heterocyclic compounds

Abstract

The present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a hydrate thereof, for treating a disease, disorder, or condition associated with NLRP3, including a disease, disorder, or condition associated with heterozygous gain-of-function mutations in the NLRP3 gene, such as cryopyrin-associated periodic syndromes (CAPS), [Formula 1] TIFF2025526692000036.tif42165 In the formula, X, Y, R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 is as defined herein.

Description

[Technical Field]

[0001] The present invention relates to heterocyclic compounds that are inhibitors of the NLRP3 inflammasome, drugs containing them, and their use for treating diseases, disorders, and / or conditions associated with NLRP3, including neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, and prion diseases. [Background technology]

[0002] More than 1% of the world's population suffers from neurodegenerative diseases, including Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and prion diseases, all of which lack effective treatments. The incidence of neurodegenerative diseases is expected to double over the next few decades, particularly affecting aging societies. See I. Fernandez-Cruz and E. Reynaud, "Proteasome Subunits Involved in Neurodegenerative Diseases," Arch Med Res. 52(1):1-14 (2021).

[0003] One of the pathological hallmarks of neurodegenerative diseases is the aggregation of certain proteins into oligomers or fibrils. These conformational changes result in neurotoxicity, leading to inflammation and neurodegeneration. Although the clinical manifestations of these diseases are heterogeneous, they often share common underlying mechanisms and pathophysiology. See B. N. Dugger and D. W. Dickson, “Pathology of Neurodegenerative Diseases,” Cold Spring Harbor Perspective Biol. 9(7):a028035 (2017). Indeed, systemic activation of the innate immune system, the first line of host defense against pathogens and tissue damage, and the subsequent neuroinflammation play a key role in the development and progression of these diseases. See S. Amor, F. Puentes, D. Baker, et al., “Inflammation in neurodegenerative diseases,” Immunology 129(2):154-69 (2010). Neuroinflammation is a physiological response to exogenous and endogenous insults targeting the central nervous system (CNS) and represents a protective response in the brain. However, excessive inflammatory responses are harmful to the CNS. See L.I. Labzin, M.T. Heneka, and E. Latz, "Innate Immunity and Neurodegeneration," Annu Rev Med 69:437-449 (2018).

[0004] Microglia, myeloid cells of the CNS, play a key role during the innate immune response in the CNS. They express pattern recognition receptors (PRRs) that enable the host to recognize pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) derived from the host or the environment. See R.M. Ransohoff and M.A. Brown, “Innate immunity in the central nervous system,” J Clin Invest 122(4):1164-71 (2012). PRRs include Toll-like receptors, C-type lectin receptors, RIG-1-like receptors, and nucleotide-binding oligomerization domain-like receptors (NLRs). See P. Broz and V.M. Dixit, “Inflammasomes: mechanism of assembly, regulation, and signaling,” Nat Rev Immunol 16(7):407-20 (2016). Binding of PRRs activates various inflammatory signaling pathways to eliminate infection and repair damaged tissue. Ongoing inflammation, seen in various neurodegenerative diseases, can be maintained by inflammasomes, important innate immune sensors of danger signals. Several different inflammasomes exist, all defined by the PRRs they contain. Among the NLR family of PRRs, NLRs (NLRP1, NLRP3, and NLRC4) and two other PRRs (pyrin and AIM2) are known to form inflammasomes. See D. Zheng, T. Liwinski, and E. Elinav, “Inflammasome activation and regulation: toward a better understanding of complex mechanisms,” Cell Discov 6:36 (2020).

[0005] The NLRP3 (nucleotide-binding domain (NOD), leucine-rich repeat-containing domain (LRR), and pyrin domain-containing 3) inflammasome has been the subject of intense interest over the past decade. See N. Kelley, D. Jeltema, Y. Duan, et al., “The NLRP3 Inflammasome: An Overview of Mechanisms of Activation and Regulation,” Int J Mol Sci 20(13):3328 (2019). The NLRP3 inflammasome consists of three major components: a pattern recognition receptor (PRR) protein (NLRP3); an apoptosis-associated speck-like protein (ASC) containing a caspase activation and recruitment domain (CARD), which functions as a central adaptor protein; and the proinflammatory caspase, caspase-1. See Kelley et al. (2019). NLRP3 contains three domains: an amino-terminal pyrin domain (PYD), a central NACHT domain with ATPase activity that is important for NLRP3 self-association and oligomerization, and a carboxy-terminal LRR domain (see Broz and Dixit (2016)).

[0006] NLRP3 inflammasome activation involves a two-step process. A first "priming" signal is generated by the detection of PAMPs or DAMPs via TLRs. This priming signal leads to NF-κB-dependent transcriptional upregulation of NLRP3 and pro-IL-1, but also regulates post-translational modifications of NLRP3. See J. Yang, Z. Liu and T.S. Xiao, "Post-translational regulation of inflammasomes," Cell Mol Immunol 14(1):65-79 (2017). This initial trigger is followed by a second "activating" signal (β-amyloid, α-synuclein, and other proteinaceous insults, ATP, crystals, nucleic acids, and toxins), which induces conformational changes in various inflammasome components, subsequently assembling and nucleating the oligomerization of monomeric NLRP3, leading to the formation and activation of the NLRP3 inflammasome. See A. Lu, V.G. Magupalli, J. Ruan, et al., “Unified polymerization mechanism for the assembly of ASC-dependent inflammasomes,” Cell 156(6):1193-1206 (2014). This large multimeric protein acts through caspase-1-dependent proteolytic cleavage of several proteins, including pro-interleukin (pro-IL)-18 and pro-IL-1β, into their mature inflammatory cytokines, IL-18 and IL-1β. See Kelley et al. (2019). Caspase-1 also cleaves gasdermin D (GSDMD), which promotes insertion of GSDMD into the plasma membrane to form pores and initiate a specific type of cell death called pyroptosis, which releases soluble intracellular fractions that promote the inflammatory response.See S. L. Fish and B. T. Cookson, “Caspase-1-dependent pore formation during pyroptosis leads to osmotic lysis of infected host macrophages,” Cell Microbiol 8(11):1812-25 (2006).

[0007] In addition to this "canonical" NLRP3 inflammasome activation pathway, a "non-canonical" NLRP3 activation pathway has been described. The non-canonical pathway involves cytosolic LPS-mediated activation of caspase-4 / 5 (or its mouse orthologue, caspase-11), which induces pyroptosis via cleavage of GSDMD and releases high-mobility group box 1 protein (HMGB1), resulting in the production of IL-1β. See M. Lamkanfi and V.M. Dixit, "Mechanisms and functions of inflammasomes," Cell 157(5):1013-22 (2014); F. Shi, Y. Yang, M. Kouadir M, et al., "Inhibition of phagocytosis and lysosomal acidification suppresses neurotoxic prion peptide-induced NALP3 inflammasome activation in BV2 microglia," J Neuroimmunol 260(1-2):121-5 (2013). In both pathways, activation of the NLRP3 inflammasome leads to the production of biologically active forms of the proinflammatory cytokines IL-1β and IL-18, which initiate inflammatory signaling cascades that contribute to neuroinflammation, neuronal injury, and cell death. See S. M. Allan, P. J. Tyrrell, and N. J. Rothwell, "Interleukin-1 and neuronal injury," Nat Rev Immunol, 5(8):629-40 (2005); A. Alboni, D. Cervia, S. Sugama, et al., "Interleukin 18 in the CNS," J Neuroinflammation, 7:9 (2010).

[0008] Heterozygous gain-of-function mutations in the NLRP3 gene are associated with the development of an autoinflammatory condition called cryopyrin-associated periodic syndrome (CAPS). See L. M. Booshehri and H. M. Offman, “CAPS and NLRP3,” J Clin Immunol 39(3):277-286 (2019). This is a rare, inherited autoinflammatory disorder characterized by inflammation throughout the body, the skin, the musculoskeletal system, and the central nervous system, and is estimated to affect approximately 1–3 people per million worldwide. See L. Cuisset, I. Jeru, B. Dumont, et al., “Mutations in the autoinflammatory cryopyrin-associated periodic syndrome gene: epidemiological study and lessons from eight years of genetic analysis in France,” Ann Rheum Dis 70(3):495-9 (2011); Erratum in: Ann Rheum Dis 71(7):1264 (2012). Clinicians classify CAPS disorders based on the severity of symptoms. The most severe form of CAPS is known as neonatal-onset multisystem inflammatory disease (NOMID / CINCA). An intermediate form of CAPS is called Muckle-Wells syndrome (MWS). Familial cold autoinflammatory syndrome (FCAS) is a milder form of CAPS that is triggered by cold temperatures. See Booshehri and Hoffman (2019). Current anti-IL-1 therapies (anakinra, rilonacept, canakinumab) have proven successful in treating CAPS, but clinical experience over the past decade has shown that some CAPS patients respond less well over time and require higher or more frequent dosing or a switch in therapy.See R. Caorsi, L. Lepore, F. Zulian, et al., "The schedule of administration of canakinumab in cryopyrin-associated periodic syndrome is driven by the phenotype severity rather than the age," Arthritis Res Ther 15(1):R33 (2013); S. Urien, C. Bardin, B. Bader-Meunier, et al., "Anakinra pharmacokinetics in children and adolescents with systemic-onset juvenile idiopathic arthritis and autoinflammatory syndromes," BMC Pharmacol Toxicol 14:40 (2013). Several small molecule inhibitors that block the NLRP3 inflammasome pathway have recently been reported. These include the prototypic NLRP3 inhibitor MCC-950. See R.C. Coll, J.R. Hill, C.J. Day, et al., "MCC950 directly targets the NLRP3 ATP-hydrolysis motif for inflammasome inhibition," Nat Chem Biol 15(6):556-559 (2019); R.C. Coll, A.A. Robertson, J.J. Chae, et al., "A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases," Nat Med 21(3):248-55 (2015). Other NLRP3 inhibitors include Bay 11-7082, CY-09, oridonin, tranilast, INF-39, glyburide, and JC-124.See W. Jiang, M. Li, F. He, et al., "Inhibition of NLRP3 inflammasome attenuates spinal cord injury-induced lung injury in mice," J Cell Physiol 234(5):6012-6022 (2019). MCC-950 has been used in many studies as a pharmacological tool to validate the NLRP3 inflammasome as a viable drug target for developing therapeutics for human disease. See S. E. Corcoran, R. Halai, and M. Cooper, "Pharmacological Inhibition of the Nod-Like Receptor Family Pyrin Domain Containing 3 Inflammasome with MCC950," Pharmacol Rev 73(3):968-1000 (2021).

[0009] Inhibitors of the NLRP3 inflammasome pathway are expected to be useful in the treatment of neurodegenerative diseases including Parkinson's disease, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, and prion diseases, as well as in the treatment of CAPS disorders associated with heterozygous gain-of-function mutations in the NLRP3 gene. Summary of the Invention

[0010] The present invention provides a heterocyclic compound, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a hydrate thereof. The present invention also provides a pharmaceutical containing a pyrazolothiazole / pyrazoloimidazole derivative, and provides its use for treating diseases, disorders, and / or conditions associated with NLRP3, including Parkinson's disease, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, and prion diseases, as well as other neurodegenerative disorders.

[0011] One aspect of the present invention provides [1] a compound of formula (I), or a salt thereof: [ka] During the ceremony, X is S or NR 7 and Y is CR 8 or N, R 1 is an optionally substituted 4-membered heterocyclic group or a 5- or 6-membered heterocyclic group, an optionally substituted C 1-6 alkyl group, or optionally substituted C 3-10 is a cycloalkyl group, R 2 is a hydrogen atom or an optionally substituted C 1-3 is an alkyl group, R 3 , R 4 , and R 5 are each independently a hydrogen atom, a halogen atom, or an optionally substituted C 1-6 Alkyl groups, optionally substituted C 3-8 a cycloalkyl group, or an optionally substituted C 1-6 is an alkoxy group, R 6 is a hydrogen atom or an optionally substituted C 1-6 is an alkyl group, R 7 is a hydrogen atom or an optionally substituted C 1-6 is an alkyl group, R 8 is a hydrogen atom, a halogen atom, or an optionally substituted C 1-6 Alkyl groups, optionally substituted C 3-8 cycloalkyl, or optionally substituted C 1-6 It is an alkoxy group.

[0012] Some embodiments of the present invention provide [2] a compound of formula (I) defined in [1] above, or a pharmaceutically acceptable salt thereof, wherein: X is S or NR 7 and Y is CR 8 or N, R 1 teeth, (1) A 4-membered heterocyclic group or a 5- or 6-membered heterocyclic group, wherein the heterocyclic group is: (a) a halogen atom, (b) an oxo group, (c) C optionally substituted with 1 to 3 substituents selected from the following: 1-6 alkyl groups, (i) a halogen atom, and (ii) C 1-6 alkoxy groups, (d)C 3-8 cycloalkyl groups, (e) a hydroxy group, (f)C 1-6 alkoxy groups, (g) C optionally substituted with 1 to 3 substituents selected from the following: 1-6 alkyl-carbonyl groups, (i) a halogen atom, (ii) a hydroxy group, (iii)C 1-6 an alkoxy group, and (iv) C 3-8 cycloalkyl groups, (h) C optionally substituted with 1 to 3 substituents selected from the following: 3-8 a cycloalkyl-carbonyl group, (i) a halogen atom, (ii) a cyano group, and (iii) a hydroxy group, (i) C optionally substituted with 1 to 3 halogen atoms 1-6 alkoxy-carbonyl groups, (j)C 3-8 cycloalkoxy-carbonyl groups, (k)C 7-16 aralkyloxy-carbonyl groups, (l) Mono- or Di-C 1-6 alkyl-carbamoyl groups, (m)C 1-6 alkylsulfonyl groups, (n)C 3-8 cycloalkylsulfonyl groups, and (o) the heterocyclic group optionally substituted with 1 to 3 substituents selected from 3- to 8-membered non-aromatic heterocyclic groups; (2) C optionally substituted with 1 to 3 substituents selected from the following: 1-6 alkyl groups, (a) a hydroxy group, (b) C optionally substituted with 1 to 3 halogen atoms 1-6 alkoxy groups, (c) C optionally substituted with 1 to 3 halogen atoms 3-8 cycloalkyl groups, (d) mono- or di-C 1-6 alkylamino groups, (e)C 1-6 alkyl-carbonylamino groups, (f) a 3- to 8-membered non-aromatic heterocyclic group optionally substituted with a hydroxy group; (g) halogen atoms, and (h) a 5- to 14-membered aromatic heterocyclyl group, or (3) C optionally substituted with 1 to 3 substituents selected from the following: 3-10 Cycloalkyl group (C 3-10 The cycloalkyl group may be a spirocyclic group or a bridged spirocyclic group. (a) a hydroxy group, (b) C optionally substituted with 1 to 3 halogen atoms 1-6 alkyl groups, and (c) C optionally substituted with 1 to 3 halogen atoms 1-6 alkoxy group and R 2 teeth, (1) a hydrogen atom, or (2) 1 to 3 Cs 1-6 C optionally substituted with an alkoxy group 1-3 Alkyl group and R 3 is a hydrogen atom, R 4 teeth, (1) a hydrogen atom, (2) a halogen atom, (3) C optionally substituted with 1 to 3 halogen atoms 1-6 an alkyl group, or (4) C optionally substituted with 1 to 3 halogen atoms 1-6 alkoxy group and R 5 is a hydrogen atom, R 6 is a hydrogen atom or C 1-6 is an alkyl group, R 7 is C 1-6 is an alkyl group, R 8 teeth, (1) a hydrogen atom, (2) a halogen atom, (3) (i) a halogen atom and (ii) C optionally substituted with 1 to 3 halogen atoms 1-6 C optionally substituted with 1 to 3 substituents selected from alkoxy groups 1-6 alkyl groups, (4) C optionally substituted with 1 to 3 halogen atoms 3-8 a cycloalkyl group, or (5) C optionally substituted with 1 to 3 halogen atoms 1-6 alkoxy group is.

[0013] Some embodiments of the present invention provide [3] a compound of formula (I) defined in [1] or [2] above, or a pharmaceutically acceptable salt thereof, wherein R 2 is a hydrogen atom.

[0014] Some embodiments of the present invention provide [4] a compound of formula (I) defined in the above [1] to [3], or a pharmaceutically acceptable salt thereof, wherein X is NR 7 is.

[0015] Some embodiments of the present invention provide [5] a compound of formula (I) defined in any one of the above [1] to [3], or a pharmaceutically acceptable salt thereof, wherein X is NR 7 and R 7 is C1-6 It is an alkyl group.

[0016] Some aspects of the present invention provide [6] a compound of formula (I) defined in any one of the above [1] to [3], or a pharmaceutically acceptable salt thereof, wherein X is S.

[0017] Some embodiments of the present invention provide [7] a compound of formula (I) defined in any one of the above [1] to [6], or a pharmaceutically acceptable salt thereof, wherein R 1 teeth, (1) A 4-membered heterocyclic group or a 5- or 6-membered heterocyclic group, wherein the heterocyclic group is: (a) a halogen atom, (b) an oxo group, (c) C optionally substituted with 1 to 3 substituents selected from the following: 1-6 alkyl groups, (i) a halogen atom, and (ii) C 1-6 alkoxy groups, (d)C 3-8 cycloalkyl groups, (e) a hydroxy group, (f)C 1-6 alkoxy groups, (g) C optionally substituted with 1 to 3 substituents selected from the following: 1-6 alkyl-carbonyl groups, (i) a halogen atom, (ii) a hydroxy group, (iii)C 1-6 an alkoxy group, and (iv) C 3-8 cycloalkyl groups, (h) C optionally substituted with 1 to 3 substituents selected from the following: 3-8 a cycloalkyl-carbonyl group, (i) a halogen atom, (ii) a cyano group, and (iii) a hydroxy group, (i) C optionally substituted with 1 to 3 halogen atoms 1-6 alkoxy-carbonyl groups, (j)C 3-8 cycloalkoxy-carbonyl groups, (k)C 7-16 aralkyloxy-carbonyl groups, (l) Mono- or Di-C 1-6 alkyl-carbamoyl groups, (m)C 1-6 alkylsulfonyl groups, (n)C 3-8 cycloalkylsulfonyl groups, and (o) the heterocyclic group optionally substituted with 1 to 3 substituents selected from 3- to 8-membered non-aromatic heterocyclic groups; (2) C optionally substituted with 1 to 3 substituents selected from the following: 1-6 alkyl groups, (a) a hydroxy group, (b) C optionally substituted with 1 to 3 halogen atoms 1-6 alkoxy groups, (c) C optionally substituted with 1 to 3 halogen atoms 3-8 cycloalkyl groups, (d) mono- or di-C 1-6 alkyl-amino groups, (e)C 1-6 alkyl-carbonylamino groups, (f) a 3- to 8-membered non-aromatic heterocyclic group optionally substituted with a hydroxy group; (g) halogen atoms, and (h) a 5- to 14-membered aromatic heterocyclyl group, or (3) C optionally substituted with 1 to 3 substituents selected from the following: 3-10 Cycloalkyl group (C 3-10 The cycloalkyl group may be a spirocyclic group or a bridged spirocyclic group. (a) a hydroxy group, (b) C optionally substituted with 1 to 3 halogen atoms 1-6 alkyl groups, and (c) C optionally substituted with 1 to 3 halogen atoms 1-6 alkoxy group is.

[0018] Some embodiments of the present invention provide [8] a compound of formula (I) defined in any one of the above [1] to [6], or a pharmaceutically acceptable salt thereof, wherein R 1 is a 4-membered heterocyclic group or a 5- or 6-membered non-aromatic heterocyclic group, which heterocyclic group is (a) a halogen atom, (b) an oxo group, (c) C optionally substituted with 1 to 3 substituents selected from the following: 1-6 alkyl groups, (i) a halogen atom, and (ii) C 1-6 alkoxy groups, (d)C 3-8 cycloalkyl groups, (e) a hydroxy group, (f)C 1-6 alkoxy groups, (g) C optionally substituted with 1 to 3 substituents selected from the following: 1-6 alkyl-carbonyl groups, (i) a halogen atom, (ii) a hydroxy group, (iii)C 1-6 an alkoxy group, and (iv) C 3-8 cycloalkyl groups, (h) C optionally substituted with 1 to 3 substituents selected from the following: 3-8 a cycloalkyl-carbonyl group, (i) a halogen atom, (ii) a cyano group, and (iii) a hydroxy group, (i) C optionally substituted with 1 to 3 halogen atoms 1-6 alkoxy-carbonyl groups, (j)C 3-8 cycloalkoxy-carbonyl groups, (k)C 7-16 aralkyloxy-carbonyl groups, (l) Mono- or Di-C 1-6 alkyl-carbamoyl groups, (m)C 1-6alkylsulfonyl groups, (n)C 3-8 cycloalkylsulfonyl groups, and (o) optionally substituted with 1 to 3 substituents selected from 3- to 8-membered non-aromatic heterocyclic groups;

[0019] Some aspects of the present invention provide [9] a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in any one of the above [1] to [6], wherein R 1 is a 4-membered heterocyclic group or a 5- or 6-membered non-aromatic heterocyclic group selected from pyrrolidinyl, piperidyl, oxetanyl, tetrahydrofuryl, and tetrahydropyranyl, each of which is (a) a halogen atom, (b) an oxo group, (c) C optionally substituted with 1 to 3 substituents selected from the following: 1-6 alkyl groups, (i) a halogen atom, and (ii) C 1-6 alkoxy groups, (d)C 3-8 cycloalkyl groups, (e) a hydroxy group, (f)C 1-6 alkoxy groups, (g) C optionally substituted with 1 to 3 substituents selected from the following: 1-6 alkyl-carbonyl groups, (i) a halogen atom, (ii) a hydroxy group, (iii)C 1-6 an alkoxy group, and (iv) C 3-8 cycloalkyl groups, (h) C optionally substituted with 1 to 3 substituents selected from the following: 3-8 a cycloalkyl-carbonyl group, (i) a halogen atom, (ii) a cyano group, and (iii) a hydroxy group, (i) C optionally substituted with 1 to 3 halogen atoms 1-6alkoxy-carbonyl groups, (j)C 3-8 cycloalkoxy-carbonyl groups, (k)C 7-16 aralkyloxy-carbonyl groups, (l) Mono- or Di-C 1-6 alkyl-carbamoyl groups, (m)C 1-6 alkylsulfonyl groups, (n)C 3-8 cycloalkylsulfonyl groups, and (o) optionally substituted with 1 to 3 substituents selected from 3- to 8-membered non-aromatic heterocyclic groups;

[0020] Some embodiments of the present invention provide a compound of formula (I) defined in any one of the above items [1] to [9], or a pharmaceutically acceptable salt thereof, wherein Y is CR 8 and R 8 teeth, (1) a hydrogen atom, (2) a halogen atom, (3) (i) a halogen atom and (ii) C optionally substituted with 1 to 3 halogen atoms 1-6 C optionally substituted with 1 to 3 substituents selected from alkoxy groups 1-6 alkyl groups, (4) C optionally substituted with 1 to 3 halogen atoms 3-8 a cycloalkyl group, or (5) C optionally substituted with 1 to 3 halogen atoms 1-6 It is an alkoxy group.

[0021] Some aspects of the present invention provide

[11] a compound of formula (I) defined in any one of the above [1], [2], [4] to [6], and

[10] , or a pharmaceutically acceptable salt thereof, wherein: R 1 teeth, (1) A 4-membered heterocyclic group or a 5- or 6-membered heterocyclic group, wherein the heterocyclic group is: (a) a halogen atom, (b) an oxo group, (c) C optionally substituted with 1 to 3 substituents selected from the following: 1-6 alkyl groups, (i) a halogen atom, and (ii) C 1-6 alkoxy groups, (d)C 3-8 cycloalkyl groups, (e) a hydroxy group, (f)C 1-6 alkoxy groups, (g) C optionally substituted with 1 to 3 substituents selected from the following: 1-6 alkyl-carbonyl groups, (i) a halogen atom, (ii) a hydroxy group, (iii)C 1-6 an alkoxy group, and (iv) C 3-8 cycloalkyl groups, (h) C optionally substituted with 1 to 3 substituents selected from the following: 3-8 a cycloalkyl-carbonyl group, (i) a halogen atom, (ii) a cyano group, and (iii) a hydroxy group, (i) C optionally substituted with 1 to 3 halogen atoms 1-6 alkoxy-carbonyl groups, (j)C 3-8 cycloalkoxy-carbonyl groups, (k)C 7-16 aralkyloxy-carbonyl groups, (l) Mono- or Di-C 1-6 alkyl-carbamoyl groups, (m)C 1-6 alkylsulfonyl groups, (n)C 3-8 cycloalkylsulfonyl groups, and (o) the heterocyclic group optionally substituted with 1 to 3 substituents selected from 3- to 8-membered non-aromatic heterocyclic groups; (2) C optionally substituted with 1 to 3 substituents selected from the following: 1-6 alkyl groups, (a) a hydroxy group, (b) C optionally substituted with 1 to 3 halogen atoms 1-6 alkoxy groups, (c) C optionally substituted with 1 to 3 halogen atoms 3-8 cycloalkyl groups, (d) mono- or di-C 1-6 alkyl-amino groups, (e)C 1-6 alkyl-carbonylamino groups, (f) a 3- to 8-membered non-aromatic heterocyclic group optionally substituted with a hydroxy group; (g) halogen atoms, and (h) a 5- to 14-membered aromatic heterocyclyl group, or (3) C optionally substituted with 1 to 3 substituents selected from the following: 3-10 Cycloalkyl group (C 3-10 The cycloalkyl group may be a spirocyclic group or a bridged spirocyclic group. (a) a hydroxy group, (b) C optionally substituted with 1 to 3 halogen atoms 1-6 alkyl groups, and (c) C optionally substituted with 1 to 3 halogen atoms 1-6 alkoxy group and R 2 is a hydrogen atom.

[0022] Some aspects of the present invention provide

[12] a compound of formula (I) defined in any one of [1], [2], and

[10] above, or a pharmaceutically acceptable salt thereof, wherein: X is S, R 1 is a 4-membered heterocyclic group or a 5- or 6-membered non-aromatic heterocyclic group, which heterocyclic group is (a) a halogen atom, (b) an oxo group, (c) C optionally substituted with 1 to 3 substituents selected from the following: 1-6 alkyl groups, (i) a halogen atom, and (ii) C 1-6 alkoxy groups, (d)C 3-8 cycloalkyl groups, (e) a hydroxy group, (f)C 1-6 alkoxy groups, (g) C optionally substituted with 1 to 3 substituents selected from the following: 1-6 alkyl-carbonyl groups, (i) a halogen atom, (ii) a hydroxy group, (iii)C 1-6 an alkoxy group, and (iv) C 3-8 cycloalkyl groups, (h) C optionally substituted with 1 to 3 substituents selected from the following: 3-8 a cycloalkyl-carbonyl group, (i) a halogen atom, (ii) a cyano group, and (iii) a hydroxy group, (i) C optionally substituted with 1 to 3 halogen atoms 1-6 alkoxy-carbonyl groups, (j)C 3-8 cycloalkoxy-carbonyl groups, (k)C 7-16 aralkyloxy-carbonyl groups, (l) Mono- or Di-C 1-6 alkyl-carbamoyl groups, (m)C 1-6 alkylsulfonyl groups, (n)C 3-8 cycloalkylsulfonyl groups, and (o) optionally substituted with 1 to 3 substituents selected from 3- to 8-membered non-aromatic heterocyclic groups; R 2 is a hydrogen atom.

[0023] Some aspects of the present invention provide a compound of formula (I) defined in any one of [1], [2], and

[10] above, or a pharmaceutically acceptable salt thereof, wherein: X is S, R 1 is a 4-membered heterocyclic group or a 5- or 6-membered non-aromatic heterocyclic group selected from pyrrolidinyl, piperidyl, oxetanyl, tetrahydrofuryl, and tetrahydropyranyl, each of which is (a) a halogen atom, (b) an oxo group, (c) C optionally substituted with 1 to 3 substituents selected from the following: 1-6 alkyl groups, (i) a halogen atom, and (ii) C 1-6 alkoxy groups, (d)C 3-8 cycloalkyl groups, (e) a hydroxy group, (f)C 1-6 alkoxy groups, (g) C optionally substituted with 1 to 3 substituents selected from the following: 1-6 alkyl-carbonyl groups, (i) a halogen atom, (ii) a hydroxy group, (iii)C 1-6 an alkoxy group, and (iv) C 3-8 cycloalkyl groups, (h) C optionally substituted with 1 to 3 substituents selected from the following: 3-8 a cycloalkyl-carbonyl group, (i) a halogen atom, (ii) a cyano group, and (iii) a hydroxy group, (i) C optionally substituted with 1 to 3 halogen atoms 1-6 alkoxy-carbonyl groups, (j)C 3-8 cycloalkoxy-carbonyl groups, (k)C 7-16 aralkyloxy-carbonyl groups, (l) Mono- or Di-C 1-6 alkyl-carbamoyl groups, (m)C 1-6 alkylsulfonyl groups, (n)C 3-8 cycloalkylsulfonyl groups, and (o) optionally substituted with 1 to 3 substituents selected from 3- to 8-membered non-aromatic heterocyclic groups; R 2 is a hydrogen atom.

[0024] Some aspects of the present invention provide a compound of formula (I) defined in any one of the above items [1], [2], [7] to [9], and

[11] to

[13] , or a pharmaceutically acceptable salt thereof, wherein: X is S, Y is CR 8 and R 8 teeth, (1) a hydrogen atom, (2) a halogen atom, (3) (i) a halogen atom and (ii) C optionally substituted with 1 to 3 halogen atoms 1-6 C optionally substituted with 1 to 3 substituents selected from alkoxy groups 1-6 alkyl groups, (4) C optionally substituted with 1 to 3 halogen atoms 3-8 a cycloalkyl group, or (5) C optionally substituted with 1 to 3 halogen atoms 1-6 alkoxy group and R 2 is a hydrogen atom.

[0025] Some aspects of the present invention provide

[15] a compound of formula (I) defined in any one of the above [1] to

[14] , or a pharmaceutically acceptable salt thereof, wherein: R 3 is a hydrogen atom, R 5 is a hydrogen atom, R 6 is a hydrogen atom or C 1-6 It is an alkyl group.

[0026] Some aspects of the present invention provide

[16] a compound of formula (I) as defined in [1], [2], and

[10] above, or a pharmaceutically acceptable salt thereof, wherein: X is S, R 1 is a 4-membered heterocyclic group or a 5- or 6-membered non-aromatic heterocyclic group, which heterocyclic group is (a) a halogen atom, (b) an oxo group, (c) C optionally substituted with 1 to 3 substituents selected from the following: 1-6 alkyl groups, (i) a halogen atom, and (ii) C 1-6 alkoxy groups, (d)C 3-8 cycloalkyl groups, (e) a hydroxy group, (f)C 1-6 alkoxy groups, (g) C optionally substituted with 1 to 3 substituents selected from the following: 1-6 alkyl-carbonyl groups, (i) a halogen atom, (ii) a hydroxy group, (iii)C 1-6 an alkoxy group, and (iv) C 3-8 cycloalkyl groups, (h) C optionally substituted with 1 to 3 substituents selected from the following: 3-8 a cycloalkyl-carbonyl group, (i) a halogen atom, (ii) a cyano group, and (iii) a hydroxy group, (i) C optionally substituted with 1 to 3 halogen atoms 1-6 alkoxy-carbonyl groups, (j)C 3-8 cycloalkoxy-carbonyl groups, (k)C 7-16 aralkyloxy-carbonyl groups, (l) Mono- or Di-C 1-6 alkyl-carbamoyl groups, (m)C 1-6 alkylsulfonyl groups, (n)C 3-8 cycloalkylsulfonyl groups, and (o) optionally substituted with 1 to 3 substituents selected from 3- to 8-membered non-aromatic heterocyclic groups; R 2 is a hydrogen atom, R 3 is a hydrogen atom, R 5 is a hydrogen atom, R 6 is a hydrogen atom or C 1-6 It is an alkyl group.

[0027] Some aspects of the present invention provide a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined in any one of the above items [1], [2], [4] to

[10] , and

[15] , wherein R 2 1 to 3 C 1-6 C optionally substituted with an alkoxy group 1-3 It is an alkyl group.

[0028] Some aspects of the present invention provide a compound of formula (I) defined in any one of [1], [2],

[10] , and

[15] above, or a pharmaceutically acceptable salt thereof, wherein: X is S, R 1 teeth, (1) A 4-membered heterocyclic group or a 5- or 6-membered heterocyclic group, wherein the heterocyclic group is: (a) a halogen atom, (b) an oxo group, (c) C optionally substituted with 1 to 3 substituents selected from the following: 1-6 alkyl groups, (i) a halogen atom, and (ii) C 1-6 alkoxy groups, (d)C 3-8 cycloalkyl groups, (e) a hydroxy group, (f)C 1-6alkoxy groups, (g) C optionally substituted with 1 to 3 substituents selected from the following: 1-6 alkyl-carbonyl groups, (i) a halogen atom, (ii) a hydroxy group, (iii)C 1-6 an alkoxy group, and (iv) C 3-8 cycloalkyl groups, (h) C optionally substituted with 1 to 3 substituents selected from the following: 3-8 a cycloalkyl-carbonyl group, (i) a halogen atom, (ii) a cyano group, and (iii) a hydroxy group, (i) C optionally substituted with 1 to 3 halogen atoms 1-6 alkoxy-carbonyl groups, (j)C 3-8 cycloalkoxy-carbonyl groups, (k)C 7-16 aralkyloxy-carbonyl groups, (l) Mono- or Di-C 1-6 alkyl-carbamoyl groups, (m)C 1-6 alkylsulfonyl groups, (n)C 3-8 cycloalkylsulfonyl groups, and (o) the heterocyclic group optionally substituted with 1 to 3 substituents selected from 3- to 8-membered non-aromatic heterocyclic groups; (2) C optionally substituted with 1 to 3 substituents selected from the following: 1-6 alkyl groups, (a) a hydroxy group, (b) C optionally substituted with 1 to 3 halogen atoms 1-6 alkoxy groups, (c) C optionally substituted with 1 to 3 halogen atoms 3-8 cycloalkyl groups, (d) Mono- or di-C 1-6 alkyl-amino groups, (e)C1-6 alkyl-carbonylamino groups, (f) a 3- to 8-membered non-aromatic heterocyclic group optionally substituted with a hydroxy group; (g) halogen atoms, and (h) a 5- to 14-membered aromatic heterocyclyl group, or (3) C optionally substituted with 1 to 3 substituents selected from the following: 3-10 Cycloalkyl group (C 3-10 The cycloalkyl group may be a spirocyclic group or a bridged spirocyclic group. (a) a hydroxy group, (b) C optionally substituted with 1 to 3 halogen atoms 1-6 alkyl groups, and (c) C optionally substituted with 1 to 3 halogen atoms 1-6 alkoxy group and R 2 1 to 3 C 1-6 C optionally substituted with an alkoxy group 1-3 It is an alkyl group.

[0029] Some embodiments of the present invention provide a compound of formula (I) as defined in [1] or [2] above, or a pharmaceutically acceptable salt thereof, wherein: X is S, Y is CR 8 and R 8 is C 1-6 is an alkyl group, R 1 is a 6-membered nitrogen-containing non-aromatic heterocyclic group substituted by one or two substituents selected from the following: (a) a halogen atom, and (b)C 1-6 alkyl groups, R 2 is a hydrogen atom, R 3 is a hydrogen atom, R 4 is C 1-6 is an alkyl group, R 5 is a hydrogen atom, R 6 is a hydrogen atom.

[0030] Some embodiments of the present invention provide a compound of formula (I) as defined in [1] or [2] above, or a pharmaceutically acceptable salt thereof, wherein: X is S, Y is CR 8 and R 8 is C 1-6 is an alkyl group, R 1 is a piperidyl group substituted by one or two substituents selected from the following: (a) a halogen atom, and (b)C 1-2 alkyl groups, R 2 is a hydrogen atom, R 3 is a hydrogen atom, R 4 is C 1-2 is an alkyl group, R 5 is a hydrogen atom, R 6 is a hydrogen atom.

[0031] Another aspect of the present invention provides a compound of formula (I) selected from the group of compounds described in the

[21] Examples (in particular, 2-(5-{[(3R,5R)-5-fluoro-1-methylpiperidin-3-yl]amino}-2H-pyrazolo[3,4-d][1,3]thiazol-2-yl)-3,5-dimethylphenol, 3,5-dimethyl-2-(5-{[(3R)-1-methylpiperidin-3-yl]amino}-2H-pyrazolo[3,4-d][1,3]thiazol-2-yl)phenol, or 3-ethyl-2-(5-{[(3R,5R)-5-fluoro-1-methylpiperidin-3-yl]amino}-2H-pyrazolo[3,4-d][1,3]thiazol-2-yl)-5-methylphenol), or a pharmaceutically acceptable salt thereof.

[0032] A further aspect of the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, or any one of the compounds or pharmaceutically acceptable salts defined in [1] to

[21] above, for use as a pharmaceutical.

[0033]

[0013] An additional aspect of the present invention provides a pharmaceutical composition (also referred to as a "pharmaceutical composition") comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, or any one of the compounds or pharmaceutically acceptable salts defined in [1] to

[21] above, and one or more pharmaceutically acceptable excipients, for treating a disease, disorder, or condition associated with NLRP3, including diseases, disorders, or conditions associated with heterozygous gain-of-function mutations in the NLRP3 gene, such as neonatal-onset multisystem inflammatory disease (NOMID / CINCA), Muckle-Wells syndrome (MWS), and cryopyrin-associated periodic syndromes (CAPS), including familial cold autoinflammatory syndrome (FCAS). The compounds of the present invention have low toxicity (e.g., acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity, and carcinogenicity) and few side effects, and therefore can be used as a preventive or therapeutic agent (collectively included in the term "pharmaceutical") or a diagnostic agent for various diseases in mammals (e.g., humans, cows, horses, dogs, cats, monkeys, mice, and rats).

[0034] Another aspect of the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, or any one of the compounds or pharmaceutically acceptable salts defined in the above [1] to

[21] , for treating a disease, disorder, or condition associated with NLRP3, including a disease, disorder, or condition associated with heterozygous gain-of-function mutations in the NLRP3 gene, such as neonatal-onset multisystem inflammatory disease (NOMID / CINCA), Muckle-Wells syndrome (MWS), and familial cold autoinflammatory syndrome (FCAS).

[0035] A further aspect of the present invention provides use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or any one of the compounds or pharmaceutically acceptable salts defined in [1] to

[21] above, for the manufacture of a medicament for treating a disease, disorder, or condition associated with NLRP3, including a disease, disorder, or condition associated with heterozygous gain-of-function mutations in the NLRP3 gene, such as neonatal-onset multisystem inflammatory disease (NOMID / CINCA), Muckle-Wells syndrome (MWS), and familial cold autoinflammatory syndrome (FCAS).

[0036] An additional aspect of the present invention provides a method for treating a disease, disorder, or condition associated with NLRP3, including a disease, disorder, or condition associated with a heterozygous gain-of-function mutation in the NLRP3 gene, such as a disease, disorder, or condition associated with NLRP3, including cryopyrin-associated periodic syndromes (CAPS), the method comprising administering to a subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or any one of the compounds or pharmaceutically acceptable salts defined in [1] to

[21] above.

[0037] Another aspect of the present invention provides a method for treating cryopyrin-associated periodic syndromes (CAPS), including neonatal-onset multisystem inflammatory disease (NOMID / CINCA), Muckle-Wells syndrome (MWS), and familial cold autoinflammatory syndrome (FCAS), which comprises administering to a subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or any one of the compounds or pharmaceutically acceptable salts defined in [1] to

[21] above.

[0038] A further aspect of the present invention provides a method for treating a neurodegenerative disease, disorder, or condition in a subject, the method comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or any one of the compounds or pharmaceutically acceptable salts defined in [1] to

[21] above.

[0039] An additional aspect of the present invention provides a method for treating Parkinson's disease, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, or prion disease in a subject, the method comprising administering to the subject an effective amount of a compound of formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, or a hydrate thereof, or any one of the compounds, pharmaceutically acceptable salts, solvates, and hydrates defined in [1] to

[21] above.

[0040] Another aspect of the present invention provides a combination drug comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, or any one of the compounds defined in the above [1] to

[21] and pharmaceutically acceptable salts thereof, and at least one additional pharmacologically active agent (sometimes referred to as a "pharmacologically active compound"), such as a β-secretase inhibitor, a γ-secretase inhibitor, an HMG-CoA reductase inhibitor, a nonsteroidal anti-inflammatory drug, vitamin E, an anti-amyloid antibody, an antidepressant, an antipsychotic, an anxiolytic, and an anticonvulsant. DETAILED DESCRIPTION OF THE INVENTION

[0041] Unless otherwise indicated, this disclosure uses the definitions provided below.

[0042] "Substituted" refers to a chemical substituent or moiety (e.g., C 1-6 When used in connection with an alkyl group, it means that one or more hydrogen atoms of that substituent or moiety are replaced with one or more non-hydrogen atoms or groups, provided that valency requirements are met and the substitution results in a chemically stable compound.

[0043] "About" or "approximately," when used in connection with a measurable, numerical variable, refers to the indicated value of that variable and all values of that variable within experimental error of the indicated value or within ±10 percent of the indicated value, whichever is greater.

[0044] "Alkyl" refers to straight-chain and branched saturated hydrocarbon groups generally having a specified number of carbon atoms (e.g., C1-3 Alkyl refers to an alkyl group having 1 to 3 (i.e., 1, 2, or 3) carbon atoms, C 1-4 Alkyl refers to an alkyl group having 1 to 4 (i.e., 1, 2, 3, or 4) carbon atoms, C 1-6 Alkyl refers to an alkyl group having 1 to 6 (i.e., 1, 2, 3, 4, 5, or 6) carbon atoms, etc.) Examples of alkyl groups include methyl, ethyl, n-propyl, i-propyl (isopropyl), n-butyl, s-butyl (sec-butyl), i-butyl (isobutyl), t-butyl (tert-butyl), pent-1-yl, pent-2-yl, pent-3-yl, 3-methylbut-1-yl, 3-methylbut-2-yl, 2-methylbut-2-yl, 2,2,2-trimethyleth-1-yl, n-hexyl, and the like.

[0045] "Alkanediyl" refers to a divalent alkyl group, where alkyl is defined above, generally having a specified number of carbon atoms (e.g., C 1-4 Alkanediyl refers to an alkanediyl group having 1 to 4 (i.e., 1, 2, 3, or 4) carbon atoms, C 1-6 Alkanediyl refers to an alkanediyl group having 1 to 6 (i.e., 1, 2, 3, 4, 5, or 6) carbon atoms, etc. Examples of alkanediyl groups include methylene, ethane-1,1-diyl, ethane-1,2-diyl, propane-1,3-diyl, propane-1,2-diyl, propane-1,1-diyl, propane-2,2-diyl, butane-1,4-diyl, butane-1,3-diyl, butane-1,2-diyl, butane-1,1-diyl, isobutane-1,3-diyl, isobutane-1,1-diyl, isobutane-1,2-diyl, and the like.

[0046] "Alkenyl" refers to straight- and branched-chain hydrocarbon groups having one or more carbon-carbon double bonds and generally having a specified number of carbon atoms (e.g., C 2-6Alkenyl refers to an alkenyl group having 2 to 6 (i.e., 2, 3, 4, 5, or 6) carbon atoms.) Examples of alkenyl groups include ethenyl, 1-propen-1-yl, 1-propen-2-yl, 2-propen-1-yl, 1-buten-1-yl, 1-buten-2-yl, 3-buten-1-yl, 3-buten-2-yl, 2-buten-1-yl, 2-buten-2-yl, 2-methyl-1-propen-1-yl, 2-methyl-2-propen-1-yl, 1,3-butadien-1-yl, 1,3-butadien-2-yl, and the like.

[0047] "Alkynyl" refers to a straight or branched chain hydrocarbon group having one or more carbon-carbon triple bonds and generally having a specified number of carbon atoms (e.g., C 2-6 Alkynyl refers to an alkynyl group having 2 to 6 (i.e., 2, 3, 4, 5, or 6) carbon atoms.) Examples of alkynyl groups include ethynyl, 1-propyn-1-yl, 2-propyn-1-yl, 1-butyn-1-yl, 3-butyn-1-yl, 3-butyn-2-yl, 2-butyn-1-yl, and the like.

[0048] "Alkoxy" refers to straight and branched chain saturated hydrocarbon groups attached through an oxygen atom, generally having the specified number of carbon atoms (e.g., C 1-4 Alkoxy refers to an alkoxy group having 1 to 4 (i.e., 1, 2, 3, or 4) carbon atoms, C 1-6 Alkoxy refers to an alkoxy group having 1 to 6 (i.e., 1, 2, 3, 4, 5, or 6) carbon atoms, etc. Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, i-butoxy, t-butoxy, pent-1-yloxy, pent-2-yloxy, pent-3-yloxy, 3-methylbut-1-yloxy, 3-methylbut-2-yloxy, 2-methylbut-2-yloxy, 2,2,2-trimethyleth-1-yloxy, n-hexoxy, and the like.

[0049] "Alkyl-carbonyl" and "alkylsulfonyl" refer to an alkyl group, as defined above, attached through a carbonyl (C(O)) or sulfonyl (SO) group, respectively, and generally having a specified number of carbon atoms (e.g., C(O)). 1-6 Alkyl-carbonyl refers to an alkyl-carbonyl group having 1 to 6 (i.e., 1, 2, 3, 4, 5, or 6) carbon atoms, excluding the carbonyl portion, C 1-6 Alkylsulfonyl refers to alkylsulfonyl groups having 1 to 6 (i.e., 1, 2, 3, 4, 5, or 6) carbon atoms, etc. Examples of alkyl-carbonyl groups include methylcarbonyl (acetyl), ethylcarbonyl, i-propylcarbonyl (propanoyl), n-propylcarbonyl, 2-methylpropanoyl, etc. Examples of alkylsulfonyl groups include methylsulfonyl, ethylsulfonyl, i-propylsulfonyl, n-propylsulfonyl, etc.

[0050] "Alkylamino," including monoalkylamino or dialkylamino groups, refers to an alkyl group as defined above attached through at least one amino group and generally having a specified number of carbon atoms (e.g., C 1-6 Alkylamino refers to a mono- or di-alkylamino group having 1 to 6 (i.e., 1, 2, 3, 4, 5, or 6) carbon atoms, etc. Examples of mono- or di-alkylamino groups include methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, diethylamino, dipropylamino, dibutylamino, N-ethyl-N-methylamino, and the like.

[0051] "Alkyl-carbamoyl," including mono- or dialkyl-carbamoyl groups, refers to an alkyl group as defined above attached through a carbamoyl (CONH) group, generally having a specified number of carbon atoms (e.g., C 1-6Alkyl-carbamoyl refers to a mono- or dialkyl-carbamoyl group (excluding the carbamoyl portion) having 1 to 6 (i.e., 1, 2, 3, 4, 5, or 6) carbon atoms, etc. Examples of mono- or dialkyl-carbamoyl groups include methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, and N-ethyl-N-methylcarbamoyl.

[0052] "Alkyl-carbonylamino" refers to an alkyl-carbonyl as defined above attached through an amino moiety and generally having a specified number of carbon atoms (e.g., C 1-6 Alkyl-carbonylamino refers to an alkyl-carbonylamino group having 1 to 6 (i.e., 1, 2, 3, 4, 5, or 6) carbon atoms (excluding the carbonyl portion), etc. 1-6 Examples of alkyl-carbonylamino groups include methylcarbonylamino (acetylamino), ethylcarbonylamino, and the like.

[0053] "Alkoxy-carbonyl" refers to an alkoxy group, as defined above, attached through a carbonyl (C(O)) group and generally having the specified number of carbon atoms (e.g., C 1-6 Alkoxy-carbonyl refers to an alkoxy-carbonyl group having 1 to 6 (i.e., 1, 2, 3, 4, 5, or 6) carbon atoms (excluding the carbonyl portion), etc. 1-6 Examples of alkoxy-carbonyl groups include methoxycarbonyl, ethoxycarbonyl, and the like.

[0054] "Halo," "halogen," and "halogeno" may be used interchangeably and refer to fluoro, chloro, bromo, and iodo.

[0055] "Haloalkyl," "haloalkenyl," and "haloalkynyl" refer to alkyl, alkenyl, and alkynyl groups (where alkyl, alkenyl, and alkynyl are defined above) substituted with one or more halogen atoms and generally having a specified number of carbon atoms. Examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 1-fluoroethyl, 1,1-difluoroethyl, 1-chloroethyl, 1,1-dichloroethyl, 1-fluoro-1-methylethyl, 1-chloro-1-methylethyl, and the like.

[0056] "Cycloalkyl" refers to saturated monocyclic, bicyclic, and tricyclic hydrocarbon groups, generally having a specified number of carbon atoms comprising the ring(s) (e.g., C 3-8 Cycloalkyl refers to a cycloalkyl group having 3 to 8 (i.e., 3, 4, 5, 6, 7, or 8) carbon atoms as ring members, C 3-10 Cycloalkyl refers to a cycloalkyl group having 3 to 10 (i.e., 3, 4, 5, 6, 7, 8, 9, or 10) carbon atoms as ring members. Bicyclic hydrocarbon groups can include separate rings (two rings that do not share carbon atoms), spiro rings (two rings that share one carbon atom), fused rings (two rings that share two carbon atoms and a bond between two common carbon atoms), and bridged rings (two rings that share two carbon atoms but do not have a common bond). Tricyclic hydrocarbon groups can include separate rings (two rings that do not share carbon atoms), spiro rings (two rings that share one carbon atom), fused rings (two rings of a tricyclic ring that share two carbon atoms and a bond between two common carbon atoms), and bridged rings (two rings of a tricyclic ring that share two carbon atoms but do not have a common bond). Cycloalkyl groups may be attached via any ring atom unless such attachment would violate valence requirements, and, where indicated, may optionally include one or more non-hydrogen substituents, but only unless such substitution would violate valence requirements.

[0057] Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. Examples of fused bicyclic cycloalkyl groups include bicyclo[2.1.0]pentanyl (i.e., bicyclo[2.1.0]pentan-1-yl, bicyclo[2.1.0]pentan-2-yl, and bicyclo[2.1.0]pentan-5-yl), bicyclo[3.1.0]hexanyl, bicyclo[3.2.0]heptanyl, bicyclo[4.1.0]heptanyl, bicyclo[3.3.0]octanyl, bicyclo[4.2.0]octanyl, bicyclo[4.3.0]nonanyl, bicyclo[4.4.0]decanyl, etc. Examples of bridged cycloalkyl groups include bicyclo[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, bicyclo[2.2.2]octanyl, bicyclo[3.2.1]octanyl, bicyclo[4.1.1]octanyl, bicyclo[3.3.1]nonanyl, bicyclo[4.2.1]nonanyl, bicyclo[3.3.2]decanyl, bicyclo[4.2.2]decanyl, bicyclo[4.3.1]decanyl, bicyclo[3.3.3]undecanyl, bicyclo[4.3.2]undecanyl, bicyclo[4.3.3]dodecanyl, adamantyl (tricyclo[3.3.1.1] 3,7 ]decanyl), and the like. Examples of spirocycloalkyl groups include spiro[3.3]heptanyl, spiro[2.4]heptanyl, spiro[3.4]octanyl, spiro[2.5]octanyl, spiro[3.5]nonanyl, and the like. Examples of split bicyclic cycloalkyl groups include those derived from bi(cyclobutane), cyclobutanecyclopentane, bi(cyclopentane), cyclobutanecyclohexane, cyclopentanecyclohexane, bi(cyclohexane), and the like.

[0058] "Cycloalkanediyl" refers to a divalent cycloalkyl group, where cycloalkyl is defined above, generally having a specified number of carbon atoms (e.g., C 3-8Cycloalkanediyl refers to a cycloalkanediyl group having 3 to 8 (i.e., 3, 4, 5, 6, 7, or 8) carbon atoms, etc. Examples of cycloalkanediyl groups include cyclopropane-1,1-diyl, cyclopropane-1,2-diyl, cyclobutane-1,1-diyl, cyclobutane-1,2-diyl, and the like.

[0059] "Cycloalkylidene" refers to a divalent monocyclic cycloalkyl group (cycloalkyl is defined above) attached through a single carbon atom of the group and generally having a specified number of carbon atoms comprising the ring (e.g., C 3-8 Cycloalkylidene refers to a cycloalkylidene group having from 3 to 8 (i.e., 3, 4, 5, 6, 7, or 8) carbon atoms as ring members. Examples of cycloalkylidene groups include cyclopropylidene, cyclobutylidene, cyclopentylidene, and cyclohexylidene.

[0060] "Cycloalkenyl" refers to partially unsaturated monocyclic and bicyclic hydrocarbon groups generally having a specified number of carbon atoms comprising the ring(s) (e.g., C 3-8 Cycloalkenyl refers to a cycloalkenyl group having 3 to 8 (i.e., 3, 4, 5, 6, 7, or 8) carbon atoms as ring members, etc. Like cycloalkyl groups, bicyclic cycloalkenyl groups can include separate rings, spiro rings, fused rings, or bridged rings. Similarly, cycloalkenyl groups can be attached via any ring atom and, where indicated, can optionally contain one or more non-hydrogen substituents, provided such attachment or substitution does not violate valence requirements. Examples of cycloalkenyl groups include partially unsaturated analogs of the above cycloalkyl groups, such as cyclobutenyl (i.e., cyclobuten-1-yl and cyclobuten-3-yl), cyclopentenyl, cyclohexenyl, bicyclo[2.2.1]hept-2-enyl, and the like.

[0061] "Cycloalkyl-carbonyl" or "cycloalkylsulfonyl" refers to a cycloalkyl group, as defined above, attached through a carbonyl (C(O)) or sulfonyl (SO) group, respectively, and generally having a specified number of carbon atoms (e.g., C 3-8 Cycloalkyl-carbonyl refers to a cycloalkyl-carbonyl group having 3 to 8 (i.e., 3, 4, 5, 6, 7, or 8) carbon atoms as ring members of the cycloalkyl group, excluding the carbonyl portion; C 3-8 Cycloalkylsulfonyl refers to a cycloalkylsulfonyl group having 3 to 8 (i.e., 3, 4, 5, 6, 7, or 8) carbon atoms as ring members of the cycloalkyl group, etc. Examples of cycloalkylcarbonyl groups include cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, etc. Examples of cycloalkylsulfonyl groups include cyclopropylsulfonyl, cyclobutylsulfonyl, cyclopentylsulfonyl, etc.

[0062] "Aryl" refers to fully unsaturated monocyclic aromatic hydrocarbons and polycyclic hydrocarbons having at least one aromatic ring, both monocyclic and polycyclic aryl groups generally having a specified number of carbon atoms constituting their ring members (e.g., C 6-14 Aryl refers to an aryl group having 6 to 14 carbon atoms as ring members, etc. The group can be attached via any ring atom and, where indicated, can optionally contain one or more non-hydrogen substituents, provided such attachment or substitution does not violate valence requirements. Examples of aryl groups include phenyl, biphenyl, cyclobutabenzenyl, indenyl, naphthyl, benzocycloheptanyl, biphenylenyl, fluorenyl, groups derived from a cycloheptatriene cation, and the like.

[0063] Examples of the "acyl group" include a formyl group, a carboxy group, a carbamoyl group, a thiocarbamoyl group, a sulfino group, a sulfo group, a sulfamoyl group, and a phosphono group, each of which is defined as "C 1-6 Alkyl group, C 2-6Alkenyl group, C 3-10 Cycloalkyl groups, C 3-10 Cycloalkenyl group, C 6-14 Aryl group, C 7-16 Optionally, one or two substituents selected from an aralkyl group, a 5- to 14-membered aromatic heterocyclic group, and a 3- to 14-membered non-aromatic heterocyclic group, each of which is a halogen atom, an optionally halogenated C 1-6 "The acyl group optionally has 1 to 3 substituents selected from an alkoxy group, a hydroxy group, a nitro group, a cyano group, an amino group, and a carbamoyl group." Examples of the "acyl group" also include a hydrocarbon-sulfonyl group, a heterocyclylsulfonyl group, a hydrocarbon-sulfinyl group, and a heterocyclylsulfinyl group. Here, the term "hydrocarbon-sulfonyl group" refers to a sulfonyl group having a hydrocarbon group bonded thereto, the term "heterocyclylsulfonyl group" refers to a sulfonyl group having a heterocyclic group bonded thereto, the term "hydrocarbon-sulfinyl group" refers to a sulfinyl group having a hydrocarbon group bonded thereto, and the term "heterocyclylsulfinyl group" refers to a sulfinyl group having a heterocyclic group bonded thereto.

[0064] Preferred examples of the "acyl group" include a formyl group, a carboxy group, and C 1~6 Alkyl-carbonyl group, C 2~6 Alkenyl-carbonyl groups (e.g., crotonoyl), C 3~10 Cycloalkyl-carbonyl groups (e.g., cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl), C 3~10 Cycloalkenyl-carbonyl groups (e.g., 2-cyclohexenecarbonyl), C 6~14 Aryl-carbonyl group, C 7~16 Aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclylcarbonyl group, 3- to 14-membered non-aromatic heterocyclylcarbonyl group, C 1~6 Alkoxy-carbonyl group, C 6~14 Aryloxy-carbonyl groups (e.g., phenyloxycarbonyl, naphthyloxycarbonyl), C 7~16Aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl, phenethyloxycarbonyl), carbamoyl group, mono- or di-C 1~6 Alkyl-carbamoyl group, mono- or di-C 2~6 Alkenyl-carbamoyl groups (e.g., diallylcarbamoyl), mono- or di-C 3~10 Cycloalkyl-carbamoyl groups (e.g., cyclopropylcarbamoyl), mono- or di-C 6~14 Aryl-carbamoyl groups (e.g., phenylcarbamoyl), mono- or di-C 7~16 Aralkyl-carbamoyl group, 5- to 14-membered aromatic heterocyclylcarbamoyl group (e.g., pyridylcarbamoyl), thiocarbamoyl group, mono- or di-C 1~6 Alkyl-thiocarbamoyl groups (e.g., methylthiocarbamoyl, N-ethyl-N-methylthiocarbamoyl), mono- or di-C 2~6 Alkenyl-thiocarbamoyl groups (e.g., diallylthiocarbamoyl), mono- or di-C 3~10 Cycloalkyl-thiocarbamoyl groups (e.g., cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl), mono- or di-C 6~14 Aryl-thiocarbamoyl groups (e.g., phenylthiocarbamoyl), mono- or di-C 7~16 Aralkyl-thiocarbamoyl groups (e.g., benzylthiocarbamoyl, phenethylthiocarbamoyl), 5- to 14-membered aromatic heterocyclylthiocarbamoyl groups (e.g., pyridylthiocarbamoyl), sulfino groups, C 1~6 Alkyl sulfinyl group (e.g., methyl sulfinyl, ethyl sulfinyl), sulfo group, C 1~6 Alkylsulfonyl group, C 6~14 Arylsulfonyl group, phosphono group and mono- or di-C 1~6 Examples include alkylphosphono groups (for example, dimethylphosphono, diethylphosphono, diisopropylphosphono, dibutylphosphono).

[0065] "Aralkyl" refers to an alkyl group, as defined above, generally having a specified number of carbon atoms, in which one of the hydrogens is replaced by an aryl group, as defined above (e.g., C 7-16 (Aralkyl refers to aralkyl groups having 7 to 16 carbon atoms, etc.) Examples of aralkyl groups include benzyl, phenethyl, naphthylmethyl, phenylpropyl, and the like.

[0066] "Aralkyloxy" refers to a hydroxy group in which the hydrogen is replaced by an aralkyl group as defined above, generally having a specified number of carbon atoms (e.g., C 7-16 (Aralkyloxy refers to an aralkyloxy group having 7 to 16 carbon atoms, etc.) Examples of aralkyloxy groups include benzyloxy, phenethyloxy, naphthylmethoxy, phenylpropyloxy, and the like.

[0067] "Aralkyloxy-carbonyl" refers to an aralkyloxy group, as defined above, attached through a carbonyl (C(O)) group and generally having a specified number of carbon atoms (e.g., C 7-16 Aralkyloxy-carbonyl refers to an aralkyloxy-carbonyl group having 7 to 16 carbon atoms (excluding the carbonyl portion), etc. Examples of aralkyloxy-carbonyl groups include benzyloxycarbonyl, phenethyloxycarbonyl, naphthylmethoxycarbonyl, phenylpropyloxycarbonyl, and the like.

[0068] "Arylene" refers to a divalent aryl group (aryl is defined above), generally having a specified number of carbon atoms comprising their ring members (e.g., C 6-14 (Arylene refers to an arylene group having 6 to 14 carbon atoms as ring members, etc.) Examples of arylene groups include o-phenylene (ie, benzene-1,2-diyl).

[0069] "Heterocycle," "heterocyclic," and "heterocyclyl" are sometimes used interchangeably and refer to saturated or partially unsaturated monocyclic or bicyclic groups having ring atoms composed of carbon atoms and one or more heteroatoms independently selected from nitrogen, oxygen, and sulfur. Both monocyclic and bicyclic groups generally have a specified number of carbon atoms in their ring(s) (e.g., C 2-6 Heterocyclyl refers to heterocyclyl groups having 2 to 6 (i.e., 2, 3, 4, 5, or 6) carbon atoms and, for example, 1 to 4 (i.e., 1, 2, 3, or 4) heteroatoms as ring members, while a 4-membered heterocyclic group or a 5- or 6-membered heterocyclic group refers to a heterocyclyl group having a total of 4 to 6 carbon and heteroatom ring members. Like bicyclic cycloalkyl groups, bicyclic heterocyclyl groups can include separate rings, spiro rings, fused rings, and bridged rings. Heterocyclyl groups can be bonded through any ring atom and, where indicated, can optionally contain one or more non-hydrogen substituents, provided that such bonding or substitution does not violate valence requirements or result in a chemically unstable compound. Examples of heterocyclyl groups include oxiranyl, thiiranyl, aziridinyl (e.g., aziridin-1-yl and aziridin-2-yl), oxetanyl, thietanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, 1,4-dioxanyl, 1,4-oxathianyl, morpholinyl, 1,4-dithianyl, piperazinyl, 1,4-azathianyl, oxepanyl, thiepanyl, azepanyl, 1,4-dioxepanyl, Examples include 1,4-oxathiepanyl, 1,4-oxazepanyl, 1,4-dithiepanyl, 1,4-thiazepanyl, 1,4-diazepanyl, 3,4-dihydro-2H-pyranyl, 3,6-dihydro-2H-pyranyl, 2H-pyranyl, 1,2-dihydropyridinyl, 1,2,3,4-tetrahydropyridinyl, 1,2,5,6-tetrahydropyridinyl, 1,6-dihydropyrimidinyl, 1,2,3,4-tetrahydropyrimidinyl, and 1,2-dihydropyrazolo[1,5-d][1,2,4]triazinyl.

[0070] "Heterocycle-diyl" refers to a heterocyclyl group (heterocyclyl is defined above) that is attached through two ring atoms of the group. They generally have a specified number of carbon atoms in their ring(s) (e.g., C 2-6 Heterocycle-diyl refers to a heterocycle-diyl group having 2 to 6 (i.e., 2, 3, 4, 5, or 6) carbon atoms and, for example, 1 to 4 (i.e., 1, 2, 3, or 4) heteroatoms as ring members.) Examples of heterocycle-diyl groups include polyvalent analogs of the above heterocycle groups, such as morpholin-3,4-diyl, pyrrolidin-1,2-diyl, 1-pyrrolidinyl-2-ylidene, 1-pyridinyl-2-ylidene, 1-(4H)-pyrazolyl-5-ylidene, 1-(3H)-imidazolyl-2-ylidene, 3-oxazolyl-2-ylidene, 1-piperidinyl-2-ylidene, 1-piperazinyl-6-ylidene, and the like.

[0071] "Heteroaromatic," "aromatic heterocyclyl / heterocycle," and "heteroaryl" are sometimes used interchangeably and refer to unsaturated monocyclic aromatic groups and polycyclic groups having at least one aromatic ring, each of which has ring atoms composed of carbon atoms and one or more heteroatoms independently selected from nitrogen, oxygen, and sulfur. Both monocyclic and polycyclic groups generally have a specified number of carbon atoms as ring members (e.g., C 1-9Heteroaryl refers to heteroaryl groups having 1 to 9 (i.e., 1, 2, 3, 4, 5, 6, 7, 8, or 9) carbon atoms and, for example, 1 to 4 (i.e., 1, 2, 3, or 4) heteroatoms as ring members. This may include any bicyclic group in which any of the monocyclic heterocycles listed above is fused to a benzene ring. Monocyclic and polycyclic groups are also 5- to 14-membered aromatic heterocyclyl groups. Heteroaryl groups may be bonded via any ring atom (or ring atom of a fused ring) and, where indicated, may optionally contain one or more non-hydrogen substituents, provided that such bonding or substitution does not violate valence requirements or result in a chemically unstable compound. Examples of heteroaryl groups include monocyclic groups such as pyrrolyl (e.g., pyrrol-1-yl, pyrrol-2-yl, and pyrrol-3-yl), furyl, thienyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, 1,2,3-triazolyl, 1,3,4-triazolyl, 1-oxa-2,3-diazolyl, 1-oxa-2,4-diazolyl, 1-oxa-2,5-diazolyl, 1-oxa-3,4-diazolyl, 1-thia-2,3-diazolyl, 1-thia-2,4-diazolyl, 1-thia-2,5-diazolyl, 1-thia-3,4-diazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl.

[0072] Examples of heteroaryl groups also include bicyclic groups, such as benzofuranyl, isobenzofuranyl, benzothienyl, benzo[c]thienyl, 1H-indolyl, 3H-indolyl, isoindolyl, 1H-isoindolyl, indolinyl, isoindolinyl, benzimidazolyl, 1H-indazolyl, 2H-indazolyl, benzotriazolyl, 1H-pyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[2,3-c]pyridinyl, 1H-pyrrolo[3,2-c]pyridinyl, 1H-pyrrolo[3,2-b]pyridinyl, 3H-imidazo[4,5-b]pyridinyl, indyl, 3H-imidazo[4,5-c]pyridinyl, 1H-pyrazolo[4,3-b]pyridinyl, 1H-pyrazolo[4,3-c]pyridinyl, 1H-pyrazolo[3,4-c]pyridinyl, 1H-pyrazolo[3,4-b]pyridinyl, 7H-purinyl, indolizinyl, imidazo[1,2-a]pyridinyl, imidazo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrrolo[1,2-b]pyridazinyl, imidazo[1,2-c]pyrimidinyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, 1 ,6-naphthyridinyl, 1,7-naphthyridinyl, 1,8-naphthyridinyl, 1,5-naphthyridinyl, 2,6-naphthyridinyl, 2,7-naphthyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[4,3-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrido[2,3-d]pyrimidinyl, pyrido[2,3-b]pyrazinyl, pyrido[3,4-b]pyrazinyl, pyrimido[5,4-d]pyrimidinyl, pyrazino[2,3-b]pyrazinyl, pyrimido[4,5-d]pyrimidinyl, 1,2,3,4-tetrahydropyrido[2,3-b] Pyrazinyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl, 2,3-dihydro-1H-benzo[d]imidazolyl, benzo[d]thiazolyl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, [1,2,4]triazolo[1,5-a]pyridinyl, 2,3-dihydro-1H-imidazo[4,5-b]pyridinyl, tetrazolo[1,5-a]pyridinyl, 7H-pyrrolo[2,3-d]pyrimidinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-a]pyrimidinyl, 4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidinyl, 2,3,6,7-tetrahydro-1H-purinyl, 5H-pyrrolo[2,3-b]pyrazinyl, imidazo[1,2-a]pyrazinyl, imidazo[1,2-b]pyridazinyl, and 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl.

[0073] "Heteroarylene" refers to heteroaryl groups (heteroaryl is defined above) that are linked through two ring atoms of the group. They generally have a specified number of carbon atoms in their ring(s) (e.g., C 3-5 Heteroarylene refers to a heteroarylene group having 3 to 5 carbon atoms and, for example, 1 to 4 (i.e., 1, 2, 3, or 4) heteroatoms as ring members.) Examples of heteroarylene groups include polyvalent analogs of the heteroaryl groups listed above, such as pyridine-2,3-diyl, pyridine-3,4-diyl, pyrazole-4,5-diyl, pyrazole-3,4-diyl, and the like.

[0074] "Non-aromatic heterocycle / heterocyclyl" (including "3- to 8-membered non-aromatic heterocyclic groups") refers to heterocyclic groups other than the above-mentioned heteroaryl groups. Preferred examples of "non-aromatic heterocyclic groups" include aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydrofuranyl, and the like. 3- to 8-membered monocyclic non-aromatic heterocyclic groups such as isoxazolyl, piperidinyl, piperazinyl, tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl, tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, azepanyl, diazepanyl, azepinyl, oxepanyl, azocanyl, and diazocanyl; Dihydrobenzofuranyl, dihydrobenzimidazolyl, dihydrobenzoxazolyl, dihydrobenzothiazolyl, dihydrobenzisothiazolyl, dihydronaphtho[2,3-b]thienyl, tetrahydroisoquinolyl, tetrahydroquinolyl, 4H-quinolidinyl, indolinyl, isoindolinyl, tetrahydrothieno[2,3-c]pyridinyl, tetrahydrobenzazepinyl, tetrahydroquinoxalinyl, tetrahydrophenanthridinyl, hexa Examples thereof include 9- to 14-membered fused polycyclic (preferably bi- or tricyclic) non-aromatic heterocyclic groups such as hydrophenothiazinyl, hexahydrophenoxazinyl, tetrahydrophthalazinyl, tetrahydronaphthyridinyl, tetrahydroquinazolinyl, tetrahydrocinnolinyl, tetrahydrocarbazolyl, tetrahydro-β-carbolinyl, tetrahydroacridinyl, tetrahydrophenazinyl, tetrahydrothioxanthenyl, and octahydroisoquinolyl.

[0075] As used herein, examples of "nitrogen-containing heterocyclic groups" include "heterocyclic groups" that contain at least one nitrogen atom as a ring-constituting atom.

[0076] As used herein, examples of "optionally substituted heterocyclic groups" include heterocyclic groups optionally bearing substituent(s) selected from Substituent A described below.

[0077] "Oxo" refers to a double-bonded oxygen (=O).

[0078] Examples of "substituents" (including "hetero substituents") include halogen atoms, cyano groups, nitro groups, optionally substituted hydrocarbon groups, optionally substituted heterocyclic groups, acyl groups, optionally substituted amino groups, optionally substituted carbamoyl groups, optionally substituted thiocarbamoyl groups, optionally substituted sulfamoyl groups, optionally substituted hydroxy groups, optionally substituted sulfanyl (SH) groups, and optionally substituted silyl groups. Examples of "hydrocarbon groups" (including "hydrocarbon groups" of "optionally substituted hydrocarbon groups") include C 1-6Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-10 Cycloalkyl groups, C 3-10 Cycloalkenyl group, C 6-14 Aryl groups, and C 7-16 Examples include aralkyl groups.

[0079] A "heterosubstituent" refers to a substituent containing at least one heteroatom. Examples of "heterosubstituents" include halogen atoms, cyano groups, nitro groups, heterocyclyl groups, heteroaryl groups, heterosubstituents (such as halo-alkyl, amino-alkyl, cyano-alkyl, and alkoxy-alkyl), cycloalkyls substituted with heterosubstituents (such as halo-cycloalkyl, cyano-cycloalkyl, and hydroxy-cycloalkyl), and optionally substituted alkoxy groups.

[0080] Examples of "optionally substituted hydrocarbon groups" include hydrocarbon groups optionally having a substituent(s) selected from the following substituent A:

[0081] [Substituent A] (1) a halogen atom, (2) a nitro group, (3) a cyano group, (4) an oxo group, (5) a hydroxy group, (6) optionally halogenated C 1-6 alkoxy groups, (7) C 6-14 aryloxy groups (e.g., phenoxy, naphthoxy); (8) C 7-16 aralkyloxy groups (e.g., benzyloxy), (9) 5- to 14-membered aromatic heterocyclyloxy groups (e.g., pyridyloxy), (10) 3- to 14-membered non-aromatic heterocyclyloxy groups (e.g., morpholinyloxy, piperidinyloxy), (11)C 1-6alkyl-carbonyloxy groups (e.g., acetoxy, propanoyloxy); (12)C 6-14 aryl-carbonyloxy groups (e.g., benzoyloxy, 1-naphthoyloxy, 2-naphthoyloxy); (13)C 1-6 alkoxy-carbonyloxy groups (e.g., methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy); (14) Mono- or di-C 1-6 alkyl-carbamoyloxy groups (e.g., methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy, diethylcarbamoyloxy); (15)C 6-14 aryl-carbamoyloxy groups (e.g., phenylcarbamoyloxy, naphthylcarbamoyloxy); (16) 5- to 14-membered aromatic heterocyclylcarbonyloxy groups (e.g., nicotinoyloxy), (17) 3- to 14-membered non-aromatic heterocyclylcarbonyloxy groups (e.g., morpholinylcarbonyloxy, piperidinylcarbonyloxy), (18) optionally halogenated C 1-6 alkylsulfonyloxy groups (e.g., methylsulfonyloxy, trifluoromethylsulfonyloxy); (19)C 1-6 C optionally substituted with alkyl groups 6-14 arylsulfonyloxy groups (e.g., phenylsulfonyloxy, toluenesulfonyloxy); (20) optionally halogenated C 1-6 alkylthio groups, (21) a 5- to 14-membered aromatic heterocyclic group, (22) a 3- to 14-membered non-aromatic heterocyclic group, (23) a formyl group, (24) a carboxy group, (25) optionally halogenated C 1-6 alkyl-carbonyl groups, (26)C 6-14aryl-carbonyl groups, (27) a 5- to 14-membered aromatic heterocyclylcarbonyl group, (28) a 3- to 14-membered non-aromatic heterocyclylcarbonyl group, (29)C 1-6 alkoxy-carbonyl groups, (30)C 6-14 aryloxy-carbonyl groups (e.g., phenyloxycarbonyl, 1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl); (31)C 7-16 aralkyloxy-carbonyl groups (e.g., benzyloxycarbonyl, phenethyloxycarbonyl), (32) a carbamoyl group, (33) a thiocarbamoyl group, (34) Mono- or di-C 1-6 alkyl-carbamoyl groups, (35)C 6-14 aryl-carbamoyl groups (e.g., phenylcarbamoyl); (36) 5- to 14-membered aromatic heterocyclylcarbamoyl groups (e.g., pyridylcarbamoyl, thienylcarbamoyl), (37) 3- to 14-membered non-aromatic heterocyclylcarbamoyl groups (e.g., morpholinylcarbamoyl, piperidinylcarbamoyl), (38) optionally halogenated C 1-6 alkylsulfonyl groups, (39)C 6-14 arylsulfonyl groups, (40) 5- to 14-membered aromatic heterocyclylsulfonyl groups (e.g., pyridylsulfonyl, thienylsulfonyl), (41) Optionally halogenated C 1-6 alkylsulfinyl groups, (42)C 6-14 arylsulfinyl groups (e.g., phenylsulfinyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl); (43) 5- to 14-membered aromatic heterocyclylsulfinyl groups (e.g., pyridylsulfinyl, thienylsulfinyl), (44) amino group, (45) Mono- or di-C 1-6 alkylamino groups (e.g., methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, diethylamino, dipropylamino, dibutylamino, N-ethyl-N-methylamino); (46) Mono- or di-C 6-14 arylamino groups (e.g., phenylamino); (47) 5- to 14-membered aromatic heterocyclylamino groups (e.g., pyridylamino), (48)C 7-16 aralkylamino groups (e.g., benzylamino), (49) formylamino group, (50)C 1-6 alkyl-carbonylamino groups (e.g., acetylamino, propanoylamino, butanoylamino); (51)(C 1-6 Alkyl)(C 1-6 alkyl-carbonyl)amino groups (e.g., N-acetyl-N-methylamino), (52)C 6-14 aryl-carbonylamino groups (e.g., phenylcarbonylamino, naphthylcarbonylamino); (53)C 1-6 alkoxycarbonylamino groups (e.g., methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino, tert-butoxycarbonylamino), (54)C 7-16 aralkyloxy-carbonylamino groups (e.g., benzyloxycarbonylamino), (55)C 1-6 alkylsulfonylamino groups (e.g., methylsulfonylamino, ethylsulfonylamino); (56)C 1-6 C optionally substituted with alkyl groups 6-14 arylsulfonylamino groups (e.g., phenylsulfonylamino, toluenesulfonylamino); (57) Optionally halogenated C1-6 alkyl groups, (58)C 2-6 alkenyl groups, (59)C 2-6 alkynyl groups, (60)C 3-10 cycloalkyl groups, (61)C 3-10 Cycloalkenyl groups and (62)C 6-14 Aryl groups.

[0082] The number of the above-mentioned substituents in the "optionally substituted hydrocarbon group" is, for example, 1 to 5, preferably 1 to 3. When the number of substituents is 2 or more, the respective substituents may be the same or different.

[0083] "Leaving group" refers to any group that leaves a molecule during a fragmentation process, including substitution, elimination, and addition-elimination reactions. Leaving groups can be nucleofugal (where the leaving group leaves with the electron pair that originally served as the bond between the leaving group and the molecule) or electrofugal (where the leaving group leaves without the electron pair). The ability of a nucleofugal leaving group to leave depends on the strength of its base, with the strongest bases being the weakest leaving groups. Common nucleofugal leaving groups include nitrogen (e.g., from diazonium salts); sulfonates, including alkyl sulfonates (e.g., mesylate), fluoroalkyl sulfonates (e.g., triflate, hexaflate, nonaflate, and tresylate), and aryl sulfonates (e.g., tosylate, brosylate, closylate, and nosylate). Others include carbonates, halide ions, carboxylate anions, phenolate ions, and alkoxides. Some stronger bases, such as NH - and OH - can be made into a better leaving group by treatment with acid. Common electron-free leaving groups include the proton, CO2, and metals.

[0084] "Opposite enantiomer" refers to a molecule that is a non-superimposable mirror image of a reference molecule and can be obtained by inverting all of the chiral centers of the reference molecule. For example, if the reference molecule has S absolute stereochemical configuration, then the opposite enantiomer has R absolute stereochemical configuration. Similarly, if the reference molecule has S,S absolute stereochemical configuration, then the opposite enantiomer has R,R stereochemical configuration, and so on.

[0085] "Stereoisomer(s)" of a compound having a given stereochemical configuration refers to the opposite enantiomer of that compound and any diastereoisomers, including geometric isomers (Z / E) of that compound. For example, if a compound has an S,R,Z stereochemical configuration, then the stereoisomers can include its opposite enantiomer having the R,S,Z configuration, as well as its diastereoisomers having the S,S,Z, R,R,Z, S,R,E, R,S,E, S,S,E, and R,R,E configurations. If the stereochemical configuration of a compound is not specified, then "stereoisomer" refers to any one of the possible stereochemical configurations of the compound.

[0086] "Substantially pure stereoisomer" and variations thereof refer to a sample containing a compound having a particular stereochemical configuration, wherein said sample comprises at least about 95% of the sample.

[0087] "Pure stereoisomer" and variations thereof refer to a sample containing a compound with a particular stereochemical configuration, which comprises at least about 99.5% of the sample.

[0088] "Subject" refers to a mammal, including a human.

[0089] A "pharmaceutically acceptable" substance refers to a substance that is suitable for administration to a subject.

[0090] "Treating" refers to reversing, alleviating, inhibiting the progression of, or preventing the disease, disorder, or condition to which such term applies, or reversing, alleviating, inhibiting the progression of, or preventing one or more symptoms of such disease, disorder, or condition.

[0091] "Treatment" refers to the act of treating, as defined immediately above.

[0092] "Drug," "drug substance," "active pharmaceutical ingredient," and the like refer to a compound (e.g., a compound of Formula (I), including generic compounds and compounds specifically named herein, or a pharmaceutically acceptable salt thereof, or solvate thereof, or hydrate thereof) that can be used to treat a subject in need thereof.

[0093] An "effective amount" of a drug, a "therapeutically effective amount" of a drug, etc. refer to the amount of drug that can be used to treat a subject, which amount may depend, inter alia, on the weight and age of the subject and the route of administration.

[0094] "Excipient" refers to any diluent or vehicle for a drug.

[0095] A "pharmaceutical product" refers to a combination of one or more drug substances and one or more excipients. Sometimes such a combination is also referred to as a "formulation" or a "pharmaceutical composition."

[0096] "Drug product," "pharmaceutical dosage form," "dosage form," "final dosage form," and the like refer to a pharmaceutical composition or drug product suitable for treating a subject in need thereof, and may generally be in the form of a tablet, capsule, sachet containing powder or granules, liquid or suspension, patch, film, and the like.

[0097] "NLRP3-associated disease, disorder, or condition" and similar phrases refer to a disease, disorder, or condition in a subject in which inhibition of the NLRP3 inflammasome pathway can provide a therapeutic or prophylactic benefit.

[0098] The following abbreviations may be used herein: Ac (acetyl); AcO (acetic anhydride); ACN (acetonitrile); AIBN (azo-bis-isobutyronitrile); AmPhos (bis(di-tert-butyl-(4-dimethylaminophenyl)phosphine)dichloropalladium(II)); API (active pharmaceutical ingredient); aq (aqueous solution); BINAP (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl); Bn( Benzyl; Boc(tert-butoxycarbonyl); BrettPhos(2-(dicyclohexylphosphino)3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl); BrettPhos-Pd-G3([(2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(I I) Methanesulfonate; Cbz (carbobenzyloxy); Troc (2,2,2-trichloroethoxycarbonyl); dba (dibenzylideneacetone); DBU (1,8-diazabicyclo[5.4.0]undec-7-ene); DCC (1,3-dicyclohexylcarbodiimide); DCE (1,1-dichloroethane); DCM (dichloromethane); DEA (diethylamine); DIAD (diisopropyl azodicarboxylate); DIPEA (N,N-diisopropylethylamine, Hunig's base); DMA (N,N-dimethylacetamide); DMAP (4-dimethylaminopyridine); DME (1,2-dimethoxyethane); DMF (N,N-dimethylformamide); DMP (Dess-Martin periodinane); DMSO (dimethyl sulfoxide); dppf (1,1'-bis(diphenylphosphino)ferrocene); DTT (dithiothreitol); EC 50(effective concentration at half-maximal response); EDA (ethoxylated dodecyl alcohol, Brj® 35); EDC (N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide); EDTA (ethylenediaminetetraacetic acid); ee (enantiomeric excess); ELS (evaporative light scattering); eq (equivalent); Et (ethyl); EtN (triethylamine); EtOAc (ethyl acetate); EtOH (ethanol); FA (formic acid); HATU (2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate(V)); HEPES (4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid); HOAc (acetic acid); HOBt (1H-benzo[d][1,2,3]triazol-1-ol); IC 50 (Concentration at 50% inhibition); IPA (Isopropanol); IPAc (Isopropyl acetate); IPE (Isopropyl ether); LDA (Lithium diisopropylamide); LiHMDS (Lithium bis(trimethylsilyl)amide); mCPBA (m-chloroperbenzoic acid); Me (Methyl); MeOH (Methanol); MTBE (Methyl tert-butyl ether); mp (Melting point); NaOt-Bu (Sodium tert-butoxide); NMM (N-Methylmorpholine); NMP (1-Methyl-pyrrolidin-2-one); OTf (Triflate); PE (Petroleum Ether); Ph (Phenyl); pEC 50 (-log 10 (EC 50 ), where EC 50 is given in molar (M) units); pIC 50 (-log 10 (I C 50 ), where IC 50are given in moles (M); PMB (p-methoxybenzyl); Pr (propyl); c-Pr (cyclopropyl), i-Pr (isopropyl); PTFE (polytetrafluoroethylene); PyBOP ((benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate); PyBroP® (bromotripyrrolidinophosphonium hexafluorophosphate); PCy3 (tricyclohexylphosphine); RT (room temperature, approximately 20°C to 25°C); SFC (supercritical fluid chromatography); T3P (2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4 ,6-trioxide); TCEP (tris(2-carboxyethyl)phosphine); TFA (trifluoroacetic acid); TFAA (2,2,2-trifluoroacetic anhydride); THF (tetrahydrofuran); TMS (trimethylsilyl); Tris buffer (2-amino-2-hydroxymethyl-propane-1,3-diol buffer); XPhos (2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl); and XPhos-Pd-G2 (chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)).

[0099] As described below, the present disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a hydrate thereof (collectively sometimes referred to herein as compound (I)). The present disclosure also relates to materials and methods for preparing the compound of formula (I), or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a hydrate thereof, medicaments containing them, and the use of the compound of formula (I), or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a hydrate thereof (optionally in combination with other pharmacologically active agents) for treating neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, prion diseases, and other diseases, disorders, and / or conditions associated with NLRP3.

[0100] The definition of each variable in formula (I) is explained in detail below.

[0101] X is S or NR 7 and R 7 is defined as follows:

[0102] In one embodiment, X is S.

[0103] In one embodiment, X is NR 7 and R 7 is defined as follows:

[0104] R 7 is a hydrogen atom or an optionally substituted C 1-6 It is an alkyl group.

[0105] R 7 is preferably an optionally substituted C 1-6 It is an alkyl group.

[0106] R 7 is more preferably C 1-6 It is an alkyl group (eg, methyl).

[0107] X is preferably S or NR 7 and R 7 is C 1-6 It is an alkyl group (eg, methyl).

[0108] X is particularly preferably S.

[0109] Y is CR 8 (R 8 is as defined below), or N.

[0110] In one embodiment, Y is CR 8 and R 8 is defined as follows:

[0111] In one embodiment, Y is N.

[0112] R 8 is a hydrogen atom, a halogen atom, or an optionally substituted C 1-6 Alkyl groups, optionally substituted C 3-8 cycloalkyl, or optionally substituted C 1-6 It is an alkoxy group.

[0113] R 8 is preferably a halogen atom, optionally substituted C 1-6 Alkyl groups, optionally substituted C 3-8 cycloalkyl, or optionally substituted C 1-6 It is an alkoxy group.

[0114] R 8 is more preferably a halogen atom, an optionally substituted C 1-6 alkyl group, or optionally substituted C 3-8 It is cycloalkyl.

[0115] R 8 is even more preferably an optionally substituted C 1-6 alkyl group, or optionally substituted C 3-8 It is cycloalkyl.

[0116] R 8 is even more preferably an optionally substituted C 1-6 It is an alkyl group.

[0117] R 8 is even more preferably optionally halogenated C 1-6 It is an alkyl group.

[0118] R 8 is particularly preferably C 1-6 It is an alkyl group.

[0119] In another embodiment, R 8 is preferably (1) a hydrogen atom, (2) a halogen atom (e.g., a chlorine atom), (3) C optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) 1-6 alkyl groups (e.g., methyl, ethyl, isopropyl); (4) C optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) 3-8 a cycloalkyl group (e.g., cyclopropyl), or (5) C optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) 1-6 An alkoxy group (eg, methoxy).

[0120] R 8 is more preferably (1) a halogen atom (e.g., a chlorine atom), (2) C optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) 1-6 alkyl groups (e.g., methyl, ethyl, isopropyl); (3) C optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) 3-8 a cycloalkyl group (e.g., cyclopropyl), or (4) C optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) 1-6 Alkoxy groups (e.g., methoxy) is.

[0121] R 8 is even more preferably (1) a halogen atom (e.g., a chlorine atom), (2) C optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) 1-6 an alkyl group (e.g., methyl, ethyl, isopropyl), or (3) C optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) 3-8 cycloalkyl groups (e.g., cyclopropyl) is.

[0122] R 8 is even more preferably (1) C optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) 1-6 an alkyl group (e.g., methyl, ethyl, isopropyl), or (2) C optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) 3-8 cycloalkyl groups (e.g., cyclopropyl) is.

[0123] R 8 is even more preferably C optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atoms). 1-6 It is an alkyl group (eg, methyl, ethyl, isopropyl).

[0124] R 8 is particularly preferably C 1-6 It is an alkyl group (eg, methyl, ethyl).

[0125] Y is preferably CR 8 and R 8 teeth, (1) a hydrogen atom, (2) a halogen atom (e.g., a chlorine atom), (3) (i) a halogen atom (e.g., a fluorine atom) and (ii) C optionally substituted with 1 to 3 halogen atoms (e.g., a fluorine atom). 1-6 C optionally substituted by 1 to 3 substituents selected from alkoxy groups (e.g., methoxy) 1-6 alkyl groups (e.g., methyl, ethyl, isopropyl); (4) C optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) 3-8 a cycloalkyl group (e.g., cyclopropyl), or (5) C optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) 1-6 Alkoxy groups (e.g., methoxy), or N is.

[0126] Y is more preferably CR 8 and R 8 teeth, (1) a hydrogen atom, (2) a halogen atom (e.g., a chlorine atom), (3) (i) a halogen atom (e.g., a fluorine atom) and (ii) C optionally substituted with 1 to 3 halogen atoms (e.g., a fluorine atom). 1-6 C optionally substituted by 1 to 3 substituents selected from alkoxy groups (e.g., methoxy) 1-6 alkyl groups (e.g., methyl, ethyl, isopropyl); (4) C optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) 3-8 a cycloalkyl group (e.g., cyclopropyl), or (5) C optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) 1-6 Alkoxy groups (e.g., methoxy) is.

[0127] Y is even more preferably CR 8 and R 8 teeth, (1) a halogen atom (e.g., a chlorine atom), (2) (i) a halogen atom (e.g., a fluorine atom) and (ii) C optionally substituted with 1 to 3 halogen atoms (e.g., a fluorine atom). 1-6 C optionally substituted by 1 to 3 substituents selected from alkoxy groups (e.g., methoxy) 1-6 alkyl groups (e.g., methyl, ethyl, isopropyl); (3) C optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) 3-8 a cycloalkyl group (e.g., cyclopropyl), or (4) C optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) 1-6 An alkoxy group (eg, methoxy).

[0128] Y is even more preferably CR 8 and R 8is (i) a halogen atom (e.g., a fluorine atom) and (ii) C optionally substituted with 1 to 3 halogen atoms (e.g., a fluorine atom). 1-6 C optionally substituted by 1 to 3 substituents selected from alkoxy groups (e.g., methoxy) 1-6 It is an alkyl group (eg, methyl, ethyl, isopropyl).

[0129] Y is particularly preferably CR 8 and R 8 is C 1-6 It is an alkyl group (eg, methyl, ethyl).

[0130] R 1 is an optionally substituted 4-membered heterocyclic group or a 5- or 6-membered heterocyclic group, an optionally substituted C 1-6 alkyl group, or optionally substituted C 3-10 It is a cycloalkyl group.

[0131] R 1 is preferably (1) an optionally substituted 4-membered heterocyclic group or a 5- or 6-membered heterocyclic group; (2) C substituted by hetero-substituent(s) 1-6 an alkyl group, or (3) C substituted by hetero-substituent(s) 3-10 cycloalkyl group is.

[0132] R 1 is more preferably an optionally substituted 4-membered heterocyclic group or a 5- or 6-membered heterocyclic group.

[0133] R 1 is even more preferably an optionally substituted 4-membered heterocyclic group or a 5- or 6-membered non-aromatic heterocyclic group.

[0134] R 1 is even more preferably an optionally substituted 4-membered heterocyclic group or a 5- or 6-membered nitrogen-containing non-aromatic heterocyclic group.

[0135] R 1 is even more preferably a group of formula (A'), [ka] During the ceremony, R 11 is a hydrogen atom or a substituent, R 10 are each independently a substituent, or two R 10 together to form an oxo group, m is 0, 1, 2, 3, or 4; k is 0, 1, or 2; l is 0, 1, or 2; k+l is 1 or 2.

[0136] R 1 is even more preferably a group of formula (A), [ka] During the ceremony, R 9 is a hydrogen atom or a substituent, R 10 are each independently a substituent, or two R 10 together to form an oxo group, m is 0, 1, 2, 3, or 4; n is 1 or 2.

[0137] R 9 is preferably (1) a hydrogen atom, (2) optionally substituted C 1-6 alkyl groups, (3) optionally substituted C 3-8 cycloalkyl groups, (4) optionally substituted C 1-6 alkyl-carbonyl groups, (5) optionally substituted C 3-8a cycloalkyl-carbonyl group, (6) optionally substituted C 1-6 alkoxy-carbonyl groups, (7) optionally substituted C 7-16 aralkyloxy-carbonyl groups, (8) optionally substituted mono- or di-C 1-6 alkyl-carbamoyl groups, (9) optionally substituted C 1-6 alkylsulfonyl groups, (10) optionally substituted C 3-8 a cycloalkylsulfonyl group, or (11) Optionally substituted 3- to 8-membered non-aromatic heterocyclic group is.

[0138] R 10 is preferably (1) a halogen atom, (2) optionally substituted C 1-6 an alkyl group, or (3) optionally substituted C 1-6 alkoxy group or The Two R's 10 together form an oxo group.

[0139] m is preferably 0, 1, or 2.

[0140] In another embodiment, R 1 is preferably (1) A 4-membered heterocyclic group or a 5- or 6-membered heterocyclic group (preferably a 4-membered heterocyclic group or a 5- or 6-membered non-aromatic heterocyclic group (e.g., oxetanyl, pyrrolidinyl, piperidyl, tetrahydrofuranyl, tetrahydropyranyl) optionally substituted with 1 to 3 substituents selected from the following: (a) a halogen atom (e.g., a fluorine atom), (b) an oxo group, (c) C optionally substituted with 1 to 3 substituents selected from the following: 1-6alkyl groups (e.g., methyl, ethyl); (i) a halogen atom (e.g., a fluorine atom), and (ii) C 1-6 alkoxy groups (e.g., methoxy), (d)C 3-8 cycloalkyl groups (e.g., cyclopropyl); (e) a hydroxy group, (f)C 1-6 alkoxy groups (e.g., methoxy), (g) C optionally substituted with 1 to 3 substituents selected from the following: 1-6 alkyl-carbonyl groups (e.g., acetyl, propanoyl, 2-methylpropanoyl); (i) a halogen atom (e.g., a fluorine atom), (ii) a hydroxy group, (iii)C 1-6 alkoxy groups (e.g., methoxy), and (iv) C 3-8 cycloalkyl groups (e.g., cyclopropyl); (h) C optionally substituted with 1 to 3 substituents selected from the following: 3-8 a cycloalkyl-carbonyl group (e.g., cyclopropylcarbonyl), (i) a halogen atom (e.g., a fluorine atom), (ii) a cyano group, and (iii) a hydroxy group, (i) C optionally substituted with 1 to 3 halogen atoms (e.g., chlorine atoms) 1-6 alkoxy-carbonyl groups (e.g., methoxycarbonyl, ethoxycarbonyl), (j)C 3-8 cycloalkoxy-carbonyl groups (e.g., cyclopropoxycarbonyl), (k)C 7-16 aralkyloxy-carbonyl groups (e.g., benzyloxycarbonyl), (l) Mono- or Di-C 1-6 alkyl-carbamoyl groups (e.g., methylcarbamoyl); (m)C 1-6alkylsulfonyl groups (e.g., methylsulfonyl), (n)C 3-8 cycloalkylsulfonyl groups (e.g., cyclopropylsulfonyl), and (o) a 3- to 8-membered non-aromatic heterocyclic group (e.g., tetrahydrofuranyl), (2) C optionally substituted with 1 to 3 substituents selected from the following: 1-6 alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, isopentyl); (a) a hydroxy group, (b) C optionally substituted with a halogen atom (e.g., a fluorine atom) 1-6 alkoxy groups (e.g., methoxy), (c) C optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) 3-8 cycloalkyl groups (e.g., cyclopropyl, cyclobutyl); (d) Mono- or di-C 1-6 alkylamino groups (e.g., dimethylamino), (e)C 1-6 alkyl-carbonylamino groups (e.g., acetylamino); (f) 3- to 8-membered non-aromatic heterocyclic groups optionally substituted with hydroxy groups (e.g., oxetanyl, morpholinyl, tetrahydrofuranyl), and (g) halogen atoms (e.g., fluorine atoms), and (h) a 5- to 14-membered aromatic heterocyclyl group (e.g., pyridyl), or (3) C optionally substituted with 1 to 3 substituents selected from the following: 3-10 Cycloalkyl groups (C 3-10 The cycloalkyl group may be a spirocyclic group or a bridged spirocyclic group, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, spiro[3.3]heptanyl, bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptanyl, adamantyl). (a) a hydroxy group, (b) C optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atoms)1-6 alkyl groups (e.g., methyl), and (c) C optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) 1-6 Alkoxy groups (e.g., methoxy) is.

[0141] R 1 is more preferably (1) a 4-membered heterocyclic group or a 5- or 6-membered heterocyclic group (preferably a 4- to 6-membered non-aromatic heterocyclic group (e.g., oxetanyl, pyrrolidinyl, piperidyl, tetrahydrofuranyl, tetrahydropyranyl)) (this heterocyclic group is optionally substituted with 1 to 3 substituents selected from the following): (a) a halogen atom (e.g., a fluorine atom), (b) an oxo group, (c) C optionally substituted with 1 to 3 substituents selected from the following: 1-6 alkyl groups (e.g., methyl, ethyl); (i) a halogen atom (e.g., a fluorine atom), and (ii) C 1-6 alkoxy groups (e.g., methoxy), (d)C 3-8 cycloalkyl groups (e.g., cyclopropyl); (e) a hydroxy group, (f)C 1-6 alkoxy groups (e.g., methoxy), (g) C optionally substituted with 1 to 3 substituents selected from the following: 1-6 alkyl-carbonyl groups (e.g., acetyl, propanoyl, 2-methylpropanoyl); (i) a halogen atom (e.g., a fluorine atom), (ii) a hydroxy group, (iii)C 1-6 alkoxy groups (e.g., methoxy), and (iv) C 3-8 cycloalkyl groups (e.g., cyclopropyl); (h) C optionally substituted with 1 to 3 substituents selected from the following: 3-8a cycloalkyl-carbonyl group (e.g., cyclopropylcarbonyl), (i) a halogen atom (e.g., a fluorine atom), (ii) a cyano group, and (iii) a hydroxy group, (i) C optionally substituted with 1 to 3 halogen atoms (e.g., chlorine atoms) 1-6 alkoxy-carbonyl groups (e.g., methoxycarbonyl, ethoxycarbonyl), (j)C 3-8 cycloalkoxy-carbonyl groups (e.g., cyclopropoxycarbonyl), (k)C 7-16 aralkyloxy-carbonyl groups (e.g., benzyloxycarbonyl), (l) Mono- or Di-C 1-6 alkyl-carbamoyl groups (e.g., methylcarbamoyl); (m)C 1-6 alkylsulfonyl groups (e.g., methylsulfonyl), (n)C 3-8 cycloalkylsulfonyl groups (e.g., cyclopropylsulfonyl), and (o) a 3- to 8-membered non-aromatic heterocyclic group (e.g., tetrahydrofuranyl), (2) C substituted with 1 to 3 substituents selected from the following: 1-6 alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, isopentyl); (a) a hydroxy group, (b) C optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) 1-6 Alkoxy groups (e.g., methoxy). (c) C substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) 3-8 cycloalkyl groups (e.g., cyclopropyl, cyclobutyl); (d) Mono- or di-C 1-6 alkylamino groups (e.g., dimethylamino), (e)C 1-6alkyl-carbonylamino groups (e.g., acetylamino); (f) 3- to 8-membered non-aromatic heterocyclic groups optionally substituted with hydroxy groups (e.g., oxetanyl, morpholinyl, tetrahydrofuranyl), (g) halogen atoms (e.g., fluorine atoms), and (h) a 5- to 14-membered aromatic heterocyclyl group (e.g., pyridyl), or (3) Substituted with one hydroxy group and one or two C 1-6 C optionally substituted with alkyl groups (e.g., methyl) 3-10 Cycloalkyl groups (C 3-10 The cycloalkyl group may be a spirocyclic group or a bridged spirocyclic group, for example, cyclobutyl, cyclopentyl, cyclohexyl, spiro[3.3]heptanyl, bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptanyl, adamantyl. is.

[0142] R 1 is even more preferably a 4-membered heterocyclic group or a 5- or 6-membered heterocyclic group (preferably a 4-membered heterocyclic group or a 5- or 6-membered non-aromatic heterocyclic group (e.g., oxetanyl, pyrrolidinyl, piperidyl, tetrahydrofuranyl, tetrahydropyranyl), which heterocyclic group is optionally substituted with 1 to 3 substituents selected from the following: (a) a halogen atom (e.g., a fluorine atom), (b) an oxo group, (c) C optionally substituted with 1 to 3 substituents selected from the following: 1-6 alkyl groups (e.g., methyl, ethyl); (i) a halogen atom (e.g., a fluorine atom), and (ii) C 1-6 alkoxy groups (e.g., methoxy), (d)C 3-8 cycloalkyl groups (e.g., cyclopropyl); (e) a hydroxy group, (f)C 1-6 alkoxy groups (e.g., methoxy), (g) C optionally substituted with 1 to 3 substituents selected from the following: 1-6 alkyl-carbonyl groups (e.g., acetyl, propanoyl, 2-methylpropanoyl); (i) a halogen atom (e.g., a fluorine atom), (ii) a hydroxy group, (iii)C 1-6 alkoxy groups (e.g., methoxy), and (iv) C 3-8 cycloalkyl groups (e.g., cyclopropyl); (h) C optionally substituted with 1 to 3 substituents selected from the following: 3-8 a cycloalkyl-carbonyl group (e.g., cyclopropylcarbonyl), (i) a halogen atom (e.g., a fluorine atom), (ii) a cyano group, and (iii) a hydroxy group, (i) C optionally substituted with 1 to 3 halogen atoms (e.g., chlorine atoms) 1-6 alkoxy-carbonyl groups (e.g., methoxycarbonyl, ethoxycarbonyl), (j)C 3-8 cycloalkoxy-carbonyl groups (e.g., cyclopropoxycarbonyl), (k)C 7-16 aralkyloxy-carbonyl groups (e.g., benzyloxycarbonyl), (l) Mono- or Di-C 1-6 alkyl-carbamoyl groups (e.g., methylcarbamoyl); (m)C 1-6 alkylsulfonyl groups (e.g., methylsulfonyl), (n)C 3-8 cycloalkylsulfonyl groups (e.g., cyclopropylsulfonyl), and (o) 3- to 8-membered non-aromatic heterocyclic groups (e.g., tetrahydrofuranyl).

[0143] R 1 is even more preferably a group of formula (A), [ka] During the ceremony, R 9 teeth, (1) a hydrogen atom, (2) C optionally substituted with 1 to 3 substituents selected from the following: 1-6 alkyl groups (e.g., methyl, ethyl); (i) a halogen atom (e.g., a fluorine atom), and (ii) C 1-6 alkoxy groups (e.g., methoxy), (3) C 3-8 cycloalkyl groups (e.g., cyclopropyl); (4) C optionally substituted with 1 to 3 substituents selected from the following: 1-6 alkyl-carbonyl groups (e.g., acetyl, propanoyl, 2-methylpropanoyl); (i) a halogen atom (e.g., a fluorine atom), (ii) a hydroxy group, (iii)C 1-6 alkoxy groups (e.g., methoxy), and (iv) C 3-8 cycloalkyl groups (e.g., cyclopropyl); (5) C optionally substituted with 1 to 3 substituents selected from the following: 3-8 a cycloalkyl-carbonyl group (e.g., cyclopropylcarbonyl), (i) a halogen atom (e.g., a fluorine atom), (ii) a cyano group, and (iii) a hydroxy group, (6) C optionally substituted with 1 to 3 halogen atoms (e.g., chlorine atoms) 1-6 alkoxy-carbonyl groups (e.g., methoxycarbonyl, ethoxycarbonyl), (7) C 7-16 aralkyloxy-carbonyl groups (e.g., benzyloxycarbonyl), (8) Mono- or di-C 1-6 alkyl-carbamoyl groups (e.g., methylcarbamoyl); (9) C1-6 alkylsulfonyl groups (e.g., methylsulfonyl), (10)C 3-8 a cycloalkylsulfonyl group (e.g., cyclopropylsulfonyl), or (11) 3- to 8-membered non-aromatic heterocyclic groups (e.g., tetrahydrofuranyl) and R 10 teeth, (1) Halogen atoms (e.g., fluorine atoms, chlorine atoms, bromine atoms), (2) C optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) 1-6 an alkyl group (e.g., methyl), or (3) C 1-6 Alkoxy groups (e.g., methoxy) or The Two R's 10 together form an oxo group, m is 0, 1, or 2; n is 1 or 2.

[0144] R 1 is even more preferably a 6-membered non-aromatic heterocyclic group (preferably a 6-membered nitrogen-containing non-aromatic heterocyclic group (e.g., piperidyl)) substituted with one or two substituents selected from the following: (a) a halogen atom (e.g., a fluorine atom), and (b)C 1-6 Alkyl groups (e.g., methyl) is.

[0145] R 1 is particularly preferably a piperidyl group substituted by one or two substituents selected from the following: (a) a halogen atom (e.g., a fluorine atom), and (b)C 1-2 Alkyl groups (e.g., methyl) is.

[0146] R 2 is a hydrogen atom or an optionally substituted C 1-3It is an alkyl group.

[0147] In one embodiment, R 2 is a hydrogen atom.

[0148] In one embodiment, R 2 is an arbitrarily substituted C 1-3 It is an alkyl group.

[0149] In another embodiment, R 2 is preferably (1) a hydrogen atom, or (2) 1 to 3 Cs 1-6 C optionally substituted with an alkoxy group (e.g., methoxy) 1-3 Alkyl groups (e.g., methyl, ethyl) is.

[0150] R 2 is particularly preferably a hydrogen atom.

[0151] R 3 , R 4 , and R 5 are each independently a hydrogen atom, a halogen atom, or an optionally substituted C 1-6 Alkyl groups, optionally substituted C 3-8 a cycloalkyl group, or an optionally substituted C 1-6 It is an alkoxy group.

[0152] R 3 is preferably a hydrogen atom, a halogen atom, an optionally substituted C 1-6 alkyl group, or optionally substituted C 3-8 It is a cycloalkyl group.

[0153] R 3 is more preferably a hydrogen atom, a halogen atom, or an optionally substituted C 1-6 It is an alkyl group.

[0154] R 3 is even more preferably a hydrogen atom, a halogen atom, or C 1-6 It is an alkyl group.

[0155] R 3 is even more preferably a hydrogen atom, or C 1-6 It is an alkyl group.

[0156] R 3 is particularly preferably a hydrogen atom.

[0157] R 4 is preferably a halogen atom, an optionally substituted C 1-6 alkyl group, or optionally substituted C 1-6 It is an alkoxy group.

[0158] R 4 is more preferably a halogen atom or an optionally substituted C 1-6 It is an alkyl group.

[0159] R 4 is even more preferably a hydrogen atom, or C 1-6 It is an alkyl group.

[0160] R 4 is particularly preferably C 1-6 It is an alkyl group.

[0161] In another embodiment, R 4 is preferably (1) a hydrogen atom, (2) halogen atoms (e.g., fluorine atoms, chlorine atoms, bromine atoms), (3) C optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) 1-6 an alkyl group (e.g., methyl, ethyl), or (4) C optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) 1-6 Alkoxy groups (e.g., methoxy) is.

[0162] R 4 is more preferably (1) Halogen atoms (e.g., fluorine atoms, chlorine atoms, bromine atoms), (2) C optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) 1-6 an alkyl group (e.g., methyl, ethyl), or (3) C optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) 1-6 Alkoxy groups (e.g., methoxy) is.

[0163] R 4 is even more preferably (1) a halogen atom (e.g., a fluorine atom, a chlorine atom, or a bromine atom), or (2) C optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) 1-6 Alkyl groups (e.g., methyl, ethyl) is.

[0164] R 4 is even more preferably (1) a halogen atom (e.g., a fluorine atom, a chlorine atom, or a bromine atom), or (2) C 1-6 Alkyl groups (e.g., methyl, ethyl) is.

[0165] R 4 is particularly preferably C 1-6 It is an alkyl group (eg, methyl).

[0166] R 5 is preferably a hydrogen atom, a halogen atom, an optionally substituted C 1-6 alkyl group, or optionally substituted C 3-8 It is a cycloalkyl group.

[0167] R 5 is more preferably a hydrogen atom, a halogen atom, or an optionally substituted C 1-6 It is an alkyl group.

[0168] R 5is even more preferably a hydrogen atom, a halogen atom, or C 1-6 It is an alkyl group.

[0169] R 5 is even more preferably a hydrogen atom, or C 1-6 It is an alkyl group.

[0170] R 5 is particularly preferably a hydrogen atom.

[0171] R 6 is a hydrogen atom or an optionally substituted C 1-6 It is an alkyl group.

[0172] R 6 is preferably a hydrogen atom or C 1-6 It is an alkyl group.

[0173] R 6 is particularly preferably a hydrogen atom.

[0174] In another embodiment, R 6 is preferably a hydrogen atom or C 1-6 It is an alkyl group (eg, methyl).

[0175] R 6 is particularly preferably a hydrogen atom.

[0176] Preferred embodiments of the compounds of formula (I) include the following compounds:

[0177] [Compound A] A compound of formula (I), wherein X is S or NR 7 and Y is CR 8 or N, R 1 but, (1) A 4-membered heterocyclic group or a 5- or 6-membered heterocyclic group (preferably a 4-membered heterocyclic group or a 5- or 6-membered non-aromatic heterocyclic group (e.g., oxetanyl, pyrrolidinyl, piperidyl, tetrahydrofuranyl, tetrahydropyranyl)), wherein the heterocyclic group is optionally substituted with 1 to 3 substituents selected from the following: (a) a halogen atom (e.g., a fluorine atom), (b) an oxo group, (c) C optionally substituted with 1 to 3 substituents selected from the following: 1-6 alkyl groups (e.g., methyl, ethyl); (i) a halogen atom (e.g., a fluorine atom), and (ii) C 1-6 alkoxy groups (e.g., methoxy), (d)C 3-8 cycloalkyl groups (e.g., cyclopropyl); (e) a hydroxy group, (f)C 1-6 alkoxy groups (e.g., methoxy), (g) C optionally substituted with 1 to 3 substituents selected from the following: 1-6 alkyl-carbonyl groups (e.g., acetyl, propanoyl, 2-methylpropanoyl); (i) a halogen atom (e.g., a fluorine atom), (ii) a hydroxy group, (iii)C 1-6 alkoxy groups (e.g., methoxy), and (iv) C 3-8 cycloalkyl groups (e.g., cyclopropyl); (h) C optionally substituted with 1 to 3 substituents selected from the following: 3-8 a cycloalkyl-carbonyl group (e.g., cyclopropylcarbonyl), (i) a halogen atom (e.g., a fluorine atom), (ii) a cyano group, and (iii) a hydroxy group, (i) C optionally substituted with 1 to 3 halogen atoms (e.g., chlorine atoms) 1-6alkoxy-carbonyl groups (e.g., methoxycarbonyl, ethoxycarbonyl), (j)C 3-8 cycloalkoxy-carbonyl groups (e.g., cyclopropoxycarbonyl), (k)C 7-16 aralkyloxy-carbonyl groups (e.g., benzyloxycarbonyl), (l) Mono- or Di-C 1-6 alkyl-carbamoyl groups (e.g., methylcarbamoyl); (m)C 1-6 alkylsulfonyl groups (e.g., methylsulfonyl), (n)C 3-8 cycloalkylsulfonyl groups (e.g., cyclopropylsulfonyl), and (o) a 3- to 8-membered non-aromatic heterocyclic group (e.g., tetrahydrofuranyl), (2) C optionally substituted with 1 to 3 substituents selected from the following: 1-6 alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, isopentyl); (a) a hydroxy group, (b) C optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) 1-6 Alkoxy groups (e.g., methoxy). (c) C optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) 3-8 cycloalkyl groups (e.g., cyclopropyl, cyclobutyl); (d) Mono- or di-C 1-6 alkylamino groups (e.g., dimethylamino), (e)C 1-6 alkyl-carbonylamino groups (e.g., acetylamino); (f) 3- to 8-membered non-aromatic heterocyclic groups optionally substituted with hydroxy groups (e.g., oxetanyl, morpholinyl, tetrahydrofuranyl), (g) halogen atoms (e.g., fluorine atoms), and (h) a 5- to 14-membered aromatic heterocyclyl group (e.g., pyridyl), or (3) C optionally substituted with 1 to 3 substituents selected from the following: 3-10 Cycloalkyl groups (C 3-10 The cycloalkyl group may be a spirocyclic group or a bridged spirocyclic group, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, spiro[3.3]heptanyl, bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptanyl, adamantyl). (a) a hydroxy group, (b) C optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) 1-6 alkyl groups (e.g., methyl), and (c) C optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) 1-6 Alkoxy groups (e.g., methoxy) and R 2 but, (1) a hydrogen atom, or (2) 1 to 3 Cs 1-6 C optionally substituted with an alkoxy group (e.g., methoxy) 1-3 Alkyl groups (e.g., methyl, ethyl) and R 3 is a hydrogen atom, R 4 but, (1) a hydrogen atom, (2) halogen atoms (e.g., fluorine atoms, chlorine atoms, bromine atoms), (3) C optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) 1-6 an alkyl group (e.g., methyl, ethyl), or (4) C optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) 1-6 Alkoxy groups (e.g., methoxy) and R 5 is a hydrogen atom, R 6 is a hydrogen atom or C 1-6 an alkyl group (e.g., methyl), R 7 But C1-6 an alkyl group (e.g., methyl), R 8 but, (1) a hydrogen atom, (2) a halogen atom (e.g., a chlorine atom), (3) (i) a halogen atom (e.g., a fluorine atom) and (ii) C optionally substituted with 1 to 3 halogen atoms (e.g., a fluorine atom). 1-6 C optionally substituted by 1 to 3 substituents selected from alkoxy groups (e.g., methoxy) 1-6 alkyl groups (e.g., methyl, ethyl, isopropyl); (4) C optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) 3-8 a cycloalkyl group (e.g., cyclopropyl), or (5) C optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) 1-6 Alkoxy groups (e.g., methoxy) The compound of formula (I)

[0178] [Compound B-1] A compound of formula (I), wherein R 1 but, (1) A 4-membered heterocyclic group or a 5- or 6-membered heterocyclic group (preferably a 4-membered heterocyclic group or a 5- or 6-membered non-aromatic heterocyclic group (e.g., oxetanyl, pyrrolidinyl, piperidyl, tetrahydrofuranyl, tetrahydropyranyl)), wherein the heterocyclic group is optionally substituted with 1 to 3 substituents selected from the following: (a) a halogen atom (e.g., a fluorine atom), (b) an oxo group, (c) C optionally substituted with 1 to 3 substituents selected from the following: 1-6 alkyl groups (e.g., methyl, ethyl); (i) a halogen atom (e.g., a fluorine atom), and (ii) C 1-6 alkoxy groups (e.g., methoxy), (d)C3-8 cycloalkyl groups (e.g., cyclopropyl); (e) a hydroxy group, (f)C 1-6 alkoxy groups (e.g., methoxy), (g) C optionally substituted with 1 to 3 substituents selected from the following: 1-6 alkyl-carbonyl groups (e.g., acetyl, propanoyl, 2-methylpropanoyl); (i) a halogen atom (e.g., a fluorine atom), (ii) a hydroxy group, (iii)C 1-6 alkoxy groups (e.g., methoxy), and (iv) C 3-8 cycloalkyl groups (e.g., cyclopropyl); (h) C optionally substituted with 1 to 3 substituents selected from the following: 3-8 a cycloalkyl-carbonyl group (e.g., cyclopropylcarbonyl), (i) a halogen atom (e.g., a fluorine atom), (ii) a cyano group, and (iii) a hydroxy group, (i) C optionally substituted with 1 to 3 halogen atoms (e.g., chlorine atoms) 1-6 alkoxy-carbonyl groups (e.g., methoxycarbonyl, ethoxycarbonyl), (j)C 3-8 cycloalkoxy-carbonyl groups (e.g., cyclopropoxycarbonyl), (k)C 7-16 aralkyloxy-carbonyl groups (e.g., benzyloxycarbonyl), (l) Mono- or Di-C 1-6 alkyl-carbamoyl groups (e.g., methylcarbamoyl); (m)C 1-6 alkylsulfonyl groups (e.g., methylsulfonyl), (n)C 3-8 cycloalkylsulfonyl groups (e.g., cyclopropylsulfonyl), and (o) a 3- to 8-membered non-aromatic heterocyclic group (e.g., tetrahydrofuranyl), (2) C substituted with 1 to 3 substituents selected from the following: 1-6 alkyl groups (e.g., methyl, ethyl, propyl, butyl, isobutyl, sec-butyl, isopentyl); (a) a hydroxy group, (b) C optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) 1-6 alkoxy groups (e.g., methoxy), (c) C substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) 3-8 cycloalkyl groups (e.g., cyclopropyl, cyclobutyl); (d) Mono- or di-C 1-6 alkylamino groups (e.g., dimethylamino), (e)C 1-6 alkyl-carbonylamino groups (e.g., acetylamino); (f) 3- to 8-membered non-aromatic heterocyclic groups optionally substituted with hydroxy groups (e.g., oxetanyl, morpholinyl, tetrahydrofuranyl), and (g) halogen atoms (e.g., fluorine atoms), and (h) a 5- to 14-membered aromatic heterocyclyl group (e.g., pyridyl), or (3) C optionally substituted with 1 to 3 substituents selected from the following: 3-10 Cycloalkyl groups (C 3-10 The cycloalkyl group may be a spirocyclic group or a bridged spirocyclic group, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, spiro[3.3]heptanyl, bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptanyl, adamantyl). (a) a hydroxy group, (b) C optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) 1-6 alkyl groups (e.g., methyl), and (c) C optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) 1-6 Alkoxy groups (e.g., methoxy) and The compound of formula (I) above, wherein the other variables are as defined in [Compound A].

[0179] [Compound B-2] A compound of formula (I), wherein R 1 is a 4-membered heterocyclic group or a 5- or 6-membered heterocyclic group (preferably a 4-membered heterocyclic group or a 5- or 6-membered non-aromatic heterocyclic group (e.g., oxetanyl, pyrrolidinyl, piperidyl, tetrahydrofuranyl, tetrahydropyranyl)), which is optionally substituted with 1 to 3 substituents selected from the following: (a) a halogen atom (e.g., a fluorine atom), (b) an oxo group, (c) C optionally substituted with 1 to 3 substituents selected from the following: 1-6 alkyl groups (e.g., methyl, ethyl); (i) a halogen atom (e.g., a fluorine atom), and (ii) C 1-6 alkoxy groups (e.g., methoxy), (d)C 3-8 cycloalkyl groups (e.g., cyclopropyl); (e) a hydroxy group, (f)C 1-6 alkoxy groups (e.g., methoxy), (g) C optionally substituted with 1 to 3 substituents selected from the following: 1-6 alkyl-carbonyl groups (e.g., acetyl, propanoyl, 2-methylpropanoyl); (i) a halogen atom (e.g., a fluorine atom), (ii) a hydroxy group, (iii)C 1-6 alkoxy groups (e.g., methoxy), and (iv) C 3-8 cycloalkyl groups (e.g., cyclopropyl); (h) C optionally substituted with 1 to 3 substituents selected from the following: 3-8a cycloalkyl-carbonyl group (e.g., cyclopropylcarbonyl), (i) a halogen atom (e.g., a fluorine atom), (ii) a cyano group, and (iii) a hydroxy group, (i) C optionally substituted with 1 to 3 halogen atoms (e.g., chlorine atoms) 1-6 alkoxy-carbonyl groups (e.g., methoxycarbonyl, ethoxycarbonyl), (j)C 3-8 cycloalkoxy-carbonyl groups (e.g., cyclopropoxycarbonyl), (k)C 7-16 aralkyloxy-carbonyl groups (e.g., benzyloxycarbonyl), (l) Mono- or Di-C 1-6 alkyl-carbamoyl groups (e.g., methylcarbamoyl); (m)C 1-6 alkylsulfonyl groups (e.g., methylsulfonyl), (n)C 3-8 cycloalkylsulfonyl groups (e.g., cyclopropylsulfonyl), and (o) 3- to 8-membered non-aromatic heterocyclic group (e.g., tetrahydrofuranyl) and The compound of formula (I) above, wherein the other variables are as defined in [Compound A].

[0180] [Compound B-3] A compound of formula (I), wherein R 1 is a group of formula (A), [ka] During the ceremony, R 9 but, (1) a hydrogen atom, (2) C optionally substituted with 1 to 3 substituents selected from the following: 1-6 alkyl groups (e.g., methyl, ethyl); (i) a halogen atom (e.g., a fluorine atom), and (ii) C 1-6 alkoxy groups (e.g., methoxy), (3) C 3-8 cycloalkyl groups (e.g., cyclopropyl); (4) C optionally substituted with 1 to 3 substituents selected from the following: 1-6 alkyl-carbonyl groups (e.g., acetyl, propanoyl, 2-methylpropanoyl); (i) a halogen atom (e.g., a fluorine atom), (ii) a hydroxy group, (iii)C 1-6 alkoxy groups (e.g., methoxy), and (iv) C 3-8 cycloalkyl groups (e.g., cyclopropyl); (5) C optionally substituted with 1 to 3 substituents selected from the following: 3-8 a cycloalkyl-carbonyl group (e.g., cyclopropylcarbonyl), (i) a halogen atom (e.g., a fluorine atom), (ii) a cyano group, and (iii) a hydroxy group, (6) C optionally substituted with 1 to 3 halogen atoms (e.g., chlorine atoms) 1-6 alkoxy-carbonyl groups (e.g., methoxycarbonyl, ethoxycarbonyl), (7) C 7-16 aralkyloxy-carbonyl groups (e.g., benzyloxycarbonyl), (8) Mono- or di-C 1-6 alkyl-carbamoyl groups (e.g., methylcarbamoyl); (9) C 1-6 alkylsulfonyl groups (e.g., methylsulfonyl), (10)C 3-8 a cycloalkylsulfonyl group (e.g., cyclopropylsulfonyl), or (11) 3- to 8-membered non-aromatic heterocyclic groups (e.g., tetrahydrofuranyl) and R10 but, (1) Halogen atoms (e.g., fluorine atoms, chlorine atoms, bromine atoms), (2) C optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) 1-6 an alkyl group (e.g., methyl), or (3) C 1-6 Alkoxy groups (e.g., methoxy) or The Two R's 10 together form an oxo group, m is 0, 1, or 2; n is 1 or 2, The compound of formula (I) above, wherein the other variables are as defined in [Compound A].

[0181] [Compound C-1] A compound of formula (I), wherein X is S, The compound of formula (I) wherein the other variables are as defined in [Compound A], [Compound B-1], [Compound B-2], or [Compound B-3].

[0182] [Compound C-2] A compound of formula (I), wherein X is NR 7 and R 7 C 1-6 an alkyl group (e.g., methyl),

[0183] The compound of formula (I) above, wherein the other variables are as defined in [Compound A], [Compound B-1], [Compound B-2], or [Compound B-3]. [Compound D-1] A compound of formula (I), wherein R 2 is a hydrogen atom, The compound of formula (I) wherein the other variables are as defined in [Compound A], [Compound B-1], [Compound B-2], [Compound B-3], [Compound C-1], or [Compound C-2].

[0184] [Compound D-2] A compound of formula (I), wherein R 2 But 1 to 3 C 1-6 C optionally substituted with an alkoxy group (e.g., methoxy) 1-3 an alkyl group (e.g., methyl, ethyl), The compound of formula (I) wherein the other variables are as defined in [Compound A], [Compound B-1], [Compound B-2], [Compound B-3], [Compound C-1], or [Compound C-2].

[0185] [Compound E-1] A compound of formula (I), wherein Y is CR 8 and R 8 but, (1) a hydrogen atom, (2) a halogen atom (e.g., a chlorine atom), (3) (i) a halogen atom (e.g., a fluorine atom) and (ii) C 1-6 C optionally substituted by 1 to 3 substituents selected from alkoxy groups (e.g., methoxy) 1-6 alkyl groups (e.g., methyl, ethyl, isopropyl); (4) C optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) 3-8 a cycloalkyl group (e.g., cyclopropyl), or (5) C optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) 1-6 Alkoxy groups (e.g., methoxy) and A compound of formula (I) wherein the other variables are as defined in [Compound A], [Compound B-1], [Compound B-2], [Compound B-3], [Compound C-1], [Compound C-2], [Compound D-1], or [Compound D-2].

[0186] [Compound E-2] A compound of formula (I), wherein Y is CR 8 and R 8 but, (1) a halogen atom (e.g., a chlorine atom), (2) (i) a halogen atom (e.g., a fluorine atom) and (ii) C 1-6 C optionally substituted by 1 to 3 substituents selected from alkoxy groups (e.g., methoxy) 1-6 alkyl groups (e.g., methyl, ethyl, isopropyl); (3) C optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) 3-8 a cycloalkyl group (e.g., cyclopropyl), or (4) C optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) 1-6 Alkoxy groups (e.g., methoxy) and A compound of formula (I) wherein the other variables are as defined in [Compound A], [Compound B-1], [Compound B-2], [Compound B-3], [Compound C-1], [Compound C-2], [Compound D-1], or [Compound D-2].

[0187] [Compound E-3] A compound of formula (I), wherein Y is CR 8 and R 8 (i) a halogen atom (e.g., a fluorine atom) and (ii) C 1-6 C optionally substituted by 1 to 3 substituents selected from alkoxy groups (e.g., methoxy) 1-6 an alkyl group (e.g., methyl, ethyl, isopropyl); A compound of formula (I) wherein the other variables are as defined in [Compound A], [Compound B-1], [Compound B-2], [Compound B-3], [Compound C-1], [Compound C-2], [Compound D-1], or [Compound D-2].

[0188] [Compound F] A compound of formula (I), wherein R 4 but, (1) Halogen atoms (e.g., fluorine atoms, chlorine atoms, bromine atoms), (2) C optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) 1-6 an alkyl group (e.g., methyl, ethyl), or (3) C optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) 1-6 Alkoxy groups (e.g., methoxy) and A compound of formula (I) wherein the other variables are as defined in [Compound A], [Compound B-1], [Compound B-2], [Compound B-3], [Compound C-1], [Compound C-2], [Compound D-1], [Compound D-2], [Compound E-1], [Compound E-2], or [Compound E-3].

[0189] [Compound G-1] A compound of formula (I), wherein X is S, Y is CR 8 and R 8 C 1-6 an alkyl group (e.g., methyl, ethyl), R 1 a 6-membered non-aromatic heterocyclic group (e.g., piperidyl) substituted with one or two substituents selected from the following: (a) halogen atoms (e.g., fluorine atoms, chlorine atoms, bromine atoms), and (b)C 1-6 Alkyl groups (e.g., methyl) and R 2 is a hydrogen atom, R 3 is a hydrogen atom, R 4 But C 1-6 an alkyl group (e.g., methyl), R 5 is a hydrogen atom, R 6 is a hydrogen atom.

[0190] [Compound G-2] A compound of formula (I), wherein X is S, Y is CR 8 and R 8 C 1-6 an alkyl group (e.g., methyl, ethyl), R 1 a 6-membered nitrogen-containing non-aromatic heterocyclic group (e.g., piperidyl) substituted with one or two substituents selected from the following: (a) halogen atoms (e.g., fluorine atoms, chlorine atoms, bromine atoms), and (b)C 1-6 Alkyl groups (e.g., methyl) and R 2 is a hydrogen atom, R 3 is a hydrogen atom, R 4 But C 1-6 an alkyl group (e.g., methyl), R 5 is a hydrogen atom, R 6 is a hydrogen atom.

[0191] [Compound G-3] A compound of formula (I), wherein X is S, Y is CR 8 and R 8 C 1-6 an alkyl group (e.g., methyl, ethyl), R 1 a piperidyl group substituted with one or two substituents selected from the following: (a) halogen atoms (e.g., fluorine atoms, chlorine atoms, bromine atoms), and (b)C 1-6 an alkyl group (e.g., methyl), R 2 is a hydrogen atom, R 3 is a hydrogen atom, R 4 But C 1-6 an alkyl group (e.g., methyl), R 5 is a hydrogen atom, R 6 is a hydrogen atom.

[0192] [Compound G-4] A compound of formula (I), wherein X is S, Y is CR 8 and R 8 C 1-6 an alkyl group (e.g., methyl, ethyl), R 1 a piperidyl group substituted with one or two substituents selected from the following: (a) a halogen atom, and (b)C 1-2 Alkyl groups (e.g., methyl) and R 2 is a hydrogen atom, R 3 is a hydrogen atom, R 4 But C 1-2 an alkyl group (e.g., methyl), R 5 is a hydrogen atom, R 6 is a hydrogen atom.

[0193] [Compound H-1] A compound of formula (I), wherein R 1 is as defined in [Compound B-1], Y is as defined in [Compound E-1], R 4 is as defined in [Compound F], The compound of formula (I) above, wherein the other variables are as defined in [Compound A].

[0194] [Compound H-2] A compound of formula (I), wherein R 1 is as defined in [Compound B-2], Y is as defined in [Compound E-1], R 4 is as defined in [Compound F], The compound of formula (I) above, wherein the other variables are as defined in [Compound A].

[0195] [Compound H-3] A compound of formula (I), wherein R 1 is as defined in [Compound B-3], Y is as defined in [Compound E-1], R 4 is as defined in [Compound F], The compound of formula (I) above, wherein the other variables are as defined in [Compound A].

[0196] [Compound H-4] A compound of formula (I), wherein R 1 is as defined in [Compound B-1], Y is as defined in [Compound E-2], R 4 is as defined in [Compound F], The compound of formula (I) above, wherein the other variables are as defined in [Compound A].

[0197] [Compound H-5] A compound of formula (I), wherein R 1 is as defined in [Compound B-2], Y is as defined in [Compound E-2], R 4 is as defined in [Compound F], The compound of formula (I) above, wherein the other variables are as defined in [Compound A].

[0198] [Compound H-6] A compound of formula (I), wherein R 1 is as defined in [Compound B-3], Y is as defined in [Compound E-2], R 4 is as defined in [Compound F], The compound of formula (I) above, wherein the other variables are as defined in [Compound A].

[0199] [Compound H-7] A compound of formula (I), wherein R 1 is as defined in [Compound B-1], Y is as defined in [Compound E-3], R 4 is as defined in [Compound F], The compound of formula (I) above, wherein the other variables are as defined in [Compound A].

[0200] [Compound H-8] A compound of formula (I), wherein R 1 is as defined in [Compound B-2], Y is as defined in [Compound E-3], R 4 is as defined in [Compound F], The compound of formula (I) above, wherein the other variables are as defined in [Compound A].

[0201] [Compound H-9] A compound of formula (I), wherein R 1 is as defined in [Compound B-3], Y is as defined in [Compound E-3], R 4 is as defined in [Compound F], The compound of formula (I) above, wherein the other variables are as defined in [Compound A].

[0202] [Compound I-1] A compound of formula (I), wherein X is S, R 1 is as defined in [Compound B-1], Y is as defined in [Compound E-1], R 4 is as defined in [Compound F], The compound of formula (I) above, wherein the other variables are as defined in [Compound A].

[0203] [Compound I-2] A compound of formula (I), wherein X is S, R 1 is as defined in [Compound B-2], Y is as defined in [Compound E-1], R 4 is as defined in [Compound F], The compound of formula (I) above, wherein the other variables are as defined in [Compound A].

[0204] [Compound I-3] A compound of formula (I), wherein X is S, R 1 is as defined in [Compound B-3], Y is as defined in [Compound E-1], R 4 is as defined in [Compound F], The compound of formula (I) above, wherein the other variables are as defined in [Compound A].

[0205] [Compound I-4] A compound of formula (I), wherein X is S, R 1 is as defined in [Compound B-1], Y is as defined in [Compound E-2], R 4 is as defined in [Compound F], The compound of formula (I) above, wherein the other variables are as defined in [Compound A].

[0206] [Compound I-5] A compound of formula (I), wherein X is S, R 1 is as defined in [Compound B-2], Y is as defined in [Compound E-2], R 4 is as defined in [Compound F], The compound of formula (I) above, wherein the other variables are as defined in [Compound A].

[0207] [Compound I-6] A compound of formula (I), wherein X is S, R 1 is as defined in [Compound B-3], Y is as defined in [Compound E-2], R 4 is as defined in [Compound F], The compound of formula (I) above, wherein the other variables are as defined in [Compound A].

[0208] [Compound I-7] A compound of formula (I), wherein X is S, R 1 is as defined in [Compound B-1], Y is as defined in [Compound E-3], R 4is as defined in [Compound F], The compound of formula (I) above, wherein the other variables are as defined in [Compound A].

[0209] [Compound I-8] A compound of formula (I), wherein X is S, R 1 is as defined in [Compound B-2], Y is as defined in [Compound E-3], R 4 is as defined in [Compound F], The compound of formula (I) above, wherein the other variables are as defined in [Compound A].

[0210] [Compound I-9] A compound of formula (I), wherein X is S, R 1 is as defined in [Compound B-3], Y is as defined in [Compound E-3], R 4 is as defined in [Compound F], The compound of formula (I) above, wherein the other variables are as defined in [Compound A].

[0211] [Compound J-1] A compound of formula (I), wherein R 3 is a hydrogen atom, R 5 is a hydrogen atom, R 6 is a hydrogen atom or C 1-6 an alkyl group (e.g., methyl), A compound of formula (I) wherein the other variables are as defined in [Compound A], [Compound B-1], [Compound B-2], [Compound B-3], [Compound C-1], [Compound C-2], [Compound D-1], or [Compound D-2].

[0212] [Compound K] 2-(5-{[(3R,5R)-5-fluoro-1-methylpiperidin-3-yl]amino}-2H-pyrazolo[3,4-d][1,3]thiazol-2-yl)-3,5-dimethylphenol, or a solvate thereof, or a hydrate thereof, 3,5-dimethyl-2-(5-{[(3R)-1-methylpiperidin-3-yl]amino}-2H-pyrazolo[3,4-d][1,3]thiazol-2-yl)pheno 3. A compound of formula (I) selected from 3-ethyl-2-(5-{[(3R,5R)-5-fluoro-1-methylpiperidin-3-yl]amino}-2H-pyrazolo[3,4-d][1,3]thiazol-2-yl)-5-methylphenol, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a hydrate thereof;

[0213] [Compound L-1] 2-(5-{[(3R,5R)-5-fluoro-1-methylpiperidin-3-yl]amino}-2H-pyrazolo[3,4-d][1,3]thiazol-2-yl)-3,5-dimethylphenol, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a hydrate thereof (Example 3).

[0214] [Compound L-2] 3,5-Dimethyl-2-(5-{[(3R)-1-methylpiperidin-3-yl]amino}-2H-pyrazolo[3,4-d][1,3]thiazol-2-yl)phenol, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a hydrate thereof (Example 4).

[0215] [Compound L-3] 3-Ethyl-2-(5-{[(3R,5R)-5-fluoro-1-methylpiperidin-3-yl]amino}-2H-pyrazolo[3,4-d][1,3]thiazol-2-yl)-5-methylphenol, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a hydrate thereof (Example 20).

[0216] Specific examples of the compound of formula (I) include the compounds of Examples 1 to 181.

[0217] Compounds of formula (I), including the embodiments described in the preceding paragraphs and compounds specifically named in the examples, may exist as salts, complexes, solvates, hydrates, and liquid crystals. Similarly, compounds of formula (I) that are salts may exist as complexes, solvates, hydrates, and liquid crystals.

[0218] The compounds of formula (I) can form pharmaceutically acceptable complexes, salts, solvates, and hydrates. These salts include acid addition salts (including diacids) and base salts. Pharmaceutically acceptable acid addition salts include salts derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, and phosphorous acid, as well as non-toxic salts derived from organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, and aliphatic and aromatic sulfonic acids. Such salts include acetate, adipate, aspartate, benzoate, besylate, bicarbonate, carbonate, bisulfate, sulfate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hybenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, and isethionate. Salts include phosphate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate, hydrogen phosphate, dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate, and xinofoate salts.

[0219] Pharmaceutically acceptable basic salts include salts derived from bases, including metal cations, such as alkali or alkaline earth metal cations, and amines. Examples of suitable metal cations include sodium, potassium, magnesium, calcium, zinc, and aluminum. Examples of suitable amines include arginine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethylamine, diethanolamine, dicyclohexylamine, ethylenediamine, glycine, lysine, N-methylglucamine, olamine, 2-amino-2-hydroxymethyl-propane-1,3-diol, and procaine. For a discussion of useful acid addition salts and base salts, see S.M. Berge et al., J.Pharm.Sci.(1977)66:1-19. See also Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection, and Use(2002).

[0220] Pharmaceutically acceptable salts can be prepared using various methods. For example, a compound of formula (I) can be reacted with an appropriate acid or base to obtain the desired salt. Alternatively, a precursor of the compound of formula (I) can be reacted with an acid or base to remove an acid- or base-labile protecting group or to open the lactone or lactam group of the precursor. In addition, a salt of the compound of formula (I) can be converted to another salt (or free form) by treating it with an appropriate acid or base or by contacting it with an ion exchange resin. If the salt precipitates from solution after the reaction, it can be recovered by filtration or by isolating the salt by evaporation. The degree of ionization of the salt can vary from completely ionized to almost non-ionized.

[0221] Compounds of formula (I) can exist in a range of solid states, from completely amorphous to completely crystalline. The term "amorphous" refers to a state in which a substance lacks long-range order at the molecular level and can exhibit the physical properties of either a solid or a liquid, depending on temperature. Typically, such substances do not produce distinctive X-ray diffraction patterns and are more formally described as liquids, although they exhibit the properties of a solid. Upon heating, a change from solid to liquid properties occurs, characterized by a change of state, typically second-order ("glass transition"). The term "crystalline" refers to a solid phase in which a substance has an internal structure with regular order at the molecular level and produces a distinctive X-ray diffraction pattern with distinct peaks. Such substances, when heated sufficiently, also exhibit the properties of a liquid, but the change from solid to liquid is characterized by a phase transition, typically first-order ("melting point").

[0222] The compound of formula (I) can exist in both unsolvated and solvated forms. The term "solvate" refers to a molecular complex containing a compound and one or more pharmaceutically acceptable solvent molecules other than water (e.g., ethanol). The term "hydrate" refers to a solvate in which the solvent is water. Pharmaceutically acceptable solvates include those in which the solvent may be isotopically substituted (e.g., DO, acetone-d6, DMSO-d6).

[0223] A currently accepted classification system for solvates and hydrates of organic compounds distinguishes between isolated site, channel, and metal ion-coordinated solvates and hydrates. See, for example, KR Morris (HGBrittain ed.) Polymorphism in Pharmaceutical Solids (1995). Isolated site hydrates and solvates are those in which the solvent (e.g., water) molecules are isolated from direct contact with each other by intervening molecules of the organic compound. In channel solvates, the solvent molecules reside in lattice channels where they are next to other solvent molecules. In metal ion-coordinated solvates, the solvent molecules are bound to the metal ion.

[0224] When the solvent or water is tightly bound, the complex has a well-defined stoichiometry independent of humidity. However, when the solvent or water is weakly bound, as in the case of channel solvates and hygroscopic compounds, the water or solvent content will depend on humidity and dryness. In such cases, non-stoichiometry will generally be observed.

[0225] The compounds of formula (I) may also exist as multicomponent complexes (other than salts and solvates) in which the compound (drug) and at least one other component are present in stoichiometric or non-stoichiometric amounts. This type of complex includes inclusion complexes (drug-host inclusion complexes) and cocrystals. The latter is typically defined as a crystalline complex of neutral molecular components bound together by noncovalent interactions, but may also be a complex of a neutral molecule with a salt. Cocrystals may be prepared by melt crystallization, recrystallization from a solvent, or by physically grinding the components together. See, for example, O. Almarsson and MJ Zaworotko, Chem. Commun. (2004) 17:1889-1896. For a review of multicomponent complexes, see JK Haleblian, J. Pharm. Sci. (1975) 64(8):1269-88.

[0226] Compounds of formula (I) can exist in a mesomorphic state (mesophase or liquid crystal) when subjected to appropriate conditions. The mesomorphic state is between the true crystalline state and the true liquid state (either melt or dissolve). Liquid crystallinity resulting from a change in temperature is described as "thermotropic", while liquid crystallinity resulting from the addition of a second component, such as water or another solvent, is described as "lyotropic". Compounds with the potential to form lyotropic mesophases are described as "amphiphilic" and contain polar ionic moieties (e.g., -COO-Na + , -COO-K + , -SO3-Na + ) or polar nonionic moieties (-NN +(CH3)3, etc. See, for example, N.H. Hartshorne and A. Stuart, Crystals and the Polarizing Microscope (4th ed., 1970).

[0227] Each compound of formula (I) may exist as polymorphs, stereoisomers, tautomers, or some combination thereof, may be isotopically labeled, may result from administration of a prodrug, or may form a metabolite following administration.

[0228] A "prodrug" refers to a compound that has little or no pharmacological activity but can be converted into a compound with the desired pharmacological activity when metabolized in vivo. Prodrugs may be prepared by replacing appropriate functional groups present in a pharmacologically active compound with a "promoiety," as described, for example, in H. Bundgaar, Design of Prodrugs (1985). Examples of prodrugs include ester, ether, or amide derivatives of compounds of formula (I) that contain carboxylic acid, hydroxy, or amino functional groups, respectively. For a detailed discussion of prodrugs, see, for example, T. Higuchi and V. Stella, "Prodrugs as Novel Delivery Systems," ACS Symposium Series 14 (1975) and EB Roche ed., Bioreversible Carriers in Drug Design (1987).

[0229] "Metabolites" refer to compounds formed in vivo upon administration of a pharmacologically active compound. Examples include hydroxymethyl, hydroxy, secondary amino, primary amino, phenol, and carboxylic acid derivatives of compounds of formula (I) bearing methyl, alkoxy, tertiary amino, secondary amino, phenyl, and amido groups, respectively.

[0230] The compounds of formula (I) can exist as stereoisomers resulting from the presence of one or more asymmetric centers, one or more double bonds, or both. The stereoisomers can be pure, substantially pure, or mixtures. Such stereoisomers can also result from acid addition or base salts in which the counterion is optically active (e.g., when the counterion is D-lactate or L-lysine).

[0231] Compounds of formula (I) may exist as tautomers, which are isomers resulting from tautomerization. Tautomeric isomerism includes, for example, imine-enamine, keto-enol, oxime-nitroso, and amide-imidic acid tautomerism.

[0232] Compounds of formula (I) may exhibit more than one type of isomerism.

[0233] Geometric (cis / trans) isomers may be separated by conventional techniques such as chromatography or fractional crystallization.

[0234] Conventional techniques for preparing or isolating compounds of a specific stereochemical configuration include chiral synthesis from appropriate optically pure precursors or resolution of the racemate (or racemate of a salt or derivative), for example, using chiral high-pressure liquid chromatography (HPLC). Alternatively, the racemate (or racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, if the compound of formula (I) contains an acidic or basic moiety, with an acid or base such as tartaric acid or 1-phenylethylamine. The resulting diastereoisomeric mixture may be separated by chromatography, fractional crystallization, or the appropriate diastereoisomer may be converted to a compound having the required stereochemical configuration. For a further discussion of techniques for separating stereoisomers, see E.L. Eliel and S.H. Wilen, Stereochemistry of Organic Compounds (1994).

[0235] Compounds of formula (I) may have isotopic variations in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature. Suitable isotopes for inclusion in compounds of formula (I) include, for example, isotopes of hydrogen, such as 2 H and 3 H; isotopes of carbon, e.g., 11 C. 13 C, and 14 C; isotopes of nitrogen, e.g., 13 N and 15 N; isotopes of oxygen, e.g., 15 O. 17 O, and 18 O; isotopes of sulfur, e.g., 35 S; isotopes of fluorine, e.g., 18 F; isotopes of chlorine, e.g., 36 Cl; as well as isotopes of iodine, e.g., 123 I and 125 Isotopic variants (e.g., deuterium, 2 The use of H) may result in certain therapeutic benefits due to increased metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements). Additionally, certain isotopic variations of the disclosed compounds may be substituted with radioactive isotopes (e.g., tritium, 3 H, or 14 C) may be incorporated, which may be useful for drug and / or substrate tissue distribution studies. 11 C. 18 F, 15 O and 13 Substitution with positron emitting isotopes, such as N, can be useful in positron emission tomography (PET) studies for examining substrate receptor occupancy. Isotopically labeled compounds may be prepared by processes analogous to those described elsewhere in this disclosure, using the appropriate isotopically labeled reagent in place of an unlabeled reagent.

[0236] Compound (I) may be prepared using the techniques described below. Some of the methods and examples may omit details of common reactions, including oxidations, reductions, and the like, separation techniques (extraction, evaporation, precipitation, chromatography, filtration, trituration, crystallization, and the like), and analytical procedures, which are known to those skilled in the art of organic chemistry. Details of such reactions and techniques can be found in several treatises, including Richard Larock's Comprehensive Organic Transformations (1999) and the multi-volume series, Compendium of Organic Synthetic Methods (since 1974), edited by Michael B. Smith et al. Starting materials and reagents may be obtained from commercial sources or prepared using literature methods. Some of the reaction schemes may omit minor products resulting from chemical transformations (e.g., alcohols from the hydrolysis of esters, CO from the decarboxylation of diacids, and the like). Additionally, in some cases, reaction intermediates may be used in subsequent steps without isolation or purification (i.e., in situ).

[0237] In the methods and examples that follow, certain compounds may be prepared using protecting groups that prevent undesired chemical reactions other than at the reactive site. Protecting groups may also be used to enhance the solubility of the compound or otherwise modify its physical properties. For a discussion of protecting group strategies, a description of materials and methods for installing and removing protecting groups, and a summary of useful protecting groups for common functional groups such as amines, carboxylic acids, alcohols, ketones, and aldehydes, see T.W. Greene and P.G. Wuts, Protecting Groups in Organic Chemistry (1999) and P. Kocienski, Protective Groups (2000).

[0238] Generally, chemical transformations described throughout this specification can be carried out using substantially stoichiometric amounts of reactants, although certain reactions may benefit from the use of an excess of one or more reactants. Additionally, although many of the reactions disclosed throughout this specification can be carried out at about room temperature (RT) and ambient pressure, some reactions may be carried out at elevated pressures or using higher (e.g., reflux conditions) or lower temperatures (e.g., −78° C. to 0° C.), depending on reaction kinetics, yield, etc. All references in this disclosure and claims to stoichiometric ranges, temperature ranges, pH ranges, etc., include the indicated endpoints, regardless of whether the word “range” is explicitly used.

[0239] Many chemical transformations may also employ one or more compatible solvents, which can affect the reaction rate and yield. Depending on the nature of the reactants, the one or more solvents may be polar protic solvents (including water), polar aprotic solvents, nonpolar solvents, or some combination. Representative solvents include saturated aliphatic hydrocarbons (e.g., n-pentane, n-hexane, n-heptane, n-octane, cyclohexane, methylcyclohexane); aromatic hydrocarbons (e.g., benzene, toluene, xylene); halogenated hydrocarbons (e.g., methylene chloride, chloroform, carbon tetrachloride); aliphatic alcohols (e.g., methanol, ethanol, propan-1-ol, propan-2-ol, butan-1-ol, 2-methyl-propan-1-ol, butan-2-ol, 2-methyl-propan-2-ol, pentan-1-ol, 3-methyl-butan-1-ol, hexane-1-ol, 2-methoxy-ethanol, 2-ethoxy-ethanol, 2-butoxy-ethanol, 2-(2-methoxy-ethoxy)-ethanol, 2-(2-ethoxy-ethoxy)-ethanol, 2-(2 ethers (e.g., diethyl ether, diisopropyl ether, dibutyl ether, 1,2-dimethoxyethane, 1,2-diethoxyethane, 1-methoxy-2-(2-methoxy-ethoxy)-ethane, 1-ethoxy-2-(2-ethoxy-ethoxy)-ethane, tetrahydrofuran, 1,4-dioxane); ketones (e.g., acetone, methyl ethyl ketone); esters (methyl acetate, ethyl acetate); nitrogen-containing solvents (e.g., formamide, N,N-dimethylformamide, acetonitrile, N-methyl-pyrrolidone, pyridine, quinoline, nitrobenzene); sulfur-containing solvents (e.g., carbon disulfide, dimethyl sulfoxide, tetrahydro-thiophene-1,1-dioxide); and phosphorus-containing solvents (e.g., hexamethylphosphoric acid triamide).

[0240] In the following schemes, the substituent identifiers (e.g., X, Y, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R7 , and R 8 ) are as defined above for Formula (I). As previously mentioned, some of the starting materials and intermediates may contain protecting groups, which are removed prior to the final product. In such cases, the substituent identifiers refer to the moieties defined in Formula (I) and those moieties bearing the appropriate protecting groups. For example, a starting material or intermediate in a synthetic method may contain a potentially reactive (secondary) amine. In such cases, the amine may include moieties with or without, for example, a Boc or Cbz group attached to the amine.

[0241] The method for producing the compound of the present invention is described below.

[0242] The starting compounds and reagents used in the following production methods and the compounds obtained in each step may each be in the form of a salt, and examples of such salts include salts similar to those of the compounds of the present invention. When the compound obtained in each step is in a free form, it can be converted into the desired salt by a method known per se. When the compound obtained in each step is a salt, it can be converted into the desired free form or another salt by a method known per se.

[0243] The compound obtained in each step can be used directly in the next reaction as a reaction mixture or as a crude product. Alternatively, the compound obtained in each step can be isolated and / or purified from the reaction mixture by a separation means known per se, such as concentration, crystallization, recrystallization, distillation, solvent extraction, fractional distillation, column chromatography, etc.

[0244] When the starting compounds and reagents used in each step are commercially available, the commercially available products can also be used directly.

[0245] In the reaction of each step, the reaction time varies depending on the reagents and solvents used, but unless otherwise specified, it is usually 1 minute to 48 hours, preferably 10 minutes to 8 hours.

[0246] In the reactions of each step, the reaction temperature varies depending on the reagents and solvents used, but is usually from -78°C to 300°C, and preferably from -78°C to 150°C, unless otherwise specified.

[0247] In the reaction of each step, the pressure varies depending on the reagents and solvents used, but unless otherwise specified, it is usually 1 atm to 20 atm, preferably 1 atm to 3 atm.

[0248] A microwave synthesis apparatus such as Biotage Initiator may be used for the reactions in each step. The reaction temperature varies depending on the reagents and solvent used, but unless otherwise specified, is usually room temperature to 300°C, and preferably 50°C to 250°C. The reaction time varies depending on the reagents and solvent used, but unless otherwise specified, is usually 1 minute to 48 hours, and preferably 1 minute to 8 hours.

[0249] In the reactions of each step, the reagents used vary depending on the reagents and solvents used, but unless otherwise specified, they are used in an amount of 0.5 to 20 equivalents, preferably 0.8 to 5 equivalents, relative to the substrate. When a reagent is used as a catalyst, it is used in an amount of 0.001 to 1 equivalent, preferably 0.01 to 0.2 equivalents, relative to the substrate. When a reagent is used as a reaction solvent, it is used in the amount of the solvent.

[0250] Unless otherwise specified, the reaction in each step is carried out without solvent or by dissolving or suspending the starting compound in an appropriate solvent. Examples of the solvent include those described in the Examples and the following solvents. Alcohols: methanol, ethanol, tert-butyl alcohol, 2-methoxyethanol, etc. Ethers: diethyl ether, diphenyl ether, tetrahydrofuran, 1,2-dimethoxyethane, etc. Aromatic hydrocarbons: chlorobenzene, toluene, xylene, etc. Saturated hydrocarbons: cyclohexane, hexane, etc. Amides: N,N-dimethylformamide, N-methylpyrrolidone, etc. Halogenated hydrocarbons: dichloromethane, carbon tetrachloride, etc. Nitriles: acetonitrile, etc. Sulfoxides: dimethyl sulfoxide, etc. Aromatic organic bases: pyridine, etc. Anhydrides: acetic anhydride, etc. Organic acids: formic acid, acetic acid, trifluoroacetic acid, etc. Inorganic acids: hydrochloric acid, sulfuric acid, etc. Esters: ethyl acetate, etc. Ketones: acetone, methyl ethyl ketone, etc. water. The above solvents may be used in a mixture of two or more kinds in an appropriate ratio.

[0251] When a base is used in the reaction of each step, examples of the base include the bases described in the Examples and the bases below. Inorganic bases: sodium hydroxide, magnesium hydroxide, sodium carbonate, calcium carbonate, sodium bicarbonate, etc. Organic bases: triethylamine, diethylamine, pyridine, 4-dimethylaminopyridine, N,N-dimethylaniline, 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]-7-undecene, imidazole, piperidine, etc. Metal alkoxides: sodium ethoxide, potassium tert-butoxide, etc. Alkali metal hydrides: sodium hydride, etc. Metal amides: sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, etc. Organolithium compounds: n-butyllithium, etc.

[0252] When an acid or an acid catalyst is used in the reaction of each step, examples thereof include the acids and acid catalysts described in the Examples and the acids and acid catalysts described below. Inorganic acids: hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, etc. Organic acids: acetic acid, trifluoroacetic acid, citric acid, p-toluenesulfonic acid, 10-camphorsulfonic acid, etc. Lewis acids: boron trifluoride diethyl ether complex, zinc iodide, anhydrous aluminum chloride, anhydrous zinc chloride, anhydrous iron chloride, etc.

[0253] Unless otherwise specified, the reactions in each step are carried out according to a method known per se, for example, Jikken Kagaku Kouza, 5th Edition, vol. 13-19 (ed. by the Chemical Society of Japan); Shin Jikken Kagaku Kouza, vol. 14-15 (ed. by the Chemical Society of Japan); Fine Organic Chemistry, Revised 2nd Edition (L.F. Tietze, Th. Eicher, Nankodo); Organic Name Reactions, the Reaction Mechanism and Essence, Revised Edition (Hideo Togo, Kodansha); ORGANIC SYNTHESES Collective Volume I-VII (John Wiley & Sons Inc.); Modern Organic Synthesis in the Laboratory: A Collection of Standard Experimental Procedures (Jie Jack Li, Oxford University); Comprehensive Heterocyclic Chemistry III, Vol. 1-Vol. 14 (Elsevier Japan); Strategic Applications of Named Reactions in Organic Synthesis (translated by The synthesis is carried out according to the methods described in Kiyoshi Tomioka, Kagakudojin; Comprehensive Organic Transformations (VCH Publishers Inc.), 1989, or the methods described in the Examples.

[0254] The processes depicted in the schemes may be modified as desired. For example, protecting groups may be added or removed, and the products may be further elaborated, for example, by alkylation, acylation, hydrolysis, oxidation, reduction, amidation, sulfonation, alkynylation, etc., to provide the desired final product. Furthermore, any intermediates or final products that contain a mixture of stereoisomers may be optionally purified by chiral column chromatography (e.g., supercritical fluid chromatography) or by derivatization with optically pure reagents, as described above, to provide the desired stereoisomer.

[0255] In each step, the protection or deprotection reaction of a functional group is carried out by a method known per se, for example, the method described in "Protective Groups in Organic Synthesis, 4th Ed," Wiley-Interscience, Inc., 2007 (Theodora W. Greene, Peter G.M.W. Buts); "Protecting Groups, 3rd Ed." Thieme, 2004 (P.J. Kocienski), or the method described in the Examples.

[0256] Examples of the protecting group for the hydroxy group of alcohols and the like and the phenolic hydroxy group include ether-type protecting groups such as methoxymethyl ether, benzyl ether, tert-butyldimethylsilyl ether, and tetrahydropyranyl ether; carboxylic acid ester-type protecting groups such as acetate ester; sulfonic acid ester-type protecting groups such as methanesulfonate ester; and carbonate-type protecting groups such as tert-butyl carbonate.

[0257] Examples of the protecting group for the carbonyl group of an aldehyde include acetal-type protecting groups such as dimethyl acetal, and cyclic acetal-type protecting groups such as 1,3-dioxane.

[0258] Examples of protecting groups for the carbonyl group of ketones include ketal-type protecting groups such as dimethyl ketal, cyclic ketal-type protecting groups such as 1,3-dioxane, oxime-type protecting groups such as O-methyloxime, and hydrazone-type protecting groups such as N,N-dimethylhydrazone.

[0259] Examples of the protecting group for a carboxyl group include ester-type protecting groups such as methyl ester, and amide-type protecting groups such as N,N-dimethylamide.

[0260] Examples of the thiol-protecting group include ether-type protecting groups such as benzylthioether, and ester-type protecting groups such as thioacetate, thiocarbonate, and thiocarbamate.

[0261] Examples of protecting groups for amino groups and aromatic heterocycles such as imidazole, pyrrole, and indole include carbamate-type protecting groups such as benzylcarbamate, amide-type protecting groups such as acetamide, alkylamine-type protecting groups such as N-triphenylmethylamine, and sulfonamide-type protecting groups such as methanesulfonamide.

[0262] The protecting group can be removed by a method known per se, for example, a method using an acid, a base, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, a trialkylsilyl halide (e.g., trimethylsilyl iodide, trimethylsilyl bromide), or the like, a reduction method, or the like.

[0263] When a reduction reaction is carried out in each step, examples of the reducing agent to be used include metal hydrides such as lithium aluminum hydride, sodium triacetoxyborohydride, sodium cyanoborohydride, diisobutylaluminum hydride (DIBAL-H), sodium borohydride, tetramethylammonium triacetoxyborohydride, etc., boranes such as borane tetrahydrofuran complex, Raney nickel, Raney cobalt, hydrogen, formic acid, triethylsilane, iron, zinc, etc. When a carbon-carbon double bond or triple bond is reduced, a method using a catalyst such as palladium-carbon or Lindlar's catalyst can be used.

[0264] When an oxidation reaction is carried out in each process step, examples of the oxidizing agent to be used include peroxides, for example, m-chloroperbenzoic acid (mCPBA), hydrogen peroxide, tert-butyl hydroperoxide, etc.; perchlorates, for example, tetrabutylammonium perchlorate, etc.; chlorates, for example, sodium chlorate, etc.; chlorites, for example, sodium chlorite, etc.; periodates, for example, sodium periodate, etc.; hypervalent iodine reagents, for example, iodosylbenzene, etc.; manganese Examples of suitable reagents include chlorine-containing reagents such as manganese dioxide and potassium permanganate, lead compounds such as lead tetraacetate, chromium-containing reagents such as pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), and Jones reagent, halogen compounds such as N-bromosuccinimide (NBS), oxygen, ozone, sulfur trioxide-pyridine complex, osmium tetroxide, selenium dioxide, and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ).

[0265] When a radical reaction is performed in each step, examples of the radical initiator used include azo compounds such as azobisisobutyronitrile (AIBN), water-soluble radical initiators such as 4-4'-azobis-4-cyanopentanoic acid (ACPA), triethylboron in the presence of air or oxygen, benzoyl peroxide, etc. Examples of the radical reagent used include tributylstannane, tristrimethylsilylsilane, 1,1,2,2-tetraphenyldisilane, diphenylsilane, samarium iodide, etc.

[0266] When a Wittig reaction is performed in each step, examples of the Wittig reagent to be used include alkylidenephosphoranes, etc. Alkylidenephosphoranes can be prepared by a method known per se, for example, by reacting a phosphonium salt with a strong base.

[0267] When performing the Horner-Emmons reaction in each step, examples of reagents that can be used include phosphonoacetic acid esters, such as methyl dimethylphosphonoacetate and ethyl diethylphosphonoacetate, and bases, such as alkali metal hydrides and organolithium compounds.

[0268] In each step of the Friedel-Crafts reaction, a Lewis acid and an acid chloride, or a Lewis acid and an alkylating agent (e.g., alkyl halide, alcohol, olefin, etc.) are used as reagents. Alternatively, an organic or inorganic acid can be used instead of the Lewis acid, and an acid anhydride, such as acetic anhydride, can be used instead of the acid chloride.

[0269] When carrying out a nucleophilic aromatic substitution reaction in each step, a nucleophile (eg, amine, imidazole, etc.) and a base (eg, inorganic base, organic base, etc.) are used as reagents.

[0270] When a nucleophilic addition reaction by a carbanion, a nucleophilic 1,4-addition reaction (Michael addition reaction) by a carbanion, or a nucleophilic substitution reaction by a carbanion is carried out in each step, examples of the base used to generate the carbanion include organolithium, metal alkoxide, inorganic base, and organic base.

[0271] When a Grignard reaction is carried out in each step, examples of the Grignard reagent to be used include arylmagnesium halides such as phenylmagnesium bromide, alkylmagnesium halides such as methylmagnesium bromide, etc. The Grignard reagent can be prepared by a method known per se, for example, by reacting an alkyl halide or aryl halide with metallic magnesium using ether or tetrahydrofuran as a solvent.

[0272] When performing the Knoevenagel condensation reaction in each step, an active methylene group having two electron-withdrawing groups (e.g., malonic acid, diethyl malonate, malononitrile, etc.) and a base (e.g., an organic base, metal alkoxide, inorganic base) are used as reagents.

[0273] In each step of the Vilsmeier-Haack reaction, phosphoryl chloride and an amide derivative (e.g., N,N-dimethylformamide) are used as reagents.

[0274] When an azidation reaction of an alcohol, an alkyl halide, or a sulfonate is carried out in each step, examples of the azidation agent used include diphenylphosphoryl azide (DPPA), trimethylsilyl azide, sodium azide, etc. For example, when azidating alcohols, a method using diphenylphosphoryl azide and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or a method using trimethylsilyl azide and a Lewis acid is used.

[0275] When a reductive amination reaction or a reductive alkylation reaction is carried out in each step, examples of the reducing agent to be used include sodium triacetoxyborohydride, sodium cyanoborohydride, hydrogen, formic acid, etc. When the substrate is an amine compound, examples of the carbonyl compound to be used include paraformaldehyde, aldehydes such as acetaldehyde, and ketones such as cyclohexanone. When the substrate is a carbonyl compound, examples of the amine to be used include ammonia, primary amines such as methylamine, and secondary amines such as dimethylamine.

[0276] When the Mitsunobu reaction is performed in each step, cyanomethylenetrialkylphosphorane (e.g., cyanomethylenetrimethylphosphorane, cyanomethylenetributylphosphorane) or azodicarboxylate (e.g., diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), etc.) and phosphine (e.g., triphenylphosphine, tri-n-butylphosphine) are used as reagents.

[0277] When an esterification reaction, an amidation reaction, or a urea-forming reaction is carried out in each step, examples of the reagent to be used include acyl halides such as acid chlorides and acid bromides, and activated carboxylic acids such as anhydrides, active esters, and sulfates. Examples of activating agents for carboxylic acids include carbodiimide condensing agents such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSCD), triazine condensing agents such as 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride n-hydrate (DMT-MM), carbonate condensing agents such as 1,1-carbonyldiimidazole (CDI), diphenylphosphoric acid azide (DPPA), benzotriazol-1-yloxy-trisdimethylaminophosphonium salt (BOP reagent), 2-chloro-1-methyl-pyridinium iodide (Mukaiyama reagent), thionyl chloride, lower alkyl haloformate esters such as ethyl chloroformate, and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium Examples of suitable condensing agents include hexafluorophosphate (HATU), sulfuric acid, and combinations thereof. When a carbodiimide condensing agent is used, an additive such as 1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu), or dimethylaminopyridine (DMAP) may be added to the reaction system.

[0278] When a carbamylation reaction is carried out in each step, examples of the reagent to be used include alkyl chloroformates such as methyl chloroformate, etc. Examples of the base include organic bases, sodium carbonate, etc.

[0279] When the carbamoylation reaction is carried out in each step, examples of the activating agent to be used include triphosgene, 1,1-carbonyldiimidazole, 4-nitrophenyl chloroformate, etc.; examples of the base include an organic base, sodium carbonate, etc.; examples of the amine include ammonia, primary amines such as methylamine, secondary amines such as dimethylamine, etc.

[0280] When a guanidine-forming reaction is carried out in each step, examples of the activating agent include 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (WSCI), etc. Examples of the base include organic bases, etc.

[0281] When a coupling reaction is carried out in each step, examples of the metal catalyst to be used include palladium compounds such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), dichlorobis(triethylphosphine)palladium(II), tris(dibenzylideneacetone)dipalladium(0), 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride, nickel compounds such as tetrakis(triphenylphosphine)nickel(0), rhodium compounds such as tris(triphenylphosphine)rhodium(III) chloride, cobalt compounds, copper compounds such as copper oxide and copper(I) iodide, platinum compounds, etc. Furthermore, a base may be added to the reaction system, and examples thereof include inorganic bases and metal alkoxides.

[0282] When a thiocarbonylation reaction is carried out in each step, diphosphorus pentasulfide is usually used as the thiocarbonylating agent. Alternatively, a reagent having a 1,3,2,4-dithiadiphosphetane-2,4-disulfide structure (e.g., 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide (Lawson's reagent)) can be used instead of diphosphorus pentasulfide.

[0283] Examples of halogenating agents used in the Wohl-Ziegler reaction include N-iodosuccinimide, N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), bromine, sulfuryl chloride, etc. The reaction can be accelerated by adding heat, light, or radical initiators such as benzoyl peroxide and azobisisobutyronitrile to the reaction system.

[0284] When halogenating a hydroxy group in each step, examples of halogenating agents include hydrohalic acids and acid halides of inorganic acids, specifically, hydrochloric acid, thionyl chloride, phosphorus oxychloride, etc. for chlorination, and 48% hydrobromic acid, etc. for bromination. Furthermore, a method for producing an alkyl halide by reacting an alcohol with triphenylphosphine and carbon tetrachloride or carbon tetrabromide, etc., can also be used. Alternatively, a method for producing an alkyl halide through two steps, including converting an alcohol to the corresponding sulfonate and then reacting the sulfonate with lithium bromide, lithium chloride, or sodium iodide, can also be used.

[0285] When Arbuzov reaction is carried out in each step, examples of the reagent to be used include alkyl halides such as ethyl bromoacetate and phosphites such as triethyl phosphite and tri(isopropyl) phosphite.

[0286] When a sulfonate esterification reaction is carried out in each step, examples of the sulfonating agent to be used include methanesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonic anhydride, p-toluenesulfonic anhydride, and the like.

[0287] In each step, an acid or base is used as a reagent for the hydrolysis of tert-butyl esters. For the acid hydrolysis of tert-butyl esters, formic acid or triethylsilane can be added to reductively trap the by-product tert-butyl cation.

[0288] When a dehydration reaction is carried out in each step, examples of the dehydrating agent that can be used include sulfuric acid, diphosphorus pentoxide, phosphorus oxychloride, N,N'-dicyclohexylcarbodiimide, alumina, polyphosphoric acid, and the like.

[0289] When the Chan-Lam reaction is carried out in each step, examples of the metal catalyst used include copper compounds such as copper(I) bromide, copper(I) iodide, copper(II) acetate, etc. Furthermore, a base may be added to the reaction system, examples of which include organic bases.

[0290] When the Ullmann reaction is carried out in each step, examples of the metal catalyst used include copper compounds such as copper(I) bromide, copper(I) iodide, and copper(II) acetate, and examples of the ligand include N,N,N',N'-tetramethylethylenediamine, etc. Furthermore, a base may be added to the reaction system, and examples of the base include organic bases and inorganic bases.

[0291] When an alkylation reaction is carried out in each step, examples of the base to be used include potassium carbonate, tripotassium phosphate, triethylamine, N,N-diisopropylethylamine, pyridine, sodium ethoxide, potassium tert-butoxide, sodium hydride, lithium hexamethyldisilazide, sodium hexamethyldisilazide, n-butyllithium, and the like.

[0292] When a deoxofluorination reaction is carried out in each step, examples of the fluorinating agent to be used include bis(2-methoxyethyl)aminosulfur trifluoride, diethylaminosulfur trifluoride, 4-tert-butyl-2,6-dimethylphenylsulfur trifluoride, N,N-diethyl-S,S-difluorosulfiriminium tetrafluoroborate, difluoro-4-morpholinylsulfonium tetrafluoroborate, and the like.

[0293] When a Hoffmann rearrangement reaction is carried out in each step, examples of the reagents that can be used include lead tetraacetate and iodobenzene diacetate.

[0294] When a thiourea-forming reaction or a thiocarbamate reaction is carried out in each step, examples of the reagent to be used include thiophosgene, and examples of the base include an organic base, sodium hydride, and the like.

[0295] When a cyclopropanation reaction is carried out in each step, examples of the reagents that can be used include diiodomethane, dibromomethane, dibromodifluoromethane, dibromofluoromethane, (trifluoromethyl)trimethylsilane, (bromodifluoromethyl)trimethylsilane, (dibromofluoromethyl)trimethylsilane, carbon tetrafluoride, sodium trifluoroacetate, and the like.

[0296] Compound (I) and intermediates for producing compound (I) may have a convertible functional group (e.g., a carboxyl group, an amino group, a hydroxyl group, a carbonyl group, a mercapto group, a C 1-6 Alkoxy-carbonyl group, C 6-14 Aryloxy-carbonyl group, C 7-16 Aroxy-carbonyl group, sulfo group, halogen atom, optionally halogenated C 1-6 alkylsulfonyloxy group, cyano group, aminocarbonyl group, boryl group, etc.), and various compounds can be produced by converting such functional groups according to methods known per se or methods analogous thereto.

[0297] The carboxyl group can be transformed by reactions such as esterification, reduction, amidation, and conversion to an optionally protected amino group.

[0298] The amino group can be transformed by reactions such as amidation, sulfonylation, nitrosation, alkylation, arylation, imidization, and the like.

[0299] The hydroxy group can be transformed by reactions such as esterification, carbamoylation, sulfonylation, alkylation, fluorination, arylation, oxidation, halogenation, and the like.

[0300] The carbonyl group can be transformed by reactions such as reduction, oxidation, fluorination, imination (including oximation and hydrazonization), (thio)ketalization, alkylidenation, and thiocarbonylation.

[0301] The mercapto group can be transformed by reactions such as alkylation, oxidation, and the like.

[0302] C 1-6 Alkoxy-carbonyl group, C 6-14 Aryloxy-carbonyl group, and C 7-16 The aralkyloxy-carbonyl group can be transformed by reactions such as reduction and hydrolysis.

[0303] The sulfo group can be converted by reactions such as sulfonamidation and reduction.

[0304] The halogen atom can be transformed, for example, by various nucleophilic substitution reactions, various coupling reactions, and the like.

[0305] Optionally halogenated C 1-6 Alkylsulfonyloxy groups can be transformed, for example, by various nucleophilic substitution reactions, various coupling reactions, and the like.

[0306] The cyano group can be transformed by reactions such as reduction, hydrolysis, and the like.

[0307] The aminocarbonyl group can be transformed by reactions such as dehydration, reduction, and the like.

[0308] The boryl group can be transformed, for example, by oxidation, various coupling reactions, and the like.

[0309] In each of the above reactions, if the compound is obtained in free form, it may be converted to a salt according to conventional methods. If it is obtained as a salt, it may be converted to the free form or to another salt according to conventional methods.

[0310] The transformation of these functional groups can be carried out according to methods known per se, for example, the methods described in Comprehensive Organic Transformations, Second Edition, Wiley-VCH, Richard C. Larock.

[0311] Compound (I) obtained in each reaction scheme can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography, etc. Furthermore, each starting compound used in each reaction scheme can be isolated and purified by the same known separation and purification means as described above. The starting compound may also be used directly in the next step as a reaction mixture without isolation.

[0312] When compound (I) contains isomers, such as optical isomers, stereoisomers, positional isomers, and rotational isomers, such isomers and mixtures thereof are also encompassed by compound (I). For example, when compound (I) contains optical isomers, optical isomers resolved from the racemate are also encompassed by compound (I). These isomers can be obtained as single products by known synthetic methods, known separation methods (e.g., concentration, solvent extraction, column chromatography, recrystallization, etc.), and optical resolution (e.g., fractional recrystallization, chiral column method, diastereomeric method, etc.).

[0313] Compound (I) may be crystalline, and the crystalline form may be a single crystalline form or a mixture of crystalline forms, both of which are encompassed by Compound (I). Crystals may be produced according to crystallization methods known per se.

[0314] Compound (I) may be a solvate (for example, a hydrate) or a non-solvate (for example, a non-hydrate), and both are encompassed by Compound (I).

[0315] Isotopes (e.g., 3 H, 11 C. 14 C. 18 F,35 S, 125 Compounds labeled with (I, etc.) are also encompassed by compound (I).

[0316] 1 H 2 The deuterium-exchanged form, which is converted to H(D), is also encompassed by Compound (I).

[0317] Compound (I) labeled or substituted with an isotope can be used, for example, as a tracer (PET tracer) used in positron emission tomography (PET), and is therefore useful in fields such as medical diagnosis.

[0318] Compound (I) of the present invention can be synthesized according to the production method described below.

[0319] Each variable in the equations of the reaction schemes is as defined above unless otherwise specified.

[0320] Compound (I) can be produced from compound (1) according to the following scheme (Scheme I): 1 is a protecting group for the phenolic hydroxyl group, A is a halogen atom, and Z 1 is a dihydroxyboryl group, a pinacolboryl group (i.e., 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl (Bpin)), or a halogen atom. Examples of protecting groups for phenolic hydroxyl groups include methoxymethyl, benzyl, and 4-methoxybenzyl groups.

[0321] Compound (2) can be produced by subjecting compound (1) to a halogenation reaction.

[0322] Compound (3) can be produced by subjecting compound (2) to Chan-Lam coupling with the corresponding aryl boronate ester or boronic acid. Alternatively, compound (3) can also be produced by subjecting compound (2) to Ullmann reaction or aromatic nucleophilic substitution reaction with the corresponding aryl halide.

[0323] Compound (4) can be produced by subjecting compound (3) to a reduction reaction.

[0324] Compound (5) can be prepared by reacting compound (4) with R 1 R 2 It can be produced by subjecting it to thiourea formation with NH.

[0325] Compound (6), in which X is S, can be produced by subjecting compound (5) to the Ullmann reaction. Alternatively, compound (6), in which X is NR 7 Compound (6), which is: can be produced by subjecting compound (7) to an Ullmann reaction.

[0326] Compound (7) can be prepared by reacting compound (5) with R 7 It can be produced by subjecting it to a guanidine-forming reaction with -NH2.

[0327] Compound (I) can be produced by subjecting compound (6) to a deprotection reaction.

[0328] Scheme I [ka]

[0329] R 1 Compound (Ia), an embodiment of compound (I) in which P is an optionally substituted 5- or 6-membered nitrogen-containing non-aromatic heterocyclic group, can be prepared from compound (6') according to the following scheme (Scheme II): 2 is an amine protecting group. Examples of amine protecting groups include a Boc group, a Cbz group, a Troc group, a PMB group, and a Bn group. R11 is preferably an alkyl group or an acyl group (e.g., C 1-6 Alkyl-carbonyl group, C 1-6 Alkoxy-carbonyl group, C 1-6 Alkyl-carbamoyl group, C 1-6 sulfonyl groups).

[0330] Compound (8) can be produced by subjecting compound (6') to a deprotection reaction.

[0331] Compound (9) can be produced by subjecting compound (8) to an N-functionalization reaction, including a reductive amination reaction, an alkylation reaction, or an acylation reaction, a carbamoylation reaction, a carbamylation reaction, or a sulfonylation reaction.

[0332] Compound (Ia) can be produced by subjecting compound (9) to a deprotection reaction.

[0333] Scheme II [ka]

[0334] Compound (5) in Scheme I above can also be produced from compound (1) according to the following scheme (Scheme III): 1 , A, and Z 1 is as defined above, Y' is CW or N, and W is a halogen atom.

[0335] Compound (10) can be produced by subjecting compound (1) to Chan-Lam coupling with the corresponding aryl boronate ester or boronic acid. Alternatively, compound (10) can also be produced by subjecting compound (1) to Ullmann reaction or aromatic nucleophilic substitution reaction with the corresponding aryl halide.

[0336] Compound (10') can be prepared by reacting compound (10) in which Y' is CW with R8 -Bpin, R 8 -B(OH)2, or R 8 -BF3K by Suzuki coupling reaction.

[0337] Compound (11) can be produced by subjecting compound (10) (wherein Y′ is N) to a reduction reaction. Compound (11) can also be produced by subjecting compound (10′) to a reduction reaction.

[0338] Compound (4) can be produced by subjecting compound (11) to a halogenation reaction.

[0339] Compound (5) can be prepared by reacting compound (4) with R 1 R 2 It can be produced by subjecting it to thiourea formation with NH.

[0340] Scheme III [ka]

[0341] Y is CR 8 and R 8 The corresponding compound (11) can be used to generate compound (I) in which B is an optionally halogenated cyclopropyl, which can be generated from compound (10) (wherein Y′ is CW) according to the following scheme (Scheme IV): 1 and B 2 are each independently selected from hydrogen and halogen atoms; P 1 and W is as defined above. 1 and B 2 is provided by the reagents used in the cyclopropanation described above.

[0342] Compound (10'a) can be produced by subjecting compound (10) in which Y' is CW to a Suzuki coupling reaction with CH2=CH-BF3K.

[0343] Compound (10"a) can be produced by subjecting compound (10'a) to a cyclopropanation reaction.

[0344] Y is CR 8 and R 8 Compound (11), in which is an optionally halogenated cyclopropyl, can be produced by subjecting compound (10"a) to a reduction reaction.

[0345] Scheme IV [ka]

[0346] Y is CR 8 and R 8 To produce compound (I) in which P is isopropyl, the corresponding compound (11) can be used, which can be produced from compound (10) (wherein Y' is CW) according to the following scheme (Scheme V): 1 and W is as defined above.

[0347] Compound (10'b) can be produced by subjecting compound (10) in which Y' is CW to Suzuki coupling reaction with CH2=C(Me)Bpin.

[0348] Y is CR 8 and R 8 Compound (11), in which is isopropyl, can be produced by subjecting compound (10'b) to a reduction reaction.

[0349] Scheme V [ka]

[0350] The compounds of formula (I) (including the compounds named above, as well as pharmaceutically acceptable complexes, salts, solvates, and hydrates thereof) should be evaluated for their biopharmaceutical properties, such as solubility and solution stability versus pH, permeability, etc., to select an appropriate dosage form and route of administration. Compounds intended for pharmaceutical use may be administered as crystalline or amorphous products, and may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, lyophilization, spray drying, evaporative drying, microwave drying, or radio frequency drying.

[0351] Compound (I) may be administered alone or in combination with one or more pharmacologically active substances different from Compound (I). When Compound (I) is administered in combination with a pharmacologically active substance ("concomitant drug"), the administration timing of Compound (I) and the concomitant drug is not limited, and Compound (I) or a pharmaceutical composition thereof, or the concomitant drug or a pharmaceutical composition thereof, may be administered to a subject simultaneously or at different times. The dose of the concomitant drug may be determined according to the dose used clinically and may be selected appropriately depending on the subject, administration route, disease, combination, etc.

[0352] The dosage form of the compound (I) and the concomitant drug is not particularly limited, as long as the compound (I) and the concomitant drug are combined at the time of administration. Examples of such dosage forms include the following: (1) Administration of a single preparation obtained by simultaneously processing compound (I) and a concomitant drug; (2) Simultaneous administration of two types of preparations of compound (I) and a concomitant drug manufactured separately by the same administration route; (3) Staggered administration of two types of preparations of compound (I) and a concomitant drug manufactured separately by the same administration route; (4) Simultaneous administration of two types of preparations of compound (I) and a concomitant drug manufactured separately by different administration routes; (5) Staggered administration of two types of preparations of compound (I) and a concomitant drug manufactured separately by different administration routes (e.g., administration of compound (I) and a concomitant drug in the order, or administration in the reverse order), etc.

[0353] The dosage of the concomitant drug can be appropriately determined based on the dosage used in clinical situations. The mixing ratio of Compound (I) and the concomitant drug can be appropriately determined depending on the administration subject, administration route, target disease, symptoms, combination, etc.

[0354] For example, the content of compound (I) in combination with concomitant drugs varies depending on the form of the formulation, and is usually about 0.01 to about 100% by weight, preferably about 0.1 to about 50% by weight, and more preferably about 0.5 to about 20% by weight based on the total formulation.

[0355] The content of the concomitant drug used in combination with Compound (I) varies depending on the form of the formulation, and is usually about 0.01 to about 100% by weight, preferably about 0.1 to about 50% by weight, and more preferably about 0.5 to about 20% by weight based on the total weight of the formulation.

[0356] The content of additives such as carriers used in combination with compound (I) and concomitant drugs varies depending on the form of the formulation, and is usually about 1 to about 99.99% by weight, preferably about 10 to about 90% by weight, based on the formulation.

[0357] Even when compound (I) and a concomitant drug are formulated separately, the same contents may be employed.

[0358] Generally, one or more of these compounds are administered as a pharmaceutical composition (formulation) together with one or more pharmaceutically acceptable excipients. The choice of excipient depends, inter alia, on the mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form. Useful pharmaceutical compositions and their preparation methods can be found, for example, in A. R. Gennaro (ed.), Remington: The Science and Practice of Pharmacy (20th ed., 2000).

[0359] Compound (I) may be administered orally. Oral administration may involve swallowing, in which case the compound enters the bloodstream through the gastrointestinal tract. Alternatively, or additionally, oral administration may involve mucosal administration (e.g., buccal, sublingual, supragingual), in which the compound enters the bloodstream through the oral mucosa.

[0360] Formulations suitable for oral administration include solid, semi-solid, and liquid systems, such as tablets; soft or hard capsules containing multiparticulates or nanoparticles, liquid, or powder; lozenges (may be filled with liquid); chewable tablets; gels; fast-dispersing dosage forms; films; vaginal suppositories; sprays; and buccal or mucoadhesive patches.Liquid formulations include suspensions, solutions, syrups, and elixirs.Such formulations can be used as fillers in soft or hard capsules (for example, those made from gelatin or hydroxypropylmethylcellulose), and typically contain carriers (for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or suitable oils), and one or more emulsifiers, suspending agents, or both.Liquid formulations can also be prepared by reconstituting solids (for example, from sachets).

[0361] Compound (I) may also be used in fast-dissolving, fast-disintegrating dosage forms such as those described in Liang and Chen, Expert Opinion in Therapeutic Patents (2001) 11(6):981-986.

[0362] For tablet dosage forms, depending on the dose, the active pharmaceutical ingredient (API) may comprise from about 1% to about 80% by weight of the dosage form, or more typically from about 5% to about 60% by weight of the dosage form. In addition to the API, tablets may contain one or more disintegrants, binders, diluents, surfactants, glidants, lubricants, antioxidants, colorants, flavorings, preservatives, and taste-masking agents. Examples of disintegrants include sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, C 1-6Included are alkyl-substituted hydroxypropylcellulose, starch, pregelatinized starch, and sodium alginate. Generally, disintegrants will comprise from about 1% to about 25%, or from about 5% to about 20% by weight of the dosage form.

[0363] Binders are generally used to give tablet formulations cohesion.Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose, and hydroxypropyl methylcellulose.Tablets may also contain diluents such as lactose (monohydrate, spray-dried monohydrate, anhydrous), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch, and calcium hydrogen phosphate dihydrate.

[0364] Tablets may also include surfactants, such as sodium lauryl sulfate and polysorbate 80, and glidants, such as silicon dioxide and talc. When present, the surfactants may comprise from about 0.2% to about 5% by weight of the tablet, and the glidants may comprise from about 0.2% to about 1% by weight of the tablet.

[0365] Tablets may also contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulfate. Lubricants may comprise from about 0.25% to about 10%, or from about 0.5% to about 3% by weight of the tablet.

[0366] Tablet blends may be compressed directly or by roller compaction to form tablets. Tablet blends, or portions of blends, may alternatively be wet-, dry-, or melt-granulated, melt-congealed, or extruded prior to tableting. If desired, one or more of the components may be sized by sieving or milling, or both, prior to blending. The final dosage form may comprise one or more layers, may be coated or uncoated, or may be encapsulated. An exemplary tablet may contain up to about 80% by weight of API, about 10% to about 90% by weight of binder, about 0% to about 85% by weight of diluent, about 2% to about 10% by weight of disintegrant, and about 0.25% to about 10% by weight of lubricant. For a discussion of blending, granulating, milling, sieving, tabletting, coating, and descriptions of alternative techniques for preparing drug products, see A.R. Gennaro (ed.), Remington: The Science and Practice of Pharmacy (20th ed., 2000); H.A. Lieberman et al. (ed.), Pharmaceutical Dosage Forms: Tablets, Vol. 1-3 (2nd ed., 1990); and D.K. Parikh & C.K. Parikh, Handbook of Pharmaceutical Granulation Technology, Vol. 81 (1997).

[0367] Consumable oral films for human or veterinary use are flexible, water-soluble or water-swellable thin film dosage forms that can be fast-dissolving or mucoadhesive. In addition to the API, typical films contain one or more film-forming polymers, binders, solvents, humectants, plasticizers, stabilizers or emulsifiers, viscosity modifiers, and solvents. Other film ingredients can include antioxidants, colorants, flavors and flavor enhancers, preservatives, saliva stimulants, cooling agents, cosolvents (including oils), emollients, bulking agents, antifoaming agents, surfactants, and taste masking agents. Some components of the formulation can perform more than one function.

[0368] In addition to dosage requirements, the amount of API in the film can depend on its solubility. If water-soluble, the API will typically comprise about 1% to about 80% by weight of the non-solvent components (solutes) in the film, or about 20% to about 50% by weight of the solutes in the film. Less soluble APIs may comprise a larger proportion of the composition, typically up to about 88% by weight of the non-solvent components in the film.

[0369] The film-forming polymer may be selected from natural polysaccharides, proteins, or synthetic hydrocolloids and typically comprises from about 0.01% to about 99% or from about 30% to about 80% by weight of the film.

[0370] Film dosage forms are typically prepared by evaporative drying of thin aqueous films coated onto a peelable backing support or paper, which may be carried out in a drying oven or tunnel (e.g., in a combined coating and drying apparatus), a freeze-drying machine, or a vacuum oven.

[0371] Solid formulations useful for oral administration can include immediate-release formulations and modified-release formulations. Modified-release formulations include delayed-release, sustained-release, pulsed-release, controlled-release, targeted-release, and programmed-release. For a general description of suitable modified-release formulations, see U.S. Patent No. 6,106,864. For details of other useful release technologies, such as high-energy dispersions and osmotic and coated particles, see Verma et al., Pharmaceutical Technology Online (2001) 25(2):1-14.

[0372] Compound (I) can also be directly administered into the bloodstream, muscle or internal organs of the subject.The techniques suitable for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial and subcutaneous administration.The device suitable for parenteral administration includes needle-type (including microneedle) injector, needleless injector and infusion device.

[0373] Parenteral formulations are typically aqueous solutions, which may contain excipients such as salts, carbohydrates, and buffers (e.g., pH of about 3 to about 9). However, for some applications, Compound (I) may be more suitably formulated as a sterile, non-aqueous solution or as a dry form for use with a suitable vehicle, such as sterile, pyrogen-free water. Preparation of parenteral formulations under sterile conditions (e.g., by lyophilization) can be readily accomplished using standard pharmaceutical techniques.

[0374] The solubility of compounds used in the preparation of parenteral solutions can be increased by appropriate formulation techniques, such as the incorporation of solubility enhancers. Formulations for parenteral administration may be formulated for immediate release or modified release. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, targeted release, and programmed release. Thus, Compound (I) can be formulated as a suspension, solid, semisolid, or thixotropic liquid for administration as an implanted depot that provides modified release of the active compound. Examples of such formulations include drug-coated stents and semisolids and suspensions containing drug-loaded poly(DL-lactic-co-glycolic acid) (PGLA) microspheres.

[0375] Compound (I) may also be administered topically, intradermally, or transdermally to the skin or mucosa. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages, and microemulsions. Liposomes may also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol, and propylene glycol. Topical formulations may also include penetration enhancers. See, for example, Finnin and Morgan, J. Pharm. Sci. 88(10):955-958 (1999).

[0376] Other means of topical administration include electroporation, iontophoresis, phonophoresis, sonophoresis, and microneedle or needle-free (e.g., Powderject (TM) and Bioject (TM) Formulations for topical administration may be formulated to be immediate or modified release as described above.

[0377] Compound (I) may also be administered intranasally or by inhalation, typically in the form of a dry powder, aerosol spray, or nasal drops. An inhaler may be used to administer the dry powder, which may include the API alone, a powder blend of the API with a diluent such as lactose, or mixed-component particles containing the API and a phospholipid such as phosphatidylcholine. For intranasal administration, the powder may also contain a bioadhesive agent such as chitosan or cyclodextrin. A pressurized container, pump, sprayer, atomizer, or nebulizer may be used to generate an aerosol spray from a solution or suspension containing the API, one or more agents to disperse, solubilize, or extend the release of the API (e.g., EtOH, with or without water), one or more solvents that function as propellants (e.g., 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane), and an optional surfactant, such as sorbitan trioleate, oleic acid, or oligolactic acid. Atomizers that use electrohydrodynamics to generate a fine mist may also be used.

[0378] Prior to use in a dry powder or suspension formulation, the drug product is usually milled to a particle size suitable for delivery by inhalation (typically 90% of the particles by volume have a largest dimension less than 5 microns). This may be achieved by any suitable size reduction method, such as spiral jet milling, fluidized bed jet milling, supercritical fluid processing, high pressure homogenization, or spray drying.

[0379] Capsules, blisters, and cartridges (made, for example, from gelatin or hydroxypropylmethylcellulose) for use in an inhaler or insufflator may be formulated containing a powder mix of the active compound, a suitable powder base such as lactose or starch, and a performance modifier such as L-leucine, mannitol, or magnesium stearate. Lactose may be anhydrous or the monohydrate. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose.

[0380] Solution formulations suitable for use in atomizers that use electrohydrodynamics to generate a fine mist may contain about 1 μg to about 20 mg of API per actuation, and actuation volumes may vary from about 1 μL to about 100 μL. A typical formulation may include one or more compounds of Compound (I), propylene glycol, sterile water, EtOH, and NaCl. Alternative solvents that can be used in place of propylene glycol include glycerol and polyethylene glycol.

[0381] Formulations for inhaled administration, intranasal administration, or both, may be formulated to be immediate or modified release, for example using PGLA. Suitable flavors, such as menthol and levomenthol, or suitable sweeteners, such as saccharin or saccharin sodium, may be added to such formulations intended for inhaled / intranasal administration.

[0382] For dry powder inhalers and aerosols, the dosage unit is determined by utilizing a valve that delivers a metered amount. The unit is typically designed to administer a metered dose or "puff" containing from about 10 μg to about 1000 μg of API. The overall daily dose typically ranges from about 100 μg to about 10 mg, which may be administered in a single dose or, more commonly, in divided doses throughout the day.

[0383] The active compound may be administered rectally or vaginally, for example, in the form of a suppository, pessary, or enema. Cocoa butter is a conventional suppository base, although various alternatives may be used where appropriate. Formulations for rectal or vaginal administration may be formulated to be immediate-release and / or modified-release, as described above.

[0384] Compound (I) may be administered directly to the eye or ear, typically in the form of droplets of a micronized suspension or solution in pH-adjusted, isotonic, sterile saline. Other formulations suitable for ocular and otic administration include ointments, gels, biodegradable implants (e.g., absorbent gel sponges, collagen), non-biodegradable implants (e.g., silicone), wafers, lenses, and microparticle or vesicular systems such as niosomes or liposomes. The formulation may contain one or more polymers and a preservative, such as benzalkonium chloride. Typical polymers include cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, cellulose polymers (e.g., hydroxypropylmethylcellulose, hydroxyethylcellulose, methylcellulose), and heteropolysaccharide polymers (e.g., gellan gum). Such formulations may also be delivered by iontophoresis. Formulations for ocular or otic administration may be formulated for immediate or modified release, as described above.

[0385] Compound (I) may be combined with soluble macromolecular entities, such as cyclodextrin and its derivatives, and polyethylene glycol-containing polymers, to improve their solubility, dissolution rate, taste-masking, bioavailability, or stability. For example, API-cyclodextrin complexes are generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes may be used. As an alternative to direct complexation with the API, cyclodextrins may be used as auxiliary additives, i.e., carriers, diluents, or solubilizers. α-, β-, and γ-cyclodextrins are commonly used for these purposes. See, for example, WO91 / 11172, WO94 / 02518, and WO98 / 55148.

[0386] As noted above, one or more compounds of formula (I), including those specifically named above, and their pharmaceutically active complexes, salts, solvates, and hydrates, may be combined with each other or with one or more other pharmaceutically active compounds to treat various diseases, conditions, and disorders. In such cases, the compounds may be combined in a single dosage form, as described above, or may be provided in the form of a kit suitable for simultaneous administration of the compositions. The kit includes (1) two or more different pharmaceutical compositions, at least one of which contains compound (I), and (2) a device for separately holding the two pharmaceutical compositions (e.g., a divided bottle or a divided foil packet). An example of such a kit is a common blister pack used to package tablets or capsules. The kit is suitable for administering different types of dosage forms (e.g., oral and parenteral), or for administering different pharmaceutical compositions at different dosing intervals, or for titrating different pharmaceutical compositions relative to each other. To aid patient compliance, the kit typically includes instructions for administration and may further provide a memory aid.

[0387] When administered to a human patient, the total daily dose of the claimed and disclosed compounds typically ranges from about 0.1 mg to about 3000 mg, depending on the route of administration. For example, oral administration may require a total daily dose of about 1 mg to about 3000 mg, while intravenous administration may require a total daily dose of only about 0.1 mg to about 300 mg. The total daily dose may be administered in a single dose or in divided doses and, at the physician's discretion, may fall outside the typical ranges set forth above. These doses are based on an average human subject weighing about 60 kg to about 70 kg, although a physician would be able to determine the appropriate dose for patients (e.g., infants) weighing outside this weight range.

[0388] As described above, compound (I) may be used to treat NLRP3-related diseases, disorders, and / or conditions in which inhibition of the NLRP3 inflammasome pathway is indicated, including diseases, disorders, and / or conditions associated with heterozygous gain-of-function mutations in the NLRP3 gene, such as cryopyrin-associated periodic syndrome (CAPS). These may include neonatal-onset multisystem inflammatory disease (NOMID / CINCA), Muckle-Wells syndrome (MWS), and familial cold autoinflammatory syndrome (FCAS).

[0389] Compound (I) may be used to treat neurodegenerative diseases and / or conditions associated with NLRP3. These may include Parkinson's disease, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, prion diseases, and other forms of dementia (i.e., severe or mild neurocognitive disorders) associated with one or more medical conditions, including frontotemporal lobar degeneration, Lewy body disease, vascular disease, traumatic brain injury, substance or drug use, HIV infection, prion diseases, Parkinson's disease, and Huntington's disease. Compound (I) may also be used to treat severe or mild neurocognitive disorders associated with depression, schizophrenia, bipolar disorder, and autism.

[0390] The claimed and disclosed compounds may be combined with one or more other pharmacologically active compounds or therapies to treat one or more disorders, diseases, and / or conditions for which inhibition of the NLRP3 inflammasome pathway is indicated. Such combinations may provide significant therapeutic benefits, including reduced side effects, improved treatment capabilities for underserved patient populations, or synergistic activity. For example, the compounds of formula (I), including the compounds specifically named above, and pharmaceutically acceptable complexes, salts, solvates, and hydrates thereof, may be administered simultaneously, sequentially, or separately in combination with one or more pharmacologically active compounds or therapies for treating Alzheimer's disease. Such compounds or therapies include beta-secretase inhibitors, gamma-secretase inhibitors, HMG-CoA reductase inhibitors, nonsteroidal anti-inflammatory drugs (NSAIDs, e.g., apazone, aspirin, celecoxib, diclofenac (with or without misoprostol), diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, meclofenamate sodium, mefenamic acid, meloxicam, nabumetone, naproxen, oxaprozin, phenylbutazone, piroxicam, choline and magnesium salicylate, salsalate, and sulindac), vitamin E, and anti-amyloid antibodies. Specific examples of compounds used to treat Alzheimer's disease include donepezil, rivastigmine, memantine, and galantamine.

[0391] In addition to drugs used to improve cognition, Compound (I) may be combined with sedatives, hypnotics, anxiolytics, antipsychotics, tranquilizers, and other medications used to treat Alzheimer's disease. For example, Compound (I) may be combined with amitriptyline, amoxapine, aripiprazole, asenapine, bupropion, chlordiazepoxide, citalopram, chlorpromazine, clozapine, desipramine, desvenlafaxine, doxepin, duloxetine, escitalopram, fluoxetine, fluphenazine, haloperidol, iloperidone, imipramine, isocarboxazid, lamotrigine, levomilnacipran, lurasidone, mirtazapine, nefazodone, nortriptyline, olanzapine, thiazolinone ... and ziprasidone.

[0392] Similarly, Compound (I) may be combined with one or more pharmaceutically active agent(s) for treating anxiety (antianxiety medications), including benzodiazepines (alprazolam, chlordiazepoxide, clobazepam, clonazepam, clorazepate, diazepam, estazolam, flurazepam, lorazepam, midazolam, oxazepam, prazepam, quazepam, temazepam, and triazolam), antihistamines (hydroxyzine), non-benzodiazepines (eszopiclone, zaleplon, zolpidem, and zopiclone), and buspirone. Compound (I) may also be combined with one or more pharmaceutically active agents for treating epilepsy (antiepileptic or anticonvulsant drugs), including acetazolamide, carbamazepine, clobazam, clonazepam, eslicarbazepine acetate, ethosuximide, gabapentin, lacosamide, lamotrigine, levetiracetam, nitrazepam, oxcarbazepine, perampanel, piracetam, phenobarbital, phenytoin, pregabalin, primidone, retigabine, rufinamide, sodium valproate, stiripentol, tiagabine, topiramate, vigabatrin, and zonisamide. [Example]

[0393] The following examples are intended to be illustrative and non-limiting and represent specific embodiments of the present invention.

[0394] In the following examples, "room temperature" generally means about 10°C to about 35°C. Ratios shown for mixed solvents are volumetric mixing ratios unless otherwise specified. % means weight % unless otherwise specified.

[0395] In the examples, elution by column chromatography was carried out under observation by TLC (thin layer chromatography) unless otherwise specified. For TLC observation, Merck 60F TLC plates were used. 254 The solvent used as the elution solvent in the column chromatography was used as the developing solvent, and a UV detector was used for detection.

[0396] In silica gel column chromatography, the notation NH means the use of aminopropylsilane-bonded silica gel, and the notation diol means the use of 3-(2,3-dihydroxypropoxy)propylsilane-bonded silica gel.

[0397] For many of the compounds in the examples below, 1H nuclear magnetic resonance (NMR) spectra were obtained. Characteristic chemical shifts (δ) are given in parts per million downfield from tetramethylsilane using conventional abbreviations for major peak designations, including s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), and br (broad). The following abbreviations are used for common solvents: CDCl3 (deuterated chloroform), DMSO-d6 (deuterated dimethyl sulfoxide), CD3OD (deuterated methanol), CD3CN (deuterated acetonitrile), and THF-d8 (deuterated tetrahydrofuran). Mass spectra ([M+H] + m / z for were recorded using electrospray ionization (ESI-MS) or atmospheric pressure chemical ionization (APCI-MS) mass spectrometry. 1 For H NMR analysis, ACD / SpecManager (trade name) software or the like was used. Peaks of hydroxyl groups, amino groups, etc., which have very gentle proton peaks, may not be recorded.

[0398] MS was measured by LC / MS. ESI or APCI was used as the ionization method. The data represent actual measurements (measured values). Molecular ion peaks are generally observed, but fragment ions may also be observed. For example, in the case of compounds with a tert-butoxycarbonyl group, peaks following elimination of the tert-butoxycarbonyl or tert-butyl group may be observed as fragment ions. In the case of compounds with a hydroxyl group, peaks following elimination of HO may be observed as fragment ions. In the case of salts, free molecular ion peaks or fragment ion peaks are generally observed.

[0399] The following abbreviations are used in the examples: MS: Mass spectrum M: Molar concentration N: Normality CDCl3: deuterated chloroform DMSO-d6: Deuterated dimethyl sulfoxide 1 H NMR: proton nuclear magnetic resonance LC / MS: Liquid chromatograph mass spectrometer ESI: electrospray ionization; APCI: atmospheric pressure chemical ionization DMA: N,N-dimethylacetamide DME: 1,2-dimethoxyethane DMF: N,N-dimethylformamide DMSO: dimethyl sulfoxide Et2O: Diethyl ether EtOH: ethanol IPE: Diisopropyl ether MeOH: Methanol NaH: sodium hydride Pd(dppf)Cl2: 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride Pd(dppf)Cl2-CH2Cl2: 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride-dichloromethane adduct TEA: Triethylamine TFA: Trifluoroacetic acid THF: tetrahydrofuran

[0400] Example 3: 2-(5-{[(3R,5R)-5-fluoro-1-methylpiperidin-3-yl]amino}-2H-pyrazolo[3,4-d][1,3]thiazol-2-yl)-3,5-dimethylphenol

[0401] A) tert-Butyl [(3R,5R)-5-fluoro-1-methylpiperidin-3-yl]carbamate

[0402] To a mixture of tert-butyl [(3R,5R)-5-fluoropiperidin-3-yl]carbamate (1 g), formaldehyde (1.270 ml), and MeOH (10 ml) was added sodium triacetoxyborohydride (2.428 g) at 0° C. The mixture was stirred at room temperature for 67 hours. Saturated aqueous sodium bicarbonate solution was added to the mixture at 0° C. The mixture was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (1.028 g).

[0403] 1 H NMR (300 MHz, DMSO-d6) δ 1.27-1.55 (1H, m), 1.38 (9H, s), 1.71 (1H, t, J = 10.4 Hz), 1.82-2.11 (2H, m), 2.15 (3H, s), 2.64-2.87 (2H, m), 3.55-3.78 (1H, m), 4.68-5.02 (1H, m), 6.81 (1H, br d, J = 7.6 Hz).

[0404] B) (3R,5R)-5-Fluoro-1-methylpiperidin-3-amine dihydrochloride

[0405] To a mixture of tert-butyl [(3R,5R)-5-fluoro-1-methylpiperidin-3-yl]carbamate (1.028 g) and ethyl acetate (15 ml), 4N hydrogen chloride in ethyl acetate (15 ml) was added at room temperature. The mixture was stirred at room temperature overnight. To the mixture, IPE (30 ml) was added at room temperature. The mixture was stirred at room temperature for 30 minutes. The precipitated solid was collected and washed with ethyl acetate / IPE to obtain the title compound (0.848 g).

[0406] 1H NMR (300 MHz, DMSO-d6) δ 1.66-1.96 (1H, m), 2.31-2.46 (1H, m), 2.59-3.14 (4H, m), 3.19-3.96 (4H, m), 5.08-5.42 (1H, m), 8.60 (3H, br s), 10.73 (1H, br s).

[0407] C) 2-Iodo-1-(methoxymethoxy)-3,5-dimethylbenzene

[0408] To a mixture of 2-iodo-3,5-dimethylphenol (8.1298 g) and DMF (116 ml) was added 60% NaH (1.742 g) at 0°C. The mixture was stirred at 0°C under a nitrogen atmosphere for 30 minutes, and then methyl chloromethyl ether (2.90 ml) was added to the mixture at 0°C, and the mixture was stirred for 1 hour. A saturated aqueous solution of ammonium chloride was added to the mixture at 0°C. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (9.49 g).

[0409] 1 H NMR (300 MHz, DMSO-d6) δ 2.23 (3H, s), 2.35 (3H, s), 3.40 (3H, s), 5.23 (2H, s), 6.74 (1H, s), 6.83 (1H, s).

[0410] D) 2-[2-(methoxymethoxy)-4,6-dimethylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0411] To a degassed mixture of 2-iodo-1-(methoxymethoxy)-3,5-dimethylbenzene (10.57 g), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (11.03 g), potassium acetate (7.10 g), and DMSO (96 ml), Pd(dppf)Cl2-CHCl2 (1.477 g) was added at room temperature. The mixture was flushed with nitrogen gas and stirred overnight at 100 °C under a nitrogen atmosphere. The mixture was filtered through NH silica gel and Celite® and flushed with ethyl acetate. Water was added to the filtrate, and the mixture was then extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (4.32 g).

[0412] 1 H NMR (300 MHz, DMSO-d6) δ 1.29 (12H, s), 2.20 (3H, s), 2.22 (3H, s), 3.36 (3H, s), 5.09 (2H, s), 6.61 (1H, s), 6.63 (1H, s).

[0413] E) 4-Bromo-1-[2-(methoxymethoxy)-4,6-dimethylphenyl]-3-nitro-1H-pyrazole

[0414] To a mixture of 4-bromo-5-nitro-1H-pyrazole (0.282 g), 2-[2-(methoxymethoxy)-4,6-dimethylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.3585 g), pyridine (0.792 ml), and DMA (7.18 ml) was added copper(II) acetate (0.447 g) at room temperature. The mixture was stirred at 90° C. overnight. The mixture was poured into saturated aqueous ammonium chloride solution and ethyl acetate at 0° C. The mixture was stirred at room temperature for 1 hour. Insoluble material was removed by filtration. The filtrate was extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous ammonium chloride solution and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (0.299 g). MS: [M+Na] + 377.9.

[0415] F) 4-Bromo-1-[2-(methoxymethoxy)-4,6-dimethylphenyl]-1H-pyrazol-3-amine

[0416] To a mixture of 4-bromo-1-[2-(methoxymethoxy)-4,6-dimethylphenyl]-3-nitro-1H-pyrazole (1.72 g), EtOH (25.8 ml), and water (6.44 ml), iron (1.618 g) and ammonium chloride (1.033 g) were added at room temperature. The mixture was stirred at 80° C. for 1 hour. The insoluble material was removed by filtration through Celite® and washed with EtOH. The filtrate was concentrated under reduced pressure. A saturated aqueous solution of sodium bicarbonate was added to the mixture. The mixture was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (1.11 g). MS: [M+H] + 325.9.

[0417] G) N-[(3R,5R)-5-Fluoro-1-methylpiperidin-3-yl]-2-[2-(methoxymethoxy)-4,6-dimethylphenyl]-2H-pyrazolo[3,4-d][1,3]thiazol-5-amine

[0418] To a mixture of 4-bromo-1-[2-(methoxymethoxy)-4,6-dimethylphenyl]-1H-pyrazol-3-amine (3 g), triethylamine (12.82 ml), and THF (60.1 ml) was added thiophosgene (0.917 ml) at 0° C. The mixture was stirred at 0° C. for 2 hours under a nitrogen atmosphere. To the mixture was added (3R,5R)-5-fluoro-1-methylpiperidin-3-amine dihydrochloride (3.1 g) at 0° C. The mixture was stirred at room temperature overnight. To the mixture was added water at room temperature. The mixture was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a brown solid (5.61 g). To a mixture of the solid (0.5 g), 1,10-phenanthroline (0.014 g), cesium carbonate (0.651 g), and DME (12.98 ml) was added copper(I) iodide (9.51 mg) at room temperature. The mixture was heated to 80°C and stirred at 80°C for 3 hours. The mixture was filtered through Celite®. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (0.260 g). MS: [M+H] + 420.0.

[0419] H) 2-(5-{[(3R,5R)-5-fluoro-1-methylpiperidin-3-yl]amino}-2H-pyrazolo[3,4-d][1,3]thiazol-2-yl)-3,5-dimethylphenol

[0420] To a mixture of N-[(3R,5R)-5-fluoro-1-methylpiperidin-3-yl]-2-[2-(methoxymethoxy)-4,6-dimethylphenyl]-2H-pyrazolo[3,4-d][1,3]thiazol-5-amine (0.35 g) and MeOH (2 ml) was added 4N hydrogen chloride in ethyl acetate (4 ml) at 0° C. The mixture was stirred at room temperature for 1 hour. The mixture was quenched with saturated aqueous sodium bicarbonate at 0° C. and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane, then MeOH / ethyl acetate) to give a yellow solid. Ethyl acetate was added to a mixture of the solid and ethyl acetate at 80° C. The mixture was stirred at 80° C. for 30 minutes. Heptane was added to the mixture at 80° C. The mixture was stirred at 80° C. for 30 minutes, cooled to room temperature, and stirred at room temperature for 66 hours. The precipitated solid was collected, washed with ethyl acetate / heptane and dried to give the title compound (0.144 g).

[0421] 1 H NMR (400 MHz, DMSO-d6) δ 1.54-1.76 (1H, m), 1.93 (3H, s), 1.99 (1H, br t, J = 9.5 Hz), 2.06-2.18 (1H, m), 2.19-2.33 (1H, m), 2.22 (3H, s), 2.24 (3H, s), 2.71-2.81 (1H, m), 2.86-2.96 (1H, m), 4.04-4.23 (1H, m), 4.71-5.08 (1H, m), 6.58 (1H, s), 6.63 (1H, s), 7.58 (1H, s), 8.01 (1H, d, J = 7.7 Hz), 9.61 (1H, br s).

[0422] Example 4: 3,5-dimethyl-2-(5-{[(3R)-1-methylpiperidin-3-yl]amino}-2H-pyrazolo[3,4-d][1,3]thiazol-2-yl)phenol

[0423] A) 2-[2-(methoxymethoxy)-4,6-dimethylphenyl]-N-[(3R)-1-methylpiperidin-3-yl]-2H-pyrazolo[3,4-d][1,3]thiazol-5-amine

[0424] To a mixture of 4-bromo-1-[2-(methoxymethoxy)-4,6-dimethylphenyl]-1H-pyrazol-3-amine (65.3 mg), TEA (0.279 ml), and THF (2 ml) was added thiophosgene (0.020 ml) at 0° C. The mixture was stirred at 0° C. for 1 hour under a nitrogen atmosphere. To the mixture was added (R)-1-methylpiperidin-3-amine dihydrochloride (74.9 mg) at 0° C. The mixture was stirred at room temperature overnight. Water was added to the mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. To a mixture of the residue, 1,10-phenanthroline (21.6 mg), cesium carbonate (131 mg), and DME (3 mL) was added copper(I) iodide (15.3 mg) at room temperature. The mixture was stirred at 80° C. for 2 hours. The mixture was purified by silica gel column chromatography (NH, ethyl acetate / hexane, then MeOH / ethyl acetate) to give the title compound (56.8 mg). MS: [M+H] + 402.2.

[0425] B) 3,5-dimethyl-2-(5-{[(3R)-1-methylpiperidin-3-yl]amino}-2H-pyrazolo[3,4-d][1,3]thiazol-2-yl)phenol

[0426] To a mixture of 2-[2-(methoxymethoxy)-4,6-dimethylphenyl]-N-[(3R)-1-methylpiperidin-3-yl]-2H-pyrazolo[3,4-d][1,3]thiazol-5-amine (55.3 mg) and thioanisole (0.161 ml) was added TFA (1 ml) at 0° C. The mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane, then MeOH / ethyl acetate) and washed with ethyl acetate / IPE to give the title compound (26.3 mg).

[0427] 1 H NMR (400 MHz, DMSO-d6) δ 1.22-1.38 (1H, m), 1.44-1.60 (1H, m), 1.64-1.77 (1H, m), 1.81-2.05 (6H, m), 2.18 (3H, s), 2.23 (3H, s), 2.52-2.58 (1H, m), 2.80-2.94 (1H, m), 3.77-3.92 (1H, m), 6.57 (1H, s), 6.63 (1H, s), 7.56 (1H, s), 7.95 (1H, d, J = 7.5 Hz), 9.56 (1H, br s).

[0428] Example 20: 3-Ethyl-2-(5-{[(3R,5R)-5-fluoro-1-methylpiperidin-3-yl]amino}-2H-pyrazolo[3,4-d][1,3]thiazol-2-yl)-5-methylphenol

[0429] A) 1,2-bis(methoxymethoxy)-4-methylbenzene

[0430] 60% NaH (1.853 g) was added to a mixture of 4-methylbenzene-1,2-diol (2.3 g) and DMF (30 ml) at 0°C. After stirring at 0°C for 5 minutes, chloromethyl methyl ether (4.22 ml) was added to the mixture. The mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. The mixture was poured into a saturated aqueous ammonium chloride solution at room temperature and extracted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (3.80 g).

[0431] 1H NMR (400 MHz, CDCl3) δ 2.28 (3H, s), 3.51 (3H, s), 3.52 (3H, s), 5.19 (2H, s), 5.21 (2H, s), 6.76 (1H, dd, J = 8.31, 1.83 Hz), 6.98 (1H, d, J = 1.83 Hz), 7.04 (1H, d, J = 8.31 Hz).

[0432] B) 2,3-bis(methoxymethoxy)-5-methylbenzaldehyde

[0433] n-Butyllithium (1.6 M in hexane) (15 ml) was added to a mixture of 1,2-bis(methoxymethoxy)-4-methylbenzene (3.50 g) and EtO (30 ml) at 0°C. After stirring at 0°C for 10 minutes, DMF (3 ml) was added to the mixture. The mixture was stirred at 0°C for 1 hour under a nitrogen atmosphere. The mixture was poured into water at room temperature and extracted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (2.75 g).

[0434] 1 H NMR (400 MHz, CDCl3) δ 2.33 (3H, s), 3.52 (3H, s), 3.57 (3H, s), 5.21 (2H, s), 5.22 (2H, s), 7.20-7.24 (1H, m), 7.29-7.32 (1H, m), 10.42 (1H, s).

[0435] C) 2-Hydroxy-3-(methoxymethoxy)-5-methylbenzaldehyde

[0436] Wet Amberlyst® 15 ion exchange resin (12.0 g) was added to a mixture of 2,3-bis(methoxymethoxy)-5-methylbenzaldehyde (31.0 g) and toluene (300 ml) at room temperature. The mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (diol, ethyl acetate / hexane) to give the title compound (16.20 g). MS: [MH] - 194.8.

[0437] D) 2-(benzyloxy)-3-(methoxymethoxy)-5-methylbenzaldehyde

[0438] 60% NaH (1.427 g) was added to a mixture of 2-hydroxy-3-(methoxymethoxy)-5-methylbenzaldehyde (7.0 g) and DMF (200 ml) at 0° C. After stirring at 0° C. for 10 minutes, benzyl bromide (4.23 ml) was added to the mixture. The mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. The mixture was poured into saturated aqueous ammonium chloride at room temperature and extracted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (4.50 g).

[0439] 1 H NMR (300 MHz, CDCl3) δ 2.33 (3H, s), 3.55 (3H, s), 5.14 (2H, s), 5.26 (2H, s), 7.22-7.44 (7H, m), 10.18 (1H, s).

[0440] E) 2-(benzyloxy)-1-ethenyl-3-(methoxymethoxy)-5-methylbenzene

[0441] n-Butyllithium (1.6 M in hexane) (12.77 ml) was added to a mixture of methyltriphenylphosphonium bromide (8.42 g) and THF (50 ml) at 0°C. After stirring at 0°C for 20 minutes, 2-(benzyloxy)-3-(methoxymethoxy)-5-methylbenzaldehyde (4.50 g) was added to the mixture. The mixture was stirred at 0°C for 1 hour under a nitrogen atmosphere. The mixture was poured into a saturated aqueous ammonium chloride solution at room temperature and extracted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (3.78 g). MS: [MH] - 283.1.

[0442] F) 2-ethyl-6-(methoxymethoxy)-4-methylphenol

[0443] A mixture of 2-(benzyloxy)-1-ethenyl-3-(methoxymethoxy)-5-methylbenzene (2.6 g) and 10% palladium on carbon (0.973 g) in EtOH (30 ml) was stirred overnight at room temperature under a hydrogen atmosphere. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (1.75 g). MS: [MH] - 195.0.

[0444] G) 2-Ethyl-6-(methoxymethoxy)-4-methylphenyl trifluoromethanesulfonate

[0445] Cesium carbonate (6.0 g) was added to a mixture of 2-ethyl-6-(methoxymethoxy)-4-methylphenol (1.75 g) and DMF (20 ml) at 0° C. After stirring at 0° C. for 10 minutes, N-phenylbis(trifluoromethanesulfonimide) (3.82 g) was added to the mixture. The mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere. The mixture was poured into a saturated aqueous ammonium chloride solution at room temperature and extracted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (2.73 g).

[0446] 1 H NMR (300 MHz, CDCl3) δ 1.23 (3H, t, J = 7.53 Hz), 2.32 (3H, s), 2.68 (2H, q, J = 7.53 Hz), 3.51 (3H, s), 5.20 (2H, s), 6.72-6.74 (1H, m), 6.90-6.94 (1H, m).

[0447] H) 2-[2-ethyl-6-(methoxymethoxy)-4-methylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0448] A mixture of 2-ethyl-6-(methoxymethoxy)-4-methylphenyl trifluoromethanesulfonate (2.25 g), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (2.262 g), potassium acetate (2.018 g), Pd(dppf)Cl2 (0.501 g), and DMSO (30 mL) was stirred overnight at 80 °C under an argon atmosphere. The mixture was poured into water at room temperature and extracted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (0.135 g).

[0449] 1H NMR (300 MHz, CDCl3) δ 1.19 (3H, t, J = 7.78 Hz), 1.37 (12H, s), 2.28 (3H, s), 2.59 (2H, q, J = 7.78 Hz), 3.47 (3H, s), 5.12 (2H, s), 6.65 (2H, s).

[0450] I) 4-Bromo-1-[2-ethyl-6-(methoxymethoxy)-4-methylphenyl]-3-nitro-1H-pyrazole

[0451] To a mixture of 4-bromo-3-nitro-1H-pyrazole (169 mg), 2-[2-ethyl-6-(methoxymethoxy)-4-methylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (135 mg), pyridine (0.284 ml), and DMA (3 ml) was added copper(II) acetate (160 mg) at room temperature. The mixture was stirred at 90° C. overnight. The mixture was poured into saturated aqueous ammonium chloride solution and ethyl acetate at 0° C. The mixture was stirred at room temperature for 1 hour. Insoluble material was removed by filtration. The filtrate was extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous ammonium chloride solution and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (128 mg). MS: [M+H] + 370.0.

[0452] J) 4-Bromo-1-[2-ethyl-6-(methoxymethoxy)-4-methylphenyl]-1H-pyrazol-3-amine

[0453] To a mixture of 4-bromo-1-[2-ethyl-6-(methoxymethoxy)-4-methylphenyl]-3-nitro-1H-pyrazole (120 mg), EtOH (24 ml), and water (6 ml) was added iron (109 mg) and ammonium chloride (69.4 mg) at room temperature. The mixture was stirred at 80° C. for 1 hour. The insoluble material was removed by filtration through Celite® and washed with EtOH. The filtrate was concentrated under reduced pressure. A saturated aqueous solution of sodium bicarbonate was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (83 mg). MS: [M+H] + 340.0.

[0454] K) 2-[2-ethyl-6-(methoxymethoxy)-4-methylphenyl]-N-[(3R,5R)-5-fluoro-1-methylpiperidin-3-yl]-2H-pyrazolo[3,4-d][1,3]thiazol-5-amine

[0455] To a mixture of 4-bromo-1-[2-ethyl-6-(methoxymethoxy)-4-methylphenyl]-1H-pyrazol-3-amine (83 mg), TEA (0.340 ml), and THF (1.5 ml) was added thiophosgene (0.024 ml) at 0° C. The mixture was stirred at 0° C. for 1 hour under a nitrogen atmosphere. To the mixture was added (3R,5R)-5-fluoro-1-methylpiperidin-3-amine dihydrochloride (85 mg) at 0° C. The mixture was stirred at room temperature overnight. Water was added to the mixture at room temperature. The mixture was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. To a mixture of the residue, 1,10-phenanthroline (25.9 mg), cesium carbonate (156 mg), and DME (3 ml), copper(I) iodide (18.28 mg) was added at room temperature. The mixture was stirred at 80° C. for 2 hours. The mixture was purified by silica gel column chromatography (NH, ethyl acetate / hexane, then MeOH / ethyl acetate) to give the title compound (68.0 mg). MS: [M+H] +434.2.

[0456] L) 3-Ethyl-2-(5-{[(3R,5R)-5-fluoro-1-methylpiperidin-3-yl]amino}-2H-pyrazolo[3,4-d][1,3]thiazol-2-yl)-5-methylphenol

[0457] To a mixture of 2-[2-ethyl-6-(methoxymethoxy)-4-methylphenyl]-N-[(3R,5R)-5-fluoro-1-methylpiperidin-3-yl]-2H-pyrazolo[3,4-d][1,3]thiazol-5-amine (68 mg) and thioanisole (0.184 ml) was added TFA (1 ml) at 0°C. The mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, MeOH / ethyl acetate) to obtain the title compound (46.0 mg).

[0458] 1 H NMR (300 MHz, CDCl3) δ 1.09-1.17 (3H, m), 2.00-2.29 (3H, m), 2.30-2.33 (3H, m), 2.34-2.37 (3H, m), 2.37-2.76 (5H, m), 2.82-2.94 (1H, m), 4.01-4.20 (1H, m) 4.75-4.99 (1H, m), 6.66-6.70 (1H, m), 6.71-6.76 (1H, m), 7.46 (1H, s), 7.63-7.88 (1H, m).

[0459] The compounds of the examples are shown in Tables 1-1 to 1-18. MS in the tables means actual measured values. The compounds of Examples 1, 2, 5 to 19, and 21 to 181 in the following tables were produced according to the methods described in the above examples or methods similar thereto.

[0460] [Table 1-1]

[0461]

Table 1-2

[0462]

Table 1-3

[0463]

Table 1-4

[0464]

Table 1-5

[0465]

Table 1-6

[0466]

Table 1-7

[0467]

Table 1-8

[0468]

Table 1-9

[0469]

Table 1-10

[0470]

Table 1-11

[0471]

Table 1-12

[0472] [Table 1-13]

[0473] [Table 1-14]

[0474] [Table 1-15]

[0475] [Table 1-16]

[0476] [Table 1-17]

[0477] [Table 1-18]

[0478] biological activity

[0479] The biological activity of Compound (I) on NLRP3 was determined using the following in vitro method.

[0480] IL-1β TR-FRET assay (IC 50 (reported as

[0481] Monocytic THP-1 cells (ATCC:TIB-202) were maintained in RPMI medium (Life Technologies, catalog no. A10491-01) according to the supplier's instructions. RPMI was supplemented with 10% heat-inactivated fetal bovine serum (Corning, catalog no. 35-010-CV). Cells were differentiated into macrophages by adding 25 ng / mL IFN-γ (PeproTech, catalog no. AF300-02-100UG) for 24 hours at 37°C / 5% CO2. The medium was replaced with fresh medium without FBS, and cells were treated with 50 ng / mL LPS (priming step) (LPS-EK: Invivogen, catalog no. tlrl-peklps). Cells were seeded at 240,000 cells per well in 384-well flat-bottom cell culture plates (FALCON, catalog no. 353962) and incubated at 37°C / 5% CO2 for 24 hours. Compounds were serially diluted in DMSO (half-log dilutions) and finally diluted in FBS-free medium. Compounds were added to the cells in the 384-well plate (1:3 addition), and the plate was then incubated at 37°C / 5% CO2 for 30 minutes. 20 mM ATP (Sigma catalog no. A3377-25G) was added to activate the NLRP3 inflammasome, and the cells were incubated at 37°C / 5% CO2 for 2 hours. At the end of the incubation period, 30 μL of supernatant was transferred to another 384-well plate and mixed on a plate shaker for 1 minute. The supernatant was mixed with an HTRF antibody (Human IL-1β kit, Cisbio, 62HIL1BPEH) in an assay plate (Greiner Bio-One, catalog no. 784075), and the assay plate was incubated at room temperature for 16–24 h in a shaded box. HTRF signals were measured using EnVision (PerkinElmer) according to the manufacturer's instructions.

[0482] TNF-α assay (IC 50 (reported as

[0483] Monocytic THP-1 cells (ATCC:TIB-202) were maintained in RPMI medium (Life Technologies, catalog number A10491-01) according to the supplier's instructions. RPMI was supplemented with 10% heat-inactivated fetal bovine serum (Hyclone catalog number SH30396.03). Cells were differentiated into macrophages by adding 25 ng / mL IFN-γ for 24 hours at 37°C / 5% CO2. The medium was replaced with fresh medium without FBS. Cells were seeded at 40,000 cells per well into 384-well flat-bottom cell culture plates (Costar 3764) containing compounds (added at 1:1000) in a 1:3.16 serial dilution series in DMSO and incubated for 30 minutes at 37°C / 5% CO2. The NF-κB pathway was activated by the addition of 50 ng / mL LPS, and cells were incubated for 3 hours at 37°C / 5% CO. At the end of the incubation period, supernatants (40 μL) were removed and IL-1β levels were monitored using an ELISA (human TNF-α ELISA, R&D systems, catalog number DY201) according to the manufacturer's instructions.

[0484] Data interpretation

[0485] I C 50 The value is Y=[bottom+(top-bottom)] / (1+10 ∧ [(Log IC 50 The percentage of inhibition was calculated from a plot of the inhibitor concentration versus the percentage of inhibition by fitting a logistic curve according to the following equation: [-X)·Hill slope] (where Y is the % inhibition at inhibitor concentration X, "bottom" is the lowest inhibition value, i.e., 0%, "top" is the maximum inhibition value, i.e., 100%, and "Hill slope" represents the slope of the sigmoidal curve between the "bottom" and "top" values). Curve fitting was performed using XLfit (version 5.5.0.5, ID Business Solutions Limited) or internally developed software.

[0486] Table 2 lists the in vitro biological assay data (IL-1β and TNF-α) for the compounds shown in the examples. These assays are described above in the section entitled Biological Activity.

[0487] [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5]

[0488] These results demonstrated that the compounds of the present invention suppressed IL-1β production. The compounds of the present invention were also confirmed to be selective for IL-1β over TNF-α. These results demonstrate that the compounds inhibit the targeted NLRP3 inflammasome activation pathway with little or no interference with the NF-κB-dependent priming pathway. Given the diversity of proinflammatory factors, which often have opposing functions, specific inhibition of the NLRP3 inflammasome pathway is necessary to achieve the most desired outcomes without interfering with the tissue repair process.

[0489] Formulation example 1 (capsule manufacturing) 1) 30 mg of the compound of Example 1 2) Microcrystalline cellulose 10mg 3) Lactose 19mg 4) Magnesium stearate 1mg Total 60mg 1), 2), 3), and 4) are mixed and filled into a gelatin capsule.

[0490] Formulation example 2 (tablet manufacturing) 1) 30 g of the compound of Example 1 2) Lactose 50g 3) 15g cornstarch 4) Carboxymethylcellulose calcium 44g 5) Magnesium stearate 1g Total 1000 tablets 140g The total amount of 1), 2), and 3) and 30 g of 4) are mixed with water, vacuum dried, and sieved. The sieved powder is mixed with 14 g of 4) and 1 g of 5), and the mixture is punched out using a tablet press. In this way, 1000 tablets containing 30 mg of the compound of Example 1 are obtained.

[0491] As used in this specification and the appended claims, singular articles such as "a," "an," and "the" may refer to a single or plural referent unless the context clearly dictates otherwise. Thus, for example, a reference to a composition containing "a compound" may include a single compound or two or more compounds. The above description is intended to be illustrative and non-limiting. Many embodiments will become apparent to those skilled in the art upon reading the above description. Accordingly, the scope of the invention is to be determined with reference to the appended claims, including the full scope of equivalents to such claims. The disclosures of all articles and references cited in this disclosure, including patents, patent applications, and publications, are hereby incorporated by reference in their entirety for all purposes.

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof, 【Chemistry 1】 During the ceremony, X is S or NR ７ And, Y is CR ８ or N, R １ However, any substituted four-membered heterocyclic group or five-membered or six-membered heterocyclic group, or any substituted C １－６ Alkyl groups, or optionally substituted C ３－１０ It is a cycloalkyl group, R ２ However, hydrogen atoms, or optionally substituted C １－３ It is an alkyl group, R ３ , R ４ , and R ５ are each independently a hydrogen atom, a halogen atom, an optionally substituted C １－６ alkyl group, an optionally substituted C ３－８ cycloalkyl group, or an optionally substituted C １－６ alkoxy group, R ６ However, hydrogen atoms, or optionally substituted C １－６ It is an alkyl group, R ７ However, hydrogen atoms, or optionally substituted C １－６ It is an alkyl group, R ８ However, hydrogen atoms, halogen atoms, and arbitrarily substituted C １－６ Alkyl alkyl groups, optionally substituted C ３－８ Cycloalkyl or optionally substituted C １－６ The compound, or a pharmaceutically acceptable salt thereof, which is an alkoxy group.

2. X is S or NR ７ And, Y is CR ８ or N, R １ but, (1) A four-membered heterocyclic group or a five-membered or six-membered heterocyclic group, wherein the heterocyclic group is (a) Halogen atom, (b) Oxo group, (c) C, which is optionally substituted with 1 to 3 substituents selected from the following. １－６ alkyl group, (i) halogen atoms, and (ii) C １－６ Alkoxy group, (d) C ３－８ Cycloalkyl groups, (e) Hydroxyl group, (f) C １－６ Alkoxy group, (g) C, which is optionally substituted with 1 to 3 substituents selected from the following: １－６ Alkyl-carbonyl group, (i) Halogen atom, (ii) Hydroxyl group, (iii) C １－６ Alkoxy groups, and (iv) C ３－８ Cycloalkyl groups, (h) C, which is optionally substituted with 1 to 3 substituents selected from the following: ３－８ Cycloalkyl-carbonyl group, (i) Halogen atom, (ii) cyano group, and (iii) Hydroxyl group, (i) C, which is arbitrarily substituted with 1 to 3 halogen atoms. １－６ Alkoxy-carbonyl group, (j) C ３－８ Cycloalkoxy-carbonyl group, (k) C ７－１６ Aralkyloxy-carbonyl group, (l) Mono or G-C １－６ Alkyl-carbamoyl group, (m) C １－６ Alkyl sulfonyl group, (n) C ３－８ Cycloalkylsulfonyl group, and (o) The heterocyclic group, which is optionally substituted with 1 to 3 substituents selected from 3 to 8-membered non-aromatic heterocyclic groups, (2) C which is optionally substituted with 1 to 3 substituents selected from the following １－６ alkyl group, (a) Hydroxyl group, (b) C, which is arbitrarily substituted with 1 to 3 halogen atoms. １－６ Alkoxy group, (c) C, which is arbitrarily substituted with 1 to 3 halogen atoms. ３－８ Cycloalkyl groups, (d) Mono or G-C １－６ Alkylamino group, (e) C １－６ Alkyl-carbonylamino group, (f) A 3- to 8-membered non-aromatic heterocyclic group optionally substituted with a hydroxyl group, (g) halogen atoms, and (h) 5-14 member aromatic heterocyclyl group, or (3) C which is optionally substituted with 1 to 3 substituents selected from the following: ３－１０ Cycloalkyl group (the C ３－１０ The cycloalkyl group may be a spirocyclic group or a crosslinked spirocyclic group. (a) Hydroxyl group, (b) C, which is arbitrarily substituted with 1 to 3 halogen atoms. １－６ alkyl groups, and (c) C, which is arbitrarily substituted with 1 to 3 halogen atoms. １－６ Alkoxy group And, R ２ but, (1) A hydrogen atom, or (2) 1 to 3 C １－６ C optionally substituted with an alkoxy group １－３ alkyl group And, R ３ That is a hydrogen atom, R ４ but, (1) Hydrogen atom, (2) Halogen atoms, (3) C which is arbitrarily substituted with 1 to 3 halogen atoms １－６ Alkyl alkyl group, or (4) C which is arbitrarily substituted with 1 to 3 halogen atoms １－６ Alkoxy group And, R ５ That is a hydrogen atom, R ６ However, hydrogen atoms or C １－６ It is an alkyl group, R ７ However, C １－６ It is an alkyl group, R ８ but, (1) Hydrogen atom, (2) Halogen atoms, (3) (i) a halogen atom and (ii) C optionally substituted with 1 to 3 halogen atoms １－６ C is optionally substituted with 1 to 3 substituents selected from alkoxy groups. １－６ alkyl group, (4) C which is arbitrarily substituted with 1 to 3 halogen atoms ３－８ Cycloalkyl groups, or (5) C which is arbitrarily substituted with 1 to 3 halogen atoms １－６ Alkoxy group The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

3. R ２ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein is a hydrogen atom.

4. X is NR ７ The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

5. X is NR ７ And R ７ C １－６ A compound according to claim 1, wherein the compound is an alkyl group, or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 1, wherein X is S, or a pharmaceutically acceptable salt thereof.

7. R １ but, (1) A four-membered heterocyclic group or a five-membered or six-membered heterocyclic group, wherein the heterocyclic group is (a) Halogen atom, (b) Oxo group, (c) C, which is optionally substituted with 1 to 3 substituents selected from the following. １－６ alkyl group, (i) halogen atoms, and (ii) C １－６ Alkoxy group, (d) C ３－８ Cycloalkyl groups, (e) Hydroxyl group, (f) C １－６ Alkoxy group, (g) C, which is optionally substituted with 1 to 3 substituents selected from the following: １－６ Alkyl-carbonyl group, (i) Halogen atom, (ii) Hydroxyl group, (iii) C １－６ Alkoxy groups, and (iv) C ３－８ Cycloalkyl groups, (h) C, which is optionally substituted with 1 to 3 substituents selected from the following: ３－８ Cycloalkyl-carbonyl group, (i) Halogen atom, (ii) cyano group, and (iii) Hydroxyl group, (i) C, which is arbitrarily substituted with 1 to 3 halogen atoms. １－６ Alkoxy-carbonyl group, (j) C ３－８ Cycloalkoxy-carbonyl group, (k) C ７－１６ Aralkyloxy-carbonyl group, (l) Mono or G-C １－６ Alkyl-carbamoyl group, (m) C １－６ Alkyl sulfonyl group, (n) C ３－８ Cycloalkylsulfonyl group, and (o) The heterocyclic group, which is optionally substituted with 1 to 3 substituents selected from 3 to 8-membered non-aromatic heterocyclic groups, (2) C which is optionally substituted with 1 to 3 substituents selected from the following １－６ alkyl group, (a) Hydroxyl group, (b) C, which is arbitrarily substituted with 1 to 3 halogen atoms. １－６ Alkoxy group, (c) C, which is arbitrarily substituted with 1 to 3 halogen atoms. ３－８ Cycloalkyl groups, (d) Mono or G-C １－６ Alkylamino group, (e) C １－６ Alkyl-carbonylamino group, (f) A 3- to 8-membered non-aromatic heterocyclic group optionally substituted with a hydroxyl group, (g) halogen atoms, and (h) 5-14 member aromatic heterocyclyl group, or C optionally substituted by 1 to 3 substituents selected from the following ３－１０ cycloalkyl group (the C ３－１０ cycloalkyl group may be a spiro ring group or a bridged spiro ring group) (a) Hydroxyl group, (b) C, which is arbitrarily substituted with 1 to 3 halogen atoms. １－６ alkyl groups, and (c) C, which is arbitrarily substituted with 1 to 3 halogen atoms. １－６ A compound according to claim 1, wherein the compound is an alkoxy group, or a pharmaceutically acceptable salt thereof.

8. R １ However, the heterocyclic group is a four-membered heterocyclic group or a five-membered or six-membered non-aromatic heterocyclic group, and the heterocyclic group is (a) Halogen atom, (b) Oxo group, (c) C, which is optionally substituted with 1 to 3 substituents selected from the following. １－６ alkyl group, (i) halogen atoms, and (ii) C １－６ Alkoxy group, (d) C ３－８ cycloalkyl group, (e) Hydroxyl group, (f) C １－６ Alkoxy group, (g) C, which is optionally substituted with 1 to 3 substituents selected from the following: １－６ Alkyl-carbonyl group, (i) Halogen atom, (ii) Hydroxyl group, (iii) C １－６ Alkoxy groups, and (iv) C ３－８ Cycloalkyl groups, (h) C, which is optionally substituted with 1 to 3 substituents selected from the following: ３－８ Cycloalkyl-carbonyl group, (i) Halogen atom, (ii) cyano group, and (iii) Hydroxyl group, (i) C, which is arbitrarily substituted with 1 to 3 halogen atoms. １－６ Alkoxy-carbonyl group, (j) C ３－８ Cycloalkoxy-carbonyl group, (k) C ７－１６ Aralkyloxy-carbonyl group, (l) Mono or G-C １－６ Alkyl-carbamoyl group, (m) C １－６ Alkyl sulfonyl group, (n) C ３－８ Cycloalkylsulfonyl group, and (o) 3- to 8-membered non-aromatic heterocyclic group A compound according to claim 1 or a pharmaceutically acceptable salt thereof, optionally substituted with one to three substituents selected from the above.

9. R １ However, the group may be a four-membered heterocyclic group or a five-membered or six-membered non-aromatic heterocyclic group selected from pyrrolidinyl, piperidyl, oxetanyl, tetrahydrofuryl, and tetrahydropyranyl. These are elementary cyclic groups, and each of them is (a) Halogen atom, (b) Oxo group, (c) C, which is optionally substituted with 1 to 3 substituents selected from the following. １－６ alkyl group, (i) halogen atoms, and (ii) C １－６ Alkoxy group, (d) C ３－８ Cycloalkyl groups, (e) Hydroxyl group, (f) C １－６ Alkoxy group, (g) C, which is optionally substituted with 1 to 3 substituents selected from the following: １－６ Alkyl-carbonyl group, (i) Halogen atom, (ii) Hydroxyl group, (iii) C １－６ Alkoxy groups, and (iv) C ３－８ Cycloalkyl groups, (h) C, which is optionally substituted with 1 to 3 substituents selected from the following: ３－８ Cycloalkyl-carbonyl group, (i) Halogen atom, (ii) cyano group, and (iii) Hydroxyl group, (i) C, which is arbitrarily substituted with 1 to 3 halogen atoms. １－６ Alkoxy-carbonyl group, (j) C ３－８ Cycloalkoxy-carbonyl group, (k) C ７－１６ Aralkyloxy-carbonyl group, (l) Mono or G-C １－６ Alkyl-carbamoyl group, (m) C １－６ Alkyl sulfonyl group, (n) C ３－８ Cycloalkylsulfonyl group, and (o) 3- to 8-membered non-aromatic heterocyclic group A compound according to claim 1 or a pharmaceutically acceptable salt thereof, optionally substituted with one to three substituents selected from the above.

10. Y is CR ８ And R ８ but, (1) Hydrogen atom, (2) Halogen atoms, (3) (i) a halogen atom and (ii) C optionally substituted with 1 to 3 halogen atoms １－６ C is optionally substituted with 1 to 3 substituents selected from alkoxy groups. １－６ alkyl group, (4) C which is arbitrarily substituted with 1 to 3 halogen atoms ３－８ Cycloalkyl groups, or (5) C which is arbitrarily substituted with 1 to 3 halogen atoms １－６ Alkoxy group The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

11. R １ but, (1) A four-membered heterocyclic group or a five-membered or six-membered heterocyclic group, wherein the heterocyclic group is (a) Halogen atom, (b) Oxo group, (c) C, which is optionally substituted with 1 to 3 substituents selected from the following. １－６ alkyl group, (i) halogen atoms, and (ii) C １－６ Alkoxy group, (d) C ３－８ Cycloalkyl groups, (e) Hydroxyl group, (f) C １－６ Alkoxy group, (g) C, which is optionally substituted with 1 to 3 substituents selected from the following: １－６ Alkyl-carbonyl group, (i) Halogen atom, (ii) Hydroxyl group, (iii) C １－６ Alkoxy groups, and (iv) C ３－８ Cycloalkyl groups, (h) C, which is optionally substituted with 1 to 3 substituents selected from the following: ３－８ Cycloalkyl-carbonyl group, (i) Halogen atom, (ii) cyano group, and (iii) Hydroxyl group, (i) C, which is arbitrarily substituted with 1 to 3 halogen atoms. １－６ Alkoxy-carbonyl group, (j) C ３－８ Cycloalkoxy-carbonyl group, (k) C ７－１６ Aralkyloxy-carbonyl group, (l) Mono or G-C １－６ Alkyl-carbamoyl group, (m) C １－６ Alkyl sulfonyl group, (n) C ３－８ Cycloalkylsulfonyl group, and (o) 3- to 8-membered non-aromatic heterocyclic group The heterocyclic group, which is optionally substituted with one to three substituents selected from the above, (2) C which is optionally substituted with 1 to 3 substituents selected from the following １－６ alkyl group, (a) Hydroxyl group, (b) C, which is arbitrarily substituted with 1 to 3 halogen atoms. １－６ Alkoxy group, (c) C, which is arbitrarily substituted with 1 to 3 halogen atoms. ３－８ Cycloalkyl groups, (d) Mono or G-C １－６ Alkylamino group, (e) C １－６ Alkyl-carbonylamino group, (f) A 3- to 8-membered non-aromatic heterocyclic group optionally substituted with a hydroxyl group, (g) halogen atoms, and (h) 5-14 member aromatic heterocyclyl group, or (3) C which is optionally substituted with 1 to 3 substituents selected from the following: ３－１０ Cycloalkyl group (the C ３－１０ The cycloalkyl group may be a spirocyclic group or a crosslinked spirocyclic group. (a) Hydroxyl group, (b) C, which is arbitrarily substituted with 1 to 3 halogen atoms. １－６ alkyl groups, and (c) C, which is arbitrarily substituted with 1 to 3 halogen atoms. １－６ Alkoxy group And, R ２ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein is a hydrogen atom.

12. X is S, R １ However, the heterocyclic group is a four-membered heterocyclic group or a five-membered or six-membered non-aromatic heterocyclic group, and the heterocyclic group is (a) Halogen atom, (b) Oxo group, (c) C, which is optionally substituted with 1 to 3 substituents selected from the following. １－６ alkyl group, (i) halogen atoms, and (ii) C １－６ Alkoxy group, (d) C ３－８ Cycloalkyl groups, (e) Hydroxyl group, (f) C １－６ Alkoxy group, (g) C, which is optionally substituted with 1 to 3 substituents selected from the following: １－６ Alkyl-carbonyl group, (i) Halogen atom, (ii) Hydroxyl group, (iii) C １－６ Alkoxy groups, and (iv) C ３－８ Cycloalkyl groups, (h) C, which is optionally substituted with 1 to 3 substituents selected from the following: ３－８ Cycloalkyl-carbonyl group, (i) Halogen atom, (ii) cyano group, and (iii) Hydroxyl group, (i) C, which is arbitrarily substituted with 1 to 3 halogen atoms. １－６ Alkoxy-carbonyl group, (j) C ３－８ Cycloalkoxy-carbonyl group, (k) C ７－１６ Aralkyloxy-carbonyl group, (l) Mono or G-C １－６ Alkyl-carbamoyl group, (m) C １－６ Alkyl sulfonyl group, (n) C ３－８ Cycloalkylsulfonyl group, and (o) 3- to 8-membered non-aromatic heterocyclic group It is optionally substituted with 1 to 3 substituents selected from the following: R ２ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein is a hydrogen atom.

13. X is S, R １ However, each of these is a four-membered heterocyclic group or a five-membered or six-membered non-aromatic heterocyclic group selected from pyrrolidinyl, piperidyl, oxetanyl, tetrahydrofuryl, and tetrahydropyranyl, and each of these is (a) Halogen atom, (b) Oxo group, (c) C, which is optionally substituted with 1 to 3 substituents selected from the following. １－６ alkyl group, (i) halogen atoms, and (ii) C １－６ Alkoxy group, (d) C ３－８ Cycloalkyl groups, (e) Hydroxyl group, (f) C １－６ Alkoxy group, (g) C, which is optionally substituted with 1 to 3 substituents selected from the following: １－６ Alkyl-carbonyl group, (i) Halogen atom, (ii) Hydroxyl group, (iii) C １－６ Alkoxy groups, and (iv) C ３－８ Cycloalkyl groups, (h) C, which is optionally substituted with 1 to 3 substituents selected from the following: ３－８ Cycloalkyl-carbonyl group, (i) Halogen atom, (ii) cyano group, and (iii) Hydroxyl group, (i) C, which is arbitrarily substituted with 1 to 3 halogen atoms. １－６ Alkoxy-carbonyl group, (j) C ３－８ Cycloalkoxy-carbonyl, (k) C ７－１６ Aralkyloxy-carbonyl group, (l) Mono or G-C １－６ Alkyl-carbamoyl group, (m) C １－６ Alkyl sulfonyl group, (n) C ３－８ Cycloalkylsulfonyl group, and (o) 3- to 8-membered non-aromatic heterocyclic group It is optionally substituted with 1 to 3 substituents selected from the following: R ２ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein is a hydrogen atom.

14. X is S, Y is CR ８ And R ８ but, (1) Hydrogen atom, (2) Halogen atoms, (3) (i) a halogen atom and (ii) C optionally substituted with 1 to 3 halogen atoms １－６ C is optionally substituted with 1 to 3 substituents selected from alkoxy groups. １－６ alkyl group, (4) C which is arbitrarily substituted with 1 to 3 halogen atoms ３－８ Cycloalkyl groups, or (5) C which is arbitrarily substituted with 1 to 3 halogen atoms １－６ Alkoxy group And, R ２ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein is a hydrogen atom.

15. R ３ That is a hydrogen atom, R ５ That is a hydrogen atom, R ６ However, hydrogen atoms or C １－６ A compound according to claim 1, wherein the compound is an alkyl group, or a pharmaceutically acceptable salt thereof.

16. X is S, R １ However, the heterocyclic group is a four-membered heterocyclic group or a five-membered or six-membered non-aromatic heterocyclic group, and the heterocyclic group is (a) Halogen atom, (b) Oxo group, (c) C, which is optionally substituted with 1 to 3 substituents selected from the following. １－６ alkyl group, (i) halogen atoms, and (ii) C １－６ Alkoxy group, (d) C ３－８ Cycloalkyl groups, (e) Hydroxyl group, (f) C １－６ Alkoxy group, (g) C, which is optionally substituted with 1 to 3 substituents selected from the following: １－６ Alkyl-carbonyl group, (i) Halogen atom, (ii) Hydroxyl group, (iii) C １－６ Alkoxy groups, and (iv) C ３－８ Cycloalkyl groups, (h) C, which is optionally substituted with 1 to 3 substituents selected from the following: ３－８ Cycloalkyl-carbonyl group, (i) Halogen atom, (ii) cyano group, and (iii) Hydroxyl group, (i) C, which is arbitrarily substituted with 1 to 3 halogen atoms. １－６ Alkoxy-carbonyl group, (j) C ３－８ Cycloalkoxy-carbonyl group, (k) C ７－１６ Aralkyloxy-carbonyl group, (l) Mono or G-C １－６ Alkyl-carbamoyl group, (m) C １－６ Alkyl sulfonyl group, (n) C ３－８ Cycloalkylsulfonyl group, and (o) 3- to 8-membered non-aromatic heterocyclic group It is optionally substituted with 1 to 3 substituents selected from the following: R ２ That is a hydrogen atom, R ３ That is a hydrogen atom, R ５ That is a hydrogen atom, R ６ However, hydrogen atoms or C １－６ A compound according to claim 1, wherein the compound is an alkyl group, or a pharmaceutically acceptable salt thereof.

17. R ２ However, 1 to 3 C １－６ C optionally substituted with an alkoxy group １－３ A compound according to claim 1, wherein the compound is an alkyl group, or a pharmaceutically acceptable salt thereof.

18. X is S, R １ but, (1) A four-membered heterocyclic group or a five-membered or six-membered heterocyclic group, wherein the heterocyclic group is (a) Halogen atom, (b) Oxo group, (c) C, which is optionally substituted with 1 to 3 substituents selected from the following. １－６ alkyl group, (i) halogen atoms, and (ii) C １－６ Alkoxy group, (d) C ３－８ Cycloalkyl groups, (e) Hydroxyl group, (f) C １－６ Alkoxy group, (g) C, which is optionally substituted with 1 to 3 substituents selected from the following: １－６ Alkyl-carbonyl group, (i) Halogen atom, (ii) Hydroxyl group, (iii) C １－６ Alkoxy groups, and (iv) C ３－８ Cycloalkyl groups, (h) C, which is optionally substituted with 1 to 3 substituents selected from the following: ３－８ Cycloalkyl-carbonyl group, (i) Halogen atom, (ii) cyano group, and (iii) Hydroxyl group, (i) C, which is arbitrarily substituted with 1 to 3 halogen atoms. １－６ Alkoxy-carbonyl group, (j) C ３－８ Cycloalkoxy-carbonyl group, (k) C ７－１６ Aralkyloxy-carbonyl group, (l) Mono or G-C １－６ Alkyl-carbamoyl group, (m) C １－６ Alkyl sulfonyl group, (n) C ３－８ Cycloalkylsulfonyl group, and (o) 3- to 8-membered non-aromatic heterocyclic group The heterocyclic group, which is optionally substituted with one to three substituents selected from the above, (2) C which is optionally substituted with 1 to 3 substituents selected from the following １－６ alkyl group, (a) Hydroxyl group, (b) C, which is arbitrarily substituted with 1 to 3 halogen atoms. １－６ Alkoxy group, (c) C, which is arbitrarily substituted with 1 to 3 halogen atoms. ３－８ Cycloalkyl groups, (d) Mono or G-C １－６ Alkylamino group, (e) C １－６ Alkyl-carbonylamino group, (f) A 3- to 8-membered non-aromatic heterocyclic group optionally substituted with one hydroxyl group, (g) halogen atoms, and (h) 5-14 member aromatic heterocyclyl group, or (3) C which is optionally substituted with 1 to 3 substituents selected from the following: ３－１０ Cycloalkyl group (the C ３－１０ The cycloalkyl group may be a spirocyclic group or a crosslinked spirocyclic group. (a) Hydroxyl group, (b) C, which is arbitrarily substituted with 1 to 3 halogen atoms. １－６ alkyl groups, and (c) C, which is arbitrarily substituted with 1 to 3 halogen atoms. １－６ Alkoxy group And, R ２ However, 1 to 3 C １－６ C optionally substituted with an alkoxy group １－３ A compound according to claim 1, wherein the compound is an alkyl group, or a pharmaceutically acceptable salt thereof.

19. X is S, Y is CR ８ And R ８ C １－６ It is an alkyl group, R １ However, a six-membered nitrogen-containing non-aromatic heterocyclic group substituted with one or two substituents selected from the following: (a) halogen atoms, and (b) C １－６ alkyl group And, R ２ That is a hydrogen atom, R ３ That is a hydrogen atom, R ４ C １－６ It is an alkyl group, R ５ That is a hydrogen atom, R ６ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein is a hydrogen atom.

20. X is S, Y is CR ８ And R ８ C １－６ It is an alkyl group, R １ However, a piperidyl group substituted with one or two substituents selected from the following: (a) halogen atoms, and (b) C １－２ alkyl group And, R ２ That is a hydrogen atom, R ３ That is a hydrogen atom, R ４ C １－２ It is an alkyl group, R ５ That is a hydrogen atom, R ６ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein is a hydrogen atom.

21. A compound selected from the title compounds of Examples 1 to 181, or a pharmaceutically acceptable salt thereof.

22. 2-(5-{[(3R,5R)-5-fluoro-1-methylpiperidine-3-yl]amino}-2H-pyrazolo[3,4-d][1,3]thiazole-2-yl)-3,5-dimethylphenol or a pharmaceutically acceptable salt thereof, 3,5-dimethyl-2-(5-{[(3R)-1-methylpiperidine-3-yl]amino}-2H-pyrazolo[3,4-d][1,3]thiazole-2-yl)phenol or a pharmaceutically acceptable salt thereof, 3-ethyl-2-(5-{[(3R,5R)-5-fluoro-1-methylpiperidine-3-yl]amino}-2H-pyrazolo[3,4-d][1,3]thiazole-2-yl)-5-methylphenol or a pharmaceutically acceptable salt thereof.

23. A combination comprising the compound defined in claim 1 or a pharmaceutically acceptable salt thereof, and at least one additional pharmacologically active agent.

24. The combination according to claim 23, wherein the additional pharmacologically active agent is selected from β-secretase inhibitors, γ-secretase inhibitors, HMG-CoA reductase inhibitors, nonsteroidal anti-inflammatory drugs, vitamin E, anti-amyloid antibodies, antidepressants, antipsychotics, anxiolytics, and anticonvulsants.

25. A pharmaceutical product comprising the compound defined in claim 1 or a pharmaceutically acceptable salt thereof.

26. The pharmaceutical product according to claim 25, which is a drug for treating a disease, disorder, or condition related to NLRP3.

27. The pharmaceutical product according to claim 25, which is a drug for treating a disease, disorder, or condition associated with a heterozygous gain-of-function mutation in the NLRP3 gene.

28. The pharmaceutical product according to claim 25, which is a drug for treating cryopyrin-associated periodic syndromes (CAPS).

29. The pharmaceutical product according to claim 28, wherein the cryopyrin-associated periodic syndrome is selected from neonatal-onset multiorgan inflammatory disease (NOMID / CINCA), Macklewells syndrome (MWS), and familial cold autoinflammatory syndrome (FCAS).

30. Use of the compound defined in claim 1 or a pharmaceutically acceptable salt thereof for manufacturing a pharmaceutical product for treating a disease, disorder, or condition associated with NLRP3.

31. Use of the compound defined in claim 1 or a pharmaceutically acceptable salt thereof for manufacturing a pharmaceutical product for treating a disease, disorder, or condition associated with a heterozygous gain-of-function mutation in the NLRP3 gene.

32. Use of the compound defined in claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical product for treating cryopyrin-associated periodic syndromes (CAPS).

33. The use according to claim 32, wherein the cryopyrin-associated periodic syndrome is selected from neonatal-onset multiorgan inflammatory disease (NOMID / CINCA), Macklewells syndrome (MWS), and familial cold autoinflammatory syndrome (FCAS).

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