New regulated compounds

Abstract

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

Description

[Technical Field]

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

[0002] Inflammasome protein complexes are key components of inflammatory signaling. These complexes assemble in response to a variety of danger signals, including molecules derived from infectious agents (pathogen-associated molecular patterns, PAMPs) as well as altered host molecules, products of sterile tissue injury, and environmental factors (damage-associated molecular patterns, DAMPs). The inflammasome family consists of NALP1-14, IPAF, and NAIP1-6, and each family member exerts specificity and toxic activity against different PAMPs / DAMPs, including nucleic acids, bacterial proteins, metabolites, and protein aggregates (Sharma, D. & Kanneganti, T.D. The cell biology of inflammasomes: mechanisms of inflammasome activation and regulation. J. Cell Biol. 213, 617-629 (2016)). Inflammasomes typically consist of a sensor (cytosolic pattern recognition receptor, PRR) and an adaptor protein called apoptosis-associated speck-like protein (ASC) containing a caspase recruitment domain (CARD), as well as an effector such as the protease caspase-1 (Broz, P.; Dixit, VM 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-described family members. It is a tripartite protein of the NLR family and contains an amino-terminal PYRIN (PYD) domain, a nucleotide-binding NACHT domain, and a carboxy-terminal leucine-rich repeat (LRR) domain. In response to various agonists, including aggregated proteins, crystals, and altered cellular ion homeostasis, the NLRP3 sensor molecule assembles into multimolecular complexes with apoptosis-associated speck-like proteins containing the caspase activation and recruitment domain (ASC, also known as PYCARD) adaptor protein. Assembly of ASC proteins into a large complex (ASC speck) leads to activation of caspase-1 effector proteins and subsequent cleavage of pro-IL-1 beta (β) and pro-IL18 into their active, secreted forms, mediating pyroptosis (Heneka et al., 2018 Nat Rev Neurosci). IL-1 beta (β) acts through the IL-1 beta (β) receptor to induce secondary proinflammatory signals, including IL-6 and TNF alpha secretion, and attract and activate 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. NLRP3 gain-of-function mutations 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 disease, liver disease, and gout.

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

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

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

[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); reviewed in Mangan et al., Nat Rev Drug Discov. 2018 Aug;17(8):588-606). These include various chemical classes such as sulfonylureas (glyburide, CP-456,773 (also known as CRID3 and MCC950) and their derivatives); the fenamate class of nonsteroidal anti-inflammatory drugs; the hydroxysulfonamide analog JC-171; a novel series of boron compounds; the benzimidazole-containing structure Fc11a-2; the polyketide spirodalesol; acrylate and acrylamide derivatives; 3,4-methylenedioxy-β-nitrostyrene; the β-sulfonylnitrile molecule OLT1177; CY-09; BOT-4-one; and Michael acceptors. Most of these compounds have mixed modes of action and limited efficacy.

[0010] WO 2016131098, WO 2017 / 140778 and WO 2018215818 relate to sulfonylureas and related compounds and their use in treating or identifying diseases or conditions that respond to inhibition of NLRP3 or inhibition of activation of NLRP3 or related components of the inflammatory process.

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

[0012] WO 2017184604, WO 2017184623, WO 2017184624, WO 2019023145, WO 2019023147, and WO 2019079119 relate to chemical entities useful for treating conditions, diseases, or disorders in which decreased or increased NLRP3 activity contributes to the pathology and / or symptoms and / or progression of the condition, disease, or disorder in a subject.

[0013] WO 2019211463, WO 2020021447, and WO 2021043966, WO 2021239885, WO 2021219784, WO 2021214284, WO 2021209552, and WO 2021209539 disclose compounds for inhibiting NLRP3 and / or the NLRP3 inflammasome pathway.

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

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

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

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

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

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

[0020] WO 2020 / 234715 discloses pyridazin-3-ylphenol compounds defined as inhibitors of NOD-like receptor protein 3 (NLRP3) inflammasome activity.

[0021] WO 2021 / 193897 relates to substituted pyridazine compounds that are described as having inhibitory effects on NLRP3 inflammasome activity.

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

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

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

[0025] [Patent Document 1] International Publication No. 2016131098 [Patent Document 2] International Publication No. 2017 / 140778 [Patent Document 3] International Publication No. 2018215818 [Patent Document 4] International Publication No. 2019008025 [Patent Document 5] International Publication No. 2019008029 [Patent Document 6] International Publication No. 2019034686 [Patent Document 7] International Publication No. 2019034688 [Patent Document 8] International Publication No. 2019034690 [Patent Document 9] International Publication No. 2019034692 [Patent Document 10] International Publication No. 2019034693 [Patent Document 11] International Publication No. 2019034696 [Patent Document 12] International Publication No. 2019034697 [Patent Document 13] International Publication No. 2019068772 [Patent Document 14] International Publication No. 2019092170 [Patent Document 15] International Publication No. 2019092171 [Patent Document 16] International Publication No. 2019092172 [Patent Document 17] International Publication No. 2017184604 [Patent Document 18] International Publication No. 2017184623 [Patent Document 19] International Publication No. 2017184624 [Patent Document 20] International Publication No. 2019023145 [Patent Document 21] International Publication No. 2019023147 [Patent Document 22] International Publication No. 2019079119 [Patent Document 23] International Publication No. 2019211463 [Patent Document 24] International Publication No. 2020021447 [Patent Document 25] International Publication No. 2021043966 [Patent Document 26] International Publication No. 2021239885 [Patent Document 27] International Publication No. 2021219784 [Patent Document 28] International Publication No. 2021214284 [Patent Document 29] International Publication No. 2021209552 [Patent Document 30] International Publication No. 2021209539 [Patent Document 31] International Publication No. 2018136890 [Patent Document 32] International Publication No. 2018225018 [Patent Document 33] International Publication No. 2019043610 [Patent Document 34] International Publication No. 2018015445 [Patent Document 35] International Publication No. 2020018975 [Patent Document 36] International Publication No. 9832733 [Patent Document 37] International Publication No. 2020018970 [Patent Document 38] International Publication No. 2020 / 234715 [Patent Document 39] International Publication No. 2021 / 193897 [Non-patent literature]

[0026] [Non-Patent Document 1] Sharma, D. & Kanneganti, TD 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, VM 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, AG, 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 (ed. 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] Handbook of Pharmaceutical Excipients, 3rd edition (ed. Arthur H. Kibbe; Amer. Pharmaceutical Assoc, 1999) [Non-Patent Document 11] Pharmaceutical Codex: Principles and Practice of Pharmaceutics, 12th edition (ed. Walter Lund; Pharmaceutical Press, London, 1994) [Non-Patent Document 12] The United States Pharmacopeia: The National Formulary (United States Pharmacopeial Convention) [Non-Patent Document 13] Fiedler's "Lexikon der Hilfsstoffe", 5th edition, Edition Cantor Verlag Aulendorf 2002 [Non-Patent Document 14] "The Handbook of Pharmaceutical Excipients", 4th edition, American Pharmaceuticals Association, 2003 [Non-Patent Document 15] Goodman and Gilman's: the Pharmacological Basis of Therapeutics (edited by Louis S. Goodman and Lee E. Limbird; McGraw Hill, 1992) [Non-Patent Document 16] Remington's Pharmaceutical Sciences, 15th edition, Mack Publishing Co., New Jersey (1975) [Non-Patent Document 17] Menu et al., Clinical and Experimental Immunology, 2011, 166, 1-15 [Non-Patent Document 18] Strowig et al., Nature, 2012, 481, 278-286 [Non-Patent Document 19] Remington's Pharmaceutical Sciences, 18th edition, Mack Publishing Company, Easton, PA, 1990, 1445 pages. [Non-Patent Document 20] Goodman and Gilman, The Pharmacological Basis of Therapeutics, 8th edition, McGraw-Hill, Int. Ed. 1992, "Biotransformation of Drugs", pp. 13-15. [Non-Patent Document 21] TW Green and PGM Wuts (2014) Protective Groups in Organic Synthesis, 5th edition, John Wiley & Sons [Non-Patent Document 22] Stancu et al., Acta Neuropathol, 2019, 137(4), 599-617 Summary of the Invention [Means for solving the problem]

[0027] In view of the above, the present invention provides compounds that may be utilized in the treatment, amelioration, or prevention of diseases, disorders, or conditions that respond to modulation, particularly inhibition, of components of the NLRP3 inflammasome pathway, or that respond to modulation, particularly reduction, of IL-1 beta and / or IL-18 levels.

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

[0029] Within one aspect of the present invention, a compound of formula (I'):

[0030] [ka]

[0031] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof provided herein. [In the formula, X' is selected from CH or N; W is N, CH, or CR c is selected from Q is selected from N and C; E is NR a and CR a is selected from Z is selected from N and C; At least one of Q and Z is C and / or E is CR a and R c is selected from the group consisting of -C1-C4 alkyl, -O-C1-C4 alkyl, -C1-C4 alkyl-OH, -halo, or -C1-C4 alkyl-Hal; R a is selected from the group consisting of -H and -C1-C3 alkyl; R A and R B are respectively,

[0032] [ka]

[0033] Selected from R A and R B On the other hand,

[0034] [ka]

[0035] and R A and R B The other is,

[0036] [ka]

[0037] and 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 NH, NR d , O, or a bond; R d is selected from the group consisting of -C1-C4 alkyl, -C1-C4 alkyl-OH, or -C1-C4 alkyl-Hal; R3 is a 4-, 5-, or 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from N and O, optionally substituted with 1 or 2 substituents independently selected from the group consisting of C1-C4 alkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl, —OH, —NR5R6, and halo; or an 8-, 9-, or 10-membered bicyclic fused heterocycloalkyl containing 1 to 3 heteroatoms independently selected from N and O, optionally substituted at any available position with one or two substituents independently selected from the group consisting of C1-C4 alkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl, —OH, —NR5R6, and halo; or C3-C6 cycloalkyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of C1-C4 alkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl, —OH, and halo; or C1-C6 alkyl optionally substituted with one or two substituents independently selected from the group consisting of -OH, halo, haloC1-C4 alkyl, C1-C4 alkoxy, and -NR5R6; is selected from the group consisting of R5 and R6 are independently selected from H and C1-C3 alkyl; m is 0, 1, or 2].

[0038] Within one aspect of the present invention, a compound having formula (II'):

[0039] [ka]

[0040] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof provided herein. [In the formula, X' is selected from CH or N; W is N, CH, or CR c is selected from Q is selected from N and C; E is NR a and CR a is selected from Z is selected from N and C; At least one of Q and Z is C and / or E is CR a and R c is selected from the group consisting of C1-C4 alkyl, —O—C1-C4 alkyl, C1-C4 alkyl-OH, halo, or haloC1-C4 alkyl; R a is selected from the group consisting of -H and -C1-C3 alkyl; 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; R A teeth,

[0041] [ka]

[0042] and Y is NH, NR d , O, or a bond; R d is selected from the group consisting of -C1-C4 alkyl, -C1-C4 alkyl-OH, or -C1-C4 alkyl-Hal; R3 is a 4-, 5-, or 6-membered heterocycloalkyl containing 1 or 2 heteroatoms, preferably 1 heteroatom, independently selected from N and O, optionally substituted with 1 or 2 substituents independently selected from the group consisting of C1-C4 alkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl, —OH, —NR5R6, and halo; or an 8-, 9-, or 10-membered bicyclic fused heterocycloalkyl containing 1 to 3 heteroatoms independently selected from N and O, optionally substituted at any available position with one or two substituents independently selected from the group consisting of C1-C4 alkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl, —OH, —NR5R6, and halo; or C3-C6 cycloalkyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of C1-C4 alkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl, —OH, and halo; or C1-C6 alkyl optionally substituted with one or two substituents independently selected from the group consisting of -OH, halo, haloC1-C4 alkyl, C1-C4 alkoxy, and -NR5R6; is selected from the group consisting of R5 and R6 are independently selected from H and C1-C3 alkyl; m is 0, 1, or 2].

[0043] Within one embodiment, a compound of formula (I):

[0044] [ka]

[0045] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof provided herein. [In the formula, Q is selected from N and C; E is NR a and CR a is selected from Z is selected from N and C; At least one of Q and Z is C and / or E is CR a and R a is selected from the group consisting of -H and -C1-C3 alkyl; R A and R B are respectively,

[0046] [ka]

[0047] Selected from R A and R B On the other hand,

[0048] [ka]

[0049] and R A and R B The other is,

[0050] [ka]

[0051] and 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 4-, 5-, or 6-membered heterocycloalkyl containing 1 or 2 heteroatoms, preferably 1 heteroatom, independently selected from N and O, and optionally substituted with 1 or 2 substituents independently selected from the group consisting of C1-C4 alkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl, —OH, and halo; C3-C6 cycloalkyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of C1-C4 alkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl, —OH, and halo; and C1-C6 alkyl optionally substituted with one or two substituents independently selected from the group consisting of -OH, halo, haloC1-C4 alkyl, C1-C4 alkoxy, and -NR5R6; is selected from the group consisting of R5 and R6 are independently selected from H and C1-C3 alkyl.

[0052] Within another embodiment, a compound of formula (II):

[0053] [ka]

[0054] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof. [In the formula, Q is selected from N and C; E is NR a and CR a is selected from Z is selected from N and C; At least one of Q and Z is C and / or E is CR a and R a is selected from the group consisting of -H and -C1-C3 alkyl; 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 4-, 5-, or 6-membered heterocycloalkyl containing 1 or 2 heteroatoms, preferably 1 heteroatom, independently selected from N and O, and optionally substituted with 1 or 2 substituents independently selected from the group consisting of C1-C4 alkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl, —OH, and halo; C3-C6 cycloalkyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of C1-C4 alkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl, —OH, and halo; and C1-C6 alkyl optionally substituted with one or two substituents independently selected from the group consisting of -OH, halo, haloC1-C4 alkyl, C1-C4 alkoxy, and -NR5R6; is selected from the group consisting of R5 and R6 are independently selected from H and C1-C3 alkyl.

[0055] In another embodiment, a compound of formula (III):

[0056] [ka]

[0057] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof. [In the formula, Q is selected from N and C; E is NR a and CR a is selected from Z is selected from N and C; At least one of Q and Z is C and / or E is CR a and R a is selected from the group consisting of -H and -C1-C3 alkyl; 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 4-, 5-, or 6-membered heterocycloalkyl containing 1 or 2 heteroatoms, preferably 1 heteroatom, independently selected from N and O, and optionally substituted with 1 or 2 substituents independently selected from the group consisting of C1-C4 alkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl, —OH, and halo; C3-C6 cycloalkyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of C1-C4 alkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl, —OH, and halo; and C1-C6 alkyl optionally substituted with one or two substituents independently selected from the group consisting of -OH, halo, haloC1-C4 alkyl, C1-C4 alkoxy, and -NR5R6; is selected from the group consisting of R5 and R6 are independently selected from H and C1-C3 alkyl.

[0058] In another embodiment, a compound of formula (II'a):

[0059] [ka]

[0060] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof. [In the formula, X' is selected from CH or N; W is N, CH, or CR c is selected from R c is selected from the group consisting of C1-C4 alkyl, —O—C1-C4 alkyl, C1-C4 alkyl-OH, halo, or haloC1-C4 alkyl; R a is selected from the group consisting of -H and -C1-C3 alkyl; 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 NH, NR d , O, or a bond; R dis selected from the group consisting of -C1-C4 alkyl, -C1-C4 alkyl-OH, or -C1-C4 alkyl-Hal; R3 is a 4-, 5-, or 6-membered heterocycloalkyl containing 1 or 2 heteroatoms, preferably 1 heteroatom, independently selected from N and O, optionally substituted with 1 or 2 substituents independently selected from the group consisting of C1-C4 alkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl, —OH, —NR5R6, and halo; or an 8-, 9-, or 10-membered bicyclic fused heterocycloalkyl containing 1 to 3 heteroatoms independently selected from N and O, optionally substituted at any available position with one or two substituents independently selected from the group consisting of C1-C4 alkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl, —OH, —NR5R6, and halo; or C3-C6 cycloalkyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of C1-C4 alkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl, —OH, and halo; or C1-C6 alkyl optionally substituted with one or two substituents independently selected from the group consisting of -OH, halo, haloC1-C4 alkyl, C1-C4 alkoxy, and -NR5R6; is selected from the group consisting of R5 and R6 are independently selected from H and C1-C3 alkyl; m is 0, 1, or 2].

[0061] In another embodiment, a compound of formula (IIa):

[0062] [ka]

[0063] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof. [In the formula, R a is selected from the group consisting of -H and -C1-C3 alkyl; 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 4-, 5-, or 6-membered heterocycloalkyl containing 1 or 2 heteroatoms, preferably 1 heteroatom, independently selected from N and O, and optionally substituted with 1 or 2 substituents independently selected from the group consisting of C1-C4 alkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl, —OH, and halo; C3-C6 cycloalkyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of C1-C4 alkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl, —OH, and halo; and C1-C6 alkyl optionally substituted with one or two substituents independently selected from the group consisting of -OH, halo, haloC1-C4 alkyl, C1-C4 alkoxy, and -NR5R6; is selected from the group consisting of R5 and R6 are independently selected from H and C1-C3 alkyl.

[0064] In another embodiment, a compound of formula (II'b):

[0065] [ka]

[0066] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof. [In the formula, X' is selected from CH or N; W is N, CH, or CR c is selected from R c is selected from the group consisting of -C1-C4 alkyl, -O-C1-C4 alkyl, -C1-C4 alkyl-OH, -halo, or C1-C4 alkyl-Hal; R a is selected from the group consisting of -H and -C1-C3 alkyl; 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 NH, NR d , O, or a bond; R d is selected from the group consisting of -C1-C4 alkyl, -C1-C4 alkyl-OH, or -C1-C4 alkyl-Hal; R3 is a 4-, 5-, or 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from N and O, optionally substituted with 1 or 2 substituents independently selected from the group consisting of C1-C4 alkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl, —OH, —NR5R6, and halo; or an 8-, 9-, or 10-membered bicyclic fused heterocycloalkyl containing 1 to 3 heteroatoms independently selected from N and O, optionally substituted at any available position with one or two substituents independently selected from the group consisting of C1-C4 alkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl, —OH, —NR5R6, and halo; or C3-C6 cycloalkyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of C1-C4 alkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl, —OH, and halo; or C1-C6 alkyl optionally substituted with one or two substituents independently selected from the group consisting of -OH, halo, haloC1-C4 alkyl, C1-C4 alkoxy, and -NR5R6; is selected from the group consisting of R5 and R6 are independently selected from H and C1-C3 alkyl; m is 0, 1, or 2].

[0067] In another embodiment, a compound of formula (IIb):

[0068] [ka]

[0069] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof. [In the formula, R a is selected from the group consisting of -H and -C1-C3 alkyl; 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 4-, 5-, or 6-membered heterocycloalkyl containing 1 or 2 heteroatoms, preferably 1 heteroatom, independently selected from N and O, and optionally substituted with 1 or 2 substituents independently selected from the group consisting of C1-C4 alkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl, —OH, and halo; C3-C6 cycloalkyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of C1-C4 alkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl, —OH, and halo; and C1-C6 alkyl optionally substituted with one or two substituents independently selected from the group consisting of -OH, halo, haloC1-C4 alkyl, C1-C4 alkoxy, and -NR5R6; is selected from the group consisting of R5 and R6 are independently selected from H and C1-C3 alkyl.

[0070] In another embodiment, a compound of formula (IV):

[0071] [ka]

[0072] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof. [In the formula, R a is selected from the group consisting of -H and -C1-C3 alkyl; 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 NH, NR d , O, or a bond; R d is selected from the group consisting of -C1-C4 alkyl, -C1-C4 alkyl-OH, or -C1-C4 alkyl-Hal; R3 is a 4-, 5-, or 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from N and O, optionally substituted with 1 or 2 substituents independently selected from the group consisting of C1-C4 alkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl, —OH, —NR5R6, and halo; or an 8-, 9-, or 10-membered bicyclic fused heterocycloalkyl containing 1 to 3 heteroatoms independently selected from N and O, optionally substituted at any available position with one or two substituents independently selected from the group consisting of C1-C4 alkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl, —OH, —NR5R6, and halo; or C3-C6 cycloalkyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of C1-C4 alkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl, —OH, and halo; or C1-C6 alkyl optionally substituted with one or two substituents independently selected from the group consisting of -OH, halo, haloC1-C4 alkyl, C1-C4 alkoxy, and -NR5R6; is selected from the group consisting of R5 and R6 are independently selected from H and C1-C3 alkyl; m is 0, 1, or 2].

[0073] In another embodiment, a compound of formula (V):

[0074] [ka]

[0075] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof. [In the formula, R ais selected from the group consisting of -H and -C1-C3 alkyl; 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 NH, NR d , O, or a bond; R d is selected from the group consisting of -C1-C4 alkyl, -C1-C4 alkyl-OH, or -C1-C4 alkyl-Hal; R3 is a 4-, 5-, or 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from N and O, optionally substituted with 1 or 2 substituents independently selected from the group consisting of C1-C4 alkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl, —OH, —NR5R6, and halo; or an 8-, 9-, or 10-membered bicyclic fused heterocycloalkyl containing 1 to 3 heteroatoms independently selected from N and O, optionally substituted at any available position with one or two substituents independently selected from the group consisting of C1-C4 alkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl, —OH, —NR5R6, and halo; or C3-C6 cycloalkyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of C1-C4 alkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl, —OH, and halo; or C1-C6 alkyl optionally substituted with one or two substituents independently selected from the group consisting of -OH, halo, haloC1-C4 alkyl, C1-C4 alkoxy, and -NR5R6; is selected from the group consisting of R5 and R6 are independently selected from H and C1-C3 alkyl; m is 0, 1, or 2].

[0076] Within the scope of the present invention, any reference to compounds of formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV) or (V), or to preferred embodiments thereof, is intended to also refer to stereoisomers, or racemic mixtures, or tautomers, or polymorphs, or pharmaceutically acceptable salts, or prodrugs, or hydrates, or solvates thereof.

[0077] Compounds of Formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV), or (V), or stereoisomers, racemic mixtures, tautomers, polymorphs, pharmaceutically acceptable salts, prodrugs, hydrates, or solvates thereof, are suitable for treating, alleviating, or preventing diseases, disorders, or conditions that respond to modulation, particularly inhibition, of a component of the NLRP3 inflammasome pathway, or modulation, particularly reduction, of IL-1 beta and / or IL-18 levels. In particular, the component of the inflammasome pathway is the NLRP3 inflammasome. Activation of the NLRP3 inflammasome pathway can lead to the formation of ASC specks, the cleavage and activation of caspase-1 and caspase-8 and the subsequent activation and release of IL-1beta, IL-18, gasdermin D cleavage and pore formation, pyroptosis, and the release of IL-1alpha, IL-33, IL-17, and high mobility group box (HMGB) proteins. Compounds of Formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV), or (V), or stereoisomers, racemic mixtures, tautomers, polymorphs, pharmaceutically acceptable salts, prodrugs, hydrates, or solvates thereof, have the ability to regulate, in particular lower, IL-1beta and / or IL-18 levels.

[0078] Compounds of Formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV), or (V), or stereoisomers, racemic mixtures, tautomers, polymorphs, pharmaceutically acceptable salts, prodrugs, hydrates, or solvates thereof, exhibit high potency in modulating, and in particular inhibiting activation of, components of the NLRP3 inflammasome pathway, particularly when the component of the inflammasome pathway is the NLRP3 inflammasome. Due to such unique design features, these compounds exhibit properties such as modulation or inhibition of activation of the NLRP3 inflammasome pathway and may be successful pharmaceuticals for treating, ameliorating, or preventing diseases, disorders, and conditions that respond to 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.

[0079] In another embodiment, the present invention relates to a pharmaceutical composition comprising a compound of Formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV), or (V), or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof, and optionally at least one pharmaceutically acceptable carrier, diluent, adjuvant, or additive.

[0080] In another embodiment, the present invention relates to a compound of Formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV), or (V), or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof, for use as a pharmaceutical.

[0081] In yet another embodiment, the present invention relates to a compound of Formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV), or (V), or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof, for use in the treatment, amelioration, or prevention of a disease, disorder, or condition that responds to modulation of a component of the NLRP3 inflammasome pathway, particularly inhibition of activation of that component, and / or that responds to modulation, particularly reduction, of IL-1 beta and / or IL-18 levels.

[0082] Another embodiment relates to the use of a compound of Formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV), or (V), or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof, for the manufacture of a medicament for treating, alleviating, or preventing a disease, disorder, or condition that responds to modulation of a component of the NLRP3 inflammasome pathway, particularly inhibition of activation of that component, and / or that responds to modulation, particularly reduction, of IL-1 beta and / or IL-18 levels.

[0083] In yet another embodiment, the present invention is directed to a method for treating, alleviating, or preventing a disease, disorder, or condition that responds to modulation, particularly inhibition of activation of a component of the NLRP3 inflammasome pathway, or that responds to modulation, particularly reduction, of IL-1 beta and / or IL-18 levels, comprising administering a therapeutically effective amount of a compound of Formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV), or (V), or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof, to a subject (e.g., patient) in need thereof.

[0084] Pharmaceutical compositions comprising a combination of a compound of formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV), or (V), or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof, and at least one other biologically active compound different from a compound of formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV), or (V), or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof, and optionally at least one pharmaceutically acceptable carrier, diluent, adjuvant, or additive, are also the subject of the present invention.

[0085] In particular, the other biologically active compound may be a compound used to treat a disease, disorder, or abnormality associated with the disease that targets a different pathological mechanism, such as an anti-amyloid beta antibody, an anti-tau antibody, an amyloid beta small molecule inhibitor, a tau aggregation small molecule inhibitor, an anti-alpha synuclein antibody or an alpha synuclein aggregation small molecule inhibitor, an anti-TDP-43 antibody or an anti-TDP-43 aggregation small molecule inhibitor, among others. When a compound of the invention is used in combination with another biologically active compound, the dosage of each compound may differ from the dosage when the compound is used as a monotherapy.

[0086] An additional embodiment relates to the use of a compound of Formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV), or (V), or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof, as an analytical standard or in vitro screening tool.

[0087] The present invention is described below. [Brief explanation of the drawings]

[0088] [Figure 1] FIG. 1 shows the inhibition of IL-1 beta release by a compound of the present invention (Example Compound 53) in a mouse model of LPS / ATP-induced acute peritonitis. [Figure 2] FIG. 1 shows the inhibition of IL-1 beta release by a compound of the present invention (compound 18) in an LPS / ATP-induced acute peritonitis mouse model. DETAILED DESCRIPTION OF THE INVENTION

[0089] The present invention relates to compounds of formula (I') and compounds of formula (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV), or (V), including stereoisomers, racemic mixtures, tautomers, polymorphs, pharmaceutically acceptable salts, prodrugs, hydrates, or solvates thereof.

[0090] The R assigned to the compounds of formula (I') and subformulas thereof A , R B , R0, R1, R2, R3, R4, R5, R6, R a , R c , R d Any of the definitions of E, Q, W, X, X', Z, Y, m, n, and / or a may be R A , R B , R0, R1, R 2、 R3, R4, R5, R6, R a , R c , R d , E, Q, W, X, X', Z, Y, m, n, and / or a, whenever used, apply equally to compounds of formula (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV), or (V).

[0091] Within one aspect of the present invention, a compound of formula (I'),

[0092] [ka]

[0093] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof provided herein. [In the formula, X' is selected from CH or N; W is N, CH, or CR c is selected from Q is selected from N and C; E is NR a and CR a is selected from Z is selected from N and C; At least one of Q and Z is C and / or E is CR a and R c is selected from the group consisting of -C1-C4 alkyl, -O-C1-C4 alkyl, -C1-C4 alkyl-OH, -halo, or C1-C4 alkyl-Hal; R a is selected from the group consisting of -H and -C1-C3 alkyl; R A and R B are respectively,

[0094] [ka]

[0095] Selected from R A and R B On the other hand,

[0096] [ka]

[0097] and R A and R B The other is,

[0098] [ka]

[0099] and 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 NH, NR d , O, or a bond; R d is selected from the group consisting of -C1-C4 alkyl, -C1-C4 alkyl-OH, or -C1-C4 alkyl-Hal; R3 is a 4-, 5-, or 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from N and O, optionally substituted with 1 or 2 substituents independently selected from the group consisting of C1-C4 alkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl, —OH, —NR5R6, and halo; or an 8-, 9-, or 10-membered bicyclic fused heterocycloalkyl containing 1 to 3 heteroatoms independently selected from N and O, optionally substituted at any available position with one or two substituents independently selected from the group consisting of C1-C4 alkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl, —OH, —NR5R6, and halo; or C3-C6 cycloalkyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of C1-C4 alkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl, —OH, and halo; or C1-C6 alkyl optionally substituted with one or two substituents independently selected from the group consisting of -OH, halo, haloC1-C4 alkyl, C1-C4 alkoxy, and -NR5R6; is selected from the group consisting of R5 and R6 are independently selected from H and C1-C3 alkyl; m is 0, 1, or 2].

[0100] The present invention relates to compounds of formula (I) as defined below:

[0101] [ka]

[0102] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof. [In the formula, Q is selected from N and C; E is NR a and CR a is selected from Z is selected from N and C; At least one of Q and Z is C and / or E is CR a and R a is selected from the group consisting of -H and -C1-C3 alkyl; R A and R B are respectively,

[0103] [ka]

[0104] Selected from R A and R B On the other hand,

[0105] [ka]

[0106] and R A and R B The other is,

[0107] [ka]

[0108] and 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 4-, 5-, or 6-membered heterocycloalkyl containing 1 or 2 heteroatoms, preferably 1 heteroatom, independently selected from N and O, and optionally substituted with 1 or 2 substituents independently selected from the group consisting of C1-C4 alkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl, —OH, and halo; C3-C6 cycloalkyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of C1-C4 alkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl, —OH, and halo; and selected from the group consisting of C1-C6 alkyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of -OH, halo, haloC1-C4 alkyl, C1-C4 alkoxy, and -NR5R6; R5 and R6 are independently selected from H and C1-C3 alkyl.

[0109] In a preferred embodiment, R0 is selected from -H and C1-C3 alkyl, more preferably -H or methyl. In one preferred embodiment, R0 is -H. In another preferred embodiment, R0 is C1-C3 alkyl, preferably methyl or ethyl, more preferably methyl.

[0110] In a preferred embodiment, R1 is selected from -CF3, -OCF3, and -OCHF2. In one preferred embodiment, R1 is -CF3. In another preferred embodiment, R1 is -OCF3. In another preferred embodiment, R1 is -OCHF2.

[0111] In another preferred embodiment, R1 is halo. When R1 is halo, the halogen (halo) is preferably chloro.

[0112] In one preferred embodiment, R2 is -OH or H, more preferably -OH. In another embodiment, R2 is -H. In another embodiment, R2 is -CF3.

[0113] In one preferred embodiment, R is -H, R is selected from -CF, -OCF, -OCHF, and -Cl, and R is -OH or -H. In one preferred embodiment, R is -H, R is -CF, and R is -OH.

[0114] In another preferred embodiment, R0 is -H or methyl, R1 is selected from -CF3 or -Cl, and R2 is -OH.

[0115] In a more preferred embodiment, R0 is -H, R1 is -CF3, and R2 is -OH; or R0 is -H, R1 is -Cl, and R2 is -OH; or R0 is -CH3, R1 is -Cl, and R2 is -OH. R0 is -CH3, R1 is -CF3, and R2 is -OH.

[0116] In one embodiment, R3 is 4-, 5-, or 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from N and / or O, optionally substituted with 1 or 2 substituents independently selected from the group consisting of -NR5R6, C1-C4 alkyl, or OH; an 8-, 9-, or 10-membered bicyclic fused heterocycloalkyl containing 1 to 3 heteroatoms independently selected from N and O, optionally substituted at any available position with one or two substituents independently selected from the group consisting of C1-C4 alkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl, —OH, —NR5R6, and halo; C3-C6 cycloalkyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of C1-C4 alkyl, —OH, and halo; Hydroxy C1-C6 alkyl; haloC1-C4 alkyl, preferably -CF3, or C1-C6 alkyl optionally substituted with -NR5R6 is selected from the group consisting of R5 and R6 are independently selected from H and C1-C3 alkyl; m is 0 or 1.

[0117] In another particular embodiment, R3 is 4-, 5-, or 6-membered heterocycloalkyl containing one heteroatom which is N or O, optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl, —OH, and halo, preferably optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl; C3-C6 cycloalkyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of C1-C4 alkyl, —OH, and halo; Hydroxy C1-C6 alkyl; and C1-C6 alkyl optionally substituted with -NR5R6 is selected from the group consisting of R5 and R6 are independently selected from H and C1-C3 alkyl.

[0118] In one preferred embodiment, R3 is selected from 4-, 5-, or 6-membered heterocycloalkyl containing 1 or 2 heteroatoms, preferably 1 heteroatom, which are N or O. The 4-, 5-, or 6-membered heterocycloalkyl is optionally substituted with 1 or 2 substituents independently selected from the group consisting of C1-C4 alkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl, —OH, and halo. The substituents may be at any available position on the heterocyclic group.

[0119] In one preferred embodiment, R3 is

[0120] [ka]

[0121] selected from the group consisting of Me, and CF [where: X is selected from O and NR4; R4 is independently selected from H, halo, or C1-C3 alkyl; R5 is independently selected from H or C1-C3 alkyl, preferably H or Me; R6 is selected from the group consisting of C1-C4 alkyl; n is selected from 0, 1, or 2.

[0122] In another preferred embodiment, R3 is

[0123] [ka]

[0124] selected from the group consisting of Me, and CF [where: X is selected from O and NR4; R4 is independently selected from H, halo, or C1-C3 alkyl; R5 is independently selected from -H or -Me; R6 is selected from the group consisting of C1-C4 alkyl; n is selected from 0, 1, or 2.

[0125] In one preferred embodiment, R3 is

[0126] [ka]

[0127] selected from the group consisting of Me, and CF [where: R4 is independently selected from H, F, or C1-C3 alkyl; R5 is methyl; n is selected from 0, 1, or 2.

[0128] In a more preferred embodiment, R3 is

[0129] [ka]

[0130] selected from the group consisting of Me, and CF [where: R4 is independently selected from -H, -F, or -C1-C3 alkyl; R5 is methyl; n is selected from 0, 1, or 2.

[0131] In one preferred embodiment, R3 is

[0132] [ka]

[0133] selected from the group consisting of [where: X is selected from O and NR4; R4 is independently selected from -H or -C1-C3 alkyl; a is selected from 0 and 1; n is selected from 0, 1, or 2.

[0134] In another preferred embodiment, R3 is

[0135] [ka]

[0136] selected from the group consisting of [where: R4 is independently selected from -H or -C1-C3 alkyl; n is selected from 0, 1, or 2.

[0137] In another preferred embodiment, R3 is

[0138] [ka]

[0139] selected from the group consisting of [where: R4 is independently selected from -H or -C1-C3 alkyl; n is selected from 0, 1, or 2.

[0140] In one preferred embodiment, R3 is a 4-, 5-, or 6-membered heterocycloalkyl containing one heteroatom which is N. The 4-, 5-, or 6-membered heterocycloalkyl is optionally substituted with one or two substituents (preferably C1-C4 alkyl) independently selected from the group consisting of C1-C4 alkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl, —OH, and halo. The substituents may be at any available position on the heterocyclic group.

[0141] In another embodiment, R3 is 、 and 4-, 5-, or 6-membered heterocycloalkyl containing one heteroatom which is O. The 4-, 5-, or 6-membered heterocycloalkyl is optionally substituted with one or two substituents (preferably C1-C4 alkyl) independently selected from the group consisting of C1-C4 alkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl, —OH, and halo. The substituents may be at any available position on the heterocyclic group.

[0142] In another preferred embodiment, R3 is C1-C6 alkyl.

[0143] In one preferred embodiment, R3 is

[0144] [ka]

[0145] is [where: X is selected from O and NR4, preferably X is NR4; R4 is independently selected from -H or -C1-C3 alkyl; a is selected from 0 and 1 (preferably, a is 0); n is selected from 0, 1 or 2. In one preferred embodiment, n is 2. In one preferred embodiment, n is 1. In another preferred embodiment, n is 0.

[0146] In one preferred embodiment, R3 is

[0147] [ka]

[0148] 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.

[0149] In another preferred embodiment, R3 is

[0150] [ka]

[0151] 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.

[0152] In another embodiment, R3 is

[0153] [ka]

[0154] wherein R4 is independently selected from -H or C1-C3 alkyl. In a preferred embodiment, R4 is H. In another embodiment, R4 is C1-C3 alkyl, such as methyl, ethyl, or propyl. In one preferred embodiment, R4 is methyl, whereby R3 is

[0155] [ka]

[0156] is.

[0157] In another embodiment, R3 is

[0158] [ka]

[0159] wherein R4 is independently selected from -H or C1-C3 alkyl. In a preferred embodiment, R4 is H. In another embodiment, R4 is C1-C3 alkyl, such as methyl, ethyl, or propyl. In one embodiment, R4 is methyl, whereby R3 is

[0160] [ka]

[0161] is.

[0162] In another embodiment, R3 is

[0163] [ka]

[0164] wherein R4 is independently selected from -H or C1-C3 alkyl. In a preferred embodiment, R4 is H. In another embodiment, R4 is C1-C3 alkyl, such as methyl, ethyl, or propyl. In one preferred embodiment, R4 is methyl, whereby R3 is

[0165] [ka]

[0166] is.

[0167] In another preferred embodiment, R3 is a 4-, 5-, or 6-membered heterocycloalkyl containing one heteroatom which is O. In one preferred embodiment, R3 is

[0168] [ka]

[0169] is.

[0170] In another embodiment, R3 is a C3-C6 cycloalkyl, preferably cyclohexyl, cyclopropyl, or cyclobutyl, more preferably cyclopropyl or cyclobutyl. The C3-C6 cycloalkyl is optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl, —OH, and halo. The substituents may be at any available position on the cycloalkyl group.

[0171] In one preferred embodiment, R3 is

[0172] [ka]

[0173] is.

[0174] In one preferred embodiment, R3 is

[0175] [ka]

[0176] 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 one preferred embodiment, R3 is

[0177] [ka]

[0178] In another preferred embodiment, R3 is

[0179] [ka]

[0180] is.

[0181] In another preferred embodiment, R3 is

[0182] [ka]

[0183] In one preferred embodiment, R3 is

[0184] [ka]

[0185] In another preferred embodiment, R3 is

[0186] [ka]

[0187] is.

[0188] In another preferred embodiment, R3 is C1-C6 alkyl, such as C1-C3 alkyl, for example, methyl, ethyl, or propyl. In one preferred embodiment, R3 is methyl. In another preferred embodiment, the alkyl is optionally substituted with one or two substituents independently selected from the group consisting of -OH, halo, haloC1-C4 alkyl, C1-C4 alkoxy, and -NR5R6, where R5 and R6 are independently selected from H and C1-C3 alkyl.

[0189] In one preferred embodiment, R3 is hydroxy C1-C6 alkyl (ie, C1-C6 alkyl substituted with -OH), more preferably hydroxy C1-C3 alkyl, with hydroxyethyl being preferred.

[0190] In one preferred embodiment, R3 is

[0191] [ka]

[0192] wherein n is 0, 1, or 2. In another preferred embodiment, R3 is

[0193] [ka]

[0194] where n is 0, 1, or 2.

[0195] In another embodiment, R3 is C1-C4 alkoxyC1-C6 alkyl (ie, C1-C6 alkyl substituted with C1-C4 alkoxy), preferably C1-C3 alkoxyC1-C4 alkyl.

[0196] In one embodiment, R3 is

[0197] [ka]

[0198] wherein R4 is -C1-C3 alkyl and n is selected from 0, 1, or 2.

[0199] In another preferred embodiment, R3 is C1-C6 alkyl substituted with -NR5R6, where R5 and R6 are independently selected from H and C1-C3 alkyl. In a preferred embodiment, R5 and R6 are both C1-C3 alkyl, such as methyl, ethyl, or propyl, more preferably R5 and R6 are both methyl. In another embodiment, R5 and R6 are both H.

[0200] In one embodiment, R3 is

[0201] [ka]

[0202] wherein R5 and R6 are independently selected from H and C1-C3 alkyl, and n is 0, 1, or 2. In a preferred embodiment, R5 and R6 are both C1-C3 alkyl, such as methyl, ethyl, or propyl, and more preferably R5 and R6 are both methyl. In another embodiment, R5 and R6 are both H.

[0203] In one preferred embodiment, R3 is

[0204] [ka]

[0205] where n is 0, 1, or 2.

[0206] In another preferred embodiment, R3 is

[0207] [ka]

[0208] wherein R4 is independently selected from -H or C1-C3 alkyl. In a preferred embodiment, R4 is C1-C3 alkyl, such as methyl, ethyl, or propyl, preferably methyl.

[0209] In another preferred embodiment, R3 is

[0210] [ka]

[0211] [wherein R5 is H and C1-C3 alkyl].

[0212] In one preferred embodiment, Z is C. In another embodiment, Z is N.

[0213] In one preferred embodiment, Q is C. In another embodiment, Q is N.

[0214] In some embodiments, one of Q and Z is C and the other is N. In one embodiment, Q is N and Z is C. In another embodiment, one of Q is C and Z is N. In one preferred embodiment, Q and Z are both C.

[0215] In some embodiments, E is NR a [where R a is selected from H and -C1-C3 alkyl. In one preferred embodiment, R a is H. In another preferred embodiment, R a is -C1-C3 alkyl. In a preferred embodiment, R a is methyl. In another preferred embodiment, R a is ethyl. In another preferred embodiment, R a is propyl or isopropyl. In another embodiment, E is CR a [where R ais selected from H and -C1-C3 alkyl. In one preferred embodiment, R a is H. In another preferred embodiment, R a is -C1-C3 alkyl, preferably R a is methyl.

[0216] In an embodiment, Q and Z are both C and E is CR a [where R a is as defined above. In a preferred embodiment, Q and Z are both C and E is NR a [where R a is as defined above. In another preferred embodiment, Q is N, Z is C, and E is CR a [where R a is as defined above].

[0217] In a preferred embodiment, X' is N. In another preferred embodiment, X' is CH.

[0218] In a preferred embodiment, W is N. In another preferred embodiment, W is CH. In another preferred embodiment, W is CR c and R c is —CH—OH, —O—CH, or F.

[0219] In one preferred embodiment, Y is NH. In another preferred embodiment, Y is O. In another preferred embodiment, Y is N-CH. In another preferred embodiment, Y is a bond.

[0220] In a preferred embodiment, R c is selected from the group consisting of -O-C1-C4 alkyl, -C1-C4 alkyl-OH, and -halo. c is selected from the group consisting of -O-C1-C2 alkyl, -C1-C4 alkyl-OH, and -F, such as -C1-C4 alkyl-OH, -OCH3, and -F.

[0221] In a preferred embodiment, R d is selected from the group consisting of C1 to C4 alkyl.

[0222] In one preferred embodiment, the compound has the formula (II'):

[0223] [ka]

[0224] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof. wherein Q, E, Z, X', W, R, R, R, R, m and Y are as defined in any of the above embodiments.

[0225] In one preferred embodiment, the compound having the formula (II):

[0226] [ka]

[0227] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof. wherein Q, E, Z, R, R, R, R, and Y are as defined in any of the above embodiments.

[0228] The following paragraphs apply to formula (II') and / or (II).

[0229] In a preferred embodiment, R0 is selected from -H and C1-C3 alkyl, more preferably -H or methyl. In one preferred embodiment, R0 is -H. In another preferred embodiment, R0 is C1-C3 alkyl, preferably methyl or ethyl, more preferably methyl.

[0230] In a preferred embodiment, R1 is selected from -CF3, -OCF3, and -OCHF2. In one preferred embodiment, R1 is -CF3. In another preferred embodiment, R1 is -OCF3. In another preferred embodiment, R1 is -OCHF2.

[0231] In another embodiment, R1 is halo. When R1 is halo, the halogen (halo) is preferably chloro.

[0232] In one preferred embodiment, R2 is -OH or H, more preferably -OH. In another embodiment, R2 is -H. In another embodiment, R2 is -CF3.

[0233] In one preferred embodiment, R is -H, R is selected from -CF, -OCF, -OCHF, and -Cl, and R is -OH or -H. In one preferred embodiment, R is -H, R is -CF, and R is -OH.

[0234] In one embodiment, R3 is 4-, 5-, or 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from N and / or O, optionally substituted with 1 or 2 substituents independently selected from the group consisting of -NR5R6, C1-C4 alkyl, or OH; an 8-, 9-, or 10-membered bicyclic fused heterocycloalkyl containing 1 to 3 heteroatoms independently selected from N and O, optionally substituted at any available position with one or two substituents independently selected from the group consisting of C1-C4 alkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl, —OH, —NR5R6, and halo; or C3-C6 cycloalkyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of C1-C4 alkyl, —OH, and halo; or hydroxy C1-C6 alkyl; or haloC1-C4 alkyl, preferably -CF3, or C1-C6 alkyl optionally substituted with -NR5R6 is selected from the group consisting of R5 and R6 are independently selected from H and C1-C3 alkyl; m is 0 or 1.

[0235] In one preferred embodiment, R3 is 4-, 5-, or 6-membered heterocycloalkyl containing one heteroatom which is N or O, optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl, —OH, and halo, preferably optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl; C3-C6 cycloalkyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of C1-C4 alkyl, —OH, and halo; Hydroxy C1-C6 alkyl; and C1-C6 alkyl optionally substituted with -NR5R6 is selected from the group consisting of R5 and R6 are independently selected from H and C1-C3 alkyl.

[0236] In one preferred embodiment, R3 is selected from 4-, 5-, or 6-membered heterocycloalkyl containing 1 or 2 heteroatoms, preferably 1 heteroatom, which are N or O. The 4-, 5-, or 6-membered heterocycloalkyl is optionally substituted with 1 or 2 substituents independently selected from the group consisting of C1-C4 alkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl, —OH, and halo. The substituents may be at any available position on the heterocyclic group.

[0237] In one preferred embodiment, R3 is

[0238] [ka]

[0239] selected from the group consisting of Me, and CF [where: X is selected from O and NR4; R4 is independently selected from H, halo, or C1-C3 alkyl; R5 is independently selected from H or C1-C3 alkyl, preferably H or Me; R6 is selected from the group consisting of C1-C4 alkyl; n is selected from 0, 1, or 2.

[0240] In one preferred embodiment, R3 is

[0241] [ka]

[0242] selected from the group consisting of wherein X is selected from O and NR4; R4 is independently selected from -H or -C1-C3 alkyl; n is selected from 0, 1, or 2; a is selected from 0 or 1].

[0243] In one preferred embodiment, R3 is

[0244] [ka]

[0245] selected from the group consisting of Me, and CF [where: X is selected from O and NR4; R4 is independently selected from H, halo, or C1-C3 alkyl; R5 is independently selected from -H or -Me; R6 is selected from the group consisting of C1-C4 alkyl; n is selected from 0, 1, or 2.

[0246] In a more preferred embodiment, R3 is

[0247] [ka]

[0248] selected from the group consisting of Me, and CF [where: R4 is independently selected from H, F, or C1-C3 alkyl; R5 is methyl; n is selected from 0, 1, or 2.

[0249] In one preferred embodiment, R3 is

[0250] [ka]

[0251] selected from the group consisting of wherein X is selected from O and NR4; R4 is independently selected from -H or -C1-C3 alkyl; a is selected from 0 and 1; n is selected from 0, 1, or 2.

[0252] In another preferred embodiment, R3 is

[0253] [ka]

[0254] 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.

[0255] In another preferred embodiment, R3 is

[0256] [ka]

[0257] 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.

[0258] In one preferred embodiment, R3 is a 4-, 5-, or 6-membered heterocycloalkyl containing one heteroatom which is N. The 4-, 5-, or 6-membered heterocycloalkyl is optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl, —OH, and halo (preferably C1-C4 alkyl). The substituents may be at any available position on the heterocyclic group.

[0259] In another embodiment, R3 is a 4-, 5-, or 6-membered heterocycloalkyl containing one heteroatom that is O. The 4-, 5-, or 6-membered heterocycloalkyl is optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl, —OH, and halo (preferably C1-C4 alkyl). The substituents may be at any available position on the heterocyclic group.

[0260] In one preferred embodiment, R3 is

[0261] [ka]

[0262] wherein X is selected from O and NR4, preferably X is NR4; R4 is independently selected from -H or -C1-C3 alkyl; a is selected from 0 and 1 (preferably, a is 0); n is selected from 0, 1, or 2. In one preferred embodiment, n is 2. In one preferred embodiment, n is 1. In another preferred embodiment, n is 0.

[0263] In one preferred embodiment, R3 is

[0264] [ka]

[0265] 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.

[0266] In another preferred embodiment, R3 is

[0267] [ka]

[0268] 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.

[0269] In another embodiment, R3 is

[0270] [ka]

[0271] wherein R4 is independently selected from -H or C1-C3 alkyl. In a preferred embodiment, R4 is H. In another embodiment, R4 is C1-C3 alkyl, such as methyl, ethyl, or propyl. In one embodiment, R4 is methyl, whereby R3 is

[0272] [ka]

[0273] is.

[0274] In another embodiment, R3 is

[0275] [ka]

[0276] wherein R4 is independently selected from -H or C1-C3 alkyl. In a preferred embodiment, R4 is H. In another embodiment, R4 is C1-C3 alkyl, such as methyl, ethyl, or propyl. In one preferred embodiment, R4 is methyl, whereby R3 is

[0277] [ka]

[0278] is.

[0279] In another preferred embodiment, R3 is a 4-, 5-, or 6-membered heterocycloalkyl containing one heteroatom which is O. In one preferred embodiment, R3 is

[0280] [ka]

[0281] is.

[0282] In another embodiment, R3 is a C3-C6 cycloalkyl, preferably cyclohexyl, cyclopropyl, or cyclobutyl, more preferably cyclopropyl or cyclobutyl. The C3-C6 cycloalkyl is optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl, —OH, and halo. The substituents may be at any available position on the cycloalkyl group.

[0283] In one preferred embodiment, R3 is

[0284] [ka]

[0285] is.

[0286] In one preferred embodiment, R3 is

[0287] [ka]

[0288] 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 another preferred embodiment, R3 is

[0289] [ka]

[0290] In another preferred embodiment, R3 is

[0291] [ka]

[0292] is.

[0293] In another preferred embodiment, R3 is

[0294] [ka]

[0295] In one preferred embodiment, R3 is

[0296] [ka]

[0297] In another preferred embodiment, R3 is

[0298] [ka]

[0299] is.

[0300] In another preferred embodiment, R3 is C1-C6 alkyl, such as C1-C3 alkyl, for example, methyl, ethyl, or propyl. In one preferred embodiment, R3 is methyl. In another preferred embodiment, alkyl is optionally substituted with one or two substituents independently selected from the group consisting of -OH, halo, haloC1-C4 alkyl, C1-C4 alkoxy, and -NR5R6, where R5 and R6 are independently selected from H and C1-C3 alkyl. In one preferred embodiment, R3 is hydroxyC1-C6 alkyl (i.e., C1-C6 alkyl substituted with -OH), more preferably hydroxyC1-C3 alkyl, preferably hydroxyethyl.

[0301] In one preferred embodiment, R3 is

[0302] [ka]

[0303] wherein n is 0, 1, or 2. In another preferred embodiment, R3 is

[0304] [ka]

[0305] where n is 0, 1, or 2.

[0306] In another embodiment, R3 is C1-C4 alkoxyC1-C6 alkyl (ie, C1-C6 alkyl substituted with C1-C4 alkoxy), preferably C1-C3 alkoxyC1-C4 alkyl.

[0307] In one embodiment, R3 is

[0308] [ka]

[0309] wherein R4 is -C1-C3 alkyl and n is selected from 0, 1, or 2.

[0310] In another preferred embodiment, R3 is C1-C6 alkyl substituted with -NR5R6, where R5 and R6 are independently selected from H and C1-C3 alkyl. In a preferred embodiment, R5 and R6 are both C1-C3 alkyl, such as methyl, ethyl, or propyl, more preferably R5 and R6 are both methyl. In another embodiment, R5 and R6 are both H.

[0311] In one embodiment, R3 is

[0312] [ka]

[0313] wherein R5 and R6 are independently selected from H and C1-C3 alkyl, and n is 0, 1, or 2. In a preferred embodiment, R5 and R6 are both C1-C3 alkyl, such as methyl, ethyl, or propyl, and more preferably R5 and R6 are both methyl. In another embodiment, R5 and R6 are both H.

[0314] In one preferred embodiment, R3 is

[0315] [ka]

[0316] where n is 0, 1, or 2.

[0317] In another preferred embodiment, R3 is

[0318] [ka]

[0319] wherein R4 is independently selected from -H or C1-C3 alkyl. In a preferred embodiment, R4 is C1-C3 alkyl, such as methyl, ethyl, or propyl, preferably methyl.

[0320] In another preferred embodiment, R3 is

[0321] [ka]

[0322] [wherein R5 is H and C1-C3 alkyl].

[0323] In another preferred embodiment, R3 is C1-C6 alkyl.

[0324] In one preferred embodiment, Z is C. In another embodiment, Z is N. In one preferred embodiment, Q is C. In another embodiment, Q is N.

[0325] In some embodiments, one of Q and Z is C and the other is N. In one embodiment, Q is N and Z is C. In another embodiment, one of Q is C and Z is N. In one preferred embodiment, Q and Z are both C.

[0326] In some embodiments, E is NR a [where R a is selected from H and -C1-C3 alkyl. In one preferred embodiment, R a is H. In another preferred embodiment, R a is -C1-C3 alkyl, preferably R a is methyl. In another embodiment, E is CR a [where R a is selected from H and -C1-C3 alkyl. In one preferred embodiment, R a is H. In another preferred embodiment, R a is -C1-C3 alkyl, preferably R a is methyl.

[0327] In one preferred embodiment, Q and Z are both C and E is NR a [where R a is as defined above. In another embodiment, Q and Z are both C and E is CR a [where R a is as defined above. In another preferred embodiment, Q is N, Z is C, and E is CR a [where R a is as defined above].

[0328] In formula (II'), in a preferred embodiment, X' is N. In another preferred embodiment, X' is CH.

[0329] In a preferred embodiment, W is N. In another preferred embodiment, W is CH. In another preferred embodiment, W is CR c and R c is —CH—OH, —O—CH, or F.

[0330] In one preferred embodiment, Y is NH. In another preferred embodiment, Y is O. In another preferred embodiment, Y is N-CH. In another preferred embodiment, Y is a bond.

[0331] In a preferred embodiment, R c is selected from the group consisting of -O-C1-C4 alkyl, C1-C4 alkyl-OH, and halo. c is selected from the group consisting of —O—C1-C2 alkyl, C1-C4 alkyl-OH, and F, such as C1-C4 alkyl-OH, OCH3, and F.

[0332] In a preferred embodiment, R d is selected from the group consisting of C1 to C4 alkyl.

[0333] In another embodiment, the compound having the formula (III'):

[0334] [ka]

[0335] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof. wherein Q, E, Z, X', W, R, R, R, R, m and Y are as defined in any of the above embodiments.

[0336] In another embodiment, the compound having the formula (III):

[0337] [ka]

[0338] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof. [In the formula, Q, E, Z, R0, R1, R 2、 R3, and Y are as defined in any of the above embodiments.

[0339] The following paragraphs apply to formula (III') and / or (III).

[0340] In a preferred embodiment, R0 is selected from -H and C1-C3 alkyl, more preferably -H or methyl. In one preferred embodiment, R0 is -H. In another preferred embodiment, R0 is C1-C3 alkyl, preferably methyl or ethyl, more preferably methyl.

[0341] In a preferred embodiment, R1 is selected from -CF3, -OCF3, and -OCHF2. In one preferred embodiment, R1 is -CF3. In another preferred embodiment, R1 is -OCF3. In another preferred embodiment, R1 is -OCHF2.

[0342] In another embodiment, R1 is halo. When R1 is halo, the halogen (halo) is preferably chloro.

[0343] In one preferred embodiment, R2 is -OH or H, more preferably -OH. In another embodiment, R2 is -H. In another embodiment, R2 is -CF3.

[0344] In one preferred embodiment, R is -H, R is selected from -CF, -OCF, -OCHF, and -Cl, and R is -OH or -H. In one preferred embodiment, R is -H, R is -CF, and R is -OH.

[0345] In one embodiment, R3 is a 4-, 5-, or 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from N and / or O, optionally substituted with 1 or 2 substituents independently selected from the group consisting of -NR5R6, C1-C4 alkyl, or OH; or an 8-, 9-, or 10-membered bicyclic fused heterocycloalkyl containing 1 to 3 heteroatoms independently selected from N and O, optionally substituted at any available position with one or two substituents independently selected from the group consisting of C1-C4 alkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl, —OH, —NR5R6, and halo; or C3-C6 cycloalkyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of C1-C4 alkyl, —OH, and halo; or hydroxy C1-C6 alkyl; or haloC1-C4 alkyl, preferably —CF3; or C1-C6 alkyl optionally substituted with -NR5R6 is selected from the group consisting of R5 and R6 are independently selected from H and C1-C3 alkyl; m is 0 or 1.

[0346] In one preferred embodiment, R3 is 4-, 5-, or 6-membered heterocycloalkyl containing one heteroatom which is N or O, optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl, —OH, and halo, preferably optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl; C3-C6 cycloalkyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of C1-C4 alkyl, —OH, and halo; Hydroxy C1-C6 alkyl; and C1-C6 alkyl optionally substituted with -NR5R6 is selected from the group consisting of R5 and R6 are independently selected from H and C1-C3 alkyl.

[0347] In one preferred embodiment, R3 is selected from 4-, 5-, or 6-membered heterocycloalkyl containing 1 or 2 heteroatoms, preferably 1 heteroatom, which are N or O. The 4-, 5-, or 6-membered heterocycloalkyl is optionally substituted with 1 or 2 substituents independently selected from the group consisting of C1-C4 alkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl, —OH, and halo. The substituents may be at any available position on the heterocyclic group.

[0348] In one preferred embodiment, R3 is

[0349] [ka]

[0350] selected from the group consisting of Me, and CF3; [Here X is selected from O and NR4; R4 is independently selected from H, halo, or C1-C3 alkyl; R5 is independently selected from H or C1-C3 alkyl, preferably H or Me; R6 is selected from the group consisting of C1-C4 alkyl; n is selected from 0, 1, or 2.

[0351] In one preferred embodiment, R3 is

[0352] [ka]

[0353] selected from the group consisting of wherein X is selected from O and NR4; R4 is independently selected from -H or -C1-C3 alkyl; a is selected from 0 and 1; n is selected from 0, 1, or 2.

[0354] In one preferred embodiment, R3 is

[0355] [ka]

[0356] selected from the group consisting of Me, and CF [where: X is selected from O and NR4; R4 is independently selected from H, halo, or C1-C3 alkyl; R5 is independently selected from -H or -Me; R6 is selected from the group consisting of C1-C4 alkyl; n is selected from 0, 1, or 2.

[0357] In one preferred embodiment, R3 is

[0358] [ka]

[0359] selected from the group consisting of wherein X is selected from O and NR4; R4 is independently selected from -H or -C1-C3 alkyl; a is selected from 0 and 1; n is selected from 0, 1, or 2.

[0360] In a further preferred embodiment, R3 is

[0361] [ka]

[0362] selected from the group consisting of Me, and CF [where: R4 is independently selected from H, F, or C1-C3 alkyl; R5 is methyl; n is selected from 0, 1, or 2.

[0363] In another preferred embodiment, R3 is

[0364] [ka]

[0365] 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.

[0366] In another embodiment, R3 is

[0367] [ka]

[0368] 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.

[0369] In one preferred embodiment, R3 is a 4-, 5-, or 6-membered heterocycloalkyl containing one heteroatom which is N. The 4-, 5-, or 6-membered heterocycloalkyl is optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl, —OH, and halo (preferably C1-C4 alkyl). The substituents may be at any available position on the heterocyclic group.

[0370] In one preferred embodiment, R3 is

[0371] [ka]

[0372] wherein X is selected from O and NR4, preferably X is NR4; R4 is independently selected from -H or -C1-C3 alkyl; a is selected from 0 and 1 (preferably, a is 0); n is selected from 0, 1, or 2. In one preferred embodiment, n is 2. In one preferred embodiment, n is 1. In another preferred embodiment, n is 0.

[0373] In one preferred embodiment, R3 is

[0374] [ka]

[0375] 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.

[0376] In another preferred embodiment, R3 is

[0377] [ka]

[0378] 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.

[0379] In another embodiment, R3 is

[0380] [ka]

[0381] wherein R4 is independently selected from -H or C1-C3 alkyl. In a preferred embodiment, R4 is H. In another embodiment, R4 is C1-C3 alkyl, such as methyl, ethyl, or propyl. In one embodiment, R4 is methyl, whereby R3 is

[0382] [ka]

[0383] is.

[0384] In another embodiment, R3 is

[0385] [ka]

[0386] wherein R4 is independently selected from -H or C1-C3 alkyl. In a preferred embodiment, R4 is H. In another embodiment, R4 is C1-C3 alkyl, such as methyl, ethyl, or propyl. In one preferred embodiment, R4 is methyl, whereby R3 is

[0387] [ka]

[0388] is.

[0389] In another preferred embodiment, R3 is a 4-, 5-, or 6-membered heterocycloalkyl containing one heteroatom which is O. In one preferred embodiment, R3 is

[0390] [ka]

[0391] is.

[0392] In another embodiment, R3 is C3-C6 cycloalkyl, preferably cyclohexyl, cyclopropyl, or cyclobutyl, more preferably cyclopropyl or cyclobutyl. The C3-C6 cycloalkyl is optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl, —OH, and halo. The substituents may be at any available position on the cycloalkyl group.

[0393] In one preferred embodiment, R3 is

[0394] [ka]

[0395] is.

[0396] In one preferred embodiment, R3 is

[0397] [ka]

[0398] 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 one preferred embodiment, R3 is

[0399] [ka]

[0400] In another preferred embodiment, R3 is

[0401] [ka]

[0402] is.

[0403] In another preferred embodiment, R3 is

[0404] [ka]

[0405] In one preferred embodiment, R3 is

[0406] [ka]

[0407] In another preferred embodiment, R3 is

[0408] [ka]

[0409] is.

[0410] In another preferred embodiment, R3 is C1-C6 alkyl, such as C1-C3 alkyl, for example, methyl, ethyl, or propyl. In one preferred embodiment, R3 is methyl. In another preferred embodiment, alkyl is optionally substituted with one or two substituents independently selected from the group consisting of -OH, halo, haloC1-C4 alkyl, C1-C4 alkoxy, and -NR5R6, where R5 and R6 are independently selected from H and C1-C3 alkyl. In one preferred embodiment, R3 is hydroxyC1-C6 alkyl (i.e., C1-C6 alkyl substituted with -OH), more preferably hydroxyC1-C3 alkyl, preferably hydroxyethyl.

[0411] In one preferred embodiment, R3 is

[0412] [ka]

[0413] wherein n is 0, 1, or 2. In another preferred embodiment, R3 is

[0414] [ka]

[0415] where n is 0, 1, or 2.

[0416] In another embodiment, R3 is C1-C4 alkoxyC1-C6 alkyl (ie, C1-C6 alkyl substituted with C1-C4 alkoxy), preferably C1-C3 alkoxyC1-C4 alkyl.

[0417] In one embodiment, R3 is

[0418] [ka]

[0419] wherein R4 is -C1-C3 alkyl and n is selected from 0, 1, or 2.

[0420] In another preferred embodiment, R3 is C1-C6 alkyl substituted with -NR5R6, where R5 and R6 are independently selected from H and C1-C3 alkyl. In a preferred embodiment, R5 and R6 are both C1-C3 alkyl, such as methyl, ethyl, or propyl, more preferably R5 and R6 are both methyl. In another embodiment, R5 and R6 are both H.

[0421] In one embodiment, R3 is

[0422] [ka]

[0423] wherein R5 and R6 are independently selected from H and C1-C3 alkyl, and n is 0, 1, or 2. In a preferred embodiment, R5 and R6 are both C1-C3 alkyl, such as methyl, ethyl, or propyl, and more preferably R5 and R6 are both methyl. In another embodiment, R5 and R6 are both H.

[0424] In one preferred embodiment, R3 is

[0425] [ka]

[0426] where n is 0, 1, or 2.

[0427] In one preferred embodiment, Z is C. In another embodiment, Z is N. In one preferred embodiment, Q is C. In another embodiment, Q is N.

[0428] In some embodiments, one of Q and Z is C and the other is N. In one embodiment, Q is N and Z is C. In another embodiment, one of Q is C and Z is N.

[0429] In one preferred embodiment, Q and Z are both C.

[0430] In some embodiments, E is NR a [where R a is selected from H and -C1-C3 alkyl. In one preferred embodiment, R a is H. In another preferred embodiment, R a is -C1-C3 alkyl, preferably R a is methyl. In another embodiment, E is CR a [where R a is selected from H and -C1-C3 alkyl. In one preferred embodiment, R a is H. In another preferred embodiment, R a is -C1-C3 alkyl, preferably R a is methyl.

[0431] In one preferred embodiment, Q and Z are both C and E is NR a [where R a is as defined above. In another embodiment, Q and Z are both C and E is CR a [where R a is as defined above. In another preferred embodiment, Q is N, Z is C, and E is CR a [where R a is as defined above].

[0432] In a preferred embodiment, X' is N. In another preferred embodiment, X' is CH.

[0433] In a preferred embodiment, W is N. In another preferred embodiment, W is CH. In another preferred embodiment, W is CR cand R c is —CH—OH, —O—CH, or F.

[0434] In one preferred embodiment, Y is NH. In another preferred embodiment, Y is O. In another preferred embodiment, Y is N-CH. In another preferred embodiment, Y is a bond.

[0435] In a preferred embodiment, R c is selected from the group consisting of -O-C1-C4 alkyl, C1-C4 alkyl-OH, and halo. c is selected from the group consisting of —O—C1-C2 alkyl, C1-C4 alkyl-OH, and F, such as C1-C4 alkyl-OH, OCH3, and F.

[0436] In a preferred embodiment, R d is selected from the group consisting of C1 to C4 alkyl.

[0437] In another preferred embodiment, R3 is

[0438] [ka]

[0439] wherein R4 is independently selected from -H or C1-C3 alkyl. In a preferred embodiment, R4 is C1-C3 alkyl, such as methyl, ethyl, or propyl, preferably methyl.

[0440] In another preferred embodiment, R3 is

[0441] [ka]

[0442] [wherein R5 is H and C1-C3 alkyl].

[0443] In an embodiment, R3 is OH.

[0444] In another preferred embodiment, R3 is C1-C6 alkyl.

[0445] In another preferred embodiment, the compound of formula (II') has the formula (II'a)

[0446] [ka]

[0447] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof. [In the formula, X', W, R0, R1, R2, R3, R a , m, and Y are as defined in any of the above embodiments].

[0448] In another preferred embodiment, the compound of formula (II) has the formula (IIa):

[0449] [ka]

[0450] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof. [In the formula, R0, R1, R2, R3, R a and Y is as defined in any of the above embodiments].

[0451] The following paragraphs apply to formula (IIa') and / or (IIa).

[0452] In a preferred embodiment, R0 is selected from -H and C1-C3 alkyl, more preferably -H or methyl. In one preferred embodiment, R0 is -H. In another preferred embodiment, R0 is C1-C3 alkyl, preferably methyl or ethyl, more preferably methyl.

[0453] In a preferred embodiment, R1 is selected from -CF3, -OCF3, and -OCHF2. In one preferred embodiment, R1 is -CF3. In another preferred embodiment, R1 is -OCF3. In another preferred embodiment, R1 is -OCHF2.

[0454] In another embodiment, R1 is halo. When R1 is halo, the halogen (halo) is preferably chloro.

[0455] In one preferred embodiment, R2 is -OH or H, more preferably -OH. In another embodiment, R2 is -H. In another embodiment, R2 is -CF3.

[0456] In one preferred embodiment, R is -H, R is selected from -CF, -OCF, -OCHF, and -Cl, and R is -OH or -H. In one preferred embodiment, R is -H, R is -CF, and R is -OH.

[0457] In one embodiment, R3 is 4-, 5-, or 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from N and / or O, optionally substituted with 1 or 2 substituents independently selected from the group consisting of -NR5R6, C1-C4 alkyl, or OH; an 8-, 9-, or 10-membered bicyclic fused heterocycloalkyl containing 1 to 3 heteroatoms independently selected from N and O, optionally substituted at any available position with one or two substituents independently selected from the group consisting of C1-C4 alkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl, —OH, —NR5R6, and halo; or C3-C6 cycloalkyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of C1-C4 alkyl, —OH, and halo; or hydroxy C1-C6 alkyl; or haloC1-C4 alkyl, preferably —CF3; or C1-C6 alkyl optionally substituted with -NR5R6 is selected from the group consisting of R5 and R6 are independently selected from H and C1-C3 alkyl; m is 0 or 1.

[0458] In another embodiment, R3 is 4-, 5-, or 6-membered heterocycloalkyl containing one heteroatom which is N or O, optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl, —OH, and halo, preferably optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl; C3-C6 cycloalkyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of C1-C4 alkyl, —OH, and halo; Hydroxy C1-C6 alkyl; and C1-C6 alkyl optionally substituted with -NR5R6 is selected from the group consisting of R5 and R6 are independently selected from H and C1-C3 alkyl.

[0459] In one preferred embodiment, R3 is selected from 4-, 5-, or 6-membered heterocycloalkyl containing 1 or 2 heteroatoms, preferably 1 heteroatom, which are N or O. The 4-, 5-, or 6-membered heterocycloalkyl is optionally substituted with 1 or 2 substituents independently selected from the group consisting of C1-C4 alkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl, —OH, and halo. The substituents may be at any available position on the heterocyclic group.

[0460] In one preferred embodiment, R3 is

[0461] [ka]

[0462] selected from the group consisting of Me, and CF [where: X is selected from O and NR4; R4 is independently selected from H, halo, or C1-C3 alkyl; R5 is independently selected from H or C1-C3 alkyl, preferably H or Me; R6 is selected from the group consisting of C1-C4 alkyl; n is selected from 0, 1, or 2.

[0463] In one preferred embodiment, R3 is

[0464] [ka]

[0465] selected from the group consisting of wherein X is selected from O and NR4; R4 is independently selected from -H or -C1-C3 alkyl; a is selected from 0 and 1; n is selected from 0, 1, or 2.

[0466] In one preferred embodiment, R3 is

[0467] [ka]

[0468] selected from the group consisting of Me, and CF [where: X is selected from O and NR4; R4 is independently selected from H, halo, or C1-C3 alkyl; R5 is independently selected from -H or -Me; R6 is selected from the group consisting of C1-C4 alkyl; n is selected from 0, 1, or 2.

[0469] In one preferred embodiment, R3 is

[0470] [ka]

[0471] selected from the group consisting of wherein X is selected from O and NR4; R4 is independently selected from -H or -C1-C3 alkyl; a is selected from 0 and 1; n is selected from 0, 1, or 2.

[0472] In another preferred embodiment, R3 is

[0473] [ka]

[0474] selected from the group consisting of Me, and CF [where: R4 is independently selected from H, F, or C1-C3 alkyl; R5 is methyl; n is selected from 0, 1, or 2.

[0475] In another preferred embodiment, R3 is

[0476] [ka]

[0477] 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.

[0478] In another preferred embodiment, R3 is

[0479] [ka]

[0480] 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.

[0481] In one preferred embodiment, R3 is a 4-, 5-, or 6-membered heterocycloalkyl containing one heteroatom which is N. The 4-, 5-, or 6-membered heterocycloalkyl is optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl, —OH, and halo (preferably C1-C4 alkyl). The substituents may be at any available position on the heterocyclic group.

[0482] In one preferred embodiment, R3 is

[0483] [ka]

[0484] wherein X is selected from O and NR4, preferably X is NR4; R4 is independently selected from -H or -C1-C3 alkyl; a is selected from 0 and 1 (preferably, a is 0); n is selected from 0, 1 or 2. In one preferred embodiment, n is 2. In one preferred embodiment, n is 1. In another preferred embodiment, n is 0.

[0485] In one preferred embodiment, R3 is

[0486] [ka]

[0487] 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.

[0488] In another preferred embodiment, R3 is

[0489] [ka]

[0490] 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.

[0491] In another embodiment, R3 is

[0492] [ka]

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

[0494] [ka]

[0495] is.

[0496] In another embodiment, R3 is

[0497] [ka]

[0498] wherein R4 is independently selected from -H or C1-C3 alkyl. In a preferred embodiment, R4 is H. In another embodiment, R4 is C1-C3 alkyl, such as methyl, ethyl, or propyl. In one preferred embodiment, R4 is methyl, whereby R3 is

[0499] [ka]

[0500] is.

[0501] In another preferred embodiment, R3 is a 4-, 5-, or 6-membered heterocycloalkyl containing one heteroatom which is O. In one preferred embodiment, R3 is

[0502] [ka]

[0503] is.

[0504] In another embodiment, R3 is C3-C6 cycloalkyl, preferably cyclohexyl, cyclopropyl, or cyclobutyl, more preferably cyclopropyl or cyclobutyl. The C3-C6 cycloalkyl is optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl, —OH, and halo. The substituents may be at any available position on the cycloalkyl group.

[0505] In one preferred embodiment, R3 is

[0506] [ka]

[0507] is.

[0508] In one preferred embodiment, R3 is

[0509] [ka]

[0510] 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 one preferred embodiment, R3 is

[0511] [ka]

[0512] In another preferred embodiment, R3 is

[0513] [ka]

[0514] is.

[0515] In another preferred embodiment, R3 is

[0516] [ka]

[0517] In one preferred embodiment, R3 is

[0518] [ka]

[0519] In another preferred embodiment, R3 is

[0520] [ka]

[0521] is.

[0522] In another preferred embodiment, R3 is C1-C6 alkyl, such as C1-C3 alkyl, for example, methyl, ethyl, or propyl. In one preferred embodiment, R3 is methyl. In another preferred embodiment, alkyl is optionally substituted with one or two substituents independently selected from the group consisting of -OH, halo, haloC1-C4 alkyl, C1-C4 alkoxy, and -NR5R6, where R5 and R6 are independently selected from H and C1-C3 alkyl. In one preferred embodiment, R3 is hydroxyC1-C6 alkyl (i.e., C1-C6 alkyl substituted with -OH), more preferably hydroxyC1-C3 alkyl, preferably hydroxyethyl.

[0523] In one preferred embodiment, R3 is

[0524] [ka]

[0525] wherein n is 0, 1, or 2. In another preferred embodiment, R3 is

[0526] [ka]

[0527] where n is 0, 1, or 2.

[0528] In another embodiment, R3 is C1-C4 alkoxyC1-C6 alkyl (ie, C1-C6 alkyl substituted with C1-C4 alkoxy), preferably C1-C3 alkoxyC1-C4 alkyl.

[0529] In one embodiment, R3 is

[0530] [ka]

[0531] wherein R4 is -C1-C3 alkyl and n is selected from 0, 1, or 2.

[0532] In another preferred embodiment, R3 is C1-C6 alkyl substituted with -NR5R6, where R5 and R6 are independently selected from H and C1-C3 alkyl. In a preferred embodiment, R5 and R6 are both C1-C3 alkyl, such as methyl, ethyl, or propyl, more preferably R5 and R6 are both methyl. In another embodiment, R5 and R6 are both H.

[0533] In one embodiment, R3 is

[0534] [ka]

[0535] wherein R5 and R6 are independently selected from H and C1-C3 alkyl, and n is 0, 1, or 2. In a preferred embodiment, R5 and R6 are both C1-C3 alkyl, such as methyl, ethyl, or propyl, and more preferably R5 and R6 are both methyl. In another embodiment, R5 and R6 are both H.

[0536] In one preferred embodiment, R3 is

[0537] [ka]

[0538] where n is 0, 1, or 2.

[0539] R a is selected from the group consisting of -H and -C1-C3 alkyl. In some embodiments, R a is H. In other embodiments, R a is —C1-C3 alkyl, such as methyl, ethyl, or propyl, preferably methyl.

[0540] In a preferred embodiment, X' is N. In another preferred embodiment, X' is CH.

[0541] In a preferred embodiment, W is N. In another preferred embodiment, W is CH. In another preferred embodiment, W is CR c and R c is —CH—OH, —O—CH, or F.

[0542] In one preferred embodiment, Y is NH. In another preferred embodiment, Y is O. In another preferred embodiment, Y is N-CH. In another preferred embodiment, Y is a bond.

[0543] In a preferred embodiment, R c is selected from the group consisting of -O-C1-C4 alkyl, C1-C4 alkyl-OH, and halo. c is selected from the group consisting of —O—C1-C2 alkyl, C1-C4 alkyl-OH, and F, such as C1-C4 alkyl-OH, OCH3, and F.

[0544] In a preferred embodiment, R d is selected from the group consisting of C1 to C4 alkyl.

[0545] In another preferred embodiment, R3 is

[0546] [ka]

[0547] wherein R4 is independently selected from -H or C1-C3 alkyl. In a preferred embodiment, R4 is C1-C3 alkyl, such as methyl, ethyl, or propyl, preferably methyl.

[0548] In another preferred embodiment, R3 is

[0549] [ka]

[0550] wherein R5 is H or C1-C3 alkyl.

[0551] In another preferred embodiment, R3 is C1-C6 alkyl.

[0552] In another preferred embodiment, the compound of formula (II) has the formula (IIb):

[0553] [ka]

[0554] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof. [In the formula, X', W, R0, R1, R2, R3, R a , m, and Y are as defined in any of the above embodiments].

[0555] In another preferred embodiment, the compound of formula (II) has the formula (IIb):

[0556] [ka]

[0557] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof. [In the formula, R0, R1, R2, R3, R a and Y is as defined in any of the above embodiments].

[0558] The following paragraphs apply to formula (II'b) and / or (IIb).

[0559] In a preferred embodiment, R0 is selected from -H and C1-C3 alkyl, more preferably -H or methyl. In one preferred embodiment, R0 is -H. In another preferred embodiment, R0 is C1-C3 alkyl, preferably methyl or ethyl, more preferably methyl.

[0560] In a preferred embodiment, R1 is selected from -CF3, -OCF3, and -OCHF2. In one preferred embodiment, R1 is -CF3. In another preferred embodiment, R1 is -OCF3. In another preferred embodiment, R1 is -OCHF2.

[0561] In another embodiment, R1 is halo. When R1 is halo, the halogen (halo) is preferably chloro.

[0562] In one preferred embodiment, R2 is -OH or H, more preferably -OH. In another embodiment, R2 is -H. In another embodiment, R2 is -CF3.

[0563] In one preferred embodiment, R is -H, R is selected from -CF, -OCF, -OCHF, and -Cl, and R is -OH or -H. In one preferred embodiment, R is -H, R is -CF, and R is -OH.

[0564] In one embodiment, R3 is 4-, 5-, or 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from N and / or O, optionally substituted with 1 or 2 substituents independently selected from the group consisting of -NR5R6, C1-C4 alkyl, or OH; an 8-, 9-, or 10-membered bicyclic fused heterocycloalkyl containing 1 to 3 heteroatoms independently selected from N and O, optionally substituted at any available position with one or two substituents independently selected from the group consisting of C1-C4 alkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl, —OH, —NR5R6, and halo; or C3-C6 cycloalkyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of C1-C4 alkyl, —OH, and halo; or hydroxy C1-C6 alkyl; or haloC1-C4 alkyl, preferably -CF3, or C1-C6 alkyl optionally substituted with -NR5R6 is selected from the group consisting of R5 and R6 are independently selected from H and C1-C3 alkyl; m is 0 or 1.

[0565] In one preferred embodiment, R3 is 4-, 5-, or 6-membered heterocycloalkyl containing one heteroatom which is N or O, optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl, —OH, and halo, preferably optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl; C3-C6 cycloalkyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of C1-C4 alkyl, —OH, and halo; Hydroxy C1-C6 alkyl; and C1-C6 alkyl optionally substituted with -NR5R6 is selected from the group consisting of R5 and R6 are independently selected from H and C1-C3 alkyl.

[0566] In one preferred embodiment, R3 is selected from 4-, 5-, or 6-membered heterocycloalkyl containing 1 or 2 heteroatoms, preferably 1 heteroatom, which are N or O. The 4-, 5-, or 6-membered heterocycloalkyl is optionally substituted with 1 or 2 substituents independently selected from the group consisting of C1-C4 alkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl, —OH, and halo. The substituents may be at any available position on the heterocyclic group.

[0567] In one preferred embodiment, R3 is

[0568] [ka]

[0569] selected from the group consisting of Me, and CF [where: X is selected from O and NR4; R4 is independently selected from H, halo, or C1-C3 alkyl; R5 is independently selected from H or C1-C3 alkyl, preferably H or Me; R6 is selected from the group consisting of C1-C4 alkyl; n is selected from 0, 1, or 2.

[0570] In one preferred embodiment, R3 is

[0571] [ka]

[0572] selected from the group consisting of wherein X is selected from O and NR4; R4 is independently selected from -H or -C1-C3 alkyl; a is selected from 0 and 1; n is selected from 0, 1, or 2.

[0573] In one preferred embodiment, R3 is

[0574] [ka]

[0575] selected from the group consisting of Me, and CF [where: X is selected from O and NR4; R4 is independently selected from H, halo, or C1-C3 alkyl; R5 is independently selected from -H or -Me; R6 is selected from the group consisting of C1-C4 alkyl; n is selected from 0, 1, or 2.

[0576] In one preferred embodiment, R3 is

[0577] [ka]

[0578] selected from the group consisting of wherein X is selected from O and NR4; R4 is independently selected from -H or -C1-C3 alkyl; a is selected from 0 and 1; n is selected from 0, 1, or 2.

[0579] In another preferred embodiment, R3 is

[0580] [ka]

[0581] 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.

[0582] In another preferred embodiment, R3 is

[0583] [ka]

[0584] selected from the group consisting of Me, and CF [where: R4 is independently selected from H, F, or C1-C3 alkyl; R5 is methyl; n is selected from 0, 1, or 2.

[0585] In another preferred embodiment, R3 is

[0586] [ka]

[0587] 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.

[0588] In one preferred embodiment, R3 is a 4-, 5-, or 6-membered heterocycloalkyl containing one heteroatom which is N. The 4-, 5-, or 6-membered heterocycloalkyl is optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl, —OH, and halo (preferably C1-C4 alkyl). The substituents may be at any available position on the heterocyclic group.

[0589] In one preferred embodiment, R3 is

[0590] [ka]

[0591] wherein X is selected from O and NR4, preferably X is NR4; R4 is independently selected from -H or -C1-C3 alkyl; a is selected from 0 and 1 (preferably, a is 0); n is selected from 0, 1, or 2. In one preferred embodiment, n is 2. In one preferred embodiment, n is 1. In another preferred embodiment, n is 0.

[0592] In one preferred embodiment, R3 is

[0593] [ka]

[0594] 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.

[0595] In another preferred embodiment, R3 is

[0596] [ka]

[0597] 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.

[0598] In another embodiment, R3 is

[0599] [ka]

[0600] wherein R4 is independently selected from -H or C1-C3 alkyl. In a preferred embodiment, R4 is H. In another embodiment, R4 is C1-C3 alkyl, such as methyl, ethyl, or propyl. In one embodiment, R4 is methyl, whereby R3 is

[0601] [ka]

[0602] is.

[0603] In another embodiment, R3 is

[0604] [ka]

[0605] wherein R4 is independently selected from -H or C1-C3 alkyl. In a preferred embodiment, R4 is H. In another embodiment, R4 is C1-C3 alkyl, such as methyl, ethyl, or propyl. In one preferred embodiment, R4 is methyl, whereby R3 is

[0606] [ka]

[0607] is.

[0608] In another preferred embodiment, R3 is a 4-, 5-, or 6-membered heterocycloalkyl containing one heteroatom which is O. In one preferred embodiment, R3 is

[0609] [ka]

[0610] is.

[0611] In another embodiment, R3 is C3-C6 cycloalkyl, preferably cyclohexyl, cyclopropyl, or cyclobutyl, more preferably cyclopropyl or cyclobutyl. The C3-C6 cycloalkyl is optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl, —OH, and halo. The substituents may be at any available position on the cycloalkyl group.

[0612] In one preferred embodiment, R3 is

[0613] [ka]

[0614] is.

[0615] In one preferred embodiment, R3 is

[0616] [ka]

[0617] 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 one preferred embodiment, R3 is

[0618] [ka]

[0619] In another preferred embodiment, R3 is

[0620] [ka]

[0621] is.

[0622] In another preferred embodiment, R3 is

[0623] [ka]

[0624] In one preferred embodiment, R3 is

[0625] [ka]

[0626] In another preferred embodiment, R3 is

[0627] [ka]

[0628] is.

[0629] In another preferred embodiment, R3 is C1-C6 alkyl, such as C1-C3 alkyl, for example, methyl, ethyl, or propyl. In one preferred embodiment, R3 is methyl. In another preferred embodiment, alkyl is optionally substituted with one or two substituents independently selected from the group consisting of -OH, halo, haloC1-C4 alkyl, C1-C4 alkoxy, and -NR5R6, where R5 and R6 are independently selected from H and C1-C3 alkyl. In one preferred embodiment, R3 is hydroxyC1-C6 alkyl (i.e., C1-C6 alkyl substituted with -OH), more preferably hydroxyC1-C3 alkyl, preferably hydroxyethyl. In one preferred embodiment, R3 is

[0630] [ka]

[0631] wherein n is 0, 1, or 2. In another preferred embodiment, R3 is

[0632] [ka]

[0633] where n is 0, 1, or 2.

[0634] In another embodiment, R3 is C1-C4 alkoxyC1-C6 alkyl (ie, C1-C6 alkyl substituted with C1-C4 alkoxy), preferably C1-C3 alkoxyC1-C4 alkyl.

[0635] In one embodiment, R3 is

[0636] [ka]

[0637] wherein R4 is -C1-C3 alkyl and n is selected from 0, 1, or 2.

[0638] In another preferred embodiment, R3 is C1-C6 alkyl substituted with -NR5R6, where R5 and R6 are independently selected from H and C1-C3 alkyl. In a preferred embodiment, R5 and R6 are both C1-C3 alkyl, such as methyl, ethyl, or propyl, more preferably R5 and R6 are both methyl. In another embodiment, R5 and R6 are both H.

[0639] In one embodiment, R3 is

[0640] [ka]

[0641] wherein R5 and R6 are independently selected from H and C1-C3 alkyl, and n is 0, 1, or 2. In a preferred embodiment, R5 and R6 are both C1-C3 alkyl, such as methyl, ethyl, or propyl, and more preferably R5 and R6 are both methyl. In another embodiment, R5 and R6 are both H.

[0642] In one preferred embodiment, R3 is

[0643] [ka]

[0644] where n is 0, 1, or 2.

[0645] R a is selected from the group consisting of -H and -C1-C3 alkyl. In some embodiments, R a is H. In other embodiments, R a is —C1-C3 alkyl, such as methyl, ethyl, or propyl, preferably methyl.

[0646] In a preferred embodiment, X' is N. In another preferred embodiment, X' is CH.

[0647] In a preferred embodiment, W is N. In another preferred embodiment, W is CH. In another preferred embodiment, W is CR c and R c is —CH—OH, —O—CH, or F.

[0648] In one preferred embodiment, Y is NH. In another preferred embodiment, Y is O. In another preferred embodiment, Y is N-CH. In another preferred embodiment, Y is a bond.

[0649] In a preferred embodiment, R c is selected from the group consisting of -O-C1-C4 alkyl, C1-C4 alkyl-OH, and halo. c is selected from the group consisting of —O—C1-C2 alkyl, C1-C4 alkyl-OH, and F, such as C1-C4 alkyl-OH, OCH3, and F.

[0650] In a preferred embodiment, R d is selected from the group consisting of C1 to C4 alkyl.

[0651] In another preferred embodiment, R3 is

[0652] [ka]

[0653] wherein R4 is independently selected from -H or C1-C3 alkyl. In a preferred embodiment, R4 is C1-C3 alkyl, such as methyl, ethyl, or propyl, preferably methyl.

[0654] In another preferred embodiment, R3 is

[0655] [ka]

[0656] wherein R5 is H or C1-C3 alkyl.

[0657] In another preferred embodiment, R3 is C1-C6 alkyl.

[0658] In another preferred embodiment, the compound of formula (IV) has the formula (IV):

[0659] [ka]

[0660] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof. [In the formula, X', W, R0, R1, R2, R d and R a is as defined in the above embodiment, and R A teeth,

[0661] [ka]

[0662] and Y is NH, NR d , O, or a bond; R3 is 4-, 5-, or 6-membered heterocycloalkyl containing 1 or 2 heteroatoms, preferably 1 heteroatom, independently selected from N and O, and optionally substituted with 1 or 2 substituents independently selected from the group consisting of C1-C4 alkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl, —OH, —NR5R6, and halo; an 8-, 9-, or 10-membered bicyclic fused heterocycloalkyl containing 1 to 3 heteroatoms independently selected from N and O, optionally substituted at any available position with one or two substituents independently selected from the group consisting of C1-C4 alkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl, —OH, —NR5R6, and halo; or C3-C6 cycloalkyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of C1-C4 alkyl, haloC1-C4 alkyl, hydroxyC1-C4 alkyl, —OH, and halo; or C1-C6 alkyl optionally substituted with one or two substituents independently selected from the group consisting of -OH, halo, haloC1-C4 alkyl, C1-C4 alkoxy, and -NR5R6; is selected from the group consisting of R5 and R6 are independently selected from H and C1-C3 alkyl; m is 0, 1, or 2].

[0663] In another preferred embodiment, the compound of formula (V) has the formula (V):

[0664] [ka]

[0665] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof. [In the formula, R0, R1, R2, R3, R a, m, and Y are as defined in the above embodiment].

[0666] In a preferred embodiment, the present invention relates to the following compounds of formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV), or (V) above, wherein: R0 is -H or -CH3; R1 is —CF3 or halo, preferably Cl; R2 is -OH].

[0667] Throughout this application, Q is N and R B but

[0668] [ka]

[0669] When Y is, Y is preferably a bond.

[0670] In another embodiment, the present invention provides the following compounds of formula (I):

[0671] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0672] or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof.

[0673] The present invention further relates to a pharmaceutical composition comprising a compound of formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV), or (V) as defined in the present invention, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof, and optionally at least one pharmaceutically acceptable carrier, diluent, adjuvant, or additive.

[0674] Various embodiments of the invention are described herein, and it will be recognized that the features specified in each embodiment may be combined with other specified features to provide additional embodiments of the invention.

[0675] The present invention relates to a compound of formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV) or (V) as defined in the present invention, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, for use as a pharmaceutical.

[0676] The present invention relates to a compound of formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV), or (V), as defined herein, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof, for use in the treatment, amelioration, or prevention of a disease, disorder, or condition that responds to modulation of a component of the NLRP3 inflammasome pathway, particularly inhibition of its activation, and / or that responds to modulation, particularly reduction, of IL-1 beta and / or IL-18 levels. In one embodiment, the modulation is reduction and / or inhibition of IL-1 beta and / or IL-18 levels. In particular, the modulation is reduction and / or inhibition of IL-1 beta.

[0677] The present invention relates to a compound of formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV), or (V) as defined in the present invention, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof, for use in the treatment, alleviation, or prevention of diseases, disorders, or conditions responsive to modulation, in particular reduction, of IL-1 beta and / or IL-18 levels.

[0678] In another embodiment, the present invention relates to a compound of formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV), or (V) as defined in the present invention, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof, for use in a method of reducing and / or inhibiting IL-1 beta and / or IL-18. In one embodiment, the present invention relates to a compound of formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV), or (V) as defined in the present invention, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof, for use in a method of reducing and / or inhibiting IL-1beta, in particular a method of inhibiting IL-1beta.

[0679] The present invention relates to a compound of formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV), or (V) as defined in the present invention, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof, for use in the treatment, amelioration, or prevention of a disease, disorder, or condition responsive to modulation of a component of the NLRP3 inflammasome pathway, in particular inhibition of the activation of that component.

[0680] The present invention relates to a compound of formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV), or (V) as defined in the present invention, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof, for use in the treatment, amelioration, or prevention of a disease, disorder, or condition responsive to modulation of the NLRP3 inflammasome, in particular inhibition of its activation.

[0681] In other words, the present invention relates to a method for treating, alleviating, or preventing a disease, disorder, or condition that responds to modulation of a component of the NLRP3 inflammasome pathway, particularly inhibition of the activation of that component, and / or to modulation, particularly reduction, of IL-1 beta and / or IL-18 levels, comprising administering a therapeutically effective amount of a compound of Formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV), or (V) as defined in the present invention, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof, to a subject (e.g., patient) in need thereof. In one embodiment, the modulation is reduction and / or inhibition of IL-1 beta and / or IL-18 levels. In particular, the modulation is reduction and / or inhibition of IL-1 beta.

[0682] In one embodiment, the present invention relates to a method for treating, preventing, or alleviating a disease, disorder, or condition responsive to modulation of a component of the NLRP3 inflammasome pathway, in particular inhibition of the activation of that component, comprising administering a therapeutically effective amount of a compound of formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV), or (V) as defined in the present invention, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof, to a subject (e.g., a patient) in need thereof.

[0683] The present invention further relates to a method for treating, preventing, or alleviating a disease, disorder, or abnormality responsive to modulation of the NLRP3 inflammasome, in particular inhibition of its activation, comprising the step of administering a therapeutically effective amount of a compound of formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV), or (V) as defined in the present invention, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof, to a subject (e.g., a patient) in need thereof.

[0684] In one embodiment, the present invention relates to a method for treating, preventing, or ameliorating a disease, disorder, or condition responsive to modulation, particularly reduction, of IL-1 beta and / or IL-18 levels, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (F), ...

[0685] The present invention relates to the use of a compound of formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV), or (V) as defined in the present invention, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof, for the manufacture of a medicament. In another embodiment, the present invention relates to the use of a compound of Formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV), or (V), or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof, as defined herein, for the manufacture of a medicament for treating, alleviating, or preventing a disease, disorder, or condition that responds to modulation of a component of the NLRP3 inflammasome pathway, particularly inhibition of its activation, and / or that responds to modulation, particularly reduction, of IL-1 beta and / or IL-18 levels. In one embodiment, the modulation is reduction and / or inhibition of IL-1 beta and / or IL-18 levels. In particular, the modulation is reduction and / or inhibition of IL-1 beta.

[0686] The present invention relates to the use of a compound of formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV), or (V), or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof, as defined in the present invention, for the manufacture of a medicament for treating, ameliorating, or preventing a disease, disorder, or condition responsive to modulation of a component of the NLRP3 inflammasome pathway, in particular inhibition of the activation of that component.

[0687] The present invention relates to the use of a compound of formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV), or (V), or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof, as defined in the present invention, for the manufacture of a medicament for treating, alleviating, or preventing a disease, disorder, or abnormality responsive to modulation of the NLRP3 inflammasome, in particular inhibition of its activation.

[0688] The present invention relates to the use of a compound of formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV), or (V) as defined in the present invention, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof, for the manufacture of a medicament for treating, alleviating, or preventing a disease, disorder, or condition responsive to modulation, in particular reduction, of IL-1 beta and / or IL-18 levels.

[0689] The present invention relates to the use of a compound of formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV), or (V), or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof, as defined herein, for the manufacture of a medicament for reducing and / or inhibiting IL-1 beta and / or IL-18 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 or inhibiting IL-1 beta.

[0690] In one embodiment, the present invention relates to a compound of formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV), or (V) as defined in the present invention, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof, for use in treating, alleviating, or preventing tauopathy by modulating a component of the inflammasome pathway, in particular by modulating the NLRP3 inflammasome pathway.

[0691] In another embodiment, the disease, disorder, or condition is responsive to modulation of one or more of IL-1β, IL-17, IL-18, IL-1a, IL-37, IL-33, and Th17 cells, preferably IL-1β and IL-18.

[0692] In yet another embodiment, the disease, disorder, or condition is a disease, disorder, or condition selected from Alzheimer's disease, Parkinson's disease, cryopyrin-associated periodic syndromes (CAPS), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and gout.

[0693] In another embodiment, the disease, disorder, or disorder is a disease, disorder, or disorder of the immune system. In an embodiment, the disease, disorder, or disorder is an inflammatory disease, disorder, or disorder. In yet another embodiment, the disease, disorder, or disorder is an autoimmune disease, disorder, or disorder. In yet another embodiment, the disease, disorder, or disorder is a disease, disorder, or disorder of the central nervous system (CNS). In yet another embodiment, the disease, disorder, or disorder can be a skin disease, disorder, or disorder or condition. The disease, disorder, or disorder can be a disease, disorder, or disorder or condition of the cardiovascular system. The disease, disorder, or disorder or condition can be a cancer, tumor, or other malignancy. The disease, disorder, or disorder or condition can be a disease, disorder, or disorder of the renal system. The disease, disorder, or disorder or condition can be a disease, disorder, or disorder of the gastrointestinal tract. The disease, disorder, or disorder or condition can be a respiratory system disease, disorder, or disorder. The disease, disorder, or abnormality or condition may be a disease, disorder, or abnormality of the endocrine system. The disease, disorder, or abnormality or condition may be a disease, disorder, or abnormality related to the liver.

[0694] In one embodiment, the disease, disorder, or condition responsive to modulation of a component of the NLRP3 inflammasome pathway, in particular inhibition of activation of that component, is Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, demyelination, viral encephalitis, epilepsy, stroke, atherosclerosis, allergic inflammation, cryopyrin-associated periodic syndromes (CAPS), Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), neonatal-onset multisystem inflammatory disease (NOMID), gout, pseudogout, inflammatory bowel disease (IBD) (including Crohn's disease, ulcerative colitis), hepatitis, non-small cell lung cancer, and the like. Alcoholic fatty liver disease, non-alcoholic steatohepatitis, hypertension, myocardial infarction, heart failure, coronary artery disease, oxalate-induced nephropathy, graft-versus-host disease, type 1 diabetes, type 2 diabetes, edema (DME), geographic atrophy (GA), rheumatoid arthritis, myelodysplastic syndrome, familial Mediterranean fever (FMF), tumor necrosis factor receptor-associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD), hyperimmunoglobulin Demia, periodic fever syndrome (HIDS), interleukin-1 receptor antagonist deficiency (DIRA), Majeed syndrome, septic arthritis, pyoderma gangrenosum, and acne (PAPA), A2 Haploinsufficiency (HA20), PLCG2-associated antibody deficiency and immunodeficiency (PLAID), childhood granulomatous arthritis (PGA), PLCG2-associated autoinflammatory, antibody deficiency and immunodeficiency (APLAID), B-cell immunodeficiency, periodic fever, sideroblastic anemia with developmental delay (SIFD), chronic nonbacterial osteomyelitis (CNO), Sweet's syndrome, chronic relapsing multifocal osteomyelitis (CRMO), synovitis, pustulosis, skin contact hypersensitivity, sunburn, psoriasis, hidradenitis suppurativa (HS), epidermolysis bullosa, acne, eczema, alopecia areata, actinic keratosis, hyperostosis, osteitis syndrome (SAPHO), vitiligo, atopic skin Inflammation, cutaneous lupus, multiple sclerosis (MS), Behcet's disease, Sjögren's syndrome, Schnitzler's syndrome, chronic obstructive pulmonary disorder (COPD), asthma, steroid-resistant asthma, coronavirus-associated inflammatory conditions including coronavirus-associated respiratory distress syndrome (CARDS), asbestosis, silicosis, cystic fibrosis, motor neuron disease, Huntington's disease, cerebral malaria, brain damage from pneumococcal meningitis, obesity, age-related macular degeneration (AMD), corneal infections, uveitis, dry eye, acute kidney injury, chronic kidney disease, lupus nephritis, diabetic nephropathy, alcoholic liver disease, osteoarthritis,The disease may be selected from systemic juvenile idiopathic arthritis, adult-onset Still's disease, relapsing polychondritis, chikungunya virus, Ross River virus, influenza, HIV, coronavirus, dengue fever, Zika virus, primary biliary cholangitis, antiphospholipid syndrome, refractory celiac disease, pancreatitis, autoimmune pancreatitis, mucocutaneous lymph node syndrome, lung cancer metastasis, pancreatic cancer, gastric cancer, myelodysplastic syndrome, leukemia; polymyositis, colitis, helminth infection, bacterial infection, abdominal aortic aneurysm, wound healing, migraine, depression, psychological stress, pain, neuropathic pain, periodontitis, pericarditis including Dressler's syndrome, ischemia-reperfusion injury, frontotemporal dementia, HIV-associated neurocognitive disorder, traumatic brain injury, traumatic spinal cord injury, ankylosing spondylitis, cytokine release syndrome,

[0695] Preferably, the disease, disorder, or abnormality is Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, demyelination, multiple sclerosis, encephalomyelitis, leukoencephalopathy, viral encephalitis, epilepsy, stroke, traumatic brain and spinal cord injury, atherosclerosis, asthma and allergic inflammation, cryopyrin-associated periodic syndromes (CAPS), gout, inflammatory bowel disease (IBD), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), hypertension, myocardial infarction, oxalate-associated steroid syndrome (OSA), steroid-resistant ... The present invention relates to a method for treating a rheumatoid arthritis, ...

[0696] More preferably, the disease, disorder, or condition is selected from Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, demyelination, multiple sclerosis, viral encephalitis, epilepsy, stroke, atherosclerosis, asthma and allergic inflammation, cryopyrin-associated periodic syndromes (CAPS), gout, inflammatory bowel disease (IBD), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), hypertension, myocardial infarction, oxalate-induced nephropathy, graft-versus-host disease, type 1 and type 2 diabetes, hidradenitis suppurativa (HS), gout, rheumatoid arthritis, acute kidney disease, chronic kidney disease, and myelodysplastic syndrome.

[0697] Even more preferably, the disease, disorder, or condition is selected from Alzheimer's disease, Parkinson's disease, multiple sclerosis, cryopyrin-associated periodic syndromes (CAPS), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), chronic kidney disease, inflammatory bowel disease (IBD), hidradenitis suppurativa (HS), rheumatoid arthritis, and gout. Even more preferably, the disease, disorder, or condition is selected from Alzheimer's disease, Parkinson's disease, multiple sclerosis, cryopyrin-associated periodic syndromes (CAPS), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), hidradenitis suppurativa (HS), chronic kidney disease, and gout.

[0698] In one embodiment, the disease, disorder, or condition responsive to modulation of a component of the NLRP3 inflammasome pathway, in particular inhibition of activation of that component, is Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, demyelination, viral encephalitis, epilepsy, stroke, atherosclerosis, asthma, allergic inflammation, cryopyrin-associated periodic syndromes (CAPS), Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), neonatal-onset multisystem inflammatory disease (NOMID), gout, pseudogout, inflammatory bowel disease, nonalcoholic fatty liver disease, nonalcoholic steroid hormone (NSHIP), and steroid hormone receptor agonists (SRH). 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), tumor necrosis factor receptor-associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD), hyperimmunoglobulin D syndrome, periodic fever syndrome (HIDS), interleukin-1 receptor antagonist deficiency (DIRA), Majeed syndrome, acne, pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA), A20 haploinsufficiency (HA20), PLCG2-associated antibody deficiency and immune dysregulation (PLAID) ), childhood granulomatous arthritis (PGA), PLCG2-associated autoinflammation, antibody deficiency and immune dysregulation (APLAID), B-cell immunodeficiency, periodic fever, sideroblastic anemia with developmental delay (SIFD), chronic nonbacterial osteomyelitis (CNO), Sweet's syndrome, chronic relapsing multifocal osteomyelitis (CRMO), synovitis, pustulosis, acne, eczema, alopecia areata, actinic keratosis, 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 damage from pneumococcal meningitis, obesity, age-related macular degeneration (AMD), corneal infection, uveitis, dry eye, chronic kidney disease, diabetic nephropathy, alcoholic liver disease, skin contact sensitivity, sunburn, osteoarthritis, systemic juvenile idiopathic arthritis, adult-onset Still's disease, relapsing polychondritis, chikungunya virus, Ross River virus, influenza, HIV, coronavirus, dengue fever, Zika virus, hidradenitis suppurativa (HS), lung cancer metastasis, pancreatic cancer, gastric cancer, myelodysplastic syndrome, leukemia;The condition may be selected from polymyositis, colitis, helminth infection, bacterial infection, abdominal aortic aneurysm, wound healing, depression, psychological stress, pericarditis including Dressler's syndrome, ischemia-reperfusion injury, frontotemporal dementia, HIV-associated neurocognitive disorder, coronavirus-associated inflammatory conditions, and traumatic brain injury;

[0699] In one embodiment, the disease, disorder, or condition is Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, demyelination, viral encephalitis, epilepsy, stroke, atherosclerosis, asthma and allergic inflammation, cryopyrin-associated periodic syndromes (CAPS), gout, inflammatory bowel disease, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), hypertension, myocardial infarction, oxaliplatin, steroid hormone receptor agonist (SRH), ... Selected from salate-induced nephropathy, graft-versus-host disease, type 1 diabetes, type 2 diabetes, rheumatoid arthritis, myelodysplastic syndrome, antineutrophil cytoplasmic antibody-associated vasculitis (AAV), lupus nephritis, antiglomerular basement membrane (GMB) disease, IgA nephropathy, glomerulonephritis (GN), systemic lupus erythematosus (SLE), focal segmental glomerulosclerosis, minimal change disease (MCD), psoriatic arthritis, and hereditary relapsing fever (HRF).

[0700] In one embodiment, the disease, disorder, or condition is selected from Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, demyelination, viral encephalitis, epilepsy, stroke, atherosclerosis, asthma and allergic inflammation, cryopyrin-associated periodic syndromes (CAPS), gout, inflammatory bowel disease, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), hypertension, myocardial infarction, oxalate-induced nephropathy, graft-versus-host disease, type 1 and type 2 diabetes, rheumatoid arthritis, and myelodysplastic syndromes.

[0701] In one embodiment, the disease, disorder, or condition is selected from Alzheimer's disease, Parkinson's disease, cryopyrin-associated periodic syndromes (CAPS), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), rheumatoid arthritis, and gout. Even more preferably, the disease, disorder, or condition is selected from Alzheimer's disease, Parkinson's disease, cryopyrin-associated periodic syndromes (CAPS), rheumatoid arthritis, and gout.

[0702] In one embodiment, the disease, disorder, or condition is selected from Alzheimer's disease and Parkinson's disease, hi another embodiment, the disease, disorder, or condition is selected from cryopyrin-associated periodic syndromes (CAPS), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and gout.

[0703] In one embodiment, the present invention relates to a compound of formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV), or (V) as defined in the present invention, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof, for use in the treatment, alleviation, or prevention of diseases associated with IL-18 and / or IL-1 beta by modulating a component of the NLRP3 inflammasome pathway, in particular by modulating the NLRP3 inflammasome pathway. IL-18 and / or IL-1 beta levels in a subject are reduced as a result of administration of a compound of formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV), or (V) as defined in the present invention, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof.

[0704] Diseases, disorders, or abnormalities associated with IL-18 and / or IL-1 beta include chronic obstructive pulmonary disease (COPD), transfusion-associated lung injury, bronchopulmonary dysplasia (BPD), acute respiratory distress syndrome (ARDS), coronavirus-associated respiratory distress syndrome (CARDS), pediatric autoinflammatory diseases or conditions, Still's disease, particularly adult Still's disease or juvenile Still's disease, juvenile rheumatoid arthritis (JRA), juvenile idiopathic arthritis (JIA), systemic juvenile-onset idiopathic arthritis (SoJIA), systemic juvenile idiopathic arthritis (sJIA), interstitial lung disease (ILD), macrophage activation syndrome (MAS), including primary, secondary, and recurrent MAS, hemophagocytic lymphohistiocytosis (HLH), perforin, munc, Immunodeficiencies such as familial (hereditary) hemophagocytic lymphohistiocytosis (FHLH) associated with gene defects in 13-4 and 18-2, syntaxin 11, and Chediak-Higashi syndrome (CHS), Griscelli syndrome (GS), X-linked lymphoproliferative syndrome (XLP2), X-linked inhibitor of apoptosis protein deficiency (XIAP), acquired hemophagocytic lymphohistiocytosis associated with infectious conditions, especially herpesviruses such as EBV and other pathogens, autoinflammatory syndromes associated with NLRC4 mutations, giant cell arteritis (GCA), acne, hidradenitis suppurativa (HS), septic arthritis, pyoderma gangrenosum, and acne (PAPA), pulmonary sarcoidosis, edema (DME), geographic atrophy (GA), heart failure, ischemic heart disease, and dry eye disease (DED), keratitis, corneal ulcers and abrasions, iritis, glaucoma, Sjogren's syndrome, autoimmune uveitis, Behcet's disease, conjunctivitis, allergic conjunctivitis, diabetes mellitus type 2, organ and blood stem cell transplantation, ischemia-reperfusion injury, familial Mediterranean fever (FMF), tumor necrosis factor receptor 1-associated periodic syndrome (TRAPS), hyper IgD syndrome (mevalonate kinase gene mutation), gout, Schnitzler syndrome, Wegener's granulomatosis, also known as granulomatosis with polyangiitis (GPA), Hashimoto's thyroiditis, Crohn's disease, early-onset inflammatory bowel disease (EOIBD), extreme EOIBD (VEOIBD), infantile IBD, neonatal IBD, ulcerative colitis, and Blau syndrome (NOD-2 mutation).

[0705] Modulation of the NLRP3 inflammasome pathway is likely to be beneficial in diseases or disorders or conditions involving altered IL-18 levels and / or IL-1beta that result in pathological inflammation.

[0706] The present invention relates to compounds of formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV), or (V) as defined in the present invention, which are regulators of NLRP3 inflammasome activity and / or regulators of IL-18 and / or IL-1β levels in a subject.

[0707] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV), or (V) as defined herein, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof, and at least one other biologically active compound. Optionally, the pharmaceutical combination can include a pharmaceutically acceptable carrier, diluent, adjuvant, or additive as described herein.

[0708] In another embodiment, the present invention relates to a pharmaceutical composition comprising a compound of formula (F), ...

[0709] In another embodiment, the present invention relates to a pharmaceutical composition comprising a compound of formula (F), ...

[0710] In particular, the other biologically active compound may be a compound used to treat a disease, disorder, or abnormality that targets a different pathological mechanism, such as an anti-amyloid beta antibody, an anti-tau antibody, an amyloid beta small molecule inhibitor, a tau aggregation small molecule inhibitor, an anti-alpha-synuclein antibody or an alpha-synuclein aggregation small molecule inhibitor, an anti-TDP-43 antibody or an anti-TDP-43 aggregation small molecule inhibitor. When the compound of the present invention is used in combination with another biologically active compound, the dosage of each compound may be different from the dosage when the compound is used as a monotherapy. Such biologically active compounds are well known in the literature. Such biologically active compounds are, for example, 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.

[0711] In another embodiment, the present invention relates to a pharmaceutical composition comprising a compound of formula (F), ...

[0712] The term "combination" refers to a fixed combination in one dosage unit form or to a combined administration in which a compound of the present invention and a combination partner (e.g., another drug, also known as a "therapeutic agent" or "another biologically active compound" as described above) can be independently administered simultaneously or separately within a time interval.

[0713] In another embodiment, the present invention relates to a combination, in particular a pharmaceutical combination, comprising a therapeutically effective amount of a compound of formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV), or (V) as defined herein, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof, and at least one other biologically active compound, optionally comprising at least one pharmaceutically acceptable carrier, diluent, adjuvant, or additive. In particular, the at least one other biologically active compound is a compound different from the compound of formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV), or (V).

[0714] In another embodiment, the present invention relates to a combination comprising a therapeutically effective amount of a compound of formula (F), ...

[0715] The present invention relates to the use of a compound of formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV), or (V) as defined in the present invention, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof, as an analytical standard or in vitro screening tool. The compound of the present invention, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof, can be used as an analytical standard or in vitro screening tool for characterizing cells in which the NLRP3 inflammasome pathway is activated and for testing compounds that target the NLRP3 inflammasome pathway.

[0716] Thus, the present invention provides the use of a compound of formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV), or (V) as defined in the present invention, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof, for treating, alleviating, or preventing a disorder or abnormality that responds to modulation of a component of the NLRP3 inflammasome pathway or to modulation, particularly a reduction, of IL-1 beta and / or IL-18 levels, wherein the medicament is prepared for administration with another biologically active substance. The present invention also provides the use of another biologically active agent to treat, alleviate, or prevent a disorder or abnormality that responds to modulation of a component of the NLRP3 inflammasome pathway or to modulation, particularly a decrease, of IL-1 beta and / or IL-18 levels, wherein the other biologically active agent is administered with a compound of the present invention, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof.

[0717] In another embodiment, the present invention provides use of a compound of formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV), or (V) as defined herein, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof, for treating, alleviating, or preventing a disorder or abnormality that responds to modulation of a component of the NLRP3 inflammasome pathway or to modulation, particularly reduction, of IL-1 beta and / or IL-18 levels, wherein the modulation is reduction and / or inhibition of IL-1 beta and / or IL-18 levels. Preferably, the modulation is reduction and / or inhibition of IL-1 beta. Preferably, the modulation is inhibition of IL-1 beta. In another embodiment, the present invention provides a compound of formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV), or (V) as defined in the present invention, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof, for use as a medicament, in particular a medicament for inhibiting IL-1 beta.

[0718] In another embodiment, the present invention provides a compound of formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV), or (V) as defined in the present invention, or a stereoisomer, racemic mixture, tautomer, or a compound thereof, for use in a method of treating, alleviating, or preventing a disease, disorder, or condition that responds to modulation of a component of the NLRP3 inflammasome pathway, or to modulation, in particular a reduction, of IL-1 beta and / or IL-18 levels. Also provided are compounds, or stereoisomers, racemic mixtures, tautomers, polymorphs, pharmaceutically acceptable salts, prodrugs, hydrates, or solvates thereof, wherein said compounds of Formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV), or (V) are formulated for administration with another biologically active compound (as defined herein).

[0719] In another embodiment, the present invention provides a method for treating, alleviating, or preventing a disease, disorder, or condition that responds to modulation of a component of the NLRP3 inflammasome pathway or to modulation, particularly a decrease, of IL-1 beta and / or IL-18 levels, including, but not limited to, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, demyelination, viral encephalitis, epilepsy, stroke, atherosclerosis, allergic inflammation, cryopyrin-associated periodic syndromes (CAPS), Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), neonatal onset. Nonalcoholic multisystem inflammatory disease (NOMID), gout, pseudogout, inflammatory bowel disease (including Crohn's disease and ulcerative colitis), nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, hypertension, myocardial infarction, heart failure, coronary artery disease, oxalate-induced nephropathy, graft-versus-host disease, type 1 diabetes, type 2 diabetes, edema (DME), geographic atrophy (GA), rheumatoid arthritis, myelodysplastic syndrome, familial Mediterranean fever (FMF), tumor necrosis factor receptor-associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD), hyperimmunoglobulin Demia, periodic fever syndrome (HIDS), interleukin (IL-1) 1 receptor antagonist deficiency (DIRA), Majeed syndrome, pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA), A20 haploinsufficiency (HA20), PLCG2-associated antibody deficiency and immunodeficiency (PLAID), childhood granulomatous arthritis (PGA), PLCG2-associated autoinflammatory, antibody deficiency, and immunodeficiency (APLAID), B-cell immunodeficiency, periodic fever, sideroblastic anemia with developmental delay (SIFD), chronic nonbacterial osteomyelitis (CNO), Sweet's syndrome, chronic relapsing multifocal osteomyelitis (CRMO), synovitis, pustulosis, skin contact hypersensitivity, sunburn, psoriasis, hidradenitis suppurativa (HS), epidermal hydrocephalus Pemphigus, acne, eczema, alopecia areata, actinic keratosis, hyperostosis, osteitis syndrome (SAPHO), vitiligo, atopic dermatitis, cutaneous lupus, multiple sclerosis (MS), Behçet's disease, Sjögren's syndrome, Schnitzler's syndrome, chronic obstructive pulmonary disorder (COPD), coronavirus-associated inflammatory conditions, coronavirus-associated respiratory distress syndrome (CARDS), steroid-resistant asthma, asbestosis, silicosis, cystic fibrosis, motor neuron disease, Huntington's disease, cerebral malaria, brain damage from pneumococcal meningitis, obesity, age-related macular degeneration (AMD), corneal infections, uveitis, dry eye,Acute kidney disease, chronic kidney disease, diabetic nephropathy, alcoholic liver disease, osteoarthritis, systemic juvenile idiopathic arthritis, adult-onset Still's disease, relapsing polychondritis, chikungunya virus, Ross River virus, influenza, HIV, coronavirus, dengue fever, Zika virus, hidradenitis suppurativa (HS), lung cancer metastasis, pancreatic cancer, gastric cancer, myelodysplastic syndrome, leukemia; polymyositis, colitis, helminth infection, bacterial infection, abdominal aortic aneurysm, wound healing, migraine, depression, psychological stress, pain, neuropathy The disorder is selected from Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, demyelination, multiple sclerosis, viral encephalitis, epilepsy, stroke, traumatic brain injury, spinal cord injury, atherosclerosis, asthma, allergic inflammation, cryopyrin-associated periodic syndrome (CAPS), gout, Inflammatory bowel disease, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), hypertension, myocardial infarction, oxalate-induced nephropathy, graft-versus-host disease, type 1 diabetes, type 2 diabetes, rheumatoid arthritis, acute kidney disease, chronic kidney disease, myelodysplastic syndrome, 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 glomerulonephritis (MCD), Also provided is a method for treating a condition selected from hidradenitis suppurativa (HS), psoriatic arthritis, and hereditary relapsing fever (HRF), the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I), (II'), (II), (II'a), (IIa), (II'b), (IIb), (III), (IV), or (V) as defined herein, or a stereoisomer, or racemic mixture, or tautomer, or polymorph, or a pharmaceutically acceptable salt, or hydrate, or solvate thereof.

[0720] In one embodiment, the disease, disorder, or abnormality that responds to modulation of a component of the NLRP3 inflammasome pathway or to modulation, particularly a decrease, of IL-1 beta and / or IL-18 levels is Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, demyelination, viral encephalitis, epilepsy, stroke, atherosclerosis, asthma, allergic inflammation, cryopyrin-associated periodic syndromes (CAPS), Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), neonatal-onset multisystem inflammatory disease (NOMID), gout, pseudogout, inflammatory bowel disease, non-alzheimer's disease, or IL-1 beta and / or IL-18. 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), Majeed syndrome, acne, pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA), A20 haploinsufficiency (HA20), PLCG2-associated antibody deficiency, and Immune dysregulation (PLAID), childhood granulomatous arthritis (PGA), PLCG2-associated autoinflammation, antibody deficiency and immune dysregulation (APLAID), B-cell immunodeficiency, periodic fever, sideroblastic anemia with developmental delay (SIFD), chronic nonbacterial osteomyelitis (CNO), Sweet's syndrome, chronic relapsing multifocal osteomyelitis (CRMO), synovitis, pustulosis, acne, eczema, alopecia areata, actinic keratosis, 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, stone Byssinosis, silicosis, cystic fibrosis, motor neuron disease, Huntington's disease, cerebral malaria, brain damage from pneumococcal meningitis, obesity, age-related macular degeneration (AMD), corneal infection, uveitis, dry eye, chronic kidney disease, diabetic nephropathy, alcoholic liver disease, skin contact sensitivity, sunburn, osteoarthritis, systemic juvenile idiopathic arthritis, adult-onset Still's disease, relapsing polychondritis, chikungunya virus, Ross River virus, influenza, HIV, coronavirus, dengue fever, Zika virus, hidradenitis suppurativa (HS), lung cancer metastasis, pancreatic cancer, gastric cancer, myelodysplastic syndrome, leukemia;The disorder is selected from polymyositis, colitis, helminth infection, bacterial infection, abdominal aortic aneurysm, wound healing, depression, psychological stress, pericarditis including Dressler's syndrome, ischemia-reperfusion injury, frontotemporal dementia, HIV-associated neurocognitive disorders, coronavirus-associated inflammatory conditions, 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 syndromes (CAPS), gout, inflammatory bowel disease, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), hypertension, myocardial infarction, oxalate-induced nephropathy, graft-versus-host disease, type 1 diabetes, type 2 diabetes, rheumatoid arthritis , myelodysplastic syndrome, antineutrophil cytoplasmic antibody-associated vasculitis (AAV), lupus nephritis, antiglomerular basement membrane (GMB) disease, IgA nephropathy, glomerulonephritis (GN), systemic lupus erythematosus (SLE), focal segmental glomerulosclerosis, minimal change disease (MCD), psoriatic arthritis, and hereditary relapsing fever (HRF), the method comprising administering to the subject a therapeutically effective amount of a compound of (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV), or (V) as defined herein, or a stereoisomer, or racemic mixture, or tautomer, or polymorph, or a pharmaceutically acceptable salt, or hydrate, or solvate thereof;

[0721] In another embodiment, the present invention also provides a method of inhibiting IL-1beta 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 (F), ...

[0722] In particular, the disease, disorder, or condition is one that responds to inhibition of activation of the NLRP3 inflammasome pathway. More particularly, the disease, disorder, or condition is responsive to modulation of one or more of, for example, but not limited to, IL-1β or IL-18. For example, the disease, disorder, or condition is responsive 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 condition is responsive to modulation of IL-1β and / or IL-18.

[0723] Any combination of the embodiments, preferred embodiments, and more preferred embodiments disclosed herein is contemplated in the present invention.

[0724] Pharmaceutical Composition While the compounds of the present invention, or their stereoisomers, racemic mixtures, tautomers, polymorphs, pharmaceutically acceptable salts, prodrugs, hydrates, or solvates, can be administered alone, it is preferable to formulate them into pharmaceutical compositions in accordance with standard pharmaceutical practice. Accordingly, the present invention also provides pharmaceutical compositions comprising a therapeutically effective amount of compound (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV), or (V), or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof, optionally in admixture with a pharmaceutically acceptable carrier, diluent, adjuvant, or excipient.

[0725] The term "therapeutically effective amount" of a compound of the invention refers to an amount of a compound of the invention (i.e., compound (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV), or (V), or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof) that elicits a biological or medical response in a subject, such as a reduction or inhibition of enzyme or protein activity, or ameliorates symptoms, alleviates a condition, slows or delays disease progression, or prevents a disease, disorder, or condition. In one embodiment, the term "therapeutically effective amount" refers to an amount of a compound of the invention that, when administered to a subject (e.g., a patient) in need thereof, is effective to at least partially alleviate, prevent, and / or ameliorate a disease, disorder, or condition that responds to modulation of a component of the NLRP3 inflammasome pathway or to modulation, particularly reduction, of IL-1beta and / or IL-18.

[0726] Pharmaceutically acceptable carriers, diluents, adjuvants, and additives are well known in the pharmaceutical art and can be found in, for example, Remington's Pharmaceutical Sciences, 18th Edition (Alfonso R. Gennaro, ed.; Mack Publishing Company, Easton, PA, 1990); Remington: the Science and Practice of Pharmacy, 19th Edition (Lippincott, Williams & Wilkins, 1995); Handbook of Pharmaceutical Excipients, 3rd Edition (Arthur H. Kibbe, ed.; Amer. Pharmaceutical Assoc, 1999); Pharmaceutical Codex: Principles and Practice of Pharmaceutics, 12th Edition (Walter Lund, ed.; Pharmaceutical Press, London, 1994); The United States Pharmacopeia: The National Formulary (United States Pharmacopeial Convention); Fiedler's "Lexikon der Hilfsstoffe", 5th Edition, Edition Cantor Verlag Aulendorf 2002; "The Handbook of Pharmaceutical Excipients," 4th ed., American Pharmaceuticals Association, 2003; and Goodman and Gilman's: The Pharmacological Basis of Therapeutics (Louis S. Goodman and Lee E. Limbird, eds.; McGraw Hill, 1992), the disclosures of which are hereby incorporated by reference.

[0727] Carriers, diluents, adjuvants, and excipients may be selected with regard to the intended route of administration and standard pharmaceutical practice. These compounds must be acceptable in the sense of not being harmful to the recipients thereof.

[0728] Pharmaceutically useful additives that can be used in formulating the pharmaceutical composition of the present invention include, for example, vehicles, solvents (monohydric alcohols such as ethanol, isopropanol, and polyhydric alcohols such as glycols), edible oils (soybean oil, coconut oil, olive oil, safflower oil, cottonseed oil, etc.), oily esters (ethyl oleate, isopropyl myristate, etc.), binders (hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), pregelatinized starch, and combinations thereof, etc.), solubilizers, thickeners, stabilizers, disintegrants (carboxymethylcellulose calcium (CMC-Ca), carboxymethylcellulose sodium (CMC-Na), cross-linked PVP (e.g., crospovidone, Polyplasdone®, or Kollidon®), and the like. XL), alginic acid, sodium alginate, guar gum, cross-linked CMC (croscarmellose sodium, e.g., Ac-Di-Sol®), carboxymethyl starch-Na (sodium starch glycolate) (e.g., Primojel® or Explotab®), preferably cross-linked PVP and / or croscarmellose sodium, etc.), flow agent (colloidal SiO2 (e.g., Aerosil®), 200), magnesium trisilicate, powdered cellulose, talc, and combinations thereof), lubricants (such as magnesium stearate, aluminum or calcium silicate, stearic acid, hydrogenated castor oil, talc, glyceryl behenate, sodium stearate fumarate, and combinations thereof), buffers, emulsifiers, wetting agents, suspending agents, sweeteners, colorants, flavorings, coating agents, preservatives, antioxidants, processing agents, drug delivery modifiers and enhancers (such as calcium phosphate), magnesium stearate, talc, monosaccharides, disaccharides, starch, gelatin, cellulose, methylcellulose, sodium carboxymethylcellulose, dextrose, hydroxypropyl-β-cyclodextrin, polyvinylpyrrolidone, low melting point waxes, and ion exchange resins.

[0729] The carrier is not particularly limited and depends on the route of administration and the form of the pharmaceutical composition (i.e., solid, liquid, etc.). Suitable carriers include, but are not limited to, polyols such as mannitol, sorbitol, xylitol, etc.; 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 carboxymethylcellulose, low-substituted hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, or mixtures thereof; cyclodextrins, and inorganic substances such as dicalcium phosphate, calcium hydrogen phosphate, hydroxyapatite, tricalcium phosphate, talcum, and silica. Microcrystalline cellulose, sucrose, and / or lactose are preferred carriers. Combinations thereof may also be used. Carriers may also include proteins and cell-penetrating peptides, and should be selected depending on the route of administration and target.

[0730] The diluent is not particularly limited and depends on the route of administration 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.

[0731] An adjuvant is an additive that has little or no pharmacological effect by itself, but that increases the effectiveness or potency of compounds of the invention when administered together.

[0732] Routes of administration (delivery) of the compounds of the invention include, but are not limited to, one or more of the following routes of administration: oral (e.g., as a tablet, capsule, or as an ingestible solution), topical, mucosal (e.g., as a nasal spray or aerosol for inhalation), nasal, parenteral (e.g., via an injectable form), gastrointestinal, intraspinal, intraperitoneal, intramuscular, intravenous, intraarterial, intrathecal, intrauterine, intraocular, intradermal, intracranial, intratracheal, intravaginal, intraventricular, intracerebral, subcutaneous, ocular (including intravitreal or intracameral), transdermal, rectal, buccal, epidural, and sublingual.

[0733] For example, the compounds may be administered orally in the form of tablets, capsules, suppositories, elixirs, solutions or suspensions, which may contain flavorings or colorants for immediate, delayed, modified, sustained, pulsed or controlled release applications.

[0734] Tablets may contain additives such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, calcium hydrogen phosphate, and glycine; disintegrants such as starch (preferably corn, potato, or tapioca starch), sodium starch glycolate, croscarmellose sodium, and certain complex silicates; and granulating binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin, and acacia. Additionally, lubricants such as magnesium stearate, stearic acid, glyceryl behenate, and talc may be included. Solid compositions of a similar type may also be utilized as fillers in gelatin capsules. Preferred additives in this regard include starch, cellulose, milk sugars, such as lactose, or high molecular weight polyethylene glycols. In aqueous suspensions and / or elixirs, the agents may 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.

[0735] When the compounds of the present invention disclosed herein are administered parenterally, examples of such administration include one or more of administering the compound intravenously, intraarterially, intraperitoneally, intrathecally, intraventricularly, intraurethrally, intrasternally, intracranially, intramuscularly, or subcutaneously; and / or using infusion techniques. For parenteral administration, the compound may be used in the form of a sterile aqueous solution which may contain other substances, for example, sufficient salts or glucose to make the solution isotonic with blood. The aqueous solution should be suitably buffered (preferably to a pH of 3 to 9), if necessary. The preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.

[0736] As indicated, the compounds of the present invention can be administered intranasally or by inhalation, conveniently delivered in the form of a dry powder inhaler or aerosol spray presentation from a pressurized container, pump, atomizer, or nebulizer using a suitable propellant, such as 1,1,1,2-tetrafluoroethane (HFA134AT) or 1,1,1,2,3,3,3-heptafluoropropane (HFA 227EA), carbon dioxide, or other suitable gas, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, or a 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, e.g., using a mixture of ethanol and propellant as a solvent, and can further contain a lubricant, e.g., sorbitan trioleate. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.

[0737] Alternatively, the compounds of the invention as defined herein may be administered in the form of a suppository or pessary, or may be applied topically in the form of a gel, hydrogel, lotion, solution, cream, ointment, or dusting powder. The compounds of the invention as defined herein may also be administered dermally or transdermally, for example by the use of a skin patch.

[0738] They can also be administered via pulmonary or rectal routes. They can also be administered via ocular routes. 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 combined with a preservative such as benzalkonium chloride. Alternatively, they can be formulated in an ointment such as petrolatum.

[0739] For topical application to the skin, the compounds of the invention can be formulated in a suitable ointment containing the active compound suspended or dissolved in a mixture of one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, emulsifying wax, and water, or in a suitable lotion or cream containing the active compound suspended or dissolved in a mixture of one or more of the following: mineral oil, sorbitan monostearate, polyethylene glycol, liquid paraffin, polysorbate 60, cetyl palmitate, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0740] Typically, a physician will determine the actual dosage that will be 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 particular compound utilized, the metabolic stability and duration of action of that compound, the age, body weight, general health, sex, diet, mode and timing of administration, rate of excretion, drug combination, the severity of the particular condition, and the individual being treated.

[0741] The claimed compounds as defined herein may be used alone or in combination with one or more other bioactive compounds as defined herein for the treatment, amelioration, or prevention of the described conditions. In particular, the other bioactive compounds may be compounds used for the treatment, amelioration, or prevention of the described diseases.

[0742] The above-mentioned combinations can be conveniently presented for use in the form of pharmaceutical formulations. The individual components of such combinations can be administered sequentially or simultaneously in separate or combined pharmaceutical formulations by any convenient route. When administration is sequential, the compound of the present invention or other biologically active compound can be administered first. When administration is simultaneous, the combinations 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 compatible with each other and with the other components of the formulation. When formulated separately, they can be provided in any convenient formulation, conveniently as known for such compounds in the art.

[0743] The pharmaceutical compositions of the present invention can be prepared in a manner 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).

[0744] The compounds according to the present invention disclosed herein may also be provided in admixture with at least one other biologically active compound and / or a pharmaceutically acceptable carrier, diluent, adjuvant, or additive, wherein the compound and / or other biologically active compound is preferably present in a therapeutically effective amount.

[0745] The nature of the other biologically active compound will depend on the intended use of the mixture. The other biologically active substance or compound may exert its biological effect by the same or a similar mechanism as the compounds according to the invention, or by an unrelated mechanism of action, or by multiple related and / or unrelated mechanisms of action.

[0746] The present invention also includes all suitable isotopic variations of the compounds of the present invention. An isotopic variation of a compound of the present invention is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass normally found in nature. Examples of isotopes that can be incorporated into compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, and chlorine, such as, for example, 2 H, 3 H, 13 C. 14 C. 15 N, 17 O. 18 O. 35 S, 18 F and 36 Some isotopic variants of the present invention, such as 3 H or 14 Those incorporating radioactive isotopes such as 1C are useful in drug and / or substrate tissue distribution studies. 3 H and carbon-14 i.e. 14 C isotopes are particularly preferred for their ease of preparation and delectability. 18 F-labeled compounds are particularly suitable for imaging applications such as PET. 2 Substitution with isotopes such as H can afford certain therapeutic advantages due to increased metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and therefore may be preferred in some circumstances. Isotopic variants of the compounds of the invention may generally be prepared by conventional procedures such as the exemplified methods, or by the preparations described in the Examples and Preparations below using appropriate isotopic variants of suitable reagents.

[0747] Methods of using the present invention There is evidence for a role for NLRP3-induced IL-1 and IL-18 in inflammatory responses associated with or resulting from a number of different diseases, disorders, or conditions that respond to modulation of components of the NLRP3 inflammasome pathway and / or modulation of IL-1beta and / or IL-18 levels (Menu et al., Clinical and Experimental Immunology, 2011, 166, 1-15; Strowig et al., Nature, 2012, 481, 278-286).

[0748] The present invention provides compounds of formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV), or (V) as defined herein, or stereoisomers, racemic mixtures, tautomers, polymorphs, pharmaceutically acceptable salts, prodrugs, hydrates, or solvates thereof, which exhibit beneficial pharmacological properties, such as NRRP3 inhibitory properties, on the NLRP3 inflammasome pathway. The compounds of the present invention may be useful in the treatment, amelioration, or prevention of diseases, disorders, or conditions that respond to modulation of components of the NLRP3 inflammasome pathway and / or that respond to modulation of IL-1 beta and / or IL-18 levels. Several diseases, disorders, or conditions have been shown to involve NLRP3, including, for example, one of the following: A. A central nervous system (CNS) disease, disorder, or abnormality, such as Alzheimer's disease, Parkinson's disease, dementia, frontotemporal dementia, Huntington's disease, cerebral malaria, brain injury from pneumococcal meningitis, motor neuron disease, traumatic brain injury, spinal cord injury, neuropathic pain, migraine, amyotrophic lateral sclerosis, or multiple sclerosis (MS); B. an immune disease, disorder, or abnormality (e.g., an autoimmune disease, disorder, or abnormality, and a disease, disorder, or abnormality involving the immune system), such as type 1 diabetes, hidradenitis suppurativa (HS), Schnitzler's syndrome, primary progressive multiple sclerosis (PPMS), Sjögren's syndrome, secondary progressive multiple sclerosis (SPMS), TNF receptor-associated periodic syndromes (TRAPS), graft-versus-host disease, antiphospholipid syndrome, refractory celiac disease, autoimmune pancreatitis, or multiple sclerosis (MS), including relapsing-remitting multiple sclerosis (RRMS); C. Inflammatory diseases, including autoinflammation and inflammation resulting from an inflammatory disease, disorder, or abnormality, such as mevalonate kinase deficiency (MKD), hyperimmunoglobulin Demia, 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, septic arthritis, pyoderma gangrenosum, and acne (PAPA), adult-onset Still's disease (AOSD), Majeed syndrome, PLCG2-associated antibody deficiency and immunodeficiency (PLAID), PLCG2-associated autoinflammation, antibody deficiency, and immunodeficiency (APLAID), septic arthritis, A20 haploinsufficiency (HA20), childhood granulomatous arthritis (PGA), or B-cell immunodeficiency, periodic fever, sideroblastic anemia with developmental delay (SIFD); D. Skin diseases, disorders, or abnormalities, including inflammatory skin conditions such as hidradenitis suppurativa (HS), dermatitis, psoriasis, skin contact sensitivity, acne, periodic fever syndrome (HIDS), Sweet's syndrome, eczema, skin lesions, burns, wounds, wound healing, trauma, sunburn, actinic keratosis, interleukin-1 receptor antagonist deficiency (DIRA), epidermolysis bullosa, vitiligo, atopic dermatitis, cutaneous lupus, or alopecia areata; E. Ocular diseases, disorders, or abnormalities, such as age-related macular degeneration (AMD), corneal infection, uveitis, glaucoma, dry eye, geographic atrophy (GA), or demyelination; F. Cardiovascular disease, disorder, or abnormality (e.g., a disease, disorder, or abnormality of the cardiovascular system), such as myocardial infarction, hypertension, ischemia-reperfusion injury, pericarditis, including Dressler's syndrome, aneurysm, including abdominal aortic aneurysm, heart failure, coronary artery disease, or stroke; G. Metabolic diseases, disorders, or abnormalities, such as type 2 diabetes, obesity, edema (DME), atherosclerosis, gout, or pseudogout; H. Respiratory diseases, disorders, or conditions (e.g., diseases, disorders, or conditions of the respiratory system), such as asbestosis, silicosis, cystic fibrosis, allergic inflammation, chronic obstructive pulmonary disorder (COPD), coronavirus-associated respiratory distress syndrome (CARDS), steroid-resistant asthma, or asthma; I. a liver disease, disorder, or abnormality (e.g., a liver disease, disorder, or abnormality), such as hepatitis, primary biliary cholangitis, cytokine release syndrome, alcoholic liver disease, alcoholic fatty liver disease (AFLD), alcoholic steatohepatitis (ASH), nonalcoholic fatty liver disease (NAFLD), including advanced fibrosis stages F3 and F4, or nonalcoholic steatohepatitis (NASH); J. Renal disease, disorder, or abnormality (e.g., a disease, disorder, or abnormality of the renal system), such as oxalate-induced nephropathy, diabetic nephropathy, lupus nephritis, chronic kidney disease, or acute kidney disease; K. Cancerous diseases, disorders, or abnormalities (e.g., cancer, tumor, or malignancy), such as lung cancer (e.g., lung cancer metastasis), pancreatic cancer, gastric cancer, leukemia, myelodysplastic syndrome (MOS), skin cancer, tumors of the endocrine system, or thyroid cancer; L. Helminth infections (e.g., from schistosomes, roundworms, tapeworms, or flukes), viral encephalitis, bacterial infections, periodontitis, human immunodeficiency virus (HIV), HIV-associated neurocognitive disorders, chronic nonbacterial osteomyelitis (CNO), chronic bacterial osteomyelitis, interleukin-1 receptor antagonist deficiency (DIRA), or epilepsy; infectious diseases, including viral infections such as alphaviruses (e.g., chikungunya virus and Ross River virus), flaviviruses (e.g., dengue fever and Zika virus), coronavirus-associated inflammatory conditions, coronaviruses, or influenza viruses; M. Psychological diseases, disorders, or abnormalities, such as depression or psychological stress; N. Inflammation, including inflammation resulting from an inflammatory disease, disorder, or condition, such as an autoinflammatory disease, inflammation occurring as a symptom of a non-inflammatory disorder, inflammation resulting from infection, or inflammation associated with trauma, injury, or autoimmunity. Examples of inflammation include: i. Joint diseases, disorders, or conditions, such as periodic fever syndromes (HIDS), rheumatoid arthritis, pustulosis, synovitis, osteoarthritis, chronic relapsing multiple osteomyelitis (CRMO), systemic juvenile idiopathic arthritis, osteitis syndrome (SAPHO), hyperostosis, relapsing polychondritis, ankylosing spondylitis, or adult-onset Still's disease; ii. a gastrointestinal disease, disorder, or abnormality (e.g., a disease, disorder, or abnormality of the gastrointestinal tract), such as colitis, ulcerative colitis, or inflammatory bowel disease; iii. Muscle diseases, disorders, or abnormalities, such as polymyositis or myasthenia gravis; iv. a disease, disorder, or abnormality of the endocrine system, such as diabetes, parathyroid disease (e.g., hypothyroidism), endocrine tumors, thyroid cancer, or hypoglycemia; and / or v. Vascular diseases, disorders, or abnormalities, such as Behçet's disease or mucocutaneous lymph node syndrome Inflammatory reactions associated with or resulting from these include:

[0749] In one embodiment, the disease, disorder, or condition is selected from Alzheimer's disease, Parkinson's disease, cryopyrin-associated periodic syndromes (CAPS), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and hidradenitis suppurativa (HS).

[0750] In particular, the disease, disorder, or abnormality may be Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, demyelination, viral encephalitis, epilepsy, stroke, cerebral hemorrhage, atherosclerosis, allergic inflammation, cryopyrin-associated periodic syndromes (CAPS), Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), neonatal-onset multisystem inflammatory disease (NOMID), gout, pseudogout, inflammatory bowel disease (IBD) (including Crohn's disease and ulcerative colitis), hepatitis, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, hypertension, myocardial infarction, Embolism, heart failure, coronary artery disease, oxalate-induced nephropathy, graft-versus-host disease, type 1 diabetes, type 2 diabetes, edema (DME), geographic atrophy (GA), rheumatoid arthritis, myelodysplastic syndrome, familial Mediterranean fever (FMF), tumor necrosis factor receptor-associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD), hyperimmunoglobulin D syndrome, periodic fever syndrome (HIDS), interleukin-1 receptor antagonist deficiency (DIRA), Majeed syndrome, septic arthritis, pyoderma gangrenosum, and acne (PAPA), A20 haploinsufficiency (HA20), PLCG2-related antibody deficiency and immunological disorders ( PLAID), childhood granulomatous arthritis (PGA), PLCG2-associated autoinflammatory, antibody deficiency and immune dysregulation (APLAID), B-cell immunodeficiency, periodic fever, sideroblastic anemia with developmental delay (SIFD), chronic nonbacterial osteomyelitis (CNO), Sweet's syndrome, chronic relapsing multifocal osteomyelitis (CRMO), synovitis, pustulosis, skin contact hypersensitivity, sunburn, psoriasis, hidradenitis suppurativa (HS), epidermolysis bullosa, acne, eczema, alopecia areata, actinic keratosis, hyperostosis, osteitis syndrome (SAPHO), vitiligo, atopic dermatitis, cutaneous lupus, multiple sclerosis (MS), Behçet's disease, Sjogren's disease Renn's syndrome, Schnitzler's syndrome, chronic obstructive pulmonary disorder (COPD), asthma, steroid-resistant asthma, coronavirus-associated inflammatory conditions including coronavirus-associated respiratory distress syndrome (CARDS), asbestosis, silicosis, cystic fibrosis, motor neuron disease, Huntington's disease, cerebral malaria, brain damage from pneumococcal meningitis, obesity, age-related macular degeneration (AMD), corneal infections, uveitis, dry eye, acute kidney injury, chronic kidney disease, lupus nephritis, diabetic nephropathy, alcoholic liver disease, osteoarthritis, systemic juvenile idiopathic arthritis, adult-onset Still's disease, relapsing polychondritis,The therapeutic agent is selected from chikungunya virus, Ross River virus, influenza, HIV, coronavirus, dengue fever, Zika virus, primary biliary cholangitis, antiphospholipid syndrome, refractory celiac disease, pancreatitis, autoimmune pancreatitis, mucocutaneous lymph node syndrome, lung cancer metastasis, pancreatic cancer, gastric cancer, myelodysplastic syndrome, leukemia; polymyositis, colitis, helminth infection, bacterial infection, abdominal aortic aneurysm, wound healing, migraine, depression, psychological stress, pain, neuropathic pain, periodontitis, pericarditis including Dressler syndrome, ischemia-reperfusion injury, frontotemporal dementia, HIV-associated neurocognitive disorder, traumatic brain injury, traumatic spinal cord injury, inflammatory pain, chronic pain, neuropathic pain, metastatic cancer-induced bone pain, chemotherapy-induced peripheral neuropathy, and migraine; ankylosing spondylitis, cytokine release syndrome. Preferably, the disease, disorder, or abnormality is Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, demyelination, multiple sclerosis, encephalomyelitis, leukoencephalopathy, viral encephalitis, epilepsy, stroke, traumatic brain and spinal cord injury, atherosclerosis, asthma and allergic inflammation, cryopyrin-associated periodic syndromes (CAPS), gout, inflammatory bowel disease (IBD), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), hypertension, myocardial infarction, oxalate-induced nephropathy, graft-versus-host disease, type 1 diabetes, type 2 diabetes, hidradenitis suppurativa (HS), rheumatoid arthritis, acute kidney disease, chronic kidney disease, myelodysplastic syndrome, antineutrophil cytoplasmic antibody-associated vasculitis (AAV). , lupus nephritis, anti-glomerular basement membrane (GMB) disease, IgA nephropathy, glomerulonephritis (GN), systemic lupus erythematosus (SLE), focal segmental glomerulosclerosis, minimal change disease (MCD), psoriatic arthritis, and hereditary relapsing fever (HRF), and amyloidosis (including AL amyloidosis, AA amyloidosis, ATTR amyloidosis, hereditary amyloidosis (including apolipoprotein AI (AApoAI), apolipoprotein A-II (AApoAII), gelsolin (AGel), fibrinogen (AFib), and lysozyme (ALys)), beta-2 microglobulin amyloidosis, and iAPP amyloidosis).

[0751] In one embodiment, the disease, disorder, or condition responsive to modulation of a component of the NLRP3 inflammasome pathway, in particular inhibition of activation of that component, is Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, demyelination, viral encephalitis, epilepsy, stroke, atherosclerosis, allergic inflammation, cryopyrin-associated periodic syndromes (CAPS), Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), neonatal-onset multisystem inflammatory disease (NOMID), gout, pseudogout, inflammatory bowel disease (IBD) (including Crohn's disease, ulcerative colitis), hepatitis, non-small cell lung cancer, and the like. Alcoholic fatty liver disease, non-alcoholic steatohepatitis, hypertension, myocardial infarction, heart failure, coronary artery disease, oxalate-induced nephropathy, graft-versus-host disease, type 1 diabetes, type 2 diabetes, edema (DME), geographic atrophy (GA), rheumatoid arthritis, myelodysplastic syndrome, familial Mediterranean fever (FMF), tumor necrosis factor receptor-associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD), hyperimmunoglobulin Demia, periodic fever syndrome (HIDS), interleukin-1 receptor antagonist deficiency (DIRA), Majeed syndrome, septic arthritis, pyoderma gangrenosum, and acne (PAPA), A2 Haploinsufficiency (HA20), PLCG2-associated antibody deficiency and immunodeficiency (PLAID), childhood granulomatous arthritis (PGA), PLCG2-associated autoinflammatory, antibody deficiency and immunodeficiency (APLAID), B-cell immunodeficiency, periodic fever, sideroblastic anemia with developmental delay (SIFD), chronic nonbacterial osteomyelitis (CNO), Sweet's syndrome, chronic relapsing multifocal osteomyelitis (CRMO), synovitis, pustulosis, skin contact hypersensitivity, sunburn, psoriasis, hidradenitis suppurativa (HS), epidermolysis bullosa, acne, eczema, alopecia areata, actinic keratosis, hyperostosis, osteitis syndrome (SAPHO), vitiligo, atopic skin Inflammation, cutaneous lupus, multiple sclerosis (MS), Behcet's disease, Sjögren's syndrome, Schnitzler's syndrome, chronic obstructive pulmonary disorder (COPD), asthma, steroid-resistant asthma, coronavirus-associated inflammatory conditions including coronavirus-associated respiratory distress syndrome (CARDS), asbestosis, silicosis, cystic fibrosis, motor neuron disease, Huntington's disease, cerebral malaria, brain damage from pneumococcal meningitis, obesity, age-related macular degeneration (AMD), corneal infections, uveitis, dry eye, acute kidney injury, chronic kidney disease, lupus nephritis, diabetic nephropathy, alcoholic liver disease, osteoarthritis,The disease may be selected from systemic juvenile idiopathic arthritis, adult-onset Still's disease, relapsing polychondritis, chikungunya virus, Ross River virus, influenza, HIV, coronavirus, dengue fever, Zika virus, primary biliary cholangitis, antiphospholipid syndrome, refractory celiac disease, pancreatitis, autoimmune pancreatitis, mucocutaneous lymph node syndrome, lung cancer metastasis, pancreatic cancer, gastric cancer, myelodysplastic syndrome, leukemia; polymyositis, colitis, helminth infection, bacterial infection, abdominal aortic aneurysm, wound healing, migraine, depression, psychological stress, pain, neuropathic pain, periodontitis, pericarditis including Dressler syndrome, ischemia-reperfusion injury, frontotemporal dementia, HIV-associated neurocognitive disorder, traumatic brain injury, traumatic spinal cord injury, ankylosing spondylitis, and cytokine release syndrome. Preferably, the disease, disorder, or abnormality is Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, demyelination, multiple sclerosis, encephalomyelitis, leukoencephalopathy, viral encephalitis, epilepsy, stroke, traumatic brain and spinal cord injury, atherosclerosis, asthma and allergic inflammation, cryopyrin-associated periodic syndromes (CAPS), gout, inflammatory bowel disease (IBD), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), hypertension, myocardial infarction. The disease is selected from thrombosis, oxalate-induced nephropathy, graft-versus-host disease, type 1 diabetes, type 2 diabetes, hidradenitis suppurativa (HS), rheumatoid arthritis, acute kidney disease, chronic kidney disease, myelodysplastic syndrome, antineutrophil cytoplasmic antibody-associated vasculitis (AAV), lupus nephritis, antiglomerular basement membrane (GMB) disease, IgA nephropathy, glomerulonephritis (GN), systemic lupus erythematosus (SLE), focal segmental glomerulosclerosis, minimal change disease (MCD), psoriatic arthritis, and hereditary relapsing fever (HRF).

[0752] definition Within the meaning of this application, the following definitions shall apply unless otherwise specified, and where appropriate, terms used in the singular shall also include the plural and vice versa.

[0753] "Alkyl" refers to a saturated straight-chain or branched organic moiety consisting of carbon and hydrogen atoms. Examples of suitable alkyl groups have from 1 to 4 carbon atoms, preferably from 1 to 3 carbon atoms, and include (as appropriate) methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, and isobutyl. The term "C1-C6 alkyl" refers to an alkyl group having from 1 to 6 carbon atoms. The terms "C1-C4 alkyl," "C1-C3 alkyl," or "C1 alkyl" should be construed accordingly.

[0754] "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.

[0755] "--O--C--C--alkyl," as "C--C--alkyl" is defined broadly above. Examples of "--O--C--alkyl" include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, pentoxy, and hexoxy.

[0756] The term "C3-C6 cycloalkyl" refers to a saturated monocyclic hydrocarbyl group having from 3 to 6 carbon atoms. The term "C5-C6 cycloalkyl" should be construed accordingly. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0757] "4-, 5-, or 6-membered heterocycloalkyl" refers to a stable 4-, 5-, or 6-membered non-aromatic monocyclic ring group containing one or two heteroatoms. The heteroatoms are independently selected from nitrogen and oxygen. Examples include azetidine, oxetane, pyrrolidine, tetrahydrofuran, oxazolidine, isoxazolidine, piperidine, and morpholine, preferably pyrrolidine and piperidine.

[0758] "8-, 9-, or 10-membered bicyclic heterocycloalkyl" refers to a stable 8-, 9-, or 10-membered non-aromatic fused bicyclic ring group containing 1, 2, or 3 heteroatoms. The heteroatoms are preferably independently selected from nitrogen and oxygen. Examples of 8-, 9-, or 10-membered bicyclic heterocycloalkyls include 6-methyloctahydro-pyrrolo[2,3-c]pyridine, e.g.,

[0759] [ka]

[0760] [wherein Re is selected from C1-C6 alkyl, haloC1-C6 alkyl, hydroxyC1-C6 alkyl, or —OH], preferably

[0761] [ka]

[0762] Examples include:

[0763] The dashed circle in the five-membered ring means that a double bond can optionally be present at any available position. According to the rules of chemistry, the Z, E, and Q options C have four bonds to adjacent atoms, and the Z, E, and Q option N has three bonds to adjacent atoms. The bonds can be single or double. Examples of five-membered rings are pyrazolones,

[0764] [ka]

[0765] or imidazo

[0766] [ka]

[0767] Examples include:

[0768] [ka]

[0769] identifies the point of attachment. For example, for compounds having formula (I'), the wavy line

[0770] [ka]

[0771] is R A and R B is attached to the core structure of the compound having formula (I') A and R B points to the atom.

[0772] [ka]

[0773] A (dashed or closed) circle means that the double bond can occur at any available position in the ring.

[0774] "Optionally substituted" in reference to a group refers to said group as being optionally substituted with one or more substituents (i.e., the substituents may or may not be present).

[0775] Unless otherwise specified, the term "compound of the invention" refers to a compound of Formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV), or (V) disclosed herein, or a subformula thereof disclosed herein, or a stereoisomer thereof, or a racemic mixture thereof, or a tautomer thereof, or a polymorph thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a hydrate thereof, or a solvate thereof. Compounds of the invention having one or more optically active carbons can exist as racemates and racemic mixtures (including mixtures in all ratios), stereoisomers (including diastereomeric mixtures and individual diastereomers, enantiomeric mixtures and single enantiomers, mixtures of conformers and single conformers), tautomers, atropisomers, and rotamers. All isomeric forms are included in the present invention. Compounds described herein that contain olefinic double bonds include E and Z geometric isomers. All pharmaceutically acceptable salts, prodrugs, hydrates, and solvates of the compounds of Formula (I'), (I), (II'), (II), (II'a), (II'b), (IIa), (IIb), (III'), (III), (IV), or (V) are included in the present invention.

[0776] Tautomers are isomers of a compound that differ only in the position of protons and electrons. The skeleton of the compound remains the same. Common tautomer pairs include ketone-enol (HOC=CH⇔O=C-CH2) and enamine-imine (H2N-C=N⇔HN=C-NH).

[0777] Solvates, hydrates, and anhydrous forms of the salts 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 Examples include alcohols (such as methanol or ethanol).

[0778] "Pharmaceutically acceptable salts" are defined as derivatives of the disclosed compounds where the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. Pharmaceutically acceptable salts include the conventional non-toxic salts or quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, and nitric acid; and salts prepared from organic acids such as, but not limited to, acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, and isethionic acid. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or a mixture of both. 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.

[0779] The compounds of the present invention as defined herein may also be provided in the form of prodrugs, i.e., compounds that are metabolized in vivo to active metabolites. As used hereinafter in the specification and claims of the present invention, the term "prodrug" refers to any covalently bonded compound that releases an active parent drug through in vivo biotransformation. The reference by Goodman and Gilman (The Pharmacological Basis of Therapeutics, 8th Edition, McGraw-Hill, Int. Ed. 1992, "Biotransformation of Drugs", pp. 13-15), which reviews prodrugs, is incorporated herein by reference.

[0780] "Pharmaceutically acceptable" is defined as compounds, materials, compositions, and / or dosage forms that are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio, within the scope of sound medical judgment.

[0781] As used herein, the term "patient" or "subject" as used herein typically refers 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.

[0782] As used herein, "NLRP3" refers to the NOD-like receptor (NLR) family pyrin domain-containing protein triad of the inflammasome. The inflammasome is an intracellular supramolecular complex containing 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-assembles into a helical fibrillar assembly, forming the so-called ASC speck or pyroptosome, which acts as a molecular platform for the activation of procaspase-1 via proximity-induced autocatalytic activation. Active caspase-1 triggers the activation and release of interleukin-1 (IL-1) family proteins, enabling the abnormal secretion of numerous cytosolic proteins. Among the proinflammatory mediators released upon NLRP3 activation are IL-1 beta (β), IL-18, high-mobility group protein B1 (HMGB1), leukotrienes, and prostaglandins.

[0783] NLRP3 inflammasome pathway activation is a key driver of inflammation, interacting with various cytokine pathways to shape the immune response to infection and injury. The formation of several pro-inflammatory cytokines is triggered by NLRP3 inflammasome pathway activation.

[0784] The terms "inhibit," "inhibition," or "inhibiting" refer to the reduction or suppression of a given condition, symptom, or disorder, or disease, or abnormality, or a significant decrease in the baseline activity of a biological activity or process, responsive to modulation of a component of the NLRP3 inflammasome pathway.

[0785] The terms "treat," "treating," or "treatment" of any disease, disorder, or condition refers to alleviating, improving, or modulating the disease, disorder, or condition (i.e., slowing or halting the development of the disease, disorder, or condition, or at least one of its clinical symptoms); or alleviating, improving, or modulating at least one physical parameter or biomarker associated with the disease, disorder, or condition, including those that may not be discernible to the subject (e.g., patient).

[0786] The terms "prevent," "preventing," or "prevention" of any disease or disorder or abnormality responsive to modulation of a component of the NLRP3 inflammasome pathway refer to the prophylactic treatment of the disease or disorder or abnormality; or the delay in the onset or progression of the disease or disorder.

[0787] The term "in need of" treatment means a subject in need of treatment if such subject would benefit biologically, medically, or in quality of life from such treatment.

[0788] As used herein, "modulation" refers to an alteration, such as upregulation, downregulation, increase or decrease, preferably a decrease.

[0789] [Table 1]

[0790] The definitions and preferred definitions set forth in the "Definitions" section apply to all of the embodiments described herein unless otherwise stated.

[0791] General synthetic scheme for the preparation of compounds of the present invention: The compounds of the present invention can be synthesized by using preparative steps generally known to those skilled in the art, such as the preparative steps of the general methods shown in the following schemes, which are provided for illustrative purposes only and should not be construed as limiting.

[0792] It is well understood that in all methods, protecting groups for sensitive or reactive groups may be employed where necessary in accordance with general principles of chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (TW Green and PGM Wuts (2014) Protective Groups in Organic Synthesis, 5th Edition, John Wiley & Sons). These groups are removed at a convenient stage of the compound synthesis using methods readily apparent to those skilled in the art.

[0793] In the following general method, R0, R1, R2, R3, R a , X', and Y are as defined above in the above embodiments.

[0794] [ka]

[0795] "Lg" means a leaving group. Examples of suitable leaving groups include -Cl, -Br, or -I.

[0796] "Pg" means a protecting group. Examples of suitable protecting groups include -CH3, -MOM, or -MEM.

[0797] Commercially available diaminopyridines can be functionalized. a When R is methyl, a two-step strategy can be applied. First, selective carbamate formation using CbzCl, followed by reduction using, for example, LAH, can lead to the desired intermediate. Alternatively, commercially available diaminopyridines can be selectively functionalized with ethyl iodide or 2-bromopropane to give the desired intermediate [where R ais ethyl or isopropyl. Cyclization using a commercially available aldehyde in the presence of sodium bisulfite in an appropriate solvent can then provide the bicyclic intermediate after purification. If the aromatic aldehyde is not commercially available, it can be prepared from commercially available starting materials via a multi-step reaction involving Suzuki coupling, nucleophilic substitution, a halogen-lithium exchange reaction using BuLi and DMF, or palladium-mediated introduction of -OCH3 using dipotassium sulfonatooxysulfate and 3-(trifluoromethyl)aniline. Finally, the bicyclic intermediate can be further functionalized using a palladium-catalyzed Buchwald reaction using a suitable amine and alcohol, or by nucleophilic substitution, to provide compounds of formula (IIa) after purification. If a protecting group is present at R2, the protecting group can be cleaved under acidic conditions (boron tribromide, TFA) to provide compounds of formula (IIb) after purification. If compounds of formula (IIa) contain a secondary amine, reductive amination conditions can be used to provide compounds of formula (IIa) containing a tertiary amine. If a racemic mixture is obtained, it can be separated by SFC to give the compound of formula (IIa).

[0798] [ka]

[0799] "Pg" means a protecting group. Examples of suitable protecting groups include -CH3, -MOM, or -MEM.

[0800] If a diaminopyridine without the desired substitution pattern is not commercially available, a bromo-containing aminopyridine derivative can be treated with a suitable amine to obtain the diaminopyridine derivative. Cyclization using a commercially available aldehyde in the presence of sodium bisulfite in a suitable solvent can then provide the bicyclic intermediate after purification. Oxidation of the bicyclic intermediate (3-chloroperoxybenzoic acid) followed by treatment with phosphoryl chloride can provide the bicyclic intermediate containing a chloro leaving group. Finally, the bicyclic intermediate can be further functionalized using a palladium-catalyzed Buchwald reaction or by nucleophilic substitution to obtain the compound of formula (IIa) after cleavage of the protecting group (BBr). If a racemic mixture is obtained, it can be separated by SFC to obtain the compound of formula (II'a).

[0801] [ka]

[0802] "Lg" means a leaving group. Examples of suitable leaving groups include -Cl, -Br, or -I.

[0803] "Pg" means a protecting group. Examples of suitable protecting groups include -CH3, -MOM, or -MEM.

[0804] Commercially available bicyclic scaffolds can be synthesized using appropriate amines or alcohols or sodium 2-chloro-2,2-difluoroacetate. N The pyrazole ring can then be functionalized with Ar. The pyrazole ring can then be reacted with an appropriate boronic acid or ester utilizing a suitable copper catalyst to provide intermediate B. If a protecting group is present at R2, the protecting group can be cleaved under acidic conditions (boron tribromide) to provide compounds of formula (IIb) after purification.

[0805] [ka]

[0806] "Lg" means a leaving group. Examples of suitable leaving groups include -Cl, -Br, or -I.

[0807] "Pg" means a protecting group. Examples of suitable protecting groups include -CH3, -MOM, or -MEM.

[0808] Commercially available bicyclic scaffolds can be synthesized using the appropriate thiols. N The pyrazole ring can then be functionalized with Ar. The pyrazole ring can then be reacted with an appropriate boronic acid or ester utilizing a suitable copper catalyst to afford intermediate B. If intermediate B contains a thioether moiety at position -Y-R3, the thioether can be converted to a leaving group by oxidation (3-chloroperoxybenzoic acid) and then displaced with a suitable amine via nucleophilic substitution to afford intermediate B. If a protecting group is present at R2, the protecting group can be cleaved under acidic conditions (boron tribromide) to afford compounds of formula (IIb) after purification.

[0809] [ka]

[0810] "Lg" means a leaving group. Examples of suitable leaving groups include -Cl, -Br, or -I.

[0811] "Pg" means a protecting group. Examples of suitable protecting groups include -CH3, -MOM, or -MEM.

[0812] Commercially available bicyclic scaffolds can be synthesized using the appropriate thiols. NThe pyrazole ring can then be functionalized with Ar. The pyrazole ring can then be reacted with an appropriate boronic acid or ester utilizing a suitable copper catalyst to afford intermediate B. If intermediate B contains a thioether moiety, the thioether can be converted to a leaving group by oxidation (3-chloroperoxybenzoic acid) and then displaced with a suitable amine via nucleophilic substitution to afford intermediate C. If a protecting group is present at R2, the protecting group can be cleaved under acidic conditions (boron tribromide) to afford compounds of formula (IIb) after purification.

[0813] [ka]

[0814] "Lg" means a leaving group. Examples of suitable leaving groups include -Cl, -Br, or -I.

[0815] "Pg" means a protecting group. Examples of suitable protecting groups include -CH3, -MOM, or -MEM.

[0816] Commercially available amino-nitropyridines can be functionalized to diaminopyridines by bromination (NBS) followed by reduction of the nitro group (Fe, acid). When Ra is methyl, a two-step strategy can be applied. First, selective carbamate formation using CbzCl, followed by reduction using, for example, LAH, can be performed to generate the desired intermediate. Cyclization using commercially available aldehydes in the presence of sodium bisulfite using an appropriate solvent can then provide the bicyclic intermediate after purification. Finally, the bicyclic intermediate can be further functionalized by nucleophilic substitution. Palladium-mediated exchange of the bromo moiety with a nitrile gave the nitrile-containing bicyclic intermediate. Saponification of the nitrile moiety to an acid followed by borane reduction gave compounds of formula (II'a) containing a primary alcohol moiety. Alternatively, cyclization using an aldehyde containing a protecting group in the presence of sodium bisulfite using an appropriate solvent can provide the bicyclic intermediate after purification. Acid-mediated (boron tribromide) cleavage of the protection gave the bicyclic intermediate after purification. Nucleophilic substitution followed by Stille coupling using a suitable tin reagent gave compounds containing a methyl-ketone moiety. Treatment of the methyl-ketone derivative with a Grignard reagent (CHMgBr) gave compounds of formula (II'a) containing a tertiary alcohol moiety.

[0817] [ka]

[0818] "Pg" means a protecting group. Examples of suitable protecting groups include -CH3, -MOM, or -MEM.

[0819] Commercially available 3-bromo-6-chloropyrazine-2-amine can be functionalized to a diaminopyrazine by amination with a suitable amine. Cyclization using an aldehyde containing the alcohol protecting group as MEM or MOM in the presence of sodium bisulfite in a suitable solvent can then provide the bicyclic intermediate after purification. Acid-mediated cleavage of the protecting group (TFA) afforded the bicyclic intermediate after purification. Finally, the bicyclic intermediate can be further functionalized by nucleophilic substitution with a suitable alcohol and amine to afford compounds of formula (II'a). If the nucleophilic substitution product contains an acetal moiety, acetal cleavage and subsequent Grignard reaction can afford compounds of formula (II'a) containing a tertiary alcohol. If a racemic mixture is obtained, it can be separated by SFC to afford compounds of formula (II'a). Alternatively, cyclization using an aldehyde containing the alcohol protecting group as methyl in the presence of sodium bisulfite in a suitable solvent can provide the bicyclic intermediate after purification. The bicyclic intermediate can be further functionalized by nucleophilic substitution with a suitable alcohol and amine or palladium-catalyzed Buchwald conditions using a suitable amine. Finally, the methyl protecting group can be cleaved under Lewis acid conditions (boron tribromide) to give compounds of formula (II'a). Alternatively, cyclization using an aldehyde containing the alcohol protecting group as methyl in the presence of sodium bisulfite using a suitable solvent can provide the bicyclic intermediate after purification. The methyl protecting group can be cleaved under Lewis acid conditions (boron tribromide) to give bicyclic intermediates containing a chloro leaving group. Finally, the bicyclic intermediate can be further functionalized by nucleophilic substitution with a suitable alcohol and amine or palladium-catalyzed Buchwald conditions using a suitable amine to give compounds of formula (II'a). If compounds of formula (II'a) contain a secondary amine, reductive amination conditions can be used to give compounds of formula (II'a) containing a tertiary amine.

[0820] [ka]

[0821] "Pg" means a protecting group. Examples of suitable protecting groups include -CH3, -MOM, or -MEM.

[0822] The bicyclic intermediate containing a methyl protecting group can be brominated (NBS) to give a bromo-containing bicyclic intermediate. The exchange of bromo for -CHOH using Stille coupling conditions gave compounds of formula (II'a) after acid-mediated (boron tribromide) cleavage of the methyl protecting group. Alternatively, the bromo-containing bicyclic intermediate can be treated with methanol under basic conditions to give compounds of formula (II'a) containing -CHOCH after acid-mediated (boron tribromide) cleavage of the methyl protecting group. If the compound of formula (II'a) contains a secondary amine, reductive amination conditions can be used to give compounds of formula (II'a) containing a tertiary amine.

[0823] [ka]

[0824] "Pg" means a protecting group. Examples of suitable protecting groups include -CH3, -MOM, or -MEM.

[0825] The ortho-ester can be used to cyclize a suitable diaminopyrazine to give a bicyclic intermediate. The bicyclic intermediate can be further functionalized by nucleophilic substitution with a suitable amino alcohol containing an amine protecting group. Iodination with 1,2,3,4,5-pentafluoro-6-iodo-benzene under basic conditions afforded a bicyclic intermediate containing an iodo moiety. Suzuki coupling using a suitable boronic ester afforded the corresponding coupling product, which can be converted to a compound of formula (II'a) after acid (boron tribromide)-mediated deprotection. If the compound of formula (II'a) contains a secondary amine, reductive amination conditions can be used to give a compound of formula (II'a) containing a tertiary amine.

[0826] [ka]

[0827] "Lg" means a leaving group. Examples of suitable leaving groups include -Cl, -Br, or -I.

[0828] "Pg" means a protecting group. Examples of suitable protecting groups include -CH3, -MOM, or -MEM.

[0829] Commercially available 2-chloropyrimidine-4,5-diamine was selectively functionalized with methyl iodide to give the desired intermediate [where R a is methyl] can be obtained. Cyclization using a commercially available aldehyde in the presence of sodium bisulfite using an appropriate solvent can then provide the bicyclic intermediate after purification. If the aromatic aldehyde is not commercially available, it can be prepared from commercially available starting materials via a multi-step reaction involving Suzuki coupling, nucleophilic substitution, a halogen-lithium exchange reaction using BuLi and DMF, or palladium-mediated introduction of -OCH3 using dipotassium sulfonatooxysulfate and 3-(trifluoromethyl)aniline. The protecting group present in R2 can be cleaved under acidic conditions (TFA) to provide the deprotected bicyclic intermediate after purification. Finally, the bicyclic intermediate can be further functionalized by nucleophilic substitution to provide the compound of formula (II'a) after purification.

[0830] [ka]

[0831] "Lg" means a leaving group. Examples of suitable leaving groups include -Cl, -Br, or -I.

[0832] "Pg" means a protecting group. Examples of suitable protecting groups include -CH3, -MOM, or -MEM.

[0833] Diaminopyridines containing leaving groups can be cyclized using a suitable reagent, such as 1,1'-carbonyldiimidazole, to afford the cyclized product after purification. Palladium-mediated Suzuki coupling of a suitable boronic acid using an appropriate base and solvent can then provide the coupled product after purification. Treatment of the coupled product with phosphoryl chloride, followed by coupling of the chloro derivative with a suitable amine, alcohol, or amino-alcohol via nucleophilic substitution, can afford the coupled product bearing the -Y-R3 substituent after purification. Finally, acid-mediated cleavage of the protecting group (p-toluenesulfonic acid, lithium chloride) under microwave conditions can afford compounds of formula (III) after purification. [Example]

[0834] The present disclosure is further illustrated by the following examples and synthetic schemes, which should not be construed as limiting the scope of the specific procedures described herein. It should be understood that the examples are provided to illustrate some embodiments and that no limitation of the scope of the disclosure is intended thereby.

[0835] [Table 2A]

[0836] [Table 2B]

[0837] Unless otherwise noted, all reagents and solvents were obtained from commercial sources and used without further purification. Chemical names were generated using CambridgeSoft's ChemDraw. Temperatures are given in degrees Celsius. Unless otherwise noted, all evaporations were carried out under reduced pressure, typically about 15 mmHg to 100 mmHg (= 20 to 133 mbar). The structure of final products, intermediates, and starting materials is confirmed by standard analytical methods, e.g., microanalysis and spectroscopic characteristics, e.g., MS, IR, NMR. 1H-NMR spectra were recorded on a Bruker 400 MHz-Avance Neo Nanobay NMR spectrometer in deuterated solvents. Chemical shifts (δ) are reported in parts per million, and coupling constants (J values) are reported in Hertz. Spin multiplicities are indicated by the following symbols: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), and bs (broad singlet). Mass spectra (MS) were obtained on 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 appropriate solvents as indicated in the examples. Flash purification was performed using a CombiFlash system and solvent gradients as indicated in the examples. Thin-layer chromatography (TLC) was performed on silica gel plates with UV detection.

[0838] Synthesis of intermediates Intermediate 1: 6-chloro-N3-methylpyridine-2,3-diamine

[0839] [ka]

[0840] Step A: To a stirred solution of 6-chloropyridine-2,3-diamine (5 g, 34.83 mmol) in DCM (50 mL) at 0 °C, EtN (14.56 mL, 104.48 mmol) followed by benzyl chloroformate (4.91 mL, 34.83 mmol) were added, and the mixture was stirred at room temperature for 2 h. The reaction was monitored by TLC. After the starting material was consumed, the reaction mixture was diluted with DCM (100 mL) and washed with brine (2 × 100 mL). The organic phase was dried over NaSO and concentrated under reduced pressure to give the crude compound. The crude compound was purified by flash chromatography (silica 100-200 mesh; eluted with ethyl acetate (40 to 50%) in hexanes). The collected pure fractions were concentrated under reduced pressure to give benzyl (2-amino-6-chloropyridin-3-yl)carbamate (5 g, 52%) as an off-white solid. MS (ESI): 278.24 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ = 7.51-7.35 (m, 6H), 6.72-6.70 (d, 1H), 6.17 (brs, 1H), 5.22 (s, 2H), 4.68 (brs, 2H).

[0841] Step B: To a stirred solution of benzyl (2-amino-6-chloropyridin-3-yl)carbamate (obtained from Step A) (5 g, 18.01 mmol) in dry THF (100 mL) was added 1.0 M LAH in THF (72.02 mL, 72.02 mmol) dropwise over 20 min at 0 °C. The mixture was stirred at 70 °C for 15 min under a N atmosphere. After the starting material was consumed, the reaction mixture was cooled to room temperature, quenched with saturated NH Cl solution (100 mL), and extracted with EtOAc (2 × 100 mL). The organic phase was dried over Na SO and concentrated under reduced pressure to give the crude compound. The crude compound was purified by flash chromatography (silica 100–200 mesh; elution with ethyl acetate (45 to 50%) in hexanes). The collected pure fractions were concentrated under reduced pressure to give 6-chloro-N3-methylpyridine-2,3-diamine (1.5 g, 53%) as a brown solid. MS (ESI): 158.16 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ = 6.52 (d, 1H), 6.45 (d, 1H), 5.86 (s, 2H), 4.95-4.96 (m, 1H), 2.68 (d, 3H).

[0842] Intermediate 2: 6-chloro-N3-ethylpyridine 2,3-diamine

[0843] [ka]

[0844] Step A: To a stirred solution of 6-chloropyridine-2,3-diamine (5.0 g, 34.3 mmol) in N,N-dimethylformamide (100 mL) was added potassium carbonate (14.44 g, 104.48 mmol) and ethyl iodide (8.400 mL, 104.48 mmol) at room temperature and stirred for 16 hours. The reaction progress was monitored by TLC. TLC indicated complete conversion of the starting material. The reaction mixture was diluted with water (300 mL) and extracted with EtOAc (2×400 mL). The combined organic layers were washed with brine solution (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product as a black oil. The crude product was purified by column chromatography using silica gel eluting with EtOAc / hexane as a gradient. The product was eluted with 30% EtOAc in hexane. The pure fractions were collected and concentrated under reduced pressure to give 6-chloro-N3-ethylpyridine 2,3-diamine (2.0 g, 33%) as a pale pink solid. MS(ESI):172.02[M+H] + .

[0845] Intermediate 3: 6-chloro-N3-isopropylpyridine-2,3-diamine

[0846] [ka]

[0847] Step A: To a stirred solution of 6-chloropyridine-2,3-diamine (5.0 g, 34.83 mmol) in N,N-dimethylacetamide (100 mL) was added potassium carbonate (14.44 g, 104.479 mmol) and 2-bromopropane (9.8 mL, 104.48 mmol) at room temperature and stirred at 100 °C for 8 h. The reaction progress was monitored by TLC. TLC indicated complete conversion of the starting material. The reaction mixture was diluted with water (300 mL) and extracted with EtOAc (2 × 400 mL). The combined organic layers were washed with brine solution (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product as a black oil. The crude product was purified by column chromatography using silica gel (100-200) eluting with a gradient of 0–50% EtOAc / hexane. The product was eluted with 20% EtOAc / hexane. The pure fractions were collected and concentrated under reduced pressure to give 6-chloro-N3-isopropylpyridine-2,3-diamine (2.5 g, 39%) as an off-white solid. MS(ESI):185.81[M+H] + .

[0848] Intermediate 4: 2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)benzaldehyde

[0849] [ka]

[0850] Step A: To a stirred solution of 3-bromo-5-(trifluoromethyl)phenol (30 g, 124.48 mmol) in 1,4-dioxane (300 mL) and water (30 mL) was added methylboronic acid (14.9 g, 248.95 mmol) and cesium carbonate (121.670 g, 373.43 mmol). The mixture was degassed with N for 20 minutes, and then [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (4.55 g, 6.22 mmol) was added at room temperature. The mixture was heated to 90 °C for 12 hours. The reaction progress was monitored by TLC. After the starting material was consumed, the reaction mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure to give the crude compound. The crude compound was purified by column chromatography using silica gel (100-200 mesh) eluting with a gradient of 0-50% EtOAc in hexanes. The product was eluted with 15% EtOAc in hexanes. Pure fractions were collected and concentrated under reduced pressure to give 3-methyl-5-(trifluoromethyl)phenol (21 g, 96%) as a pale yellow liquid. MS (ESI): 175.05 [MH] - . 1 H NMR (400 MHz, CDCl3): δ = 7.00 (s, 1H), 6.88 (s, 1H), 6.82 (s, 1H), 5.00 (s, 1H), 2.36 (s, 3H).

[0851] Step B: To a stirred solution of 3-methyl-5-(trifluoromethyl)phenol (obtained from Step A) (12 g, 68.13 mmol) in toluene (420 mL) was added 57-63% sodium hydride dispersion in oil (6.86 g, 204.39 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min. Iodine (19 g, 74.94 mmol) was then added portionwise at 0 °C, and stirring was continued for 3 h. After the starting material was consumed, the reaction mixture was quenched with ice-cold water (80 mL), acidified with 1 N HCl solution, and extracted with EtOAc (2 × 200 mL). The combined organic layers were washed with brine solution (80 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography using silica gel (100-200 mesh) eluting with 0-50% EtOAc in hexane as a gradient. The product was eluted with 15% EtOAc in hexanes. Pure fractions were collected and concentrated under reduced pressure to give 2-iodo-3-methyl-5-(trifluoromethyl)phenol (13.5 g, 65%) as a yellow oil. MS(ESI):301.17[MH] - .

[0852] Step C: To a stirred solution of 2-iodo-3-methyl-5-(trifluoromethyl)phenol (obtained from Step B) (13.5 g, 44.70 mmol) in THF (135 mL) under an argon atmosphere at 0 °C, N,N-diisopropylethylamine (31 mL, 178.79 mmol) and methoxymethyl chloride (8.49 mL, 111.74 mmol) were added dropwise. The reaction mixture was stirred at room temperature for 16 h. After the starting material was consumed, the reaction mixture was concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography using silica gel (100-200 mesh) and eluted with hexane as a gradient. Pure fractions were collected and concentrated under reduced pressure to give 2-iodo-1-(methoxymethoxy)-3-methyl-5-(trifluoromethyl)benzene (12 g, 78%) as a colorless oil. MS (ESI): 346.0 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ = 7.17 (s, 1H), 7.08 (s, 1H), 5.27 (s, 2H), 3.52 (s, 3H), 2.53 (s, 3H).

[0853] Step D: To a stirred solution of 2-iodo-1-(methoxymethoxy)-3-methyl-5-(trifluoromethyl)benzene (obtained from Step C) (12.0 g, 31.08 mmol) in THF (120 mL) was added n-butyllithium (1.6 M) in hexanes (25 mL, 40.34 mmol) at −78 °C, and the mixture was stirred for 5 min. N,N-Dimethylformamide (2.9 mL, 37.29 mmol) was added, and the mixture was stirred at the same temperature for 10 min. After the starting material was consumed, the reaction mixture was quenched with saturated NH4Cl solution and extracted with EtOAc (2 × 40 mL). The combined organic layers were washed with brine solution (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude 2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)benzaldehyde (6.5 g, 84%) as an oil. 1 H NMR (400 MHz, DMSO-d6): δ = 10.55 (s, 1H), 7.43 (s, 1H), 7.32 (s, 1H), 5.43 (s, 2H), 3.38 (s, 3H), 2.36 (s, 3H).

[0854] Intermediate 5: 4-Chloro-2-methoxy-6-methylbenzaldehyde

[0855] [ka]

[0856] Step A: To a stirred solution of 2-bromo-4-chloro-6-methylaniline (20 g, 90.71 mmol) in methanol (100 mL) was added sodium methoxide, approximately 30% w / w in methanol (60 mL), and copper(I) iodide (19 g, 99.78 mmol) at room temperature and heated to 100° C. for 18 hours. The reaction progress was monitored by TLC. TLC indicated complete conversion of the starting material. The reaction mixture was diluted with water (500 mL) and extracted with DCM (2×500 mL). The combined organic layers were washed with brine solution (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product as a liquid. The crude product was purified by column chromatography using silica gel eluting with EtOAc in hexane as a gradient. The product was eluted with 5% EtOAc in hexane. Pure fractions were collected and concentrated under reduced pressure to give the pure compound (5.9 g, 38%). MS(ESI):172.27[M+H] + .

[0857] Step B: To a stirred solution of 4-chloro-2-methoxy-6-methylaniline (6.0 g, 34.96 mmol) in acetonitrile (150 mL) at 0 °C was added isoamyl nitrite, 97%, stabilized (7.06 mL, 52.44 mmol). The reaction mixture was stirred for 30 min. CuBr2 (8.43 g, 37.78 mmol) was then added at 0 °C. The reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. TLC indicated complete conversion of the starting material. The reaction mixture was diluted with water (250 mL) and extracted with EtOAc (2 × 250 mL). The combined organic layers were washed with brine solution (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product as a liquid. The crude product was purified by column chromatography using silica gel (100–200) eluting with EtOAc in hexane as a gradient. The product was eluted with 2% EtOAc in hexane. The pure fractions were collected and concentrated under reduced pressure to give the pure compound (4.47 g, 55%). MS(ESI):233.94[M+H] + .

[0858] Step C: To a stirred solution of 2-bromo-5-chloro-1-methoxy-3-methylbenzene (4.2 g, 17.83 mmol) in THF (50 mL) was added n-BuLi (1.6 M in hexanes) (16.71 mL, 26.75 mmol) at -78 °C, and the reaction mixture was stirred for 10 min. N,N-Dimethylformamide (4.11 mL, 53.502 mmol) was then added at -78 °C, and the reaction mixture was stirred for 30 min. The progress of the reaction was monitored by TLC. TLC showed completion. The reaction mixture was quenched with saturated NH4Cl solution and extracted with EtOAc (2 × 250 mL). The combined organic layers were washed with brine solution (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product as a solid. The crude product was purified by column chromatography using silica gel (100-200) eluting with EtOAc in hexane as a gradient. The product was eluted with 5% EtOAc in hexanes. Pure fractions were collected and concentrated under reduced pressure to give the pure compound (2.87 g, 88%). MS(ESI):183.9[M+H] + .

[0859] Intermediate 6: 2-(5-chloro-1-methyl-1H-imidazo[4,5-b]pyridin-2-yl)-3-methyl-5-(trifluoromethyl)phenol

[0860] [ka]

[0861] Step A: To a stirred solution of 6-chloro-N3-methylpyridine-2,3-diamine (Intermediate 1) (1.8 g, 11.42 mmol) and 2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)benzaldehyde (Intermediate 2) (6.52 g, 26.27 mmol) in DMA (10 mL) was added sodium bisulfite (1.43 g, 13.71 mmol) at room temperature, and the reaction mixture was stirred at 100 °C for 16 h. After the starting material was consumed, the reaction mixture was quenched with ice-cold water (30 mL) and extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with brine solution (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography using silica gel (100–200 mesh) eluting with EtOAc in hexane as a gradient. The product was eluted with 30% EtOAc in hexane. The pure fractions were collected and concentrated under reduced pressure to give 5-chloro-2-(2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl)-1-methyl-1H-imidazo[4,5-b]pyridine (4.2 g, 95%) as an oil. MS (ESI): 386.29 [M+H]+. 1 H NMR (400 MHz, DMSO-d6): δ = 8.23-8.21 (d, 1H), 7.49-7.42 (d, 3H), 5.32-5.31 (d, 1H), 5.23-5.21 (d, 1H), 3.63 (s, 3H), 3.24 (s, 3H), 2.15 (s, 3H).

[0862] Step B: To a stirred solution of 5-chloro-2-(2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl)-1-methyl-1H-imidazo[4,5-b]pyridine (obtained from Step A) (4.2 g, 10.89 mmol) in DCM (84 mL) was added trifluoroacetic acid (63 mL) at 0 °C, and the reaction mixture was stirred at room temperature for 2 h. After the starting material was consumed, the reaction mixture was quenched with ice-cold water (50 mL) and stirred for 10 min. The precipitated solid was filtered, washed with water (100 mL), and evaporated to dryness in vacuo to give 2-(5-chloro-1-methyl-1H-imidazo[4,5-b]pyridin-2-yl)-3-methyl-5-(trifluoromethyl)phenol (3.5 g, 94%) as an off-white solid. MS (ESI): 342.25 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ =10.79 (s, 1H) 8.22-8.20 (d, 1H), 7.44-7.424 (d, 1H), 7.25 (s, 1H), 7.15 (s, 1H), 3.64 (s, 3H), 2.16 (s, 3H).

[0863] Intermediate 7: 2-(5-chloro-1-methyl-1H-imidazo[4,5-b]pyridin-2-yl)-5-(trifluoromethyl)phenol

[0864] [ka]

[0865] Step A: To a stirred solution of 6-chloro-N3-methylpyridine-2,3-diamine (Intermediate 1) (0.2 g, 1.27 mmol) and 2-hydroxy-4-(trifluoromethyl)benzaldehyde (0.241 g, 1.27 mmol) in DMA (5 mL) was added sodium bisulfite (0.158 g, 1.52 mmol) at room temperature, and the reaction mixture was stirred at 100 °C for 16 h. After the starting material was consumed, the reaction mixture was diluted with ice water (50 mL) and stirred for 10 min. The precipitate was collected by filtration and dried to give 2-(5-chloro-1-methyl-1H-imidazo[4,5-b]pyridin-2-yl)-5-(trifluoromethyl)phenol (0.2 g, 48%) as a pale yellow solid. MS (ESI): 328.22 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ = 11.24 (brs, 1H), 8.21-8.19 (d, 1H), 7.75-7.73 (d, 1H), 7.43-7.41 (d, 1H), 7.36-7.34 (m, 2H), 3.77 (s, 3H).

[0866] The following intermediates were prepared similarly as above using the corresponding amine and appropriate aldehyde as shown in table 1, optionally followed by a deprotection step:

[0867] [Table 3A]

[0868] [Table 3B]

[0869] [Table 3C]

[0870] Intermediate 16: 2-Methoxy-6-methyl-4-(trifluoromethyl)benzaldehyde

[0871] [ka]

[0872] Step A: To a solution of 1-bromo-3-methyl-5-(trifluoromethyl)benzene (45 g, 188.26 mmol, 1.0 equiv.) in a mixture of dioxane (450 mL) and HO (45 mL), LiOH.HO (13.53 g, 564.78 mmol, 3.0 equiv.), Pd(dba) (3.45 g, 3.77 mmol, 0.02 equiv.), and di-tert-butyl-[2-(1,3,5-triphenylpyrazol-4-yl)pyrazol-3-yl]phosphane (3.82 g, 7.53 mmol, 0.04 equiv.) were added sequentially and degassed three times with N. The resulting reaction mixture was heated to 100 °C and stirred at 100 °C under N for 12 h. TLC (PE / EA = 10 / 1, Rf of product = 0.50, developer: UV 254 nm) showed the reaction was complete. The reaction mixture was poured onto HO (500 mL) followed by EA (50 mL), and then the pH was adjusted to 4 with 2 M HCl. The aqueous phase was then separated and extracted with EA (80 mL × 3). The combined organic layers were washed successively with water (20 mL × 2) and brine (20 mL × 1), dried over anhydrous NaSO, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 100 / 1 to 10 / 1). 3-Methyl-5-(trifluoromethyl)phenol (44 g, 249.81 mmol, yield 66.35%, purity data not available) was obtained as a yellow oil. 1 H NMR (400 MHz, chloroform-d) δ = 7.01 (s, 1H), 6.89 (s, 1H), 6.82 (s, 1H), 5.04 (s, 1H), 2.37 (s, 3H)

[0873] Step B: To a solution of 3-methyl-5-(trifluoromethyl)phenol (39 g, 221.42 mmol, 1.0 equiv.) in toluene (800 mL) was added NaH (17.71 g, 442.84 mmol, 60% purity, 2.0 equiv.) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min, and then I (39.34 g, 154.99 mmol, 31.22 mL, 0.7 equiv.) was added. The resulting reaction mixture was stirred at 0 °C for 1.5 h. TLC (PE / EA = 10 / 1, product Rf = 0.45, developer: UV 254 nm) showed the reaction was complete. The reaction mixture was poured into saturated NH Cl (200 mL), and the pH was adjusted to 4 with 2 M HCl. The resulting solution was then extracted with EA (100 mL × 3). The combined organic layers were washed successively with water (200 mL × 2) and brine (200 mL × 1), dried over anhydrous Na2SO4, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 10 / 1). 2-iodo-3-methyl-5-(trifluoromethyl)phenol (38.6 g, 127.80 mmol, 57.72% yield, no purity data) was obtained as a yellow solid. 1 H NMR (400 MHz, chloroform-d) δ = 7.07 (s, 2H), 5.62 (s, 1H), 2.52 (s, 3H)

[0874] Step C: To a solution of 2-iodo-3-methyl-5-(trifluoromethyl)phenol (5.6 g, 18.54 mmol, 1.0 equiv.) in acetone (60 mL) was added KCO (5.12 g, 37.08 mmol, 2.0 equiv.), followed by CHCl (5.26 g, 37.08 mmol, 2.31 mL, 2.0 equiv.). The resulting reaction mixture was stirred at 20 °C for 12 h. TLC (PE / EA = 10 / 1, product Rf = 0.70, developer: UV 254 nm) indicated the reaction was complete. The reaction solution was filtered to remove KCO and then concentrated to give a residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 100 / 0 to 98 / 2). 2-Iodo-1-methoxy-3-methyl-5-(trifluoromethyl)benzene (5.3 g, 16.77 mmol, 90.44% yield, purity data not available) was obtained as a white solid. 1 H NMR (400 MHz, chloroform-d) δ = 7.14 (s, 1H), 6.82 (s, 1H), 3.94 (s, 3H), 2.54 (s, 3H)

[0875] Step D: To a solution of 2-iodo-1-methoxy-3-methyl-5-(trifluoromethyl)benzene (8 g, 25.31 mmol, 1.0 equiv.) in THF (80 mL), n-BuLi (2.5 M, 25.31 mL, 2.5 equiv.) was added, and the reaction mixture was stirred at −70° C. for 30 min. DMF (18.50 g, 253.12 mmol, 19.48 mL, 10 equiv.) was then added. The resulting reaction mixture was stirred at −70° C. for 6 h. TLC (PE / EA=4 / 1, product Rf=0.60, developer: UV 254 nm) indicated the reaction was complete. The reaction mixture was quenched at 0° C. with HO (100 mL) followed by DCM (30 mL). The aqueous phase was then separated and extracted with DCM (30 mL × 3). The combined organic layers were washed successively with water (20 mL × 2) and brine (20 mL × 1), dried over anhydrous Na2SO4, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 10 / 1). 2-Methoxy-6-methyl-4-(trifluoromethyl)benzaldehyde (4 g, 18.33 mmol, 72.43% yield) was obtained as a yellow oil. 1 H NMR (400 MHz, chloroform-d) δ = 10.65 (s, 1H), 7.07 (d, J = 8.8 Hz, 2H), 3.97 (s, 3H), 2.62 (s, 3H)

[0876] Intermediate 18: 4-Chloro-2-methoxy-6-methylbenzaldehyde

[0877] [ka]

[0878] Step A: To a solution of 4-chloro-2-methyl-benzaldehyde (2 g, 12.94 mmol, 1.0 equiv) in DCE (70 mL) was added MeOH (8.29 g, 258.74 mmol, 10.47 mL, 20.0 equiv), Pd(OAc) (435.67 mg, 1.94 mmol, 0.15 equiv), dipotassium sulfonate oxysulfate (6.99 g, 25.87 mmol, 5.18 mL, 2.0 equiv), 3-(trifluoromethyl)aniline (2.08 g, 12.94 mmol, 1.62 mL, 1.0 equiv), and the resulting reaction mixture was stirred in a sealed tube at 95 °C for 48 h. LCMS indicated 29% starting material remaining and 46% desired product. The reaction mixture was poured onto HO (300 mL) followed by DCM (100 mL). The aqueous phase was then separated and extracted with DCM (100 mL × 2). The combined organic layers were washed successively with water (20 mL × 2) and brine (20 mL × 1), dried over anhydrous NaSO, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 100 / 1 to 20 / 1) and then triturated with PE (20 mL) to give the pure product. The residue was purified by preparative HPLC (column: Waters Xbridge C18 150 × 50 mm × 10 μm; mobile phase: [HO (10 mM NH4HCO3)-ACN]; gradient: 35% to 65% B over 8.0 min) to give the title product. The residue was purified by preparative HPLC (Column: Waters Xbridge C18 150 × 50 mm × 10 μm; Mobile phase: [HO (10 mM NH4HCO3)-ACN]; Gradient: 35% to 65% B over 8.0 min) to give the title product: 4-chloro-2-methoxy-6-methyl-benzaldehyde (1.5 g, 8.12 mmol, 20.93% yield, purity data not available) as a white solid. LC-MS(ES+, m / z): 185.1[(M+H) + ]. 1 H NMR (400 MHz, DMSO-d6) δ = 10.43 (s, 1H), 7.18 (s, 1H), 6.99 (s, 1H), 3.91 (s, 3H), 2.46 (s, 3H)

[0879] Intermediate 19:

[0880] [ka]

[0881] Step A: To a solution of 4-fluoro-2-methyl-benzaldehyde (500 mg, 3.62 mmol, 1.0 equiv.) in DCE (15 mL), Pd(OAc) (81.26 mg, 361.96 μmol, 0.1 equiv.), dipotassium sulfonate oxysulfate (1.96 g, 7.24 mmol, 1.45 mL, 2.0 equiv.), MeOH (2.32 g, 72.39 mmol, 2.93 mL, 20.0 equiv.), and 3-(trifluoromethyl)aniline (233.28 mg, 1.45 mmol, 180.84 μL, 0.4 equiv.) were added, and the reaction mixture was stirred in a sealed tube at 80 °C for 48 h. The reaction mixture was poured into HO (20 mL) followed by EtOAc (10 mL). The aqueous phase was then separated and extracted with EtOAc (20 mL × 2). The combined organic layers were washed successively with water (20 mL × 2) and brine (20 mL × 1), dried over anhydrous Na2SO4, filtered, and concentrated to give a residue. The residue was purified by preparative TLC (SiO2, PE: EtOAc = 10:1). 4-Fluoro-2-methoxy-6-methyl-benzaldehyde (0.5 g, 2.97 mmol, 82.14% yield, no purity data) was obtained as a white solid. 1 H NMR (400 MHz, CDCl3) δ = 10.54 (s, 1H), 6.58 - 6.50 (m, 2H), 3.90 (s, 3H), 2.59 (s, 3H). MS: 168.7 [(M+H) + ].

[0882] Synthesis of Invention Examples

[0883] Example 1 2-(5-((2-hydroxyethyl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-2-yl)-5-(trifluoromethyl)phenol

[0884] [ka]

[0885] Step A: A stirred solution of 2-(5-chloro-1-methyl-1H-imidazo[4,5-b]pyridin-2-yl)-5-(trifluoromethyl)phenol (Intermediate 7) (0.2 g, 0.61 mmol) and 2-aminoethan-1-ol (0.075 g, 1.22 mmol) in THF (10 mL) was degassed with nitrogen gas for 10 minutes. BrettPhos Pd G3 (0.028 g, 0.031 mmol) was then added at room temperature, followed by LiHMDS (1.0 M in THF) (1.83 mL, 1.83 mmol). The reaction mixture was stirred at 70 °C for 24 hours. After the starting material was consumed, the reaction mixture was diluted with ice-cold water (50 mL) and extracted with ethyl acetate (2 × 50 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give the crude compound. The crude compound was purified by preparative HPLC (column XBridge C18 (150 mm × 19 mm, 5 μm), buffer: 10 mM ammonium bicarbonate, mobile phase: acetonitrile, flow rate: 14 mL / min), and the product-containing fractions were collected and lyophilized to give 2-(5-((2-hydroxyethyl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-2-yl)-5-(trifluoromethyl)phenol (22 mg, 6%) as an off-white solid. MS (ESI): 353.27 [M+H] + . 1H NMR (400 MHz, DMSO-d6): δ = 12.40 (brs, 1H), 7.91-7.89 (d, 1H), 7.77-7.75 (d, 1H), 7.36-7.29 (m, 2H), 6.59-6.48 (m, 2H), 4.76 (brs, 1H), 3.83 (s, 3H), 3.57-3.56 (m, 2H), 3.40-3.36 (q, 2H).

[0886] Following the procedure of Example 1, the following examples were prepared using haloaromatic intermediates and the corresponding commercially available amines as shown in Table 2:

[0887] [Table 4A]

[0888] [Table 4B]

[0889] [Table 4C]

[0890] [Table 4D]

[0891] [Table 4E]

[0892] [Table 4F]

[0893] (Examples 18 to 18A and 18B) Enantiopure 3-methyl-2-(1-methyl-5-((1-methylpyrrolidin-3-yl)amino)-1H-imidazo[4,5-b]pyridin-2-yl)-5-(trifluoromethyl)phenol

[0894] [ka]

[0895] The racemic product (prepared as described in Example 1 starting from Intermediate 6 and the commercially available racemic amine 1-methylpyrrolidin-3-amine) was obtained in 78% yield and separated by chiral SFC (column: Chiralpak IK, 250 mm × 30 mm, 5 μm, 30°C, eluent B: MeOH 15% + 0.5% diethylamine, flow rate: 90 g / min, pressure: 100 bar, cycle time: 18 min) to give the two enantiomers Example 18A (first eluting) and Example 18B (second eluting). Example 18A 1 H NMR (400 MHz, DMSO-d6): δ =10.53 (brs, 1H), 7.70-7.68 (d, 1H), 7.19 (s, 1H), 7.11 (s, 1H), 6.57-6.55 (d, 1H), 6.51-6.49 (d, 1H), 4.41-4.38 (m, 1H), 3.47 (s, 3H), 3.00-2.98 (m, 1H), 2.92-2.88 (m, 1H), 2.67-2.66 (m, 2H), 2.43 (s, 3H), 2.33-2.26 (m, 1H), 2.14 (s, 3H), 1.76-1.73 (m,1H). MS (ESI): 406.34 [M+H] + . Example 18B 1H NMR (400 MHz, DMSO-d6): δ =10.62 (brs, 1H), 7.66-7.64 (d, 1H), 7.15 (s, 1H), 7.08 (s, 1H), 6.49-6.44 (m, 2H), 4.36-4.35 (m, 1H), 3.46 (s, 3H), 2.75-2.74 (m, 1H), 2.66-2.58 (m, 1H), 2.38-2.35 (m, 2H), 2.30-2.29 (m, 4H), 2.13 (s, 3H), 1.60-1.63 (m, 1H). MS (ESI): 406.34 [M+H] + .

[0896] Example 19 Enantiopure 2-(1-methyl-5-((1-methylpyrrolidin-3-yl)amino)-1H-imidazo[4,5-b]pyridin-2-yl)-5-(trifluoromethyl)phenol

[0897] [ka]

[0898] The racemic product (prepared as described in Example 1 starting from Intermediate 7 and commercially available racemic 1-methylpyrrolidin-3-amine) was separated by chiral SFC (column: Chiralpak IE, 250 mm × 10 mm, 5 μm, 30°C, eluent B: MeOH 15% + 0.2% diethylamine, flow rate: 2 mL / min, cycle time: 18 min) to give the pure enantiomer Example 19 (eluting second). 1H NMR (400 MHz, DMSO-d6): δ = 12.40 (brs, 1H), 7.89-7.87 (d, 1H), 7.75-7.73 (d, 1H), 7.30-7.27 (m, 2H), 6.67-6.65 (d, 1H), 6.56-6.54 (d, 1H), 4.39-4.34 (m, 1H), 3.82 (s, 3H), 2.76-2.72 (m, 1H), 2.67-2.57 (m, 1H), 2.40-2.32 (m, 2H), 2.27-2.19 (m, 4H), 1.65-1.57 (m, 1H). MS (ESI): 392.41 [M+H] + .

[0899] Example 20 (trans) Enantiopure 2-(5-((2-hydroxycyclohexyl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-2-yl)-3-methyl-5-(trifluoromethyl)phenol

[0900] [ka]

[0901] The racemic product (prepared as described in Example 1 starting from Intermediate 6 and commercially available trans-racemic 2-aminocyclohexan-1-ol) was separated by chiral SFC (column: Chiralpak IC, 150 mm × 4.6 mm, 5 μm, 30 °C, eluent B: MeOH 20%, flow rate: 100 g / min, cycle time: 18 min, pressure: 100 bar) to give the pure enantiomer Example 20 (eluting first). 1H NMR (400 MHz, DMSO-d6): δ =10.50 (s, 1H), 7.68-7.66 (d, 1H), 7.10 (s, 1H), 7.10 (s, 1H), 6.54-6.52 (d, 1H), 6.19-6.14 (m, 1H), 5.09-4.94 (d, 1H), 3.64-3.60 (m, 1H), 3.47 (s, 3H), 3.36-3.34 (m, 1H), 2.14 (s, 3H), 2.07-2.05 (m, 1H), 1.91-1.89 (m, 1H), 1.67-1.63 (m, 2H), 1.32-1.12 (m, 4H). MS (ESI): 421.14 [M+H] + .

[0902] Example 21 (trans) Enantiopure 2-(5-((3-hydroxycyclohexyl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-2-yl)-3-methyl-5-(trifluoromethyl)phenol

[0903] [ka]

[0904] The racemic product (prepared as described in Example 1 starting from Intermediate 6 and commercially available trans-racemic 3-aminocyclohexan-1-ol) was obtained in 93% yield and separated by chiral SFC (column: Chiralpak IK, 250 mm × 30 mm, 5 μm, 30 °C, eluent B: MeOH 20% + 0.5% IPA, flow rate: 90 g / min, cycle time: 18 min, pressure: 100 bar) to give the pure enantiomer Example 21 (eluting first). 1H NMR (400 MHz, DMSO-d6): δ =10.37 (brs, 1H), 7.64-7.62 (d, 1H), 7.17 (s, 1H), 7.09 (s, 1H), 6.48-6.46 (d, 1H), 6.09-6.07 (d, 1H), 4.40 (s, 1H), 4.21-4.18 (m, 1H), 3.93-3.89 (m, 1H), 3.46 (s, 3H), 2.14 (s, 3H), 1.80-1.47 (m, 7H), 1.35-1.28 (m, 1H). MS (ESI): 421.67 [M+H] + .

[0905] Examples 22A and 22B (trans) Enantiopure 2-(5-((3-hydroxycyclohexyl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-2-yl)-5-(trifluoromethyl)phenol

[0906] [ka]

[0907] The racemic product (prepared as described in Example 1 starting from Intermediate 7 and commercially available trans-racemic 3-aminocyclohexan-1-ol) was obtained in 38% yield and separated by chiral SFC (column: Chiralpak IK, 250 mm × 4.6 mm, 5 μm, 30°C, eluent B: MeOH 25% + 0.5% IPA, flow rate: 3 mL / min, pressure: 1500 psi, cycle time: 26 min) to give two enantiomers, Example 22A (first eluting) and Example 22B (second eluting). Example 22A 1H NMR (400 MHz, DMSO-d6) δ 12.48 (s, 1H), 7.91 (d, 1H), 7.74 (d, 1H), 7.35 - 7.28 (m, 2H), 6.55 (d, 1H), 6.32 (d, 1H), 4.43 (d, 1H), 4.21 (td, 1H), 4.01 - 3.90 (m, 1H), 3.84 (s, 3H), 1.89 - 1.64 (m, 3H), 1.63 - 1.40 (m, 4H), 1.37 - 1.25 (m, 1H). MS (ESI): 407.38 [M+H] + . Example 22B 1 H NMR (400 MHz, DMSO-d6) δ 12.42 (s, 1H), 7.90 (d, 1H), 7.73 (d, 1H), 7.32 (s, 1H), 7.29 (dd, 1H), 6.55 (d, 1H), 6.31 (d, 1H), 4.52 - 4.34 (m, 1H), 4.21 (tt, 1H), 3.98 - 3.90 (m, 1H), 3.84 (s, 3H), 1.88 - 1.63 (m, 3H), 1.62 - 1.40 (m, 4H), 1.35 - 1.25 (m, 1H). MS (ESI): 407.38 [M+H] + .

[0908] Example 23 (2-(5-methoxy-1-methyl-1H-imidazo[4,5-b]pyridin-2-yl)-3-methyl-5-(trifluoromethyl)phenol

[0909] [ka]

[0910] Step A: To a stirred solution of 2-(5-chloro-1-methyl-1H-imidazo[4,5-b]pyridin-2-yl)-3-methyl-5-(trifluoromethyl)phenol (Intermediate 6) (0.200 g, 0.59 mmol) and methanol (0.038 g, 1.17 mmol) in THF (10 mL) was added sodium hydride, 60% dispersion in mineral oil (0.4 g, 3.51 mmol) at room temperature, and the reaction mixture was heated to 70 °C for 96 h. After the starting material was consumed, the reaction mixture was diluted with water (10 mL) and extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with brine solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product as a yellow solid. The crude compound was purified by preparative HPLC (Mobile phase A: 10 mM ammonium bicarbonate (aqueous), Mobile phase B: acetonitrile:MeOH (60:40), Column: Inertsil ODS, Flow rate: 19 ml / min, Method: (t / %B): 0 / 40, 1 / 40, 11 / 60, 15 / 20, 15.1 / 100, 17 / 100, 17.1 / 40, 19 / 40, Solubility: ACN + THF + water, Temperature: Ambient). Pure fractions were lyophilized to give (2-(5-methoxy-1-methyl-1H-imidazo[4,5-b]pyridin-2-yl)-3-methyl-5-(trifluoromethyl)phenol (78 mg, 39%) as an off-white solid. MS (ESI): 338.13 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ =10.65 (brs, 1H), 8.02-7.99 (d, 1H), 7.21 (s, 1H), 7.12 (s, 1H), 6.77-6.75 (d, 1H), 3.90 (s, 3H), 3.57 (s, 3H), 2.14 (s, 3H).

[0911] Following the procedure of Example 23, the following examples were prepared using haloaromatic intermediates and alcohols as shown in Table 3:

[0912] [Table 5A]

[0913] [Table 5B]

[0914] [Table 5C]

[0915] [Table 5D]

[0916] Example 36 Cis enantiopure 2-(5-(hydroxycyclopentyl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-2-yl)-3-methyl-5-(trifluoromethyl)phenol

[0917] [ka]

[0918] The racemic product (prepared as described in Example 1 starting from Intermediate 6 and commercially available cis racemic 2-aminocyclopentan-1-ol) was obtained in 50% yield and separated by chiral SFC (Column: Lux-Cellulose-5C, 150 mm × 4.6 mm, 3 μm, 30°C, Eluent B: MeOH 25% + 0.5% IPA, Flow rate: 3 mL / min, Pressure: 1500 psi, Run time: 14 min) to give the pure cis enantiomer Example 25 (eluting second). 1H NMR (400 MHz, DMSO-d6) δ 10.63 (s, 1H), 7.70 (d, 1H), 7.15 (s, 1H), 7.08 (d, 1H), 6.53 (d, 1H), 6.43 (dd, 1H), 5.57 (d, 1H), 3.93 - 3.77 (m, 2H), 3.48 (s, 3H), 2.19 - 2.05 (m, 4H), 1.89 (ddt, 1H), 1.77 - 1.60 (m, 2H), 1.59 - 1.44 (m, 2H). MS (ESI): 407.3 [M+H] + .

[0919] Examples 37A and 37B trans-2-(5-((3-hydroxycyclopentyl)oxy)-1-methyl-1H-imidazo[4,5-b]pyridin-2-yl)-5-(trifluoromethyl)phenol

[0920] [ka]

[0921] The racemic product (prepared as described in Example 1 starting from Intermediate 7 and commercially available trans racemic cyclopentane-1,3-diol) was obtained in 13% yield and separated by chiral SFC (Column: Chiralpak IG, 250 mm × 4.6 mm, 5 μm, 30 °C, Eluent B: MeOH 40% + 0.5% IPA, Flow rate: 3 mL / min, Pressure: 1500 psi, Run time: 18 min) to give the pure trans enantiomer. Example 37A (first eluting). 1H NMR (400 MHz, DMSO-d6) δ 11.58 (s, 1H), 8.01 (d, 1H), 7.79 (d, 1H), 7.31 (d, 2H), 6.72 (d, 1H), 5.51 (tt, 1H), 4.60 (d, 1H), 4.35 - 4.21 (m, 1H), 3.78 (s, 3H), 2.23 (dtd, 1H), 2.04 (dddd, 1H), 1.99 - 1.82 (m, 2H), 1.74 - 1.63 (m, 1H), 1.61 - 1.47 (m, 1H). MS (ESI): 394.22 [M+H] + . Example 37B (second eluting). 1 H NMR (400 MHz, DMSO-d6) δ 11.58 (s, 1H), 8.01 (d, 1H), 7.79 (d, 1H), 7.34 - 7.28 (m, 2H), 6.72 (d, 1H), 5.51 (tt, 1H), 4.60 (d, 1H), 4.34 - 4.25 (m, 1H), 3.78 (s, 3H), 2.23 (dtd, 1H), 2.04 (dddd, 1H), 1.99 - 1.83 (m, 2H), 1.74 - 1.62 (m, 1H), 1.60 - 1.48 (m, 1H). MS (ESI): 394.23 [M+H] + .

[0922] Example 38 5-chloro-3-methyl-2-(1-methyl-5-(2,2,2-trifluoroethoxy)-1H-imidazo[4,5-b]pyridin-2-yl)phenol

[0923] [ka]

[0924] Step A: To a stirred solution of 5-chloro-2-(5-chloro-1-methyl-1H-imidazo[4,5-b]pyridin-2-yl)-3-methylphenol (200 mg, 0.649 mmol) (Intermediate 13) and 2,2,2-trifluoroethan-1-ol (325 mg, 3.245 mmol) in toluene (10 mL) was added potassium tert-butoxide (218 mg, 1.947 mmol) at room temperature, and the mixture was purged with nitrogen gas for 5 minutes. BrettPhos-Pd G3 (59 mg, 0.065 mmol) was added to the above mixture, and the mixture was irradiated at 100 °C under microwave irradiation for 1 hour. The progress of the reaction was monitored by TLC. The reaction mixture was cooled to room temperature, filtered over a celite bed, and washed with EtOAc (50 mL). The resulting filtrate was concentrated under reduced pressure to give the crude product. The crude compound was purified by preparative HPLC. Conditions: Mobile phase A: 10 mM ammonium bicarbonate in water, Mobile phase B: acetonitrile, Column: UNISIL, Flow rate: 19 mL / min. Method: (% of T / % of B): 0 / 45, 3 / 50, 13 / 60, 15 / 60, 15.1 / 99, 20 / 99, 20.1 / 45, 24 / 45. Solubility: ACN + THF + water, Temperature: Ambient.

[0925] The pure fractions were collected and lyophilized to give pure 5-chloro-3-methyl-2-(1-methyl-5-(2,2,2-trifluoroethoxy)-1H-imidazo[4,5-b]pyridin-2-yl)phenol (38 mg, 156%) as an off-white solid. MS (ESI): 372.17 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.64 (s, 1H), 8.09 (d, 1H), 6.91 - 6.83 (m, 3H), 5.04 (q, 2H), 3.58 (s, 3H), 2.05 (s, 3H).

[0926] Example 39 5-chloro-2-(5-(3,3-difluorocyclobutoxy)-1-methyl-1H-imidazo[4,5-b]pyridin-2-yl)-3-methylphenol

[0927] [ka]

[0928] Step A: To a stirred solution of 5-chloro-2-(5-chloro-1-methyl-1H-imidazo[4,5-b]pyridin-2-yl)-3-methylphenol (800 mg, 2.596 mmol) (Intermediate 13) in THF (8 mL) was added dropwise N,N-diisopropylethylamine (1.8 mL, 10.384 mmol) and methoxymethyl chloride (0.59 mL, 7.79 mmol) under an argon atmosphere at 0° C. The reaction mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. TLC indicated that the starting material had been consumed. The reaction mixture was diluted with ice water (100 mL) and extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine solution (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product as a liquid. The crude product was purified by column chromatography using silica gel. The product was eluted with 40% EtOAc in hexanes. Pure fractions were collected and concentrated under reduced pressure to give pure 5-chloro-2-(4-chloro-2-(methoxymethoxy)-6-methylphenyl)-1-methyl-1H-imidazo[4,5-b]pyridine (501 mg, 55%). MS(ESI):352.14[M+H] + .

[0929] Step B: To a stirred solution of 5-chloro-2-(4-chloro-2-(methoxymethoxy)-6-methylphenyl)-1-methyl-1H-imidazo[4,5-b]pyridine (400 mg, 1.136 mmol) and 3,3-difluorocyclobutan-1-ol (613.76 mg, 5.678 mmol) in toluene (10 mL) was added potassium tert-butoxide (382.30 mg, 3.407 mmol) at room temperature. The mixture was purged with nitrogen gas for 5 minutes, then BrettPhos Pd G3 (103 mg, 0.114 mmol) was added, and the mixture was heated to 100 °C in a sealed condition for 16 hours. The progress of the reaction was monitored by TLC. TLC indicated the reaction was complete. The reaction mixture was cooled to room temperature, filtered over a bed of Celite, washed with EtOAc (250 mL), and concentrated under reduced pressure to give the crude product 2-(4-chloro-2-(methoxymethoxy)-6-methylphenyl)-5-(3,3-difluorocyclobutoxy)-1-methyl-1H-imidazo[4,5-b]pyridine (400 mg, 15%). MS(ESI):424.24[M+H] + .

[0930] Step C: To a stirred solution of 2-(4-chloro-2-(methoxymethoxy)-6-methylphenyl)-5-(3,3-difluorocyclobutoxy)-1-methyl-1H-imidazo[4,5-b]pyridine (400 mg, 0.944 mmol) in trifluoroethanol (12.5 mL) was added chlorotrimethylsilane (5.0 mL) at 0° C., and the reaction mixture was stirred at room temperature for 1 hour. The progress of the reaction was monitored by TLC. TLC showed that the reaction was complete. The reaction mixture was evaporated under reduced pressure, then diluted with ice / water (100 mL), and extracted with DCM (2×100 mL). The combined organic layers were washed with brine solution (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product as a solid. The crude compound was purified by preparative HPLC. Preparative HPLC conditions: Mobile phase A: ammonium bicarbonate, Mobile phase B: acetonitrile, Column: HYPERSIL BDS (20 mm x 250 mm) 5 μM, Flow rate: 19 mL / min. Method: (T / % B): -0 / 45, 2 / 45, 6 / 65, 10.50 / 65, 10.51 / 100, 16 / 100, 16.01 / 45, 20 / 45. Solubility: ACN + THF + water. Pure fractions were pooled and lyophilized to give pure 5-chloro-2-(5-(3,3-difluorocyclobutoxy)-1-methyl-1H-imidazo[4,5-b]pyridin-2-yl)-3-methylphenol (6.5 mg, 11%) as a yellow solid. MS (ESI): 378.19 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.99 (d, 1H), 6.80 - 6.69 (m, 3H), 5.18 (qd, 1H), 3.55 (s, 3H), 3.23 - 3.12 (m, 2H), 2.82 - 2.64 (m, 2H), 2.03 (s, 3H).

[0931] Example 40 (R)-2-(6-((1-methylpiperidin-3-yl)amino)-2H-pyrazolo[3,4-b]pyridin-2-yl)-5-(trifluoromethyl)phenol formate

[0932] [ka]

[0933] Step A: To a solution of 6-chloro-2H-pyrazolo[3,4-b]pyridine (600 mg, 3.91 mmol, 1.0 equiv.) in NMP (6 mL), (3R)-1-methylpiperidin-3-amine (1.34 g, 11.72 mmol, 3.0 equiv.) and DIEA (1.51 g, 11.72 mmol, 2.04 mL, 3.0 equiv.) were added, and the resulting reaction mixture was stirred at 180 °C for 16 h under microwave irradiation. LC-MS indicated the reaction was complete. The residue was purified by preparative HPLC (column: Waters Xbridge BEH C18, 100 × 30 mm, 10 μm; mobile phase: [water (NH4HCO3)-can]; B%: 10% to 40%, 8 min) to give the title product. (R)-N-(1-methylpiperidin-3-yl)-2H-pyrazolo[3,4-b]pyridin-6-amine (400 mg, 1.73 mmol, 44% yield) was obtained as a yellow solid. MS (ESI): 232.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ = 12.71 (br s, 1H), 7.-0 - 7.62 (m, 2H), 6.80 (br d, 1H), 6.37 (d, 1H), 4.-4 - 3.93 (m, 1H), 2.85 (br d, 1H), 2.-8 - 2.52 (m, 1H), 2.15 (s, 3H), 1.95 (br t, 1H), 1.-4 - 1.65 (m, 3H), 1.-2 - 1.42 (m, 1H), 1.33 - 1.15 (m, 1H).

[0934] Step B: To a solution of [2-methoxy-4-(trifluoromethyl)phenyl]boronic acid (172 mg, 778.22 μmol, 1.2 equiv.) in a mixture of pyridine (0.1 mL) and THF (0.4 mL), N-[(3R)-1-methyl-3-piperidyl]-2H-pyrazolo[3,4-b]pyridin-6-amine (150 mg, 648.52 μmol, 1 equiv.), Cu(OAc) (235.58 mg, 1.30 mmol, 2 equiv.), and 4Å molecular sieves (140 mg) were added sequentially, and the mixture was then degassed with N three times. The resulting reaction mixture was heated to 80°C and stirred at 80°C under N for 6 hours. LCMS indicated the reaction was complete. The reaction solution was filtered to remove the 4Å molecular sieves and then concentrated to give the crude product. The residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 100 mm × 30 mm, 10 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 35% to 55%, 8 min) to give the title product: 2-[2-methoxy-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methyl-3-piperidyl]pyrazolo[3,4-b]pyridin-6-amine (42 mg, 104 μmol, 16% yield) as a pale yellow solid. MS(ESI):406.3[M+H] + .

[0935] Step C: A solution of 2-[2-methoxy-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methyl-3-piperidyl]pyrazolo[3,4-b]pyridin-6-amine (40 mg, 98.66 μmol, 1.0 equiv.) in DCM (4 mL) was cooled to 0 °C, and then BBr3 (74.15 mg, 295.99 μmol, 28.52 μL, 3 equiv.) was added dropwise at 0 °C. After the addition was complete, the reaction mixture was stirred at 20 °C for 0.5 h. LCMS showed the reaction was complete. The reaction solution was concentrated to give the crude product. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 100 mm × 30 mm, 5 μm; mobile phase: [water (FA)-ACN]; B%: 1% to 35%, 8 min) to give the title product. 2-[6-[[(3R)-1-Methyl-3-piperidyl]amino]pyrazolo[3,4-b]pyridin-2-yl]-5-(trifluoromethyl)phenol (10 mg, 25 μmol, 25% yield, 98% purity) was obtained as a white solid. LC-MS (ESI): 392.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ = 11.92 (br s, 1H), 8.84 (s, 1H), 8.18 (s, 1H), 8.09 (d, 1H), 7.77 (d, 1H), 7.36 (s, 1H), 7.32 (br d, 1H), 7.14 (d, 1H), 6.54 (d, 1H), 4.21 - 4.00 (m, 1H), 2.90 (br d, 1H), 2.65 - 2.56 (m, 1H), 2.21 (s, 3H), 2.04 (br s, 1H), 1.92 (br s, 1H), 1.84 (brdd, 12.1Hz, 1H), 1.73 (br dd, 1H), 1.56 (br dd, 1H), 1.30 (br d, 1H).

[0936] Following the procedure of Example 40, the following examples were prepared using the corresponding commercially available amines as shown in Table 4:

[0937] [Table 6]

[0938] Example 42 2-(6-Methoxypyrazolo[3,4-b]pyridin-2-yl)-5-(trifluoromethyl)cyclohexa-2,4-dien-1-ol

[0939] [ka]

[0940] Step A: To a solution of 30% NaOMe in MeOH (19.54 mL, 6.51 mmol, 1 equiv.) was added 6-chloro-2H-pyrazolo[3,4-b]pyridine (1 g, 6.51 mmol, 1 equiv.), and the resulting reaction mixture was stirred at 80° C. for 24 h. LC-MS showed the reaction was complete. The reaction mixture was poured onto HO (30 mL) followed by EtOAc (30 mL). The aqueous phase was then separated and extracted with EtOAc (2×30 mL). The combined organic layers were washed successively with water (2×20 mL) and brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 10 / 1) to give the desired product 6-methoxy-2H-pyrazolo[3,4-b]pyridine (0.7 g, 4.69 mmol, 72%) as a yellow solid. MS (ESI): 150.0 [M+H] + .

[0941] Step B: Following Example 43, Step B, 2-(6-methoxypyrazolo[3,4-b]pyridin-2-yl)-5-(trifluoromethyl)-cyclohexa-2,4-dien-1-ol (5.5 mg, 17.67 μmol, 14%) was obtained as a white solid. MS (ESI): 309.8 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ = 11.61 (br s, 1H), 9.04 (s, 1H), 8.15 (d, J = 8.9 Hz, 1H), 8.10 (d, J = 8.4 Hz, 1H), 7.38 (s, 1H), 7.33 (br d, J = 8.5 Hz, 1H), 6.69 (d, J = 8.9 Hz, 1H), 3.95 (s, 3H)

[0942] Example 43 (R)-5-chloro-2-(6-((1-methylpiperidin-3-yl)amino)-2H-pyrazolo[3,4-b]pyridin-2-yl)phenol

[0943] [ka]

[0944] Step A: To a solution of 6-chloro-2H-pyrazolo[3,4-b]pyridine (8 g, 52.09 mmol, 1.0 equiv) in dioxane (20 mL) was added NaSMe (365 g, 1.04 mol, 332 mL, 20 equiv), and the resulting reaction mixture was stirred at 130 °C for 24 h. LC-MS showed that 34% of the starting material remained and 64% of the desired product was obtained. The reaction mixture was poured onto HO (500 mL) followed by EtOAc (120 mL). The aqueous phase was then separated and extracted with EtOAc (2 × 120 mL). The combined organic layers were washed successively with water (2 × 200 mL) and brine (120 mL), dried over anhydrous NaSO, filtered, and concentrated to give a residue. The residue was purified by preparative HPLC (column: Agela DuraShell C18, 250 mm × 70 mm, 10 μm; mobile phase: [HO (10 mM NH4HCO3)-ACN]; gradient: 12% to 42% B over 17 min) to give the title product: 6-methylsulfanyl-2H-pyrazolo[3,4-b]pyridine (3 g, 18.16 mmol, 35%) as a white solid. MS (ESI): 166.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ = 13.53 (br s, 1H), 8.02 (t, 2H), 7.05 (d, 1H), 2.58 (s, 3H).

[0945] Step B: To a solution of 6-methylsulfanyl-2H-pyrazolo[3,4-b]pyridine (700 mg, 4.24 mmol, 1.0 equiv.) in pyridine (8 mL), (4-chloro-2-methoxy-phenyl)boronic acid (1.03 g, 5.51 mmol, 1.3 equiv.), Cu(OAc) (769.55 mg, 4.24 mmol, 1.0 equiv.), and 4A MS (700 mg, 4.24 mmol, 1.0 equiv.) were added, and the resulting reaction mixture was stirred at 100 °C under an O atmosphere for 72 h. LC-MS indicated the reaction was complete. The reaction mixture was poured onto HO (20 mL) followed by EtOAc (10 mL). The aqueous phase was then separated and extracted with EtOAc (2 × 10 mL). The combined organic layers were washed successively with water (2 × 20 mL) and brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1). 2-(4-chloro-2-methoxy-phenyl)-6-methylsulfanyl-pyrazolo[3,4-b]pyridine (150 mg, 491 μmol, 12%) was obtained as a yellow oil. MS (ESI): 306.0 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ = 8.75 (s, 1H), 8.25 (s, 1H), 8.10 (d, 1H), 8.04 (d, 1H), 7.84 (d, 1H), 7.48 (d, 1H), 7.44 (d, 1H), 7.39 (d, 1H), 7.23 - 7.23 (m, 1H), 7.23 (dd, 1H), 7.21 - 7.14 (m, 2H), 7.01 (d, 1H), 3.94 (s, 2H), 3.77 (s, 3H), 2.59 (s, 2H), 2.45 (s, 3H).

[0946] Step C: To a solution of 2-(4-chloro-2-methoxy-phenyl)-6-methylsulfanyl-pyrazolo[3,4-b]pyridine (350 mg, 1.14 mmol, 1 equiv.) in DCM (8 mL) was added m-CPBA (465 mg, 2.29 mmol, 85% purity, 2 equiv.) at 0 °C, and the resulting reaction mixture was stirred at 20 °C for 2 h. LC-MS showed the reaction was complete. The reaction mixture was poured into HO (20 mL) followed by DCM (10 mL). The aqueous phase was then separated and extracted with DCM (2 × 10 mL). The combined organic layers were washed successively with water (2 × 20 mL) and brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated to give a residue. The residue was purified by preparative TLC (SiO, petroleum ether / ethyl acetate = 1:1). 2-(4-Chloro-2-methoxy-phenyl)-6-methylsulfonyl-pyrazolo[3,4-b]pyridine (90 mg, 266 μmol, 23%) was obtained as a yellow solid. MS (ESI): 338.0 [M+H] + .

[0947] Step D: To a solution of 2-(4-chloro-2-methoxy-phenyl)-6-methylsulfonyl-pyrazolo[3,4-b]pyridine (10 mg, 29.60 μmol, 1 equiv.) in DMF (1 mL) was added (3R)-1-methylpiperidin-3-amine (17 mg, 148 μmol, 5 equiv.), Pd(dba) (27 mg, 30 μmol, 1 equiv.), CsCO (19 mg, 59 μmol, 2 equiv.), and XPhos (28 mg, 59 μmol, 2 equiv.), and the resulting reaction mixture was stirred at 120 °C for 12 h. LC-MS indicated the reaction was complete. The reaction mixture was poured onto HO (15 mL) followed by EtOAc (10 mL). The aqueous phase was then separated and extracted with EtOAc (2 × 10 mL). The combined organic layers were washed successively with water (2 × 15 mL) and brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated to give a residue. The residue was purified by preparative TLC (SiO, DCM:MeOH = 5:1). 2-(4-chloro-2-methoxy-phenyl)-N-[(3R)-1-methyl-3-piperidyl]pyrazolo[3,4-b]pyridin-6-amine (15 mg, 40.34 μmol, 23%) was obtained as a yellow oil. MS(ESI):372.2[M+H] + .

[0948] Step E: Following Example 46, Step F, (R)-5-chloro-2-(6-((1-methylpiperidin-3-yl)amino)-2H-pyrazolo[3,4-b]pyridin-2-yl)phenol (3 mg, 9 μmol, 23%) was obtained as a white solid. MS (ESI): 358.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ = 12.22 - 11.49 (m, 1H), 8.70 (s, 1H), 7.85 (d, 1H), 7.75 (d, 1H), 7.11 (d, 1H), 7.07 (d, 1H), 7.03 (dd, 1H), 6.52 (d, 1H), 4.17 - 4.03 (m, 1H), 2.90 (br d, 1H), 2.60 (br d, J = 10.3 Hz, 1H), 2.21 (s, 3H), 2.04 (br s, 1H), 1.97 - 1.79 (m, 2H), 1.78 - 1.66 (m, 1H), 1.56 (br dd, 1H), 1.29 (br d, 1H).

[0949] Example 44 2-[6-(difluoromethoxy)pyrazolo[3,4-b]pyridin-2-yl]-5-(trifluoromethyl)phenol

[0950] [ka]

[0951] Step A: To a solution of 2,7-dihydropyrazolo[3,4-b]pyridin-6-one (330 mg, 2.44 mmol, 1 equiv.) and sodium 2-chloro-2,2-difluoroacetate (559 mg, 3.66 mmol, 1.5 equiv.) in DMF (5 mL) was added K2CO3 (169 mg, 1.22 mmol, 0.5 equiv.). The mixture was stirred at 90 °C for 3 h. LC-MS showed the reaction was complete. After completion, the precipitate was collected by filtration to give the crude product. The residue was purified by preparative HPLC (column: Waters Xbridge C18, 150 mm × 50 mm, 10 μm; mobile phase: [HO (10 mM NH4HCO3)-ACN]; gradient: 1 to 55% B over 8 min) to give the compound 6-(difluoromethoxy)-2H-pyrazolo[3,4-b]pyridine (140 mg, 756 μmol, 31%) as a white solid. MS (ESI): 184.7 [MH] - . 1 H NMR (400 MHz, DMSO-d6) δ = 13.77 - 13.65 (m, 1H), 8.33 (d, 1H), 8.16 - 8.10 (m, 1H), 7.94 -7.58 (m, 1H), 6.86 (d, 1H)

[0952] Step B: Following Example 43, Step B, [2-benzyloxy-4-(trifluoromethyl)phenyl]boronic acid was used to give 2-[2-benzyloxy-4-(trifluoromethyl)phenyl]-6-(difluoromethoxy)pyrazolo[3,4-b]pyridine (45 mg, 104 μmol, 14%) as a white solid. MS (ESI): 436.1 [M+H] + .

[0953] Step C: To a mixture of 2-[2-benzyloxy-4-(trifluoromethyl)phenyl]-6-(difluoromethoxy)pyrazolo[3,4-b]pyridine (30 mg, 68.9 μmol, 1 equiv.) in MeOH (5 mL) was added Pd / C (73 mg, 69 μmol, 10% purity, 1 equiv.) and the mixture was stirred under a H atmosphere at 25° C. for 1 h. LCMS showed the reaction was complete. After completion, the reaction mixture was filtered and the filtrate was collected to give the crude product. The crude product was purified by preparative HPLC (Waters Xbridge BEH C18 100 × 30 mm, 10 μm; mobile phase: [HO (10 mM NH4HCO3)-ACN]; gradient: 40 to 70% B over 8 min) to give the title compound 2-[6-(difluoromethoxy)pyrazolo[3,4-b]pyridin-2-yl]-5-(trifluoromethyl)phenol (4.5 mg, 13 μmol, 19%) as a white solid. MS (ESI): 346.0 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ = 11.66 (br s, 1H), 9.18 (s, 1H), 8.41 (d, 1H), 8.09 (d, 1H), 8.10 -7.70 (m, 1H), 7.39 (s, 1H), 7.33 (br d, 1H), 6.88 (d, 1H)

[0954] Example 45 2-[6-(trifluoromethoxy)pyrazolo[3,4-b]pyridin-2-yl]-5-(trifluoromethyl)phenol

[0955] [ka]

[0956] Step A: Following Example 47, Step B, 2-[2-methoxy-4-(trifluoromethyl)phenyl]pyrazolo[3,4-b]pyridine (450 mg, 1.53 mmol, 4%) was obtained as a white solid. MS (ESI): 294.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ = 8.97 (s, 1H), 8.70 (dd, 1H), 8.30 (dd, J = 1.6, 8.4 Hz, 1H), 8.10 (d, 1H), 7.66 (s, 1H), 7.56 (d, 1H), 7.17 (dd, 1H), 4.02 (s, 3H).

[0957] Step B: To a solution of 2-[2-methoxy-4-(trifluoromethyl)phenyl]pyrazolo[3,4-b]pyridine (450 mg, 1.53 mmol, 1 equiv) in EtOAc (20 mL) was added m-CPBA (779 mg, 3.84 mmol, 85% purity, 2.5 equiv) at 0 °C. The mixture was stirred at 50 °C for 6 h. LC-MS showed the reaction was complete. The reaction mixture was diluted with HO (30 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (2 × 20 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, DCM:MeOH=10:1) to give 2-[2-methoxy-4-(trifluoromethyl)phenyl]-7-oxide-pyrazolo[3,4-b]pyridin-7-ium (200 mg, 647 μmol, 42%) as a pale yellow solid. MS(ESI):310.2[M+H] + .

[0958] Step C: To a solution of 2-[2-methoxy-4-(trifluoromethyl)phenyl]-7-oxide-pyrazolo[3,4-b]pyridin-7-ium (150 mg, 485 μmol, 1 equiv.) in DME (15 mL) was added trifluoromethyl trifluoromethanesulfonate (212 mg, 970 μmol, 2 equiv.), and the mixture was stirred at 20° C. for 2 hours. The mixture was stirred at 60° C. for 10 hours. LC-MS showed the reaction was complete. The reaction mixture was concentrated in vacuo. The residue was purified by preparative TLC (SiO, DCM:MeOH=20:1) to give the product. 2-[2-methoxy-4-(trifluoromethyl)phenyl]-6-(trifluoromethoxy)pyrazolo[3,4-b]pyridine (20 mg, 53.02 μmol, 11%) was obtained as a pale yellow solid. MS (ESI): 378.1 [M+H] + .

[0959] Step D: Following Example 46, Step F, 2-[6-(trifluoromethoxy)pyrazolo[3,4-b]pyridin-2-yl]-5-(trifluoromethyl)phenol (6 mg, 16 μmol, 30%) was obtained as a white solid. MS (ESI): 363.9 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ = 11.57 (br s, 1H), 9.17 (s, 1H), 8.53 (d, 1H), 8.11 (d, 1H), 7.43 (s, 1H), 7.39 (br d, 1H), 7.02 (d, 1H).

[0960] Example 46 (R)-2-(6-fluoro-1-methyl-5-((1-methylpyrrolidin-3-yl)amino)-1H-imidazo[4,5-b]pyridin-2-yl)-3-methyl-5-(trifluoromethyl)phenol

[0961] [ka]

[0962] Step A: To a solution of 3-bromo-5-fluoro-pyridin-2-amine (3 g, 15.71 mmol, 1.0 equiv.) in 40% aqueous MeNH (9.32 g, 120.00 mmol, 20 mL, 40% purity, 7.64 equiv.), copper sulfate pentahydrate (250.69 mg, 1.57 mmol, 241.05 μL, 0.1 equiv.) was added, and the reaction mixture was stirred at 100 °C for 12 h. The reaction mixture was filtered through Celite. The Celite pad was rinsed with DCE:MeOH 9:1 (3 × 50 mL) and concentrated in vacuo to give the crude product. The crude product was purified by column chromatography (SiO, petroleum ether / ethyl acetate 100 / 1 to 0 / 1). The crude product was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1) to give 5-fluoro-N3-methyl-pyridine-2,3-diamine (2 g, 14.17 mmol, 90.21% yield) as a dark brown solid. LC-MS(ES + , m / z): 142.7 [(M + H) + ].

[0963] Step B: To a solution of 5-fluoro-N3-methyl-pyridine-2,3-diamine (1.5 g, 10.63 mmol, 1.0 equiv.) in DMA (15 mL) was added NaHSO (1.33 g, 12.75 mmol, 896.66 μL, 1.2 equiv.) and 2-methoxy-6-methyl-4-(trifluoromethyl)benzaldehyde (2.32 g, 10.63 mmol, 1 equiv.). The resulting reaction mixture was stirred at 100 °C for 12 h. LCMS showed the reaction was complete. The reaction mixture was poured into HO (50 mL) followed by DCM (20 mL). The aqueous phase was then separated and extracted with DCM (20 mL × 3). The combined organic layers were washed successively with water (20 mL × 2) and brine (20 mL × 1), dried over anhydrous NaSO, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 100 / 1 to 1 / 1) to give 6-fluoro-2-[2-methoxy-6-methyl-4-(trifluoromethyl)phenyl]-1-methyl-imidazo[4,5-b]pyridine (2.6 g, 7.66 mmol, 72.11% yield, no purity data) as a yellow solid. LC-MS(ES + , m / z): 340.4 [(M+H) + ]. 1 H NMR (400 MHz, DMSO-d6) δ = 8.45 (s, 1H), 8.16 (dd, J = 2.8, 8.9 Hz, 1H), 7.43 (s, 1H), 7.36 (s, 1H), 3.84 (s, 3H), 3.56 (s, 3H), 2.17 (s, 3H)

[0964] Step C: To a solution of 6-fluoro-2-[2-methoxy-6-methyl-4-(trifluoromethyl)phenyl]-1-methyl-imidazo[4,5-b]pyridine (2.6 g, 7.66 mmol, 1.0 equiv.) in DCM (30 mL) was added m-CPBA (3.11 g, 15.33 mmol, 85% purity, 2.0 equiv.) at 0 °C. The resulting reaction mixture was stirred at 20 °C for 12 h. LCMS showed the reaction was complete. The reaction mixture was poured into HO (50 mL) followed by DCM (20 mL). The aqueous phase was then separated and extracted with DCM (20 mL × 3). The combined organic layers were washed successively with water (20 mL × 2) and brine (20 mL × 1), dried over anhydrous NaSO, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO, DCM / MeOH = 100 / 1 to 15 / 1) to give 6-fluoro-2-[2-methoxy-6-methyl-4-(trifluoromethyl)phenyl]-1-methyl-4-oxide-imidazo[4,5-b]pyridin-4-ium (2.4 g, 6.08 mmol, 79.34% yield, 90% purity) as a yellow solid. LC-MS(ES + , m / z): 356.2 [(M+H) + ]. 1 H NMR (400 MHz, DMSO-d6) δ = 8.54 (dd, J = 1.8, 5.8 Hz, 1H), 7.97 - 7.82 (m, 1H), 7.44 (s, 1H), 7.37 (s, 1H), 3.85 (s, 3H), 3.56 (s, 3H), 2.18 (s, 3H)

[0965] Step D: To a solution of 6-fluoro-2-[2-methoxy-6-methyl-4-(trifluoromethyl)phenyl]-1-methyl-4-oxide-imidazo[4,5-b]pyridin-4-ium (2.4 g, 6.08 mmol, 1.0 equiv.) in toluene (25 mL) was added POCl (2.80 g, 18.24 mmol, 1.70 mL, 3.0 equiv.). The resulting reaction mixture was stirred at 110 °C for 1 h. LCMS showed the reaction was complete. The reaction mixture was poured onto HO (50 mL) followed by DCM (20 mL). The aqueous phase was then separated and extracted with DCM (20 mL × 3). The combined organic layers were washed successively with water (20 mL × 2) and brine (20 mL × 1), dried over anhydrous NaSO, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 100 / 1 to 4 / 1) to give 5-chloro-6-fluoro-2-[2-methoxy-6-methyl-4-(trifluoromethyl)phenyl]-1-methyl-imidazo[4,5-b]pyridine (1.8 g, 1.20 mmol, 19.81% yield, 25% purity) as a white solid. LC-MS(ES + , m / z): 374.4 [(M+H) + ]. 1 H NMR (400 MHz, DMSO-d6) δ = 8.59 (d, J = 2.0 Hz, 1H), 7.44 (s, 1H), 7.37 (s, 1H), 3.85 (s, 3H), 3.77 (s, 3H), 2.18 (s, 3H)

[0966] Step E: To a solution of 5-chloro-6-fluoro-2-[2-methoxy-6-methyl-4-(trifluoromethyl)phenyl]-1-methyl-imidazo[4,5-b]pyridine (100.00 mg, 66.89 μmol, 25% purity, 1.0 equiv.) in THF (2 mL), (3R)-1-methylpyrrolidin-3-amine (40.20 mg, 401.36 μmol, 2.0 equiv.), BINAP (24.99 mg, 40.14 μmol, 0.2 equiv.), t-BuONa (57.86 mg, 602.04 μmol, 3.0 equiv.), and Pd(OAc) (9.01 mg, 40.14 μmol, 0.2 equiv.) were added. The resulting reaction mixture was stirred at 100 °C for 12 hours. LCMS showed the reaction was complete. The reaction mixture was poured onto saturated NH4Cl (20 mL) followed by DCM (10 mL) at 0°C. The aqueous phase was then separated and extracted with DCM (20 mL x 2). The combined organic layers were washed successively with water (20 mL x 2) and brine (20 mL x 1), dried over anhydrous Na2SO4, filtered, and concentrated to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 100 mm × 30 mm × 5 μm; mobile phase: [HO (0.2% FA)-ACN]; gradient: 10% to 40% B over 8.0 min) to afford the title product, 6-fluoro-2-[2-methoxy-6-methyl-4-(trifluoromethyl)phenyl]-1-methyl-N-[(3R)-1-methylpyrrolidin-3-yl]imidazo[4,5-b]pyridin-5-amine (two batches total, 40 mg, 91.44 μmol, 68.4% yield, purity data not available) as a white solid. LC-MS(ES + , m / z): 438.2 [(M+H) + ]. 1H NMR (400 MHz, DMSO-d6) δ = 7.86 (d, J = 11.0 Hz, 1H), 7.39 (s, 1H), 7.31 (s, 1H), 6.30 (br s, 1H), 4.45 (br s, 1H), 3.81 (s, 3H), 3.44 (s, 3H), 2.90 (br t, J = 6.6 Hz, 1H), 2.68 (br s, 1H), 2.56 (br s, 2H), 2.35 - 2.29 (m, 3H), 2.24 (br d, J = 5.3 Hz, 1H), 2.15 (s, 3H), 1.88 - 1.75 (m, 1H)

[0967] Step F: To a solution of 6-fluoro-2-[2-methoxy-6-methyl-4-(trifluoromethyl)phenyl]-1-methyl-N-[(3R)-1-methylpyrrolidin-3-yl]imidazo[4,5-b]pyridin-5-amine (40 mg, 91.44 μmol, 1.0 equiv.) in DCM (1 mL) was added BBr3 (114.54 mg, 457.21 μmol, 44.05 μL, 5.0 equiv.) at 0° C. The resulting reaction mixture was stirred at 20° C. for 0.5 hours. LCMS showed the reaction was complete. After completion, the solvent was removed by concentration to give a residue. The residue was purified by preparative HPLC (Column: Waters Xbridge BEH C18 100 mm × 30 mm × 10 μm; Mobile phase: [HO (10 mM NH4HCO3)-ACN]; Gradient: 20% to 50% B over 8.0 min) to give the title product: 2-[6-fluoro-1-methyl-5-[[(3R)-1-methylpyrrolidin-3-yl]amino]imidazo[4,5-b]pyridin-2-yl]-3-methyl-5-(trifluoromethyl)phenol (17.0 mg, 39.70 μmol, 43.42% yield, 98.88% purity) as a white solid. LC-MS(ES + , m / z): 424.2 [(M+H) + ]. 1H NMR (400 MHz, DMSO-d6) δ = 10.76 - 10.43 (m, 1H), 7.84 (d, J = 11.0 Hz, 1H), 7.18 (s, 1H), 7.10 (s, 1H), 6.22 (br d, J = 6.5 Hz, 1H), 4.50 - 4.38 (m, 1H), 3.48 (s, 3H), 2.84 - 2.79 (m, 1H), 2.62 - 2.54 (m, 1H), 2.45 - 2.38 (m, 2H), 2.26 (d, J = 3.9 Hz, 3H), 2.24 - 2.18 (m, 1H), 2.14 (s, 3H), 1.83 - 1.71 (m, 1H)

[0968] Example 47 (R)-5-chloro-2-(6-fluoro-1-methyl-5-((1-methylpyrrolidin-3-yl)amino)-1H-imidazo[4,5-b]pyridin-2-yl)-3-methylphenol formate

[0969] [ka]

[0970] Step A: To 3-bromo-5-fluoro-pyridin-2-amine (3 g, 15.71 mmol, 1.0 equiv.) in MeNH (3.00 g, 28.98 mmol, 30% purity, 1.85 equiv.) in HO was added CuSO.5HO (392.17 mg, 1.57 mmol, 0.1 equiv.), and the resulting reaction mixture was stirred at 100 °C for 12 h. LCMS showed the reaction was complete. The reaction mixture was poured onto HO (100 mL) followed by EA (60 mL). The aqueous phase was then separated and extracted with EA (60 mL × 2). The combined organic layers were washed successively with water (50 mL × 2) and brine (50 mL × 1), dried over anhydrous NaSO, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1). 5-Fluoro-N3-methyl-pyridine-2,3-diamine (2.9 g, 20.55 mmol, 65.41% yield, purity data not available) was obtained as a grey solid. LC-MS(ES + , m / z): 142.1 [(M+H) + ]. 1 H NMR (400 MHz, DMSO-d6) δ = 7.15 (d, J = 2.6 Hz, 1H), 6.42 (dd, J = 2.5, 11.0 Hz, 1H), 5.33 (s, 2H), 5.26 (br d, J = 3.1 Hz, 1H), 2.69 (d, J = 4.9Hz, 3H)

[0971] Step B: To a solution of 5-fluoro-N3-methyl-pyridine-2,3-diamine (600 mg, 4.25 mmol, 1.0 equiv) in DMA (6 mL) were added 4-chloro-2-methoxy-6-methyl-benzaldehyde (784.80 mg, 4.25 mmol, 1.0 equiv) and NaHSO3 (884.71 mg, 8.50 mmol, 597.78 μL, 2.0 equiv), and the resulting reaction mixture was stirred at 100 °C for 12 h. LCMS showed the reaction was complete. The reaction mixture was poured onto HO (20 mL) followed by EA (10 mL). The aqueous phase was then separated and extracted with EA (10 mL × 2). The combined organic layers were washed successively with water (20 mL × 2) and brine (20 mL × 1), dried over anhydrous Na2SO4, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1) to give 2-(4-chloro-2-methoxy-6-methyl-phenyl)-6-fluoro-1-methyl-imidazo[4,5-b]pyridine (1 g, 3.27 mmol, 76.94% yield, no purity data) as a white solid. LC-MS(ES + , m / z): 306.1 [(M+H) + ]. 1 H NMR (400 MHz, DMSO-d6) δ = 8.43 - 8.43 (m, 1H), 8.43 (dd, J = 2.0, 2.6 Hz, 1H), 7.16 (dd, J = 1.4, 12.2 Hz, 2H), 3.77 (s, 3H), 3.54 (s, 3H), 2.08 (s, 3H)

[0972] Step C: To a solution of DCM (9 mL), 2-(4-chloro-2-methoxy-6-methyl-phenyl)-6-fluoro-1-methyl-imidazo[4,5-b]pyridine (1 g, 3.27 mmol, 1.0 equiv.) was added, followed by m-CPBA (1.33 g, 6.54 mmol, 85% purity, 2.0 equiv.) at 0 °C. The resulting reaction mixture was stirred at 25 °C for 24 h. LCMS showed the reaction was complete. The reaction mixture was poured into HO (20 mL) followed by DCM (10 mL). The aqueous phase was then separated and extracted with DCM (10 mL × 2). The combined organic layers were washed successively with water (20 mL × 2) and brine (20 mL × 1), dried over anhydrous NaSO, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO, DCM / MeOH = 100 / 1 to 1 / 1). 2-(4-Chloro-2-methoxy-6-methyl-phenyl)-6-fluoro-1-methyl-4-oxide-imidazo[4,5-b]pyridin-4-ium (950 mg, 2.95 mmol, 90.28% yield, purity data not available) was obtained as a white solid. LC-MS(ES + , m / z): 322.0 [(M+H) + ]. 1 H NMR (400 MHz, DMSO-d6) δ = 8.52 (dd, J = 2.1, 5.9 Hz, 1H), 7.87 (dd, J = 2.1, 7.8 Hz, 1H), 7.21 - 7.12 (m, 2H), 3.78 (s, 3H), 3.54 (s, 3H), 2.09 (s, 3H)

[0973] Step D: To a solution of 2-(4-chloro-2-methoxy-6-methyl-phenyl)-6-fluoro-1-methyl-4-oxide-imidazo[4,5-b]pyridin-4-ium (950 mg, 2.95 mmol, 1.0 equiv.) in toluene (10 mL) was added POCl (905.50 mg, 5.91 mmol, 550.46 μL, 2.0 equiv.), and the resulting reaction mixture was stirred at 110 °C for 1 h. LCMS showed the reaction was complete. The reaction mixture was poured onto HO (20 mL) followed by EA (10 mL). The aqueous phase was then separated and extracted with EA (10 mL × 2). The combined organic layers were washed successively with water (20 mL × 2) and brine (20 mL × 1), dried over anhydrous NaSO, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1) to give 5-chloro-2-(4-chloro-2-methoxy-6-methyl-phenyl)-6-fluoro-1-methyl-imidazo[4,5-b]pyridine (760 mg, 558.53 μmol, yield 18.92%, purity 25%) as a white solid. LC-MS(ES + , m / z): 340.1 [(M+H) + ]. 1 H NMR (400 MHz, chloroform-d) δ = 7.53 (d, J = 7.6 Hz, 1H), 7.00 (s, 1H), 6.87 (d, J = 1.4 Hz, 1H), 3.84 (s, 3H), 3.79–3.74 (m, 3H), 2.18–2.17 (m, 3H).

[0974] Step E: To a solution of 5-chloro-2-(4-chloro-2-methoxy-6-methyl-phenyl)-6-fluoro-1-methyl-imidazo[4,5-b]pyridine (200 mg, 146.98 μmol, 1.0 equiv.) in THF (2 mL), (3R)-1-methylpyrrolidin-3-amine (29.44 mg, 293.96 μmol, 2.0 equiv.), BINAP (18.30 mg, 29.40 μmol, 0.2 equiv.), t-BuONa (28.25 mg, 293.96 μmol, 2 equiv.), and Pd(OAc) (3.30 mg, 14.70 μmol, 0.1 equiv.) were added, and the resulting reaction mixture was stirred at 100 °C for 24 h. LCMS indicated the reaction was complete. The reaction mixture was poured onto HO (20 mL) followed by EA (10 mL). The aqueous phase was then separated and extracted with EA (10 mL × 2). The combined organic layers were washed successively with water (20 mL × 2) and brine (20 mL × 1), dried over anhydrous Na2SO4, filtered, and concentrated to give a residue. The residue was purified by preparative TLC (SiO2, DCM:MeOH = 10:1). The residue was purified by preparative HPLC (column: Phenomenex Luna C18 100 mm × 30 mm × 5 μm; mobile phase: [HO (0.2% FA)-ACN]; gradient: 1% to 35% B over 8.0 min) to give the title product. 2-(4-Chloro-2-methoxy-6-methyl-phenyl)-6-fluoro-1-methyl-N-[(3R)-1-methylpyrrolidin-3-yl]imidazo[4,5-b]pyridin-5-amine (10 mg, 24.76 μmol, 16.85% yield, purity data not available) was obtained as a yellow gum. LC-MS(ES + , m / z): 404.2 [(M+H) + ]. 1H NMR (400 MHz, DMSO-d6) δ = 7.82 (d, J = 11.0 Hz, 1H), 7.11 (d, J = 6.8 Hz, 2H), 6.24 (br d, J = 4.4 Hz, 1H), 4.51 - 4.37 (m, 1H), 3.75 (s, 3H), 3.42 (s, 3H), 2.86 (ddd, J = 2.6, 6.8, 9.3 Hz, 1H), 2.69 - 2.58 (m, 2H), 2.48 - 2.42 (m, 1H), 2.29 (d, J = 3.9 Hz, 3H), 2.26 - 2.18 (m, 1H), 2.06 (s, 3H), 1.86 - 1.71 (m, 1H)

[0975] Step F: To a solution of 2-(4-chloro-2-methoxy-6-methyl-phenyl)-6-fluoro-1-methyl-N-[(3R)-1-methylpyrrolidin-3-yl]imidazo[4,5-b]pyridin-5-amine (8 mg, 19.81 μmol, 1 equiv.) in DCM (0.5 mL) was added BBr3 (24.81 mg, 99.04 μmol, 9.54 μL, 5.0 equiv.) at 0°C, and the resulting reaction mixture was stirred at 20°C for 1 h. LCMS showed the reaction was complete. After completion, the solvent was removed by concentration to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 100 mm × 30 mm × 5 μm; mobile phase: [HO (0.2% FA)-ACN]; gradient: 1% to 20% B over 8.0 min) to give the title product. 5-Chloro-2-[6-fluoro-1-methyl-5-[[(3R)-1-methylpyrrolidin-3-yl]amino]imidazo[4,5-b]pyridin-2-yl]-3-methyl-phenol (4.65 mg, 11.91 μmol, 60.14% yield, 99.87% purity) was obtained as a white solid. LC-MS(ES + , m / z): 390.3 [(M+H) + ]. 1H NMR (400 MHz, DMSO-d6) δ = 10.39 (br s, 1H), 7.82 (d, J = 11.0 Hz, 1H), 6.89 (br d, J = 19.1 Hz, 2H), 6.24 (br d, J = 6.4 Hz, 1H), 4.53 - 4.39 (m, 1H), 3.46 (s, 3H), 2.91 (br t, J = 8.3 Hz, 2H), 2.67 (br s, 2H), 2.33 (br s, 3H), 2.24 (br dd, J = 6.2, 13.2 Hz, 1H), 2.05 (s, 3H), 1.81 (br d, J = 6.9 Hz, 1H).

[0976] Example 49 5-chloro-2-(1-methyl-5-(trifluoromethyl)-1H-imidazo[4,5-b]pyridin-2-yl)phenol

[0977] [ka]

[0978] Step A: To a stirred solution of 2-chloro-6-(trifluoromethyl)pyridin-3-amine (4.0 g, 20.35 mmol) and NEt3 (5.67 mL, 40.70 mmol) in chloroform (30 mL) was added pivaloyl chloride (2.70 g, 22.39 mmol) at 0 °C, and the mixture was stirred at 0 °C for 30 min. The reaction mixture was heated to 60 °C for 2 h. The progress of the reaction was monitored by TLC. TLC indicated that the reaction was complete. The reaction mixture was cooled to room temperature, diluted with DCM (100 mL), washed with water (100 mL), and concentrated to give the crude product. The crude product was purified by Combiflash chromatography. The product was eluted with 10% EtOAc in hexane. Pure fractions were collected and concentrated under reduced pressure to give N-(2-chloro-6-(trifluoromethyl)pyridin-3-yl)pivalamide (5.6 g, 98%) as an oil. MS(ESI):281.31[M+H]+ .

[0979] Step B: To a stirred solution of N-(2-chloro-6-trifluoromethylpyridin-3-yl)-2,2-dimethylpropionamide (4.5 g, 16.03 mmol) in THF (45 mL) was added sodium hydride, 57-63% dispersion in oil (1.54 g, 32.07 mmol) at 0 °C, and the mixture was stirred at room temperature for 30 min. The reaction mixture was cooled, and then methyl iodide (6.83 g, 48.10 mmol) was added, and the mixture was stirred at room temperature for 5 h. The progress of the reaction was monitored by TLC. TLC indicated the reaction was complete. The reaction mixture was poured into ice / water (200 mL) and extracted with ethyl acetate (2 × 100 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give N-(2-chloro-6-(trifluoromethyl)pyridin-3-yl)-N-methylpivalamide (4.2 g, 88%) as a pale yellow solid. MS(ESI):295.08[M+H] + .

[0980] Step C: A solution of N-(2-chloro-6-(trifluoromethyl)pyridin-3-yl)-N-methylpivalamide (4.2 g, 14.252 mmol) in IPA (21 mL):acetonitrile (42 mL):concentrated HCl (21 mL) was stirred at room temperature for 2 hours and heated to 80° C. for 18 hours. The progress of the reaction was monitored by TLC. TLC showed the reaction was complete. The reaction mixture was cooled to room temperature. The reaction mixture was quenched with saturated aqueous sodium bicarbonate (200 mL) and extracted with ethyl acetate (2×200 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give the crude product. The crude product was purified by Combiflash chromatography. The product was eluted with 10% EtOAc in hexanes. Pure fractions were collected and concentrated under reduced pressure to give 2-chloro-N-methyl-6-(trifluoromethyl)pyridin-3-amine (2.1 g, 70%) as an oil. MS(ESI):211.03[M+H] + .

[0981] Step D: To a stirred solution of 2-chloro-N-methyl-6-(trifluoromethyl)pyridin-3-amine (500 mg, 2.374 mmol) and diphenylmethanimine (860 mg, 4.75 mmol) in toluene (15 mL) was added potassium tert-butoxide (800 mg, 7.123 mmol), and the mixture was degassed with N for 5 minutes. BrettPhos Pd G3 (215 mg, 0.24 mmol) was added, and the mixture was heated to 100 °C for 3 hours. The progress of the reaction was monitored by TLC. TLC showed that the reaction was complete. The reaction mixture was diluted with DCM (30 mL) and washed with water (30 mL). The organic layer was concentrated to give the crude product. The crude product was purified by column chromatography using silica gel. The product was eluted with 10% EtOAc in hexane. Pure fractions were collected and concentrated under reduced pressure to give the desired compound as an oil (500 mg). MS(ESI):356.34[M+H] + .

[0982] Step E: To a stirred solution of 2-((diphenylmethylene)amino)-N-methyl-6-(trifluoromethyl)pyridin-3-amine (500 mg, 1.407 mmol) in 1,4-dioxane (10 mL) was added 4.0 M HCl in dioxane (3.0 ml) and the mixture was stirred at room temperature for 18 hours. The progress of the reaction was monitored by TLC. The reaction mixture was diluted with EtOAc (10 ml), washed with water, and concentrated to give the crude compound (200 mg). MS(ESI):192.22[M+H] + .

[0983] Step F: To a stirred solution of N3-methyl-6-(trifluoromethyl)pyridine-2,3-diamine (200 mg, 1.046 mmol) and 4-chloro-2-hydroxybenzaldehyde (164 mg, 1.046 mmol) in DMA (5 mL) was added sodium bisulfite (130 mg, 1.256 mmol) at room temperature, and the reaction mixture was stirred at 100° C. for 16 hours. The reaction progress was monitored by TLC. TLC indicated that the starting material had been consumed. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (2×10 mL). The combined organic layers were washed with brine solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product as an oil. The crude product was purified by preparative HPLC. Conditions: Mobile phase A: 10 mM aqueous ammonium bicarbonate solution, Mobile phase B: acetonitrile. Column: Inertial, Flow rate: 20 mL / min. Method: (T / % B): 0 / 10, 2 / 10, 11 / 60, 15 / 60, 15.1 / 100, 17 / 100, 17.1 / 10. Solubility: ACN + THF + HO. Temperature: Ambient. The pure compound fractions were evaporated and lyophilized to give 5-chloro-2-(1-methyl-5-(trifluoromethyl)-1H-imidazo[4,5-b]pyridin-2-yl)phenol (22 mg, 6% over 3 steps) as a...

Claims

1. Compounds having formula (I') 【Chemical 1】 or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof [In the formula, X' is selected from CH or N; W is N, CH, or CR c is selected from Q is selected from N and C; E is NR a and CR a is selected from Z is selected from N and C; At least one of Q and Z is C and / or E is CR a and R c -C 1 ~C 4 Alkyl, -OC 1 ~C 4 Alkyl, -C 1 ~C 4 Alkyl-OH, -halo, or -C 1 ~C 4 alkyl-Hal; R a -H and -C 1 ~C 3 is selected from the group consisting of alkyl, R A and R B are respectively, 【Chemistry 2】 Selected from R A and R B On the other hand, 【Chemistry 3】 and R A and R B The other is, 【Chemistry 4】 and R 0 -H, C 1 ~C 3 selected from the group consisting of alkyl, and halo; R 1 -CF 3 , -OCF 3 , -OCHF 2 and halo; R 2 -OH, -H, and -CF 3 is selected from the group consisting of Y is NH, NR d , O, or a bond; R d -C 1 ~C 4 Alkyl, -C 1 ~C 4 Alkyl-OH or -C 1 ~C 4 alkyl-Hal; R 3 teeth, a 4-, 5-, or 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from N and O, 1 ~C 4 Alkyl, HaloC 1 ~C 4 Alkyl, Hydroxy C 1 ~C 4 Alkyl, -OH, -NR 5 R 6 a 4-, 5-, or 6-membered heterocycloalkyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of: 8-, 9-, or 10-membered bicyclic fused heterocycloalkyl containing 1 to 3 heteroatoms independently selected from N and O, and C at any available position 1 ~C 4 Alkyl, HaloC 1 ~C 4 Alkyl, hydroxy C 1 ~C 4 Alkyl, -OH, -NR 5 R 6 an 8-, 9-, or 10-membered bicyclic fused heterocycloalkyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of: C 1 ~C 4 Alkyl, HaloC 1 ~C 4 Alkyl, Hydroxy C 1 ~C 4 C optionally substituted with 1 or 2 substituents independently selected from the group consisting of alkyl, —OH, and halo 3 ~C 6 cycloalkyl, or -OH, Halo, Halo C 1 ~C 4 Alkyl, C 1 ~C 4 Alkoxy and -NR 5 R 6 C optionally substituted with 1 or 2 substituents independently selected from the group consisting of 1 ~C 6 Alkyl is selected from the group consisting of R 5 and R 6 is H and C 1 ~C 3 independently selected from alkyl, m is 0, 1, or 2].

2. The compound of claim 1 having the formula (II'): 【Chemistry 5】 or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof [In the formula, X' is selected from CH or N; W is N, CH, or CR c is selected from Q is selected from N and C; E is NR a and CR a is selected from Z is selected from N and C; At least one of Q and Z is C and / or E is CR a and R c is C 1 ~C 4 Alkyl, -OC 1 ~C 4 Alkyl, C 1 ~C 4 Alkyl-OH, halo, or haloC 1 ~C 4 is selected from the group consisting of alkyl, R d -C 1 ~C 4 Alkyl, -C 1 ~C 4 Alkyl-OH or -C 1 ~C 4 alkyl-Hal; R a -H and -C 1 ~C 3 is selected from the group consisting of alkyl, R 0 -H, C 1 ~C 3 selected from the group consisting of alkyl, and halo; R 1 -CF 3 , -OCF 3 , -OCHF 2 and halo; R 2 -OH, -H, and -CF 3 is selected from the group consisting of R A teeth, 【Chemistry 6】 and Y is NH, NR d , O, or a bond; R 3 teeth, a 4-, 5-, or 6-membered heterocycloalkyl containing 1 or 2 heteroatoms, preferably 1 heteroatom, independently selected from N and O, and 1 ~C 4 Alkyl, HaloC 1 ~C 4 Alkyl, Hydroxy C 1 ~C 4 Alkyl, -OH, -NR 5 R 6 a 4-, 5-, or 6-membered heterocycloalkyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of: 8-, 9-, or 10-membered bicyclic fused heterocycloalkyl containing 1 to 3 heteroatoms independently selected from N and O, and C at any available position 1 ~C 4 Alkyl, HaloC 1 ~C 4 Alkyl, Hydroxy C 1 ~C 4 Alkyl, -OH, -NR 5 R 6 an 8-, 9-, or 10-membered bicyclic fused heterocycloalkyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of: C 1 ~C 4 Alkyl, HaloC 1 ~C 4 Alkyl, hydroxy C 1 ~C 4 C optionally substituted with 1 or 2 substituents independently selected from the group consisting of alkyl, —OH, and halo 3 ~C 6 cycloalkyl; or -OH, Halo, Halo C 1 ~C 4 Alkyl, C 1 ~C 4 Alkoxy and -NR 5 R 6 C optionally substituted with 1 or 2 substituents independently selected from the group consisting of 1 ~C 6 Alkyl is selected from the group consisting of R 5 and R 6 is H and C 1 ~C 3 independently selected from alkyl, m is 0, 1, or 2].

3. The compound of claim 1 having the formula (I): 【Chemistry 7】 or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof [In the formula, Q is selected from N and C; E is NR a and CR a is selected from Z is selected from N and C; At least one of Q and Z is C and / or E is CR a and R a -H and -C 1 ~C 3 is selected from the group consisting of alkyl, R A and R B are respectively, 【Chemistry 8】 Selected from R A and R B On the other hand, 【Chemistry 9】 and R A and R B The other is, 【Chemistry 10】 and R 0 -H, C 1 ~C 3 selected from the group consisting of alkyl, and halo; R 1 -CF 3 , -OCF 3 , -OCHF 2 and halo; R 2 -OH, -H, and -CF 3 is selected from the group consisting of Y is selected from NH and O; R 3 teeth, a 4-, 5-, or 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from N and O, preferably containing 1 heteroatom, 1 ~C 4 Alkyl, HaloC 1 ~C 4 Alkyl, Hydroxy C 1 ~C 4 a 4-, 5-, or 6-membered heterocycloalkyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of alkyl, —OH, and halo; C 1 ~C 4 Alkyl, HaloC 1 ~C 4 Alkyl, hydroxy C 1 ~C 4 C optionally substituted with 1 or 2 substituents independently selected from the group consisting of alkyl, —OH, and halo 3 ~C 6 cycloalkyl; and -OH, Halo, Halo C 1 ~C 4 Alkyl, C 1 ~C 4 Alkoxy and -NR 5 R 6 C optionally substituted with 1 or 2 substituents independently selected from the group consisting of 1 ~C 6 Alkyl is selected from the group consisting of R 5 and R 6 is H and C 1 ~C 3 alkyl].

4. A compound according to any one of claims 1 to 3 having the formula (II): 【Chemistry 11】 or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof [In the formula, Q is selected from N and C; E is NR a and CR a is selected from Z is selected from N and C; At least one of Q and Z is C and / or E is CR a and R a -H and -C 1 ~C 3 is selected from the group consisting of alkyl, R 0 -H, C 1 ~C 3 selected from the group consisting of alkyl, and halo; R 1 -CF 3 , -OCF 3 , -OCHF 2 and halo; R 2 -OH, -H, and -CF 3 is selected from the group consisting of Y is selected from NH and O; R 3 teeth, a 4-, 5-, or 6-membered heterocycloalkyl containing 1 or 2 heteroatoms, preferably 1 heteroatom, independently selected from N and O, and 1 ~C 4 Alkyl, HaloC 1 ~C 4 Alkyl, hydroxy C 1 ~C 4 a 4-, 5-, or 6-membered heterocycloalkyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of alkyl, —OH, and halo; C 1 ~C 4 Alkyl, HaloC 1 ~C 4 Alkyl, hydroxy C 1 ~C 4 C optionally substituted with 1 or 2 substituents independently selected from the group consisting of alkyl, —OH, and halo 3 ~C 6 cycloalkyl; and -OH, Halo, Halo C 1 ~C 4 Alkyl, C 1 ~C 4 Alkoxy and -NR 5 R 6 C optionally substituted with 1 or 2 substituents independently selected from the group consisting of 1 ~C 6 Alkyl is selected from the group consisting of R 5 and R 6 is H and C 1 ~C 3 alkyl].

5. A compound according to claim 1 or 3 having the formula (III): 【Chemistry 12】 or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof [In the formula, Q, E, Z, R 0 , R 1 , R 2 , R 3 , and Y are as defined in claim 1 or 3].

6. The compound of claim 2 having the formula (II'a): 【Chemistry 13】 or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof [In the formula, X', W, R 0 , R 1 , R 2 , R 3 , R a , m, and Y are as defined in claim 1].

7. The compound of claim 2 having the formula (II'b): 【Chemistry 14】 or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof [In the formula, X', W, R 0 , R 1 , R 2 , R 3 , R a , m, and Y are as defined in claim 1].

8. A compound according to any one of claims 2 to 4, having the formula (IIa): 【Chemistry 15】 or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof [In the formula, R 0 , R 1 , R 2 , R 3 , R a , and Y are as defined in any one of claims 2 to 4].

9. A compound according to any one of claims 2 to 4, having the formula (IIb): 【Chemistry 16】 or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof [In the formula, R 0 , R 1 , R 2、 R 3 , R a , and Y are as defined in any one of claims 2 to 4].

10. The compound of claim 2 having the formula (IV): 【Chemistry 17】 or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof [In the formula, R 0 , R 1 , R 2 , R 3 , R a , m, and Y are as defined in claim 2].

11. The compound of claim 2 having the formula (V): 【Chemistry 18】 or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof [In the formula, R 0 , R 1 , R 2 , R 3 , R a , m, and Y are as defined in claim 2].

12. R 3 but, 4-, 5-, or 6-membered heterocycloalkyl containing one heteroatom which is N or O, 1 ~C 4 a 4-, 5-, or 6-membered heterocycloalkyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of alkyl; C 1 ~C 4 C optionally substituted with 1 or 2 substituents independently selected from the group consisting of alkyl, —OH, and halo 3 ~C 6 cycloalkyl; Hydroxy C 1 ~C 6 alkyl; and -NR 5 R 6 C optionally replaced with 1 ~C 6 Alkyl is selected from the group consisting of R 5 and R 6 However, H and C 1 ~C 3 independently selected from alkyl, 12. A compound according to any one of claims 1 to 11.

13. R 3 but, 【Chemistry 19】 Me, and CF 3 A compound according to any one of claims 1 to 12, selected from the group consisting of [where: X is O and NR 4 is selected from R 4 is H, halo, or C 1 ~C 3 independently selected from alkyl, R 5 is H or C 1 ~C 3 independently selected from alkyl, preferably H or Me; R 6 is C 1 ~C 4 is selected from the group consisting of alkyl, n is selected from 0, 1, or 2.

14. R 3 but, 【Chemistry 20】 Me, and CF 3 A compound according to any one of claims 1 to 10, selected from the group consisting of [where: X is O and NR 4 is selected from R 4 is H, halo, or C 1 ~C 3 independently selected from alkyl, R 5 is independently selected from -H or -Me; R 6 is C 1 ~C 4 is selected from the group consisting of alkyl, n is selected from 0, 1, or 2.

15. R 3 but, 【Chemical 21】 Me, and CF 3 The compound of claim 11 selected from the group consisting of [where: R 4 is H, F, or C 1 ~C 3 independently selected from alkyl, R 5 is methyl, n is selected from 0, 1, or 2.

16. R 3 but, 【Chemical 22】 A compound according to any one of claims 1 to 10, selected from the group consisting of [where: X is O and NR 4 is selected from R 4 is -H or -C 1 ~C 3 independently selected from alkyl, a is selected from 0 and 1; n is selected from 0, 1, or 2.

17. R 3 but, 【Chemical 23】 The compound of claim 16, selected from the group consisting of [where: R 4 is -H or -C 1 ~C 3 independently selected from alkyl, n is selected from 0, 1, or 2.

18. R 0 is -H or -CH 3 and R 1 But -CF 3 or -halo, preferably -Cl; R 2 is -OH, 18. A compound according to any one of claims 1 to 17. [Request 19] [Chemical 24-A] 【Hua 24-B】 【Chemical 24-C】 【Chemical 24-D】 【Chemistry 24-E】 【Chemical 24-F】 【Chemical 24-G】 19. The compound of any one of claims 1 to 18, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof, selected from:

20. 20. A pharmaceutical composition comprising a compound of any one of claims 1 to 19, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof, and optionally at least one pharmaceutically acceptable carrier, diluent, adjuvant, or additive.

21. 20. A compound according to any one of claims 1 to 19, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof, for use as a pharmaceutical.

22. 20. A compound according to any one of claims 1 to 19, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof, for use in the treatment, amelioration, or prevention of a disease or disorder or abnormality responsive to modulation of a component of the NLRP3 inflammasome pathway and / or responsive to modulation of IL-1 beta and / or IL-18 levels.

23. 23. The compound for use according to claim 22, wherein the modulation is a reduction and / or inhibition of IL-1 beta.

24. 23. The compound for use according to claim 22, wherein the component of the inflammasome pathway is the NLRP3 inflammasome.

25. 25. The compound for use according to claim 22 or 24, wherein activation of the NLRP3 inflammasome pathway is inhibited.

26. The disease, disorder, or abnormality is Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, demyelination, viral encephalitis, epilepsy, stroke, atherosclerosis, allergic inflammation, cryopyrin-associated periodic syndromes (CAPS), Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), neonatal-onset multisystem inflammatory disease (NOMID), gout, pseudogout, inflammatory bowel disease (IBD) (including Crohn's disease and ulcerative colitis), hepatitis, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, hypertension, myocardial infarction, heart failure, coronary artery disease, or oxaliplatin. Salate-induced nephropathy, graft-versus-host disease, type 1 diabetes, type 2 diabetes, edema (DME), geographic atrophy (GA), rheumatoid arthritis, myelodysplastic syndrome, familial Mediterranean fever (FMF), tumor necrosis factor receptor-associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD), hyperimmunoglobulin D syndrome, periodic fever syndrome (HIDS), interleukin-1 receptor antagonist deficiency (DIRA), Majeed syndrome, pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA), A20 haploinsufficiency (HA20), PLCG2-associated antibody deficiency and immunodeficiency (PLAID), childhood granulomatous disease Arthritis of the gallbladder (PGA), PLCG2-associated autoinflammation, antibody deficiency and immune dysregulation (APLAID), B-cell immunodeficiency, periodic fever, sideroblastic anemia with developmental delay (SIFD), chronic nonbacterial osteomyelitis (CNO), Sweet's syndrome, chronic recurrent multifocal osteomyelitis (CRMO), synovitis, pustulosis, skin contact hypersensitivity, sunburn, psoriasis, hidradenitis suppurativa (HS), epidermolysis bullosa, acne, eczema, alopecia areata, actinic keratosis, hyperostosis, osteitis syndrome (SAPHO), vitiligo, atopic dermatitis, cutaneous lupus, multiple sclerosis (MS), psoriasis, Behçet's disease, Sjögren's syndrome, Schnitz syndrome Lehr's syndrome, chronic obstructive pulmonary disorder (COPD), asthma, steroid-resistant asthma, coronavirus-associated inflammatory conditions including coronavirus-associated respiratory distress syndrome (CARDS), asbestosis, silicosis, cystic fibrosis, motor neuron disease, Huntington's disease, cerebral malaria, brain damage from pneumococcal meningitis, obesity, age-related macular degeneration (AMD), corneal infections, uveitis, dry eye, acute kidney disease, chronic kidney disease, lupus nephritis, diabetic nephropathy, alcoholic liver disease, skin contact sensitivity, sunburn, osteoarthritis, systemic juvenile idiopathic arthritis, adult-onset Still's disease, relapsing polychondritis,Chikungunya virus, Ross River virus, influenza, HIV, coronavirus, dengue fever, Zika virus, primary biliary cholangitis, antiphospholipid syndrome, refractory celiac disease, pancreatitis, autoimmune pancreatitis, mucocutaneous lymph node syndrome, lung cancer metastasis, pancreatic cancer, gastric cancer, myelodysplastic syndrome, leukemia; polymyositis, colitis, helminth infections, bacterial infections, abdominal aortic aneurysm, wound healing, migraine, depression, psychological stress, pain, neuropathic pain, pericarditis including Dressler syndrome, ischemia-reperfusion injury, frontotemporal dementia, HIV-associated neurocognitive disorders and / or a combination of the above. The therapeutic agent is selected from the group consisting of: intellectual disability, traumatic spinal cord injury, traumatic brain injury, inflammatory pain, chronic pain, neuropathic pain, metastatic cancer-induced bone pain, chemotherapy-induced peripheral neuropathy, and migraine; ankylosing spondylitis and cytokine release syndrome, preferably wherein the disorder is selected from Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, demyelination, multiple sclerosis, encephalomyelitis, leukoencephalopathy, viral encephalitis, epilepsy, stroke, traumatic brain injury, spinal cord injury, atherosclerosis, asthma, allergic inflammation, cryopyrin-associated periodic syndrome (CAPS), gout, inflammatory bowel disease (IBD), Non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), hypertension, myocardial infarction, oxalate-induced nephropathy, graft-versus-host disease, type 1 diabetes, type 2 diabetes, rheumatoid arthritis, myelodysplastic syndrome, antineutrophil cytoplasmic antibody-associated vasculitis (AAV), acute kidney disease, chronic kidney disease, lupus nephritis, anti-glomerular basement membrane (GMB) disease, IgA nephropathy, glomerulonephritis (GN), systemic lupus erythematosus (SLE), focal segmental glomerulosclerosis, minimal change glomerulonephritis (MCD), psoriatic arthritis, hereditary relapsing fever (HRF), acne, atopic dermatitis 26. The compound for use according to any one of claims 22 to 25, selected from dermatitis, hidradenitis suppurativa (HS), and amyloidosis (including AL amyloidosis, AA amyloidosis, ATTR amyloidosis, hereditary amyloidosis (including apolipoprotein AI (AApoAI), apolipoprotein A-II (AApoAII), gelsolin (AGel), fibrinogen (AFib), and lysozyme (ALys)), beta-2 microglobulin amyloidosis, iAPP amyloidosis).

27. 27. The compound for use according to claim 26, wherein the disease, disorder or condition is selected from Alzheimer's disease, Parkinson's disease, and multiple sclerosis.

28. 27. The compound for use according to claim 26, wherein the disease, disorder, or abnormality is selected from cryopyrin-associated periodic syndromes (CAPS), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), chronic kidney disease, and gout.

29. 27. The compound for use according to claim 26, wherein the disease, disorder, or condition is a skin disease, disorder, or condition selected from hidradenitis suppurativa (HS), dermatitis, psoriasis, cutaneous contact sensitivity, acne, periodic fever syndrome (HIDS), Sweet's syndrome, eczema, skin lesions, burns, wounds, wound healing, trauma, sunburn, actinic keratosis, interleukin-1 receptor antagonist deficiency (DIRA), epidermolysis bullosa, vitiligo, atopic dermatitis, cutaneous lupus, and alopecia areata.

30. 30. The compound for use according to claim 29, wherein the disease, disorder, or condition is hidradenitis suppurativa (HS).

31. 20. Use of a compound of any one of claims 1 to 19, or a stereoisomer, racemic mixture, tautomer, polymorph, pharmaceutically acceptable salt, prodrug, hydrate, or solvate thereof, as an analytical standard or in vitro screening tool.

Images