and the reaction mixture was heated to 100 °C for 1 hour. The progress of the reaction was monitored by TLC. The reaction mixture was quenched with ice-cold water (50 mL) and stirred for 10 minutes. The precipitate was filtered, washed with water (50 mL) and dried in vacuo to give 1-(2-methoxy-4-(trifluoromethyl)phenyl)pyrrolo[1,2-d][1,2,4]triazin-4(3H)-one (0.90 g, 82.25%) as an off-white solid. MS: 310.35 [M+H] + 。

[0500] Step 2: A stirred solution of 1-(2-methoxy-4-(trifluoromethyl)phenyl)pyrrolo[1,2-d][1,2,4]triazin-4(3H)-one (0.60 g, 1.940 mmol) in pyridine (6.0 mL) was added with phosphorus pentasulfide (1.725 g, 3.880 mmol) at room temperature, and the reaction mixture was heated to 150 °C for 3 hours in a sealed tube. The progress of the reaction was monitored by TLC. The reaction mixture was diluted with ice-cold water (50 mL) and stirred for 10 minutes. The precipitated solid was filtered, washed with water (50 mL) and dried in vacuo to give 1-(2-methoxy-4-(trifluoromethyl)phenyl)pyrrolo[1,2-d][1,2,4]triazin-4(3H)-thione (0.50 g, 79.22%) as an off-white solid. MS: 326.26 [M+H] + 。

[0501] Step 3: A stirred solution of degassed 1-(2-methoxy-4-(trifluoromethyl)phenyl)pyrrolo[1,2-d][1,2,4]triazin-4(3H)-thione (0.50 g, 1.537 mmol) in tetrahydrofuran (20.0 mL) and water (10.0 mL) was added with ethyl 2-bromoacetate (0.513 g, 3.074 mmol) and potassium carbonate (1.062 g, 7.685 mmol) at room temperature, and the reaction mixture was stirred for 3 hours. The progress of the reaction was monitored by TLC. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with brine solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product as a brownish oil. MS: 412.28 [M+H] + 。

[0502] Step 4: To a stirred solution of ethyl 2-((1-(2-methoxy-4-(trifluoromethyl)phenyl)pyrrolo[1,2-d][1,2,4]triazin-4-yl)thio)acetate (0.50 g, 1.215 mmol) and (1s,3s)-3-amino-1-methylcyclobutan-1-ol hydrochloride (0.334 g, 2.431 mmol) in N,N-dimethylformamide (10.0 mL) was added N,N-diisopropylethylamine (0.635 mL, 3.646 mmol) at room temperature, and the reaction mixture was heated to 100 °C and stirred in a sealed tube for 16 hours. The progress of the reaction was monitored by TLC. The reaction mixture was diluted with ice-cold water (50 mL) and extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with cold brine solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product as a brownish rubbery solid. The crude product was purified by column chromatography using silica gel (100 - 200) and eluting with a gradient of 0 - 10% MeOH in DCM. The pure fractions were collected and concentrated under reduced pressure to obtain (1s,3s)-3-((1-(2-methoxy-4-(trifluoromethyl)phenyl)pyrrolo[1,2-d][1,2,4]triazin-4-yl)amino)-1-methylcyclobutan-1-ol (0.30 g, 63%) as an off-white solid. MS: 393.36 [M+H] + 。

[0503] Step 5: (1s,3s)-3-((1-(2-Methoxy-4-(trifluoromethyl)phenyl)pyrrolo[1,2-d][1,2,4]triazin-4-yl)amino)-1-methylcyclobutan-1-ol (0.150 g, 0.382 mmol) was added to a stirred solution in dichloromethane (7.5 mL) at -78 °C with 1.0 M boron tribromide in dichloromethane (1.147 mL, 1.147 mmol). The reaction mixture was stirred for 10 minutes. The progress of the reaction was monitored by TLC. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with brine solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product as a yellow solid. The crude product was purified by preparative HPLC (column: Luna C18 (25 × 150 mm) 10 μm; buffer A: 10 mM ABC buffer B: acetonitrile mobile phase conditions (T / %B): 0 / 30, 2 / 30, 10 / 70, 15 / 70, 15.1 / 98, 20 / 98, 20.1 / 98 flow rate: 19 mL / min, fraction volume: 200 mL). The fractions were collected, concentrated under reduced pressure, and lyophilized to give 2-(4-(((1s,3s)-3-Hydroxy-3-methylcyclobutyl)-amino)pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol (0.047 g, 32%) as an off-white solid. 1H NMR (400 MHz, DMSO) δ 13.60 (s, 1H), 8.14 (d, 1H), 8.09 (d, 1H), 8.06 - 7.90 (m, 1H), 7.36 - 7.24 (m, 2H), 7.21 (d, 1H), 7.14 - 7.06 (m, 1H), 5.08 (s, 1H), 4.30 - 4.13 (m, 1H), 2.49 - 2.46 (m, 2H), 2.21 (dd, 2H), 1.34 (s, 3H). MS: 379.25 [M+H] + .

[0504] (Example 12) 2-(1-(((1s,3s)-3-hydroxy-3-methylcyclobutyl)amino)pyrrolo[1,2-d][1,2,4]triazin-4-yl)-5-(trifluoromethyl)phenol

[0505] [Chemical formula]

[0506] Step 1: To a stirred solution of 1H-pyrrole-2-carbohydrazide (15 g, 119.874 mmol) and tetramethyl orthocarbonate (24.239 mL, 179.812 mmol) in acetonitrile (250 mL) was added aluminum isopropoxide (4.897 g, 23.975 mmol) at room temperature, and the reaction mixture was stirred in a sealed tube at 120 °C for 5 days. The progress of the reaction was monitored by TLC. The reaction mixture was cooled to room temperature, diluted with ACN (40 mL), and the resulting precipitate was filtered off and dried thoroughly under vacuum to give 4-methoxypyrrolo[1,2-d][1,2,4]triazin-1(2H)-one (7.5 g, 38%) as a yellow solid. MS: 166.31 [M+H] + .

[0507] Step 2: To a stirred solution of 60% sodium hydride (3.270 g, 136.238 mmol) in N,N-dimethylformamide (60 mL) was added 4-methoxypyrrolo[1,2-d][1,2,4]triazin-1(2H)-one (7.5 g, 45.413 mmol) at 0 °C, and the reaction mixture was stirred for 10 minutes, then benzyl bromide (6.473 mL, 54.495 mmol) was added at 0 °C. The resulting mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. The reaction mixture was quenched with ice-cold water (120 mL) and stirred for 30 minutes. The precipitated solid was filtered off, washed with water (10 mL), and dried under vacuum to give 2-benzyl-4-methoxypyrrolo[1,2-d][1,2,4]triazin-1(2H)-one (6 g, 55%) as an off-white solid. MS: 256.11 [M+H] + 。

[0508] Step 3: To a stirred solution of 2-benzyl-4-methoxypyrrolo[1,2-d][1,2,4]triazin-1(2H)-one (6 g, 23.504 mmol) in acetonitrile (120 mL) was added chlorotrimethylsilane (6.563 mL, 51.709 mmol) and sodium iodide (7.751 g, 51.709 mmol) at room temperature, and the reaction mixture was stirred at 80 °C for 1 hour. The progress of the reaction was monitored by TLC. The reaction mixture was quenched with ice-cold water (150 mL) and stirred for 30 minutes. The solid precipitated, was filtered, washed with water (20 mL), and dried under vacuum to give 2-benzyl-4-hydroxypyrrolo[1,2-d][1,2,4]triazin-1(2H)-one (5 g, 88%) as an off-white solid. MS: 242.07 [M+H] + 。

[0509] Step 4: To a stirred solution of 2-benzyl-4-hydroxypyrrolo[1,2-d][1,2,4]triazin-1(2H)-one (2.0 g, 8.290 mmol) in DCM (200 mL) was added dropwise triethylamine (2.311 mL, 16.580 mmol) and trifluoromethanesulfonic anhydride (2.784 mL, 16.580 mmol) at 0 °C, and the reaction mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. The reaction mixture was diluted with water (60 mL) and extracted with DCM (2 × 60 mL). The combined organic layers were dried over Na2SO4, filtered, and evaporated under reduced pressure to give the crude compound as a brown rubbery material. The crude compound was purified by column chromatography using silica gel (100 - 200) and eluting with DCM as a gradient. The product was eluted in 100% DCM. The pure fractions were collected and concentrated under reduced pressure to give 2-benzyl-1-oxo-1,2-dihydropyrrolo[1,2-d][1,2,4]triazin-4-yl trifluoromethanesulfonate (1.9 g, 61%) as an off-white solid. MS: 374.36 [M+H] + 。

[0510] Step 5: To a solution of degassed (2-methoxy-4-(trifluoromethyl)phenyl)boronic acid (1.679 g, 7.634 mmol) and triethylamine (2.128 mL, 15.269 mmol) in 1,4-dioxane (10 mL) at room temperature, Xantphos Pd G4 (0.490 g, 0.509 mmol) was added and the reaction mixture was stirred at 100 °C for 3 minutes. Then 2-benzyl-1-oxo-1,2-dihydropyrrolo[1,2-d][1,2,4]triazin-4-yl trifluoromethanesulfonate (1.9 g, 5.090 mmol) in 1,4-dioxane (10 mL) was added dropwise over 20 minutes and the reaction mixture was stirred at the same temperature for 20 minutes. The progress of the reaction was monitored by TLC. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2 × 70 ml). The combined organic layers were dried over Na2SO4, filtered and evaporated under reduced pressure to give the crude compound as a brown rubbery solid. The crude product was purified by column chromatography using silica gel (100 - 200) and eluting with EtOAc in petroleum ether as a gradient. The product was eluted with 20% EtOAc in petroleum ether. The pure fractions were collected and concentrated under reduced pressure to give 2-benzyl-4-(2-methoxy-4-(trifluoromethyl)phenyl)pyrrolo[1,2-d][1,2,4]triazin-1(2H)-one (1.5 g, 73.79%) as an off-white solid. MS: 400.20 [M+H] + 。

[0511] Step 6: To 2-benzyl-4-(2-methoxy-4-(trifluoromethyl)phenyl)pyrrolo[1,2-d][1,2,4]triazin-1(2H)-one (500 mg, 1.252 mmol), phosphoryl chloride (6 mL) was added dropwise at 0 °C, and the reaction mixture was stirred at 110 °C for 48 h. The progress of the reaction was monitored by LCMS. The crude material was evaporated under reduced pressure. The reaction mixture was quenched with ice-cooled saturated bicarbonate solution (12 mL) and extracted with EtOAc (2 × 30 mL). The combined organic layers were washed with brine solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product as a brownish rubbery solid. The crude product was purified by column chromatography using silica gel (100 - 200) and eluting with EtOAc in petroleum ether as a gradient. The product was eluted with 20% EtOAc in petroleum ether. The pure fractions were collected and concentrated under reduced pressure to obtain 1-chloro-4-(2-methoxy-4-(trifluoromethyl)phenyl)pyrrolo[1,2-d][1,2,4]triazine (60 mg, 14.62%) as an off-white solid. MS: 328.10[M+H] + 。

[0512] Step 7: To a stirred solution of 1-chloro-4-(2-methoxy-4-(trifluoromethyl)phenyl)pyrrolo[1,2-d][1,2,4]triazine (40 mg, 0.122 mmol) in DCM (4 mL), boron tribromide 1 M in dichloromethane (0.366 mL, 0.366 mmol) was added at -78 °C, and the reaction mixture was slowly warmed to room temperature and stirred for 2 h. The progress of the reaction was monitored by LCMS. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (2 × 30 mL). The combined organic layers were washed with brine solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product as an off-white rubbery solid. MS: 314.12[M+H] + 。

[0513] Step 8: A stirred solution of 2-(1-chloropyrrolo[1,2-d][1,2,4]triazin-4-yl)-5-(trifluoromethyl)phenol (45 mg, 0.143 mmol) in N,N-diisopropylethylamine (0.5 mL) was added to (1s,3s)-3-amino-1-methylcyclobutan-1-ol hydrochloride (23.690 mg, 0.172 mmol) in a sealed tube, and the reaction mixture was stirred at 120 °C for 3 h. The progress of the reaction was monitored by LCMS. The reaction mixture was evaporated under reduced pressure to give a crude residue as a yellow solid. This product was purified by preparative HPLC (mobile phase: 10 mM ammonium bicarbonate (aqueous solution): MeCN, column: Xselect-CSH, flow rate 5 ml / min, gradient method: 0 / 30, 10 / 60, 10.01 / 100, 16 / 100, 16.01, 30, 21 / 30) to give 2-(1-(((1s,3s)-3-hydroxy-3-methylcyclobutyl)amino)pyrrolo[1,2-d][1,2,4]triazin-4-yl)-5-(trifluoromethyl)phenol (5 mg, 9.2%) as an off-white solid. 1H NMR (400 MHz, DMSO) δ 10.82 (s, 1H), 7.64 (d, 1H), 7.43 (d, 1H), 7.38 - 7.24 (m, 2H), 7.14 - 6.99 (m, 2H), 6.71 (dd, 1H), 5.01 (s, 1H), 4.15 (h, 1H), 2.47 - 2.39 (m, 2H), 2.22 - 2.04 (m, 2H), 1.31 (s, 3H). MS: 379.30 [M+H] + .

[0514] (Example 13) 2-(4-((1s,3s)-3-hydroxy-3-methylcyclobutoxy)pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol

[0515]

Chemical formula

[0516] Step 1: To a stirred solution of 1-(2-methoxy-4-(trifluoromethyl)phenyl)pyrrolo[1,2-d][1,2,4]triazin-4(3H)-thione (0.30 g, 0.922 mmol) in DCM (15.0 mL) at -78 °C was added boron tribromide 1.0 M in DCM (2.767 mL, 2.767 mmol). The reaction mixture was stirred for 1 hour. The progress of the reaction was monitored by TLC. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with brine solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product as a pale yellow solid. MS: 312.33 [M+H] + 。

[0517] Step 2: To a stirred solution of degassed 1-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrrolo[1,2-d][1,2,4]triazin-4(3H)-thione (0.25 g, 0.803 mmol) in THF (10.0 mL) and water (5.0 mL) at room temperature were added ethyl 2-bromoacetate (0.134 g, 0.803 mmol) and potassium carbonate (0.166 g, 1.205 mmol). The reaction mixture was stirred for 2 hours. The progress of the reaction was monitored by TLC. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2 × 200 mL). The combined organic layers were washed with brine solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product as a yellow solid. MS: 398.23 [M+H] + 。

[0518] Step 3: A stirred solution of 1-methylcyclobutane-1,3-diol (0.964 g, 9.437 mmol) in THF (6.0 mL) was added with 1 M LiHMDS solution (3.146 mL, 3.146 mmol) in THF at once at room temperature, and the reaction mixture was heated to 65 °C for 10 minutes. Then, ethyl 2-((1-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrrolo[1,2-d][1,2,4]triazin-4-yl)thio)acetate (0.250 g, 0.629 mmol) in THF (4.0 mL) was added to the suspension at room temperature, and the reaction mixture was heated to 65 °C and stirred in a sealed tube for 16 hours. The progress of the reaction was monitored by TLC. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2 × 200 mL). The combined organic layers were washed with brine solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product as a brown rubbery substance. The crude product was purified by preparative HPLC. (Buffer A: 10 mM ABC, Buffer B: ACN, mobile phase conditions (B%): 0 / 40, 2 / 40, 10 / 70, 16 / 70, 16.01 / 9, column: inersil flow rate - 19 mL / min). The pure fractions were collected, concentrated under reduced pressure, and lyophilized to obtain 2-(4-((1s,3s)-3-hydroxy-3-methylcyclobutoxy)pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol (0.017 g, 7%) as an off-white solid. 1H NMR (400 MHz, DMSO) δ 12.23 (s, 1H), 7.84 (d, 1H), 7.77 (dd, 1H), 7.25 (s, 1H), 7.20 (d, 1H), 7.05 (dd, 1H), 6.96 (dd, 1H), 5.46 - 5.10 (m, 2H), 2.74 - 2.61 (m, 2H), 2.44 - 2.33 (m, 2H), 1.32 (s, 3H). MS: 380.26 [M+H] + .

[0519] (Example 14) 2-[8-[[(3R)-1-Ethyl-3-piperidyl]amino]imidazo[1,2-d][1,2,4]triazin-5-yl]-5-(trifluoromethyl)phenol

[0520]

Chem.

[0521] Step 1: A mixture of 8-chloro-5-methylsulfanyl-imidazo[1,2-d][1,2,4]triazine (0.5 g, 2.49 mmol, 1 equiv), (3R)-1-ethylpiperidin-3-amine (1.00 g, 4.98 mmol, 2 equiv, 2HCl), DIEA (1.29 g, 9.97 mmol, 1.74 mL, 4 equiv), and KF (289.54 mg, 4.98 mmol, 116.75 μL, 2 equiv) in DMSO (5 mL) was degassed and purged with N2 three times, then the mixture was stirred at 100 °C for 14 h under a N2 atmosphere. The reaction mixture was quenched by the addition of H2O (50 mL), then extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (50 mL × 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 4 / 1 to 1 / 1 then DCM:MeOH:TEA = 40:2:1 to DCM:MeOH:TEA = 20:2:1, TLC (PE:EtOAc = 1:1, R f = 0, DCM:MeOH:TEA = 20:2:1, R f = 0.2). The purified product was diluted with EtOAc (50 mL), then washed with brine 150 mL (50 mL × 3) to give the title compound N-[(3R)-1-ethyl-3-piperidyl]-5-methylsulfanyl-imidazo[,2-d][1,2,4]triazin-8-amine (470 mg, 43%) as a yellow oil. 11H NMR (400 MHz, DMSO-d6) δ= 7.90 - 7.85 (m, 1H), 7.67 (d, J = 1.3 Hz, 1H), 7.14 - 6.95 (m, 1H), 4.25 - 4.13 (m, 1H), 2.93 - 2.85 (m, 1H), 2.71 (s, 3H), 2.66 - 2.60 (m, 1H), 2.43 - 2.33 (m, 2H), 2.21 - 2.03 (m, 2H), 1.84 - 1.74 (m, 1H), 1.72 - 1.64 (m, 1H), 1.62 - 1.46 (m, 2H), 1.05 - 0.98 (m, 3H). MS: 293.0 [M+H] + .

[0522] Step 2: A mixture of N-[(3R)-1-ethyl-3-piperidyl]-5-methylsulfanyl-imidazo[1,2-d][1,2,4]triazin-8-amine (0.18 g, 615.59 μmol, 1 equiv), [2-hydroxy-4-(trifluoromethyl)phenyl]boronic acid (253.53 mg, 1.23 mmol, 2 equiv), cuprous(I) 2-hydroxy-3-methyl-benzoate (660.79 mg, 3.08 mmol, 5 equiv) and Pd(PPh3)4 (426.81 mg, 369.35 μmol, 0.6 equiv) in THF (10 mL) was degassed and purged with N2 three times, then the mixture was stirred at 100 °C for 4.5 h under a N2 atmosphere. The reaction mixture was poured into EDTA (50 mL) and stirred at room temperature for 1 h. The mixture was extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL × 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 2 / 1 to 1 / 2 then DCM:MeOH:TEA = 20:2:1, TLC (PE:EtOAc = 1:1, R f = 0, DCM:MeOH:TEA = 20:2:1, R fPurified by ( = 0.2)), then by column chromatography (SiO2, petroleum ether / ethyl acetate = 2 / 1 to 1 / 2 then DCM:MeOH:TEA = 20:2:1, TLC (PE:EtOAc = 1:1, R f = 0, DCM:MeOH:TEA = 20:2:1, R f Purified by ( = 0.2)), then by preparative HPLC (column: Waters Xbridge Prep OBD C18 150×40mm×10um; mobile phase: [H2O(10mM NH4HCO3)-ACN]; gradient: 15% - 45% B over 8.0 minutes) to obtain 2-[8-[[(3R)-1-ethyl-3-piperidyl]amino]imidazo[1,2-d][1,2,4]triazin-5-yl]-5-(trifluoromethyl)phenol (36.75 mg, 14%) as a white solid. LC-MS (ES+, m / z): 407.1[(M+H) + . 1H NMR (400 MHz, DMSO-d6) δ = 11.41 - 10.70 (m, 1H), 7.77 - 7.66 (m, 1H), 7.64 - 7.57 (m, 1H), 7.56 - 7.49 (m, 1H), 7.39 - 7.20 (m, 3H), 4.44 - 4.22 (m, 1H), 2.99 - 2.83 (m, 1H), 2.74 - 2.57 (m, 1H), 2.39 (q, 2H), 2.25 - 2.02 (m, 2H), 1.88 - 1.79 (m, 1H), 1.77 - 1.46 (m, 3H), 1.02 (t, 3H). MS: 407.1 [M+H] + .

[0523] (Example 15) 5-Chloro-2-[8-[[(3R)-1-ethyl-3-piperidyl]amino]imidazo[1,2-d][1,2,4]triazin-5-yl]phenol

[0524]

Chemical Structure

[0525] N-[(3R)-1-Ethyl-3-piperidyl]-5-methylsulfanyl-imidazo[1,2-d][1,2,4]triazin-8-amine (0.18 g, 615.59 μmol, 1 equiv), (4-chloro-2-hydroxy-phenyl)boronic acid (212.22 mg, 1.23 mmol, 2 equiv), cuprous(I) 2-hydroxy-3-methyl-benzoate (660.79 mg, 3.08 mmol, 5 equiv) and Pd(PPh3)4 (426.81 mg, 369.35 μmol, 0.6 equiv) in THF (10 mL) were degassed and purged with N2 three times, then the mixture was stirred at 100 °C for 4.5 h under a N2 atmosphere in a sealed tube. The reaction mixture was poured into EDTA (50 mL) and stirred at room temperature for 1 h. The mixture was extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL × 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 2 / 1 to 1 / 2 then DCM:MeOH:TEA = 20:2:1, TLC (PE:EtOAc = 1:1, R f = 0, DCM:MeOH:TEA = 20:2:1, R f = 0.2)) and further purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150×40 mm×10 um; mobile phase: [H2O(10 mM NH4HCO3)-ACN]; gradient: 15% - 45% B over 8.0 min) to give 5-chloro-2-[8-[[(3R)-1-ethyl-3-piperidyl]amino]imidazo[1,2-d][1,2,4]triazin-5-yl]phenol (42.27 mg, 18%) as a white solid. 11H NMR (400 MHz, DMSO-d6) δ = 11.30 - 10.15 (m, 1H), 7.66 - 7.56 (m, 1H), 7.50 (br s, 2H), 7.32 - 7.15 (m, 1H), 7.09 - 6.97 (m, 2H), 4.37 - 4.19 (m, 1H), 2.98 - 2.82 (m, 1H), 2.71 - 2.56 (m, 1H), 2.42 - 2.33 (m, 2H), 2.24 - 2.01 (m, 2H), 1.88 - 1.77 (m, 1H), 1.76 - 1.45 (m, 3H), 1.01 (t, 3H). MS: 373.1 [M+H] + .

[0526] Description of Biological Assays 1.1 NLRP3 Inhibition Assay The following assays were used to determine the inhibitory activity of test compounds against the NLRP3 inflammasome pathway using the co-stimuli nigericin (Invivogen) or monosodium urate crystals (MSU) (Invivogen).

[0527] Cell Culture Human monocyte-like cells were cultured in RPMI-1640 Glutamax medium supplemented with 10% heat-inactivated FBS (fetal bovine serum) and 50 U / mL penicillin-streptomycin (Life Technologies).

[0528] NLRP3 Inflammasome Pathway Activation Assay Human monocyte-like cells were seeded at 25,000 cells per well in a 384-well plate and differentiated into macrophages overnight with 10 ng / mL PMA (phorbol 12-myristate 13-acetate). The next day, medium containing 10 ng / mL LPS (lipopolysaccharide) was added. After 3 hours of LPS priming, test compounds at concentrations ranging from 100 μM to 380 pM were added 30 minutes prior to a 3-hour stimulation of the NLRP3 inflammasome pathway using 3.75 μM nigericin or 200 μg / mL MSU.

[0529] Measurement of IL-1β For IL-1β quantification, the HTRF kit (Cisbio 62HIL1BPEH) was used according to the manufacturer's instructions, and the supernatant was analyzed. Briefly, in a 384-well ProxiPlate™ microplate, 8 μl of the sample was mixed with 5 μl of Anti-IL1β Cryptate antibody (40-fold) and Anti-IL1β XL antibody (40-fold). Then, it was incubated overnight at room temperature. Reading was performed using an EnVision Reader (PerkinElmer).

[0530] Using GraphPad Prism 9, the IC 50 (concentration corresponding to 50% inhibition) was determined.

[0531] The following example compounds were measured.

[0532]

Table 5

[0533] The compounds tested showed inhibition of IL-1 beta release using MSU or nigericin as activators in human monocyte-like cells. See Table 1 (Table 5).

[0534] The tested compounds 8 and 11 of the present invention [where Z1 = N and Z2 = C] surprisingly showed a significantly increased inhibition of IL-1 beta release in human monocyte-like cells using MSU or nigericin as activators, compared to the equivalent compounds 13 and 12 [where Z1 = C and Z2 = N], respectively. See Table 1 (Table 5).

[0535] The results show that the compounds of the present invention [where Z1 = N and Z2 = C] surprisingly show a significantly increased inhibition of IL-1 beta release in human monocyte-like cells using MSU or nigericin as activators, compared to the equivalent compounds [where Z1 = C and Z2 = N].

[0536] 1.2 Inhibition of Interleukin-1 beta (IL-1β) in a Lipopolysaccharide / ATP-induced Acute Peritonitis Mouse Model The efficacy of Compound 5 in LPS / ATP-induced acute peritonitis was evaluated. Lipopolysaccharide (LPS) and adenosine triphosphate (ATP) were administered to BALB / c mice by intraperitoneal (i.p.) injection to induce an acute inflammatory response in the peritoneal cavity.

[0537] Methods Mice (BALB / c mice, 6 - 8 weeks old, female) were administered 50 μg / kg of LPS by intraperitoneal (i.p.) injection. 120 minutes after LPS injection, ATP was injected i.p. at 50 mM in 200 μL. Compound 5 was formulated in 0.5% sodium carboxymethyl cellulose and 0.2% Tween 80 in water at a dose of 10 mL / kg. Compound 5 was administered 30 minutes before LPS injection. 30 minutes after ATP injection, the animals were sacrificed by CO2. For peritoneal wash (PW) collection, a 25G needle was used to inject 3 mL of cold phosphate-buffered saline (PBS) / heparin (25 U / mL) into the peritoneal cavity and the abdomen was gently massaged for 2 minutes. The wash solution was collected, centrifuged (300 x g, 10 minutes at 4°C), and the supernatant was collected. The volume of the supernatant was reported and aliquoted into three 250 μL Eppendorf-type tubes. The tubes were snap-frozen in dry ice.

[0538] A cytometric bead array (CBA) assay for IL-1 beta detection was performed on the PW supernatant as follows. The supernatant or cytokine standard was incubated with the capture bead mixture for 1 hour at room temperature. Dilution factors in peritoneal wash: for TNF-α and IL-1b, the samples were diluted 2-fold. For IL-6, the samples were diluted 20-fold. The capture beads were then incubated with a phycoerythrin (PE) detection reagent mixture containing PE-conjugated anti-mouse IL-1β, TNF, and IL-6 for 1 hour at room temperature. After washing in a wash buffer containing 1x PBS, blocking protein, and detergent, the beads were resuspended and analyzed by flow cytometry.

[0539] Data was exported and plotted using GraphPad Prism 7. Cytokine analysis raw data was analyzed using FACP. Data was expressed as mean ± SD. One-way ANOVA was used to compare the significant differences between groups.

[0540] Results Mice administered with LPS and ATP showed an increase in IL-1 beta levels in plasma and peritoneal wash (PW), suggesting the success of model induction. As shown in Figure 1, compound 5 significantly reduced IL-1β release in PW in a dose-responsive manner in the LPS-ATP acute peritonitis model (n = 8, one-way ANOVA with Dunnett's multiplicity adjustment. Comparison with the LPS-ATP, 0 mg / kg group. ****p > 0.0001). It was further confirmed that compound 5 did not show inhibition against IL-6 or TNF-α in plasma or PW (data not shown).

Claims

1. A compound of formula (I) 【Chemical 1】 or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof [wherein, Z 1 and Z 2 is each selected from N and C, and when Z 1 is N, Z 2 is C, and when Z 1 is C, Z 2 is N, V, X, and E are each independently selected from N and CR a and At least one of V, X, and E is CR a and R a is independently selected from the group consisting of -H, -C 1 ~C 3 alkyl, -CF 3 , and halo R 0 is selected from the group consisting of -H, C 1 ~C 3 alkyl, and halo R 1 is selected from the group consisting of -CF 3 , -OCF 3 , -OCHF 2 , and halo; R 2 is selected from the group consisting of -OH, -H, and -CF 3 and Y is selected from NH and O, R 3 is A 4-, 5-, or 6-membered heterocycloalkyl having one or two heteroatoms, preferably one heteroatom, which is N, and which is optionally substituted with one or two substituents independently selected from the group consisting of C 1 -C 4 alkyl, halo-C 1 -C 4 alkyl, hydroxy-C 1 -C 4 alkyl, -OH, and halo; A 5- or 6-membered aryl or heteroaryl containing one or two heteroatoms which are N, optionally substituted with one or two substituents independently selected from the group consisting of C 1 -C 4 alkyl, hydroxy C 1 -C 4 alkyl, halo C 1 -C 4 alkyl, -CN, and halo; a 5- or 6-membered aryl or heteroaryl optionally substituted with C 1 ~C 4 alkyl, halo C 1 ~C 4 alkyl, hydroxy C 1 ~C 4 C optionally substituted with one or two substituents independently selected from the group consisting of alkyl, -OH, and halo 3 ~C 6 cycloalkyl; and -OH, halo, haloC 1 ~C 4 alkyl and C 1 ~C 4 C substituted with one or two substituents independently selected from the group consisting of alkoxy 1 ~C 6 alkyl is selected from the group consisting of].

2. A compound of formula (I') 【Chemical Formula 2】 or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof [wherein, Z 1 is N, Z 2 is C, V, X, and E are each independently selected from N and CR a and are independent of each other, At least one of V, X, and E is CR a and R a is independently selected from the group consisting of -H, -C 1 to -C 3 alkyl, -CF 3 , and halo R 0 is selected from the group consisting of -H, C 1 ~C 3 alkyl, and halo R 1 is selected from the group consisting of -CF 3 , -OCF 3 , -OCHF 2 , and halo; R 2 is selected from the group consisting of -OH, -H, and -CF 3 and Y is selected from NH and O, R 3 is A 4-, 5-, or 6-membered heterocycloalkyl containing one or two heteroatoms, preferably one heteroatom, which is N, and being optionally substituted with one or two substituents independently selected from the group consisting of C 1 -C 4 alkyl, haloC 1 -C 4 alkyl, hydroxyC 1 -C 4 alkyl, -OH, and halo; A 5- or 6-membered aryl or heteroaryl containing one or two heteroatoms which are N, optionally substituted with one or two substituents independently selected from the group consisting of C 1 -C 4 alkyl, hydroxy C 1 -C 4 alkyl, halo C 1 -C 4 alkyl, -CN, and halo; a 5- or 6-membered aryl or heteroaryl optionally substituted with C 1 to C 4 alkyl, halo C 1 to C 4 alkyl, hydroxy C 1 to C 4 C optionally substituted with one or two substituents independently selected from the group consisting of alkyl, -OH, and halo 3 to C 6 cycloalkyl; and -OH, halo, haloC 1 ~C 4 alkyl, and C 1 ~C 4 C substituted with one or two substituents independently selected from the group consisting of alkoxy 1 ~C 6 alkyl is selected from the group consisting of].

3. The compound according to claim 1 having formula (Ib), [Chemical 3] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof [wherein, R 0 , R 1 , R 2 , R 3 , E, and Y are as defined in claim 1].

4. The compound according to claim 1 having formula (Ic), 【Chemical 4】 or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof [wherein, R 0 , R 1 , R 2 , R 3 , E and Y are as defined in claim 1, preferably E is CR a , and CR a is as defined in claim 1].

5. The compound according to claim 1 having formula (Ie), 【Chemical Formula 5】 or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof [wherein, X is selected from N and CR a and R a is -C 1 to -C 3 alkyl, -CF 3 and is selected from the group consisting of halo, R 0 、R 1 、R 2 、R 3 、and Y are as defined in claim 1.]

6. The compound according to claim 1 having formula (Ia), 【Chemical Formula 6】 or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof [wherein, E is selected from N and CR a and is selected from R a is selected from the group consisting of -H, -C 1 ~C 3 alkyl, and -CF 3 and is selected from the group consisting of R 0 、R 1 、R 2 、R 3 、and Y are as defined in claim 1.

7. The compound according to claim 1 having formula (Id), 【Chemical Formula 7】 or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof [wherein R 0 , R 1 , R 2 , R 3 , X, and Y are as defined in claim 1, preferably X is CR a , and CR a is as defined in claim 1].

8. R 3 is A 4-, 5-, or 6-membered heterocycloalkyl containing one heteroatom which is N, optionally substituted with one or two substituents independently selected from the group consisting of C 1 ~C 4 alkyl; a 4-, 5-, or 6-membered heterocycloalkyl optionally substituted with one or two substituents independently selected from the group consisting of C A 5- or 6-membered heteroaryl containing one or two heteroatoms which are N, wherein C 1 ~C 4 A 5- or 6-membered heteroaryl optionally substituted with one or two substituents independently selected from the group consisting of alkyl; C 1 ~C 4 C optionally substituted with one or two substituents independently selected from the group consisting of alkyl, -OH, and halo 3 ~C 6 cycloalkyl; and Hydroxy C 1 ~C 6 alkyl A compound of formula I, I', Ia, Ib, Ic, Id, or Ie according to any one of claims 1 to 7, selected from the group consisting of.

9. R 3 is [Chemical Formula 8] Preferably 【Chemical Formula 9】 A compound of formula I, I', Ia, Ib, Ic, Id, or Ie according to any one of claims 1 to 8, selected from the group consisting of [Here, R 4 is independently selected from -H or -C 1 ~C 3 alkyl, n is selected from 0, 1, or 2].

10. R 0 is -H or -CH 3 and R 1 is -CF 3 and R 2 is -OH, A compound of formula I, I', Ia, Ib, Ic, Id, or Ie according to any one of claims 1 to 9 (preferably a compound of formula I', Ib, Ic, or Ie).

11. 【Fig. 10】 A compound of formula I, I', Ia, Ib, Ic, Id, or Ie according to any one of claims 1 to 10, selected from the group consisting of, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof.

12. A pharmaceutical composition comprising the compound according to any one of claims 1 to 11, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof, optionally containing at least one pharmaceutically acceptable carrier, diluent, adjuvant, or excipient.

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

14. The compound according to any one of claims 1 to 11, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof, for use in the treatment, alleviation, or prevention of a disease, disorder, or abnormality that responds to the modulation of components of the NLRP3 inflammasome pathway and / or to the modulation of IL-1 beta and / or IL-18 levels.

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

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

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

18. The disease, disorder, or abnormality is Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, demyelination, viral encephalitis, epilepsy, stroke, cerebral hemorrhage, atherosclerosis, asthma, allergic inflammation, cryopyrin-associated periodic syndrome (CAPS), Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), neonatal-onset multisystem inflammatory disease (NOMID), gout, pseudogout, inflammatory bowel disease, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, hypertension, myocardial infarction, oxalate-induced nephropathy, graft-versus-host disease, type 1 diabetes, type 2 diabetes, rheumatoid arthritis, myelodysplastic syndrome, familial Mediterranean fever (FMF), TNF receptor-associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD), hyperimmunoglobulin D syndrome, periodic fever syndrome (HIDS), interleukin 1 receptor antagonist deficiency (DIRA), Magid syndrome, acne, pyogenic arthritis - pyoderma gangrenosum - acne (PAPA), A20 haploinsufficiency (HA20), PLCG2-related antibody deficiency and immune dysregulation (PLAID), pediatric granulomatous arthritis (PGA), PLCG2-related autoinflammation, antibody deficiency and immune dysregulation (APLAID), B cell immunodeficiency, periodic fever, sideroblastic anemia with developmental delay (SIFD), chronic non-bacterial osteomyelitis (CNO), Sweet syndrome, chronic recurrent multifocal osteomyelitis (CRMO), synovitis, pustulosis, acne, eczema, alopecia areata, actinic keratosis, hyperostosis, synovitis, acne, pustulosis, hyperostosis, osteitis syndrome (SAPHO), multiple sclerosis (MS), psoriasis, Behçet's disease, Sjögren's syndrome, Schnitzler's syndrome, chronic obstructive pulmonary disease (COPD), steroid-resistant asthma, asbestosis, silicosis, cystic fibrosis, motor neuron disease, Huntington's disease, cerebral malaria, brain injury from pneumococcal meningitis, obesity, age-related macular degeneration (AMD), corneal infection, uveitis, dry eye, chronic kidney disease, diabetic nephropathy, alcoholic liver disease, skin contact allergy, sunburn, osteoarthritis, systemic juvenile idiopathic arthritis, adult-onset Still's disease, relapsing polychondritis, chikungunya virus, Ross River virus, influenza, HIV, coronavirus, dengue fever, Zika virus, hidradenitis suppurativa (HS), lung cancer metastasis, pancreatic cancer, gastric cancer, myelodysplastic syndrome, leukemia;Selected from polymyositis, colitis, helminth infection, bacterial infection, abdominal aortic aneurysm, wound healing, depression, psychological stress, pericarditis including Dressler syndrome, ischemia-reperfusion injury, frontotemporal dementia, HIV-associated neurocognitive disorder, coronavirus-associated inflammatory disease, traumatic brain and spinal cord injury, inflammatory pain, chronic pain, neuropathic pain, metastatic cancer-induced bone pain, chemotherapy-induced peripheral neuropathy, and migraine. Preferably, the disorder is Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, demyelination, viral encephalitis, epilepsy, stroke, atherosclerosis, asthma, allergic inflammation, cryopyrin-associated periodic syndrome (CAPS), gout, inflammatory bowel disease, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), hypertension, myocardial infarction, oxalate-induced nephropathy, graft-versus-host disease, type 1 diabetes, type 2 diabetes, rheumatoid arthritis, myelodysplastic syndrome, antineutrophil cytoplasmic antibody-associated vasculitis (AAV), lupus nephritis, anti-glomerular basement membrane (GMB) disease, IgA nephropathy, glomerulonephritis (GN), systemic lupus erythematosus (SLE), focal segmental glomerulosclerosis, minimal change disease (MCD), psoriatic arthritis, hereditary recurrent fever (HRF), and amyloidosis (including AL amyloidosis, AA amyloidosis, ATTR amyloidosis, hereditary amyloidosis (including apolipoprotein A-I (AApoAI), apolipoprotein A-II (AApoAII), gelsolin (AGel), fibrinogen (AFib), and lysozyme (ALys)), beta-2 microglobulin amyloidosis, iAPP amyloidosis), a compound for use according to any one of claims 14 to 17.;

19. The compound for use according to claim 18, wherein the disease, disorder, or abnormality is selected from Alzheimer's disease and Parkinson's disease.

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

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

Images